The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1beta Activation

Published: November 27, 2018Intrinsic apoptosis resulting from BAX/BAK-mediated mitochondrial membrane damage is regarded as immunologically silent. We show here that in macrophages, BAX/BAK activation results in inhibitor of apoptosis (IAP) protein degradation to promote caspase-8-mediated activation of IL-1β. Furthermore, BAX/BAK signaling induces a parallel pathway to NLRP3 inflammasome-mediated caspase-1-dependent IL-1β maturation that requires potassium efflux. Remarkably, following BAX/BAK activation, the apoptotic executioner caspases, caspase-3 and -7, act upstream of both caspase-8 and NLRP3-induced IL-1β maturation and secretion. Conversely, the pyroptotic cell death effectors gasdermin D and gasdermin E are not essential for BAX/BAK-induced IL-1β release. These findings highlight that innate immune cells undergoing BAX/BAK-mediated apoptosis have the capacity to generate pro-inflammatory signals and provide an explanation as to why IL-1β activation is often associated with cellular stress, such as during chemotherapy.James E. Vince, Dominic De Nardo, Wenqing Gao, Angelina J. Vince, Cathrine Hall, Kate McArthur, Daniel Simpson, Swarna Vijayaraj, Lisa M. Lindqvist, Philippe Bouillet, Mark A. Rizzacasa, Si Ming Man, John Silke, Seth L. Masters, Guillaume Lessene, David C.S. Huang, Daniel H.D. Gray, Benjamin T. Kile, Feng Shao, and Kate E. Lawlo

Metabolomic analysis of male combat veterans with post traumatic stress disorder

10.1371/journal.pone.0213839PLoS ONE143e021383

Potential BSE risk posed by the use of ruminant collagen and gelatine in feed for non-ruminant farmed animals

EFSA was requested to estimate the cattle bovine spongiform encephalopathy (BSE) risk (C-, L- and H-BSE) posed by ruminant collagen and gelatine produced from raw material fit for human consumption, or from material classified as Category 3 animal by-products (ABP), to be used in feed intended for non-ruminant animals, including aquaculture animals. Three risk pathways (RP) were identified by which cattle could be exposed to ruminant feed cross-contaminated with ruminant collagen or gelatine: 1) recycled former foodstuffs produced in accordance with Regulation (EC) No 853/2004 (RP1), 2) technological or nutritional additives or 3) compound feed, produced either in accordance with Regulation (EC) No 853/2004 (RP2a) or Regulation (EU) No 142/2011 (RP2b). A probabilistic model was developed to estimate the BSE infectivity load measured in cattle oral ID50 (CoID50)/kg, in the gelatine produced from the bones and hide of one infected animal older than 30 months with clinical BSE (worst-case scenario). The amount of BSE infectivity (50th percentile estimate) in a member state (MS) with negligible risk status was 7.6  7 10\u20132 CoID50/kg, and 3.1  7 10\u20134 CoID50/kg in a MS with controlled risk status. The assessment considered the potential contamination pathways and the model results (including uncertainties) regarding the current epidemiological situation in the EU and current statutory controls. Given the estimated amount of BSE infectivity to which cattle would be exposed in a single year, and even if all the estimated undetected BSE cases in the EU were used for the production of collagen or gelatine (either using raw materials fit for human consumption or Category 3 ABP raw materials), it was concluded that the probability that no new case of BSE in the cattle population would be generated through any of the three RP is 99\u2013100% (almost certain)

Effects of soil matric suction on retention and percolation of Bacillus subtilis in intact soil cores

Bacillus subtilis endospores (resistant to rifampicin) irrigated on the surface of intact soil cores (20 cm diameter x 8 cm length) which were equilibrated under selected suctions, i.e. 0, 0.5, 2, 5, 10 kPa, were then percolated by saturated water flow. The bacterial retention and percolation percentage were significantly correlated with the suctions. The higher retention with higher suction was explained by micropore storage, attachment to static air-water interface (AWI), and irreversible adsorption to soil particles. The bacterial percolation was mainly controlled by initial replacement of pore water storage, and following reversible detachment process. Another sensitivity experiment with four replicates using lincomycin-resistant B. subtilis at 0 and 0.5 kPa suctions revealed that small increase (0 to 0.5 kPa) in soil matric suction incurred a substantial higher level of bacterial retention. Based on our experimental results, soil matric suction was proposed as a comprehensive parameter to monitor bacterial transport and fate for animal waste disposal (irrigation) and subsurface bioremediation