Visually Analyzing Company-wide Software Service Dependencies: An Industrial Case Study

Managing dependencies between software services is a crucial task for any company operating cloud applications. Visualizations can help to understand and maintain these complex dependencies. In this paper, we present a force-directed service dependency visualization and filtering tool that has been developed and used within SAP. The tool's use cases include guiding service retirement as well as understanding service deployment landscapes and their relationship to the company's organizational structure. We report how we built and adapted the tool under strict time constraints to address the requirements of our users. We further share insights on how we enabled internal adoption. For us, starting with a minimal viable visualization and then quickly responding to user feedback was essential for convincing users of the tool's value. The final version of the tool enabled users to visually understand company-wide service consumption, supporting data-driven decision making.Comment: 5 pages, 3 figures, 1 table, 11th IEEE Working Conference on Software Visualization (VISSOFT 2023

Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis

The tumor suppressor protein prostate apoptosis response-4 (PAR-4) is silenced in a subset of human cancers and its down-regulation serves as a mechanism for cancer cell survival following chemotherapy. PAR-4 re-expression selectively causes apoptosis in cancer cells but how its pro-apoptotic functions are controlled and executed precisely is currently unknown. We demonstrate here that UV-induced apoptosis results in a rapid caspase-dependent PAR-4 cleavage at EEPD131¯G, a sequence that was preferentially recognized by caspase-8. To investigate the effect on cell growth for this cleavage event we established stable cell lines that express wild-type-PAR-4 or the caspase cleavage resistant mutant PAR-4 D131G under the control of a doxycycline-inducible promoter. Induction of the wild-type protein but not the mutant interfered with cell proliferation, predominantly through induction of apoptosis. We further demonstrate that TNFα-induced apoptosis leads to caspase-8-dependent PAR-4-cleavage followed by nuclear accumulation of the C-terminal PAR-4 (132-340) fragment, which then induces apoptosis. Taken together, our results indicate that the mechanism by which PAR-4 orchestrates the apoptotic process requires cleavage by caspase-8

Functional analysis of the Caspase-mediated cleavage of the pro-apoptotic tumor suppressor protein PAR-4

The pro-apoptotic tumor suppressor protein prostate apoptosis response-4 (PAR-4) is silenced in a well-defined subset of human cancers including lung, prostate and breast cancer and its down-regulation serves as a mechanism for cancer cell survival following chemotherapy. PAR-4 re-expression selectively causes apoptosis in cancer cells but how its pro-apoptotic functions are controlled and executed precisely is poorly understood.In the present study it is demonstrated that UV- or TNFα-induced apoptosis results in a rapid Caspase-8-specific PAR-4 cleavage at EEPD131↓G, which separates the unstructured N-terminal part from the C-terminal region that contains the NLS, SAC and LZ domains. I further demonstrate that TNFα-mediated hydrolysis of PAR-4 requires Caspase-8 and leads to nuclear accumulation of the C-terminal cleavage fragment of the tumor suppressor and thereby induces apoptosis. Taken together, these results indicate that Caspase-8-mediated cleavage induced nuclear translocation of the C-terminal part of PAR-4 is critical in regulating cell death triggered by TNFα.Recent evidence implicates down-regulation of PAR-4 as a critical step for breast cancer recurrence. Down-regulation of PAR-4 allows tumor cells to survive tumor regression following targeted therapy and chemotherapy and is both a necessary and sufficient step for tumor recurrence. Hence, PAR-4 expression was analyzed in a panel of breast cancer cell lines and low PAR-4 expression was observed in the majority of triple negative breast cancer (TNBC) cells. Interestingly, Caspase-8-mediated PAR-4 cleavage was also observed in TNBC cells following DNA-damage-induced apoptosis using genotoxic drugs. I further demonstrate that loss of PAR-4 in TNBC cells mediates resistance to DNA-damage induced apoptosis and surprisingly also interferes with Caspase-8 activation, indicating that PAR-4 is capable to amplify Caspase-8 activation via an unknown feedback mechanism.Low PAR-4 expression promotes tumor cell survival following therapy but the pathways controlling PAR-4 expression are not identified. Using an unbiased mass spectrometry approach I was able to identify nine physical PAR-4 interaction partners out of which two belong to the family of E3 ubiquitin-protein ligases (MYCBP2 and UBR5) and one to the family of deubiquitylases (USP7). These novel PAR-4 binding proteins suggest that down-regulation of PAR-4 might be specifically linked to disordered ubiquitin signaling in cancer.In summary, the results provide evidence that the mechanism by which PAR-4 orchestrates the apoptotic process requires cleavage by Caspase-8 following TNFα- or genotoxic drug-induced apoptosis and functions by cleavage-induced nuclear translocation of the C-terminal part

