Regulation of TNFR1 signalling by LUBAC-dependent and -associated proteins

The linear ubiquitin chain assembly complex (LUBAC) modulates signalling outcomes of the tumour necrosis factor receptor 1 signalling complex (TNFR1-SC) by placing linear ubiquitin linkages on target proteins in this complex, which in turn leads to recruitment of effector and regulatory molecules. Thereby, LUBAC promotes TNF-induced gene-activatory signalling. Furthermore, LUBAC activity is crucial for the protection from TNF-induced cell death by limiting the formation of the death-inducing cytoplasmic signalling complex II. This thesis demonstrates that HOIP, the enzymatically active subunit of LUBAC, in its function as an adaptor or via its enzymatic activity, orchestrates the recruitment of a multitude of TNFR1-SC components and thereby specifically regulates TNFR1-SC signalling outcome with respect to gene-activatory signalling and cell death. The deubiquitinases CYLD and A20, respectively recruited by LUBAC or linear ubiquitin chains, cooperatively restrict gene activation but exert opposing effects on M1-linked ubiquitin chain stability and, thereby also on cell death. Whilst CYLD-mediated cleavage of M1 chains sensitizes cells to TNF-induced cell death, A20 binding to them prevents their hydrolysis which inhibits cell death. Furthermore, it is shown that the IKK-related kinases TBK1 and IKKε are recruited to the TNFR1-SC in a LUBAC activity-dependent manner. Whilst TBK1 can be recruited via the adaptors TANK or NAP1, IKKε recruitment to the TNFR1-SC solely requires TANK. Importantly, inhibition of the kinase activity of TBK1 and IKKε or abrogation of their recruitment to the TNFR1-SC results in sensitization to TNF-induced RIP1-activity-mediated cell death. Mechanistically, these non-canonical kinases prevent RIP1 from transitioning to complex II and, thereby, from triggering apoptosis or necroptosis. In summary, this PhD thesis elucidates how LUBAC regulates TNF-induced signalling outcomes in terms of gene-activatory signalling and cell death. In doing so, it identifies a previously unrecognised molecular mechanism which facilitates the recruitment and activation of the non-canonical kinases TBK1 and IKKε at the TNFR1-SC

[μ-3,3′-Bis(tri­hydro­bor­yl)[3]ferroceno­phane]bis­(chlorido­zirconocene)

The title compound, [FeZr2(C5H5)4Cl2(C13H18B2)], is a heteronuclear complex that consists of a [3]ferrocenophane moiety substituted at each cyclo­penta­dienyl (Cp) ring by a BH3 group; the BH3 group is bonded via two H atoms to the Zr atom of the zirconocene chloride moiety in a bidentate fashion. The two Cp rings of the [3]ferrocenophane moiety are aligned at a dihedral angle of 8.9 (4)° arising from the strain of the propane-1,3-diyl bridge linking the two Cp rings. [One methyl­ene group is disordered over two positions with a site-occupation factor of 0.552 (18) for the major occupied site.] The dihedral angles between the Cp rings at the two Zr atoms are 50.0 (3) and 51.7 (3)°. The bonding Zr(...)H distances are in the range 1.89 (7)–2.14 (7) Å. As the two Cp rings of the ferrocene unit are connected by an ansa bridge, the two Zr atoms approach each other at 6.485 (1) Å. The crystal packing features C—H(...)Cl inter­actions

Basic Considerations on Business Process Quality

Quality management practices in manufacturing and logistics have led to proven results for organisations with respect to competitiveness and protability. At the same time, business process management not only addresses a comprehensive functional scope including the ever more important administrative functions and business services, but also contributes to realising potentials (e.g. in the field of process automation) through extensive use of information technology. Integrating quality management with business process management concepts is thus very promising from a business perspective. The evolution of a clear understanding of business process quality constitutes a fundamental prerequisite for progress in this field as only a concise definition will point out the issues that need to be addressed in more detailed research. This report aims at discussing basic considerations in this respect. We look into requirements to be posed towards a definition of business process quality, discuss various basic quality views and their fit with business process management, provide a fundamental if not yet practically applicable business process quality definition, and examine related aspects of business processes as well as related work. While this approach will not lead to a finally applicable definition of business process quality, its contribution will lie in entering into a more systematic discussion to encompass the wide array of existing results that can be correlated with business process quality and giving directions for future research

Formalizing Concepts for Efficacy-aware Business Process Modeling

In business process design, business objective models can fulfill the role of formal requirement denitions. Matching process models against objective models would, for instance, enable sound comparison of implementation alternatives. For that purpose, objective models should be available independently of their concrete implementation in a business process. This issue is not addressed by common business process management concepts yet. Moreover, process models are currently not sufficiently expressive to determine business process efficacy in the sense of fulfilling a business objective. Therefore, this paper develops and integrates constructs required for efficacy-aware process modeling and apt to extend common modeling approaches. The concept is illustrated with a sample scenario. Overall, it serves as an enabler for progressive applications like automated process optimization

