Robert Passey

S100A8: emerging functions and regulation

The functional importance of members of the S100 Ca2+‐binding protein family is becoming apparent. Murine (m)S100A8 (initially named CP‐10) is a potent chemoattractant (10−13 to 10−11 M) for myeloid cells and the chemotactic activity of other S100s has since been reported, suggesting a new class of chemoattractants. Murine S100A8 has been associated with a number of acute and chronic inflammatory conditions including bacterial infection, atherogenesis, and cystic fibrosis. It is expressed constitutively with S100A9 in neutrophils and is regulated by inflammatory stimulants in macrophages and microvascular endothelial cells. The lack of co‐expression of S100A9 with S100A8 in activated macrophages suggests distinct functions for the proteins expressed by different cell types. Glucocorticoids up‐regulate induction of mS100A8 by inflammatory mediators, and its exquisite sensitivity to oxidation suggests that it may protect against oxidative tissue damage. Inactivation of the mS100A8 gene is embryonic lethal, providing the first evidence for non‐redundant function of a member of the S100 gene family. S100A8 may have an immunoregulatory role by contributing to the regulation of fetal‐maternal interactions. It may play a protective role and its absence may allow infiltration by maternal cells, a process eventually manifesting as resorption. This review focuses on the variety of emerging functions attributed to murine S100A8, a protein implicated in embryogenesis, growth, differentiation, and immune and inflammatory processes. J. Leukoc. Biol. 66: 549–556; 1999.

Regulation of S100A8 by Glucocorticoids

S100A8 (A8) has roles in inflammation, differentiation and development and is associated with oxidative defense. Murine A8 (mA8) is up-regulated in macrophages, fibroblasts, and microvascular endothelial cells by LPS. Glucocorticoids (GCs) amplified LPS-induced mA8 in these cells. Relative to stimulation by LPS, GCs increased mA8 gene transcription and mRNA half-life. Enhancement required new protein synthesis, IL-10 and products of the cyclooxygenase-2 pathway, and both ERK1/2 and p38 MAPK. Protein kinase A positively and protein kinase C negatively regulated this process. Promoter analysis indicated element(s) essential for LPS and dexamethasone enhancement colocated within the region −178 to 0 bp. In the absence of glucocorticoid response elements, NF1 motif at −58 is a candidate for mediation of enhancement. Gel shift analysis detected no differences between LPS- and LPS/dexamethasone-treated complexes within this region. GCs increased constitutive levels of A8 and S100A9 (A9) mRNA in human monocytes. The synovial membrane of rheumatoid patients treated with high dose i.v. methylprednisolone contained higher numbers of A8/A9-positive macrophages than pre- or posttreatment samples. Results support the proposal that A8 has anti-inflammatory properties that may be independent of hetero-complex formation with A9 and may also enable localized defense in the absence of overriding deleterious host responses.

G551D Cystic Fibrosis Mice Exhibit Abnormal Regulation of Inflammation in Lungs and Macrophages

The major cause of death in cystic fibrosis (CF) is chronic lung disease associated with persistent infection by the bacterium, Pseudomonas aeruginosa. S100A8, an S-100 calcium-binding protein with chemotactic activity, is constitutively expressed in the lungs and serum of CF patients. Levels of S100A8 mRNA were found to be three to four times higher in the lungs of mice carrying the G551D mutation in CF transmembrane conductance regulator compared with littermate controls. Intravenous injection of bacterial LPS induced S100A8 mRNA in the lung to a greater extent in G551D mice than in wild-type littermates. Localization of S100A8 mRNA and protein in the lung indicate that it is a marker for neutrophil accumulation. Bone marrow-derived macrophages from G551D mice were shown to also exhibit hypersensitivity to LPS, measured by induction of TNF-α. These results provide evidence that the pathology of CF relates to abnormal regulation of the immune system.

The fall (and rise) of carbon pricing in Australia: a political strategy analysis of the carbon pollution reduction scheme

In April 2010, Prime Minister Kevin Rudd announced the deferral of his flagship climate-change policy, the Carbon Pollution Reduction Scheme, after it twice failed to gain the support of the Australian Senate. The decision contributed to the curtailment of Rudds premiership and confirmed climate change as one of the most toxic issues in Australian politics. Although deficits in policy design and structural obstacles caused by Australias carbon-intensive economy were major obstacles for the Carbon Pollution Reduction Scheme, it could have passed into legislation had more effective political strategies been used to counter political opposition. A policy network framework is used to explore these political obstacles and how alternative political strategies may help to counter political obstacles to and public concern about new climate policies. In conclusion, the wider merits of policy network and political strategy approaches for the analysis of national climate politics are considered.

