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Catherine Emma Diamond,1,2 Hanif Javanmard Khameneh,1 David Brough,2 Alessandra Mortellaro,1 1Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore; 2Faculty of Life Sciences, University of Manchester, Manchester, UK Abstract: Inflammasomes are cytosolic multi-protein complexes that regulate the secretion of the proinflammatory cytokines, IL-1β and IL-18, and induce pyroptosis, an inflammatory form of cell death. The NLRP3 inflammasome is the most well-characterized member of this family and functions by sensing intracellular pathogen- and damage-associated molecular patterns and activating caspase-1, which processes the biologically inactive IL-1β and IL-18 precursors into active cytokines. Recent studies have identified an alternative mechanism of inflammasome activation, termed the non-canonical inflammasome, which is triggered by cytosolic sensing of lipopolysaccharide (LPS) derived from bacteria that have escaped phagolysosomes. This pathway is independent of Toll-like receptor 4 (TLR4), the well-known extracellular receptor for LPS, but instead depends on the inflammatory protease, caspase-11. Although our understanding of caspase-11 activation is still in its infancy, it appears to be an essential mediator of septic shock and attenuates intestinal inflammation. In this review, we bring together the latest data on the roles of caspase-11 and the mechanisms underlying caspase-11-mediated activation of the non-canonical inflammasome, and consider the implications of this pathway on TLR4-independent immune responses to LPS. Keywords: caspase-11, caspase-1, LPS, NLRP3, IL-1β, IL-18

James Galea,1 David Brough21Manchester Academic Health Sciences Center, Brain Injury Research Group, Clinical Sciences Building, Salford Royal Foundation Trust, Salford, UK; 2Faculty of Life Sciences, University of Manchester, AV Hill Building, Manchester, UKAbstract: Acute cerebrovascular disease can affect people at all stages of life, from neonates to the elderly, with devastating consequences. It is responsible for up to 10% of deaths worldwide, is a major cause of disability, and represents an area of real unmet clinical need. Acute cerebrovascular disease is multifactorial with many mechanisms contributing to a complex pathophysiology. One of the major processes worsening disease severity and outcome is inflammation. Pro-inflammatory cytokines of the interleukin (IL)-1 family are now known to drive damaging inflammatory processes in the brain. The aim of this review is to discuss the recent literature describing the role of IL-1 in acute cerebrovascular disease and to provide an update on our current understanding of the mechanisms of IL-1 production. We also discuss the recent literature where the effects of IL-1 have been targeted in animal models, thus reviewing potential future strategies that may limit the devastating effects of acute cerebrovascular disease.Keywords: cerebral ischemia, stroke, inflammation, microglia, interleukin-1, caspase-1

Summary: The safety of a replication‐deficient, human adenovirus‐vectored foot‐and‐mouth disease virus (FMDV) serotype A24 Cruzeiro capsid‐based subunit vaccine (AdtA24) was evaluated in five independent safety studies. The target animal safety studies were designed in compliance with United States (U.S.) regulatory requirements (Title 9, U.S. Code of Federal Regulation [9CFR]) and international standard guidelines (VICH Topic GL‐44) for veterinary live vaccines. The first three studies were conducted in a total of 22 vaccinees and demonstrated that the AdtA24 master seed virus (MSV) was safe, did not revert to virulence and was not shed or spread from vaccinees to susceptible cattle or pigs. The fourth safety study conducted in 10 lactating cows using an AdtA24 vaccine serial showed that the vaccine was completely absent from milk. The fifth safety study was conducted under typical U.S. production field conditions in 500 healthy beef and dairy cattle using two AdtA24 vaccine serials. These results demonstrated that the vaccine was safe when used per the product label recommendations. Additional data collected during these five studies confirmed that AdtA24 vaccinees developed FMDV A24 and the HAd5 vaccine vector serum neutralization antibodies that test negative in a FMDV non‐structural protein antibody test, confirming AdtA24 vaccine's capability to differentiate infected from vaccinated animals (DIVA). In conclusion, results from this comprehensive set of cattle studies demonstrated the safety of the replication‐deficient AdtA24 vaccine and fulfilled safety‐related requirements for U.S. regulatory requirements. [ABSTRACT FROM AUTHOR]

The mammalian organ of Corti, the sensory epithelium of the inner ear, is a mosaic composed of sensory cells (hair cells) and nonsensory supporting cells. All cells are highly differentiated in structure and function. Because no undifferentiated cells are held in reserve to replace damaged cells, hearing impairment due to loss of hair cells is permanent. Differentiation of complex tissues like the organ of Corti typically is governed by specific cascades of gene expression. In mice, a critical gene in the differentiation of hair cells is the basic helix-loop-helix transcription factor Math1, a homolog of the Drosophila gene atonal Previous studies have shown that inoculating inner ears of normal adult guinea pigs with an adenovirus vector expressing Math1 (Ad.Math1) can generate new cochlear hair cells in regions normally occupied only by supporting cells. In this study, we deafened adult guinea pigs by administration with ototoxic drugs (kanamycin and ethacrynic acid) prior to inoculating their inner ears with Ad.Math1 and evaluated differences in hair cell number and hearing thresholds before and after treatment. This research is supported by GenVec and by NIH-NIDCD grants R01 DC01634 and P30 DC 05188.