•Discussion of general mechanisms of welding residual stress generation and their relaxation behavior under fatigue loading.•Residual stress effects on crack propagation and fatigue strength of ...welded joints.•Treatment of residual stresses in fracture mechanics calculations with regard to the IBESS-model in particular.
Welding residual stresses have an impact on the performance of welded structures, on their fracture resistance, their resistance against fatigue crack propagation and, most important, their fatigue strength and fatigue lifetime. The present paper provides an overview on the issue mainly from the point of view of the application of fracture mechanics to the determination of the fatigue strength as the topic of this Special issue. Besides own experimental and theoretical data a comprehensive discussion is provided in that context which includes the definition and interaction of short- and long-range (or reaction) residual stresses, the effect of cyclic mechanical loading and its treatment in fracture and fatigue analyses.
Foxp3+ T-regulatory cells (Tregs) normally serve to attenuate immune responses and are key to maintenance of immune homeostasis. Over the past decade, Treg cells have become a major focus of research ...for many groups, and various functional subsets have been characterized. Recently, the Ikaros family member, Helios, was reported as a marker to discriminate naturally occurring, thymic-derived Tregs from those peripherally induced from naïve CD4+ T cells. We investigated Helios expression in murine and human T cells under resting or activating conditions, using well-characterized molecules of naïve/effector/memory phenotypes, as well as a set of Treg-associated markers. We found that Helios-negative T cells are enriched for naïve T cell phenotypes and vice versa. Moreover, Helios can be induced during T cell activation and proliferation, but regresses in the same cells under resting conditions. We demonstrated comparable findings using human and murine CD4+Foxp3+ Tregs, as well as in CD4+ and CD8+ T cells. Since Helios expression is associated with T cell activation and cellular division, regardless of the cell subset involved, it does not appear suitable as a marker to distinguish natural and induced Treg cells.
•Fracture mechanics-based fatigue strength assessment of welded joints.•Modelling of short crack propagation with focus on crack closure effects.•Modelling of multiple crack propagation and ...interaction.•Probabilistic simulations based on random sampling of geometric variables at the weld toe.•Validation against a large set of experimental data for three different types of weldments.
The work presents the procedure developed within the German research project IBESS, which allows for the fracture mechanics-based prediction of the fatigue strength of welded joints under constant amplitude loading. Based on the experimental observations of the crucial failure mechanisms, the approach focuses on the short crack propagation, where elastic-plastic fracture mechanics and the build-up of closure effects must be considered, as well as the variability of the local geometry at the weld toe and the modelling of multiple crack interaction. Analytical solutions are provided for the approximation of the through-thickness stress profiles at the weld toe and for the determination of the crack driving force in the form of a plasticity-corrected stress intensity factor range ΔKp. Proposals for the determination of the initial crack size and the crack closure factor are also included.
The approach is validated against a large number of experimental data, which comprises fatigue tests on individual cracks monitored by heat-tinting and beach-marking techniques, as well as stress life curves. Three kinds of welded joints, two steels of significant different strength, two welding techniques and three stress ratios are considered. The results show that the procedure provides good estimations of the statistical distribution of the fatigue strength of welded joints both for the finite and infinite life regime. Furthermore, the predictions are compared with available benchmark data for structural steels.
Sirtuin-1 (Sirt1), a member of the NAD-dependent sirtuin family of histone/protein deacetylases (HDAC), is an important target for immunotherapy due to its role in deacetylating the transcription ...factors Foxp3 and thymic retinoid acid receptor related orphan receptor gamma (RORγt). Sirt1 inhibition can increase Foxp3 acetylation and promote the production and functions of Foxp3
T-regulatory (Treg) cells, whereas the acetylation of RORγt decreases its transcriptional activity DNA binding and decreases the differentiation of proinflammatory Th17 cells. Pharmacologic inhibitors of Sirt1 increase allograft survival and decrease autoimmune colitis and experimental allergic encephalomyelitis. However, in contrast to its role in T cells, Sirt1 has anti-inflammatory effects in myeloid cells, and, context dependent, in Th17 cells. Here, inhibition of Sirt1 can have proinflammatory effects. In addition to effects arising from the central role of Sirt1 in cellular metabolism and NAD-dependent reactions, such proinflammatory effects further complicate the potential of Sirt1 for therapeutic immunosuppression. This review aims to reconcile the opposing literature on pro- and anti-inflammatory effects of Sirt1, provides an overview of the role of Sir1 in the immune system, and discusses the pros and cons associated with inhibiting Sirt1 for control of inflammation and immune responses.
Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are ...immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD+), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD+-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). We show that increased lactate leads to a block at GAPDH and PGDH, leading to the depletion of post-GAPDH glycolytic intermediates, as well as the 3-phosphoglycerate derivative serine that is known to be important for T cell proliferation. Supplementing serine rescues the ability of T cells to proliferate in the presence of lactate-induced reductive stress. Directly targeting the redox state may be a useful approach for developing novel immunotherapies in cancer and therapeutic immunosuppression.
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•Lactate is metabolized by T cells and reduces NAD+ to NADH•NAD+ reduction to NADH impairs glycolytic flux via GAPDH•Lactate depletes post-GAPDH glycolytic intermediates and glucose-derived serine•Adding serine rescues T cell proliferation from lactate-induced reductive stress
Quinn et al. report that lactate has an acidity-independent suppressive effect on effector T cell proliferation mediated through a shift from NAD+ to NADH (lactate-induced reductive stress). This impairs glycolysis and glucose-derived serine production, which is required for effector T cell proliferation.
•Comprehensive review on fracture mechanics application to weldments.•Discussion of recent developments in areas such as materials testing, strength mismatch and secondary stresses.•Discussion of ...crack initiation and early crack propagation in welds.
Welding is one of the most common methods in industrial practice for joining components. Its main advantages are high speed in manufacturing combined with low costs and, usually, a high degree of flexibility, integrity and reliability. Nevertheless, welding is a highly complex metallurgical process and, therefore, weldments are susceptible to material discontinuities, flaws and residual stresses which may lead to structural failure and life time reduction. As a consequence weldments are an important field of fracture mechanics methods although its application is more complex than for homogeneous or non-welded structures. The aim of the paper is to provide an overview on the current state of fracture mechanics application to weldments. It starts by discussing the specific features which any fracture mechanics analysis of weldments has to take into account. Then, the experimental determination of fracture toughness, fatigue crack propagation and tensile properties of weldments is addressed. Finally, the analytical determination of the crack driving force in components and structural integrity assessment approaches for weldments are presented.
Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An ...alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.
The transcription factor MEF2D is important in the regulation of differentiation and adaptive responses in many cell types. We found that among T cells, MEF2D gained new functions in Foxp3+ T ...regulatory (Treg) cells due to its interactions with the transcription factor Foxp3 and its release from canonical partners, like histone/protein deacetylases. Though not necessary for the generation and maintenance of Tregs, MEF2D was required for the expression of IL-10, CTLA4, and Icos, and for the acquisition of an effector Treg phenotype. At these loci, MEF2D acted both synergistically and additively to Foxp3, and downstream of Blimp1. Mice with the conditional deletion in Tregs of the gene encoding MEF2D were unable to maintain long-term allograft survival despite costimulation blockade, had enhanced antitumor immunity in syngeneic models, but displayed only minor evidence of autoimmunity when maintained under normal conditions. The role played by MEF2D in sustaining effector Foxp3+ Treg functions without abrogating their basal actions suggests its suitability for drug discovery efforts in cancer therapy.
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