Caspase-dependent cleavage of the mono-ADP-ribosyltransferase ARTD10 interferes with its pro-apoptotic function

ADP-ribosylation is a post-translational modification that regulates various physiological processes, including DNA damage repair, gene transcription and signal transduction. Intracellular ADP-ribosyltransferases (ARTDs or PARPs) modify their substrates either by poly- or mono-ADP-ribosylation. Previously we identified ARTD10 (formerly PARP10) as a mono-ADP-ribosyltransferase, and observed that exogenous ARTD10 but not ARTD10-G888W, a catalytically inactive mutant, interferes with cell proliferation. To expand on this observation, we established cell lines with inducible ARTD10 or ARTD10-G888W. Consistent with our previous findings, induction of the wild-type protein but not the mutant inhibited cell proliferation, primarily by inducing apoptosis. During apoptosis, ARTD10 itself was targeted by caspases. We mapped the major cleavage site at EIAMD406S, a sequence that was preferentially recognized by caspase6. Caspase-dependent cleavage inhibited the pro-apoptotic activity of ARTD10, as ARTD10(1406) and ARTD10(4071025), either alone or together, were unable to induce apoptosis, despite catalytic activity of the latter. Deletion of the Nterminal RNA recognition motif in ARTD10(2571025) also resulted in loss of pro-apoptotic activity. Thus our findings indicate that the RNA recognition motif contributes to the pro-apoptotic effect, together with the catalytic domain. We suggest that these two domains must be physically linked to stimulate apoptosis, possibly targeting ARTD10 through the RNA recognition motif to specific substrates that control cell death. Moreover, we established that knockdown of ARTD10 reduced apoptosis in response to DNA-damaging agents. Together, these findings indicate that ARTD10 is involved in the regulation of apoptosis, and that, once apoptosis is activated, ARTD10 is cleaved as part of negative feedback regulation

cytotoxicity and genotoxicity of size-fractionated iron oxide (magnetite) in a549 human lung epithelial cells: role of ROS, JNK, and NF-κB

Airborne particulate matter (PM) of varying size and composition is known to cause health problems in humans. The iron oxide Fe₃O₄ (magnetite) may be a major anthropogenic component in ambient PM and is derived mainly from industrial sources. In the present study, we have investigated the effects of four different size fractions of magnetite on signaling pathways, free radical generation, cytotoxicity, and genotoxicity in human alveolar epithelial-like type-II cells (A549). The magnetite particles used in the exposure experiments were characterized by mineralogical and chemical techniques. Four size fractions were investigated: bulk magnetite (0.2–10 μm), respirable fraction (2–3 μm), alveolar fraction (0.5–1.0 μm), and nanoparticles (20–60 nm). After 24 h of exposure, the A549 cells were investigated by transmission electron microscopy (TEM) to study particle uptake. TEM images showed an incorporation of magnetite particles in A549 cells by endocytosis. Particles were found as agglomerates in cytoplasm-bound vesicles, and few particles were detected in the cytoplasm but none in the nucleus. Increased production of reactive oxygen species (ROS), as determined by the 2′,7′-dichlorfluorescein-diacetate assay (DCFH-DA), as well as genotoxic effects, as measured by the cytokinesis block-micronucleus test and the Comet assay, were observed for all of the studied fractions after 24 h of exposure. Moreover, activation of c-Jun N-terminal kinases (JNK) without increased nuclear factor kappa-B (NF-κB)-binding activity but delayed IκB-degradation was observed. Interestingly, pretreatment of cells with magnetite and subsequent stimulation with the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) led to a reduction of NF-κB DNA binding compared to that in stimulation with TNFα alone. Altogether, these experiments suggest that ROS formation may play an important role in the genotoxicity of magnetite in A549 cells but that activation of JNK seems to be ROS- independent