Caspase-8 in Cell Death and Inflammation

Pathogenic organisms express virulence factors that can inhibit immune signaling pathways. Thus, the immune system is faced with the challenge of eliciting an effective inflammatory response to pathogens that actively suppress inflammation. The mechanisms that regulate this response are largely undefined. Here, I used the gram-negative extracellular bacterial pathogen Yersinia pseudotuberculosis to investigate anti-pathogen responses, as the Yersinia virulence factor YopJ blocks NF-κB and MAPK signaling, resulting in reduced cytokine production and target cell death. I set out to first, determine the molecular mechanism of Yersinia-mediated cell death and second, examine the impact of cell death on immune responses in vivo. Multiple caspases are activated during Yersinia infection, including caspase-1, which regulates pyroptosis, and caspase-3 and -8, which elicit apoptosis. I found that caspase-8 and receptor-interacting protein kinase-3 (RIPK3), RIPK1 and FADD are required for Yersinia-induced cell death. My studies also showed that caspase-8 is required for the activation of caspase-1 and -3 during Yersinia infection. Interestingly, mice lacking caspase-8 were severely susceptible to Yersinia infection and had defective pro-inflammatory cytokine production. These findings highlight a possible mechanism of immune defense that can overcome pathogen inhibition of cell-intrinsic pro-inflammatory immune responses. Caspases are proteases that are best characterized for their abilities to regulate apoptotic or pyroptotic cell death programs, both of which are critical for the proper operation of the mammalian immune system. Within this family of proteins is caspase-8, which is unusual as it can promote both cell death, and inflammatory gene expression induced by Toll-like Receptors. How these two dichotomous outcomes occur independently of the other, is mysterious. Using mice that specifically ablate caspase-8 auto-processing, I have demonstrated that caspase-8 enzymatic, but not autoprocessing activity, mediates induction of inflammatory cytokines by a wide variety of TLR stimuli. Since uncleaved caspase-8 functions together with its homolog, cFLIP, our findings implicate the activity of a caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new mechanistic insight into how caspase-8 regulates gene expression

Assessment of applicability and transferability of evidence-based antenatal interventions to the Australian indigenous setting

There is a need for public health interventions to be based on the best available evidence. Unfortunately, well-conducted studies from settings similar to that in which an intervention is to be implemented are often not available. Therefore, health practitioners are forced to make judgements about proven effective interventions in one setting and their suitability to make a difference in their own setting. The framework of Wang et al. has been proposed to help with this process. This paper provides a case study on the application of the framework to a decision-making process regarding antenatal care in Aboriginal and Torres Strait Islander communities in Queensland. This method involved undertaking a systematic search of the current available evidence, then conducting a second literature search to determine factors that may affect the applicability and transferability of these interventions into these communities. Finally, in consideration of these factors, clinical judgement decisions on the applicability and transferability of these interventions were made. This method identified several interventions or strategies for which there was evidence of improving antenatal care or outcomes. By using the framework, we concluded that several of these effective interventions would be feasible in Aboriginal and Torres Strait Islander communities within Queensland

Mammalian class E vps proteins recognize ubiquitin and act in the removal of endosomal protein–ubiquitin conjugates

There is increasing evidence that ubiquitination of receptors provides an important endosomal sorting signal. Here we report that mammalian class E vacuolar protein-sorting (vps) proteins recognize ubiquitin. Both tumor susceptibility gene 101 (TSG101)/human VPS (hVPS)28 and hepatocyte growth factor receptor substrate (Hrs) cytosolic complexes bind ubiquitin-agarose. TSG101 and hVPS28 are localized to endosomes that contain internalized EGF receptor and label strongly for ubiquitinated proteins. Microinjection of anti-hVPS28 specifically retards EGF degradation and leads to endosomal accumulation of ubiquitin–protein conjugates. Likewise, depletion of TSG101 impairs EGF trafficking and causes dramatic relocalization of ubiquitin to endocytic compartments. Similar defects are found in cells overexpressing Hrs, further emphasizing the links between class E protein function, receptor trafficking, and endosomal ubiquitination

Sign and Image: Representations of Plants on the Warka Vase of Early Mesopotamia

The Warka Vase is an iconic artifact of Mesopotamia. In the absence of rigorous botanical study, the plants depicted on the lowest register are usually thought to be flax and grain. This analysis of the image identified as grain argues that its botanical characteristics, iconographical context and similarity to an archaic sign found in proto-writing demonstrates that it should be identified as a date palm sapling. It confirms the identification of flax. The correct identification of the plants furthers our understanding of possible symbolic continuities spanning the centuries that saw the codification of text as a representation of natural language

Critical Reflections on Building a Community of Conversation about Water Governance in Australia

Water governance has emerged as a field of research endeavour in response to failures of current and historical management approaches to adequately address persistent decline in ecological health of many river catchments and pressures on associated communities. Attention to situational framing is a key aspect of emerging approaches to water governance research, including innovations that build capacity and confidence to experiment with approaches capable of transforming situations usefully framed as ‘wicked’. Despite international investment in water governance research, a national research agenda on water governance was lacking in Australia in the late 2000s as were mechanisms to build the capacity of interdisciplinary and transdisciplinary research and collaborative policy practice. Through a two-year Water Governance Research Initiative (WGRI), we designed and facilitated the development of a community of conversation between researchers concerned with the dynamics of human-ecological systems from the natural sciences, humanities, social sciences, policy, economics, law and philosophy. The WGRI was designed as a learning system, with the intention that it would provide opportunities for conversations, learning and reflection to emerge. In this paper we outline the starting conditions and design of the WGRI, critically reflect on new narratives that arose from this initiative, and evaluate its effectiveness as a boundary organisation that contributed to knowledge co-production in water governance. Our findings point to the importance of investment in institutions that can act as integrative and facilitative governance mechanisms, to build capacity to work with and between research, policy, local stakeholders and practitioners

A protocol for a systematic review of randomised evaluations of strategies to improve recruitment of rural participants to randomised controlled trials

Peer reviewedPublisher PD