Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling and cell death in the immature central nervous system after hypoxia-ischemia and inflammation

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family. The interaction of TRAIL with death receptor 4 (DR4) and DR5 can trigger apoptotic cell death. The aim of this study was to investigate the role of TRAIL signaling in neonatal hypoxia-ischemia (HI). Using a neonatal mouse model of HI, mRNA, and protein expression of TRAIL, DR5 and the TRAIL decoy receptors osteoprotegerin (OPG), mDcTRAILR1, and mDcTRAILR2 were determined. In vitro, mRNA expression of these genes was measured in primary neurons and oligodendrocyte progenitor cells (OPCs) after inflammatory cytokine (TNF-α/IFN-γ) treatment and/or oxygen and glucose deprivation (OGD). The toxicity of these various paradigms was also measured. The expression of TRAIL, DR5, OPG, and mDcTRAILR2 was significantly increased after HI. In vitro, inflammatory cytokines and OGD treatment significantly induced mRNAs for TRAIL, DR5, OPG, and mDcTRAILR2 in primary neurons and of TRAIL and OPG in OPCs. TRAIL protein was expressed primarily in microglia and astroglia, whereas DR5 co-localized with neurons and OPCs in vivo. OGD enhanced TNF-α/IFN-γ toxicity in both neuronal and OPC cultures. Recombinant TRAIL exerted toxicity alone or in combination with OGD and TNF-α/IFN-γ in primary neurons but not in OPC cultures. The marked increases in the expression of TRAIL and its receptors after cytokine exposure and OGD in primary neurons and OPCs were similar to those found in our animal model of neonatal HI. The toxicity of TRAIL in primary neurons suggests that TRAIL signaling participates in neonatal brain injury after inflammation and HI

The effect of cutting speed and heat treatment on the fatigue life of Grade 5 and Grade 23 Ti-6Al-4V alloys

High speed machining is a necessary manufacturing method for ensuring productivity and profitability. However, research has demonstrated that the high speed machining process impairs the surface characteristics of materials such as Ti-6Al-4V including surface roughness and subsurface microstructural damage. Therefore, there is concern that high speed machining detrimentally influences the fatigue properties of Ti-6Al-4V components. This paper investigates the effect of cutting speed on the surface integrity and fatigue properties of Ti-6Al-4V (ASTM Grade 5) and Ti-6Al-4V ELI (ASTM Grade 23) alloys in the beta annealed and mill annealed heat treated conditions. It was found that the surface roughness and fatigue properties are not significantly influenced by cutting speed, however, the microstructure substantially influences the properties

Constitutive ablation of caspase-6 reduces the inflammatory response and behavioural changes caused by peripheral pro-inflammatory stimuli

Abstract Traditionally, the family of caspases has been subcategorised according to their respective main roles in mediating apoptosis or inflammation. However, recent studies have revealed that caspases participate in diverse cellular functions beyond their canonical roles. Caspase-6 (C6) is one such protease known for its role as a pro-apoptotic executioner caspase and its aberrant activity in several neurodegenerative diseases. In addition to apoptosis, C6 has been shown to regulate B-cell activation and differentiation in plasma cells as well as macrophage activation. Furthermore, C6 has recently been postulated to play a role in mediating the inflammatory response through the production of TNF-α. In this study we further examine the role of C6 in mediating the inflammatory response and its contribution to the manifestation of behavioural abnormalities in mice. We find that C6 is a positive regulator of TNF-α transcription in macrophages and that ablation of C6 reduces lipopolysaccharide (LPS)-induced TNF-α levels in plasma. Furthermore, loss of C6 attenuates LPS-induced behavioural changes in mice and protects neurons from cytokine-mediated toxicity. These data further support the involvement of C6 in the inflammatory response and point to a previously unknown role for C6 in the pathophysiology of depression