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"Tolerance"
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From tolerance allocation to tolerance-cost optimization: a comprehensive literature review
It is widely acknowledged that the allocation of part tolerances is a highly responsible task due to the complex repercussions on both product quality and cost. As a consequence, since its beginnings in the 1960s, least-cost tolerance allocation using optimization techniques, i.e. tolerance-cost optimization, was continuously in focus of numerous research activities. Nowadays, increasing cost and quality pressure, availability of real manufacturing data driven by Industry 4.0 technologies, and rising computational power result in a continuously growing interest in tolerance-cost optimization in both research and industry. However, inconsistent terminology and the lack of a classification of the various relevant aspects is an obstacle for the application of tolerance-cost optimization approaches. There is no literature comprehensively and clearly summarizing the current state of the art and illustrating the relevant key aspects. Motivated to overcome this drawback, this article provides a comprehensive as well as detailed overview of the broad research field in tolerance-cost optimization for both beginners and experts. To facilitate the first steps for readers who are less familiar with the topic, the paper initially outlines the fundamentals of tolerance-cost optimization including its basic idea, elementary terminology and mathematical formulation. These fundamentals serve as a basis for a subsequent detailed discussion of the key elements with focus on the different characteristics concerning the optimization problem, tolerance-cost model, technical system model and the tolerance analysis model. These aspects are gathered and summarized in a structured mind map, which equips the reader with a comprehensive graphical overview of all the various facets and aspects of tolerance-cost optimization. Beside this, the paper gives a retrospect of the past fifty years of research in tolerance cost-optimization, considering 290 relevant publications. Based thereon, current issues and future research needs in tolerance-cost optimization were identified.
Journal Article
The multiple pathways to autoimmunity
Efforts to understand autoimmunity have been pursued relentlessly for several decades. It has become apparent that the immune system evolved multiple mechanisms for controlling self-reactivity, and defects in one or more of these mechanisms can lead to a breakdown of tolerance. Among the multitude of lesions associated with disease, the most common seem to affect peripheral tolerance rather than central tolerance. The initial trigger for both systemic autoimmune disorders and organ-specific autoimmune disorders probably involves the recognition of self or foreign molecules, especially nucleic acids, by innate sensors. Such recognition, in turn, triggers inflammatory responses and the engagement of previously quiescent autoreactive T cells and B cells. Here we summarize the most prominent autoimmune pathways and identify key issues that require resolution for full understanding of pathogenic autoimmunity.
Journal Article
A class B heat shock factor selected for during soybean domestication contributes to salt tolerance by promoting flavonoid biosynthesis
• Soybean (Glycine max) production is severely affected in unfavorable environments. Identification of the regulatory factors conferring stress tolerance would facilitate soybean breeding.
• In this study, through coexpression network analysis of salt-tolerant wild soybeans, together with molecular and genetic approaches, we revealed a previously unidentified function of a class B heat shock factor, HSFB2b, in soybean salt stress response.
• We showed that HSFB2b improves salt tolerance through the promotion of flavonoid accumulation by activating one subset of flavonoid biosynthesis-related genes and by inhibiting the repressor gene GmNAC2 to release another subset of genes in the flavonoid biosynthesis pathway. Moreover, four promoter haplotypes of HSFB2b were identified from wild and cultivated soybeans. Promoter haplotype II from salt-tolerant wild soybean Y20, with high promoter activity under salt stress, is probably selected for during domestication. Another promoter haplotype, III, from salt-tolerant wild soybean Y55, had the highest promoter activity under salt stress, had a low distribution frequency and may be subjected to the next wave of selection.
• Together, our results revealed the mechanism of HSFB2b in soybean salt stress tolerance. Its promoter variations were identified, and the haplotype with high activity may be adopted for breeding better soybean cultivars that are adapted to stress conditions.
Journal Article
Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial
There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials
Journal Article
Locke on toleration
\"John Locke's Letter Concerning Toleration (1689) is one of the most widely-read texts in the political theory of toleration, and a key text for the liberal tradition. However, Locke also defended toleration more extensively in three subsequent Letters, which he wrote in response to criticism by an Anglican cleric, Jonas Proast. This edition, which includes a new translation of the original Letter, by Michael Silverthorne, enables readers to assess John Locke's theory of toleration by studying both his classic work and essential extracts from the later Letters. An introduction by Richard Vernon sets Locke's theory in its historical context and examines the key questions for contemporary political theorists which arise from this major work in the history of political thought\"-- Provided by publisher.
Book
Tolerance to Plant Pathogens: Theory and Experimental Evidence
The two major mechanisms of plant defense against pathogens are resistance (the host's ability to limit pathogen multiplication) and tolerance (the host's ability to reduce the effect of infection on its fitness regardless of the level of pathogen multiplication). There is abundant literature on virtually every aspect of plant resistance to pathogens. Although tolerance to plant pathogens is comparatively less understood, studies on this plant defense strategy have led to major insights into its evolution, mechanistic basis and genetic determinants. This review aims at summarizing current theories and experimental evidence on the evolutionary causes and consequences of plant tolerance to pathogens, as well as the existing knowledge on the genetic determinants and mechanisms of tolerance. Our review reveals that (i) in plant-pathogen systems, resistance and tolerance generally coexist, i.e., are not mutually exclusive; (ii) evidence of tolerance polymorphisms is abundant regardless of the pathogen considered; (iii) tolerance is an efficient strategy to reduce the damage on the infected host; and (iv) there is no evidence that tolerance results in increased pathogen multiplication. Taken together, the work discussed in this review indicates that tolerance may be as important as resistance in determining the dynamics of plant-pathogen interactions. Several aspects of plant tolerance to pathogens that still remain unclear and which should be explored in the future, are also outlined.
Journal Article