Pathogenetic insights from the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities. Cytokine inhibitors have definitively proven a critical role for tumour necrosis factor α and interleukin 6 in disease pathogenesis and possibly also for granulocyte-macrophage colony-stimulating factor. More recently, clinical trials with Janus kinase (JAK) inhibitors have shown that cytokine receptors that signal through the JAK/STAT signalling pathway are important for disease, informing the pathogenetic function of additional cytokines (such as the interferons). Finally, successful use of costimulatory blockade and B-cell depletion in the clinic has revealed that the adaptive immune response and the downstream events initiated by these cells participate directly in synovial inflammation. Taken together, it becomes apparent that understanding the effects of specific immune interventions can elucidate definitive molecular or cellular nodes that are essential to maintain complex inflammatory networks that subserve diseases like rheumatoid arthritis

Kruskal's Tree Theorem for Acyclic Term Graphs

In this paper we study termination of term graph rewriting, where we restrict our attention to acyclic term graphs. Motivated by earlier work by Plump we aim at a definition of the notion of simplification order for acyclic term graphs. For this we adapt the homeomorphic embedding relation to term graphs. In contrast to earlier extensions, our notion is inspired by morphisms. Based on this, we establish a variant of Kruskal's Tree Theorem formulated for acyclic term graphs. In proof, we rely on the new notion of embedding and follow Nash-Williams' minimal bad sequence argument. Finally, we propose a variant of the lexicographic path order for acyclic term graphs.Comment: In Proceedings TERMGRAPH 2016, arXiv:1609.0301

Osteoimmunology in rheumatic diseases

This review summarizes the recent advances of osteoimmunology, a new research field that investigates the interaction of the immune system with the skeleton. Osteoimmunology has contributed significantly to the understanding of joint destruction in rheumatoid arthritis and other forms of arthropathies. In particular, the molecular regulation of osteoclast formation and its control by proinflammatory cytokines have helped investigators to understand the mechanisms of bone erosion in rheumatic diseases. Osteoimmunology has also allowed an improvement in our knowledge of the structure-sparing effects of antirheumatic drug therapy. Moreover, recent advances in the understanding of the molecular regulation of osteophyte formation are based on the characterization of the regulation of bone formation by inflammation. This review highlights the key insights into the regulation of bone destruction and formation in arthritis. Moreover, concepts of how bone influences the immune system are discussed

Solution of ordinary differential equations by means of Lie series

Solution of ordinary differential equations by Lie series - Laplace transformation, Weber parabolic-cylinder functions, Helmholtz equations, and applications in physic

Cost Reduction With Guarantees: Formal Reasoning Applied To Blockchain Technologies

Blockchain technologies are moving fast and their distributed nature as well as their high-stake (financial) applications make it crucial to “get things right”. Moreover, blockchain technologies often come with a high cost for maintaining blockchain infrastructure and for running applications. In this thesis formal reasoning is used for guaranteeing correctness while reducing the cost of (i) maintaining the infrastructure by optimising blockchain protocols, and (ii) running applications by optimising blockchain programs—so called smart contracts. Both have a clear cost measure: for protocols the amount of exchanged messages, and for smart contracts the monetary cost of execution. In the first result for blockchain protocols starting from a proof of correctness for an abstract blockchain consensus protocol using infinitely many messages and infinite state, a refinement proof transfers correctness to a concrete implementation of the protocol reducing the cost to finite resources. In the second result I move from a blockchain to a block graph. This block graph embeds the run of a deterministic byzantine fault tolerant protocol, thereby getting parallelism “for free” and reducing the exchanged messages to the point of omission. For blockchain programs, I optimise programs executed on the Ethereum blockchain. As a first result, I use superoptimisation and encode the search for cheaper, but observationally equivalent, program as a search problem for an automated theorem prover. Since solving this search problem is in itself expensive, my second result is an efficient encoding of the search problem. Finally for reusing found optimisations, my third results gives a framework to generate peephole optimisation rules for a smart contract compiler