Modeling Business Objectives for Business Process Management

For application scenarios such as the management of business process variants or business process quality, business objective models assume the role of formal requirements definitions as in software engineering. However, effective concepts in this area still constitute a gap in the presently available array of business process management methods. To address this issue, this paper develops and shortly evaluates a refined business objective modeling approach. Our approach builds on use case-based effectiveness criteria, and on insights gained from assessing the state of the art. It derives required constructs and interrelations from application scenarios, and integrates these into a business objective meta-model. As an initial validation of our concept, we model a sample scenario and match the results against effectiveness criteria

Demonstrating the Effectiveness of Process Improvement Patterns

Improving the operational efficiency of processes is an important goal of business process management (BPM). There exist many proposals with regard to process improvement patterns (PIPs) as practices that aim at supporting this task. Nevertheless, there is still a gap with respect to validating PIPs in terms of their actual business value for a specific organization. Based on empirical research and experience from consulting projects, this paper proposes a method to tackle this challenge. Our approach towards a-priori validation of process improvement patterns considers real-world constraints such as the role of senior stakeholders and opportunities such as process mining techniques. In the sense of an experience report, our approach as well as results are illustrated on the basis of a real-world business process from human resources management, covering a transactional volume of about 29,000 process instances over the period of one year. Overall, our proposal enables practitioners and researchers to subject PIPs to a sound validation procedure before taking any process implementation decision

Effective application of process improvement patterns to business processes

Improving the operational effectiveness and efficiency of processes is a fundamental task of business process management (BPM). There exist many proposals of process improvement patterns (PIPs) as practices that aim at supporting this goal. Selecting and implementing relevant PIPs are therefore an important prerequisite for establishing process-aware information systems in enterprises. Nevertheless, there is still a gap regarding the validation of PIPs with respect to their actual business value for a specific application scenario before implementation investments are incurred. Based on empirical research as well as experiences from BPM projects, this paper proposes a method to tackle this challenge. Our approach toward the assessment of process improvement patterns considers real-world constraints such as the role of senior stakeholders or the cost of adapting available IT systems. In addition, it outlines process improvement potentials that arise from the information technology infrastructure available to organizations, particularly regarding the combination of enterprise resource planning with business process intelligence. Our approach is illustrated along a real-world business process from human resource management. The latter covers a transactional volume of about 29,000 process instances over a period of 1 year. Overall, our approach enables both practitioners and researchers to reasonably assess PIPs before taking any process implementation decision

Multiple roles of class I HDACs in proliferation, differentiation, and development

Class I Histone deacetylases (HDACs) play a central role in controlling cell cycle regulation, cell differentiation, and tissue development. These enzymes exert their function by deacetylating histones and a growing number of non-histone proteins, thereby regulating gene expression and several other cellular processes. Class I HDACs comprise four members: HDAC1, 2, 3, and 8. Deletion and/or overexpression of these enzymes in mammalian systems has provided important insights about their functions and mechanisms of action which are reviewed here. In particular, unique as well as redundant functions have been identified in several paradigms. Studies with small molecule inhibitors of HDACs have demonstrated the medical relevance of these enzymes and their potential as therapeutic targets in cancer and other pathological conditions. Going forward, better understanding the specific role of individual HDACs in normal physiology as well as in pathological settings will be crucial to exploit this protein family as a useful therapeutic target in a range of diseases. Further dissection of the pathways they impinge on and of their targets, in chromatin or otherwise, will form important avenues of research for the futur

Towards Measuring and Quantifying the Comprehensibility of Process Models -- The Process Model Comprehension Framework

Process models constitute crucial artifacts in modern information systems and, hence, the proper comprehension of these models is of utmost importance in the utilization of such systems. Generally, process models are considered from two different perspectives: process modelers and readers. Both perspectives share similarities and differences in the comprehension of process models (e.g., diverse experiences when working with process models). The literature proposed many rules and guidelines to ensure a proper comprehension of process models for both perspectives. As a novel contribution in this context, this paper introduces the Process Model Comprehension Framework (PMCF) as a first step towards the measurement and quantification of the perspectives of process modelers and readers as well as the interaction of both regarding the comprehension of process models. Therefore, the PMCF describes an Evaluation Theory Tree based on the Communication Theory as well as the Conceptual Modeling Quality Framework and considers a total of 96 quality metrics in order to quantify process model comprehension. Furthermore, the PMCF was evaluated in a survey with 131 participants and has been implemented as well as applied successfully in a practical case study including 33 participants. To conclude, the PMCF allows for the identification of pitfalls and provides related information about how to assist process modelers as well as readers in order to foster and enable a proper comprehension of process models.Comment: 16 pages, 5 Figures, 1 Table, additional materials in appendi