Regulation of CAT protein by ribozyme and antisense mRNA in transgenic mice

Transgenic mouse lines were engineered to express stably antisense mRNA or antisense mRNA containing catalytic ribozyme (rbz) structures complementary to bacterial chloramphenicol acetyltransferase (CAT) gene transcripts. One transgenic line expressed antisense mRNA that specifically targeted full-length CAT coding sequences (ACAT). Another transgenic line expressed full-length antisense CAT mRNA which was modified by mutagensis to include four rbz cassettes (rbz-ACAT) in order to compare antisense versus antisense-rbz function in vivo. Preliminary data were also collected from a transgenic mouse line expressing antisense mRNA targeting 72% of the 5′ region of CAT coding sequences (5′ ACAT). All constructs contained similar control elements in their design. Promoter elements were derived from the bovine αs1-casein gene, while the small t intron and 3′ control sequences were derived from SV40. The ability of these various constructs to down-regulate CAT p rotein levels was compared by analysis of CAT protein production in lactating double-hemizygous transgenic female mice. Every double-hemizygous mouse analysed expressed mRNA from the αs1-casein-CAT construct (Clarke et al., 1994) and equivalent levels of mRNA from one of the three antisense constructs. Transgenic mouse lines expressing both ACAT and CAT mRNA down-regulated CAT protein levels by 90% of that found in the CAT only transgenic population. Similarly, double-hemizygous transgenic lines expressing both rbz-ACAT and CAT mRNA regulated CAT protein levels by 87%. Preliminary data suggests that expression of mRNA from 5′ ACAT/CAT double-hemizygote mice allowed approximately 67% down-regulation of normal CAT protein levels. We conclude that incorporation of multiple ribozymes within the full-length antisense CAT construct does not enhance the effectiveness of antisense mRNA in the down-regulation of CAT protein production in our system

Exon skipping in the ovine αs1-casein gene

The reported cDNA sequences for the bovine (Bos taurus) and ovine (Ovis aries) alpha s1-caseins display a high degree of identity with the exception that a 24 bp region, corresponding to bovine exon 16, is absent in the ovine sequence. Here we show that the ovine gene for alpha s1-casein contains a sequence block displaying 23/24 identity to bovine exon 16, indicating that the absence of this block from ovine mRNA is due not to genomic deletion but to exon skipping. Analysis of the products obtained by reverse transcription of ovine alpha s1-casein mRNA followed by amplification, demonstrated the presence of mRNA species containing the exon 16 sequence as well as the species in which it had been spliced out. It was estimated that the latter constitutes 20% of the total ovine alpha s1-casein mRNA. We propose that a substitution within the donor splice site is responsible for the partial skipping of exon 16, possibly through the formation of an inhibitory RNA secondary structure.

The limited role for Carbon Capture and Storage (CCS) technologies in a sustainable Australian energy future

There is considerable debate regarding the potential role of Carbon Capture and Storage (CCS) technologies in reducing Australias greenhouse emissions. The latest climate change science suggests that major (60% or more by 2050), rapid (peaking within 20 years) cuts in global emissions may be required to avoid dangerous climate change. There are a number of existing abatement options including energy efficiency, various renewable energy technologies, nuclear power and fuel switching to natural gas; as well as emerging options including CCS. We outline a simple technology assessment framework for policymakers to evaluate these different options given the climate change imperative. This framework includes technology status, delivered energy services, present and possible future costs, potential scale of abatement, potential speed of deployment and other possible social outcomes. Application of this framework to CCS suggests that it should be considered as a promising, but still somewhat unproven, option that potentially offers very significant abatement potential and good integration into the existing energy industry. There are, however, some outstanding questions regarding its effectiveness and safety, its abatement is likely to come at significant cost, and it is unlikely to be able to make a significant contribution for well over a decade. The Australian policy implications are that while government support for R&D and Demonstration of CCS is appropriate and should in our view be expanded, the major priority should be to support greater deployment of existing abatement options including energy efficiency, efficient gas-fired generation and cogeneration and renewable energy. Such policy support is noticeably lacking at present.

Trading in Energy Efficiency – A Market-Based Solution to Market Failure, or Just Yet Another Market Failure?

In this chapter we describe the underlying theory, rationale, and mixed performance to date of policy measures that establish a trading market in “energy savings.” Such approaches, under names that include White Certificates, Energy Efficiency Portfolio Standards, Energy Savings, and Energy Efficiency Certificate Trading, are receiving growing policy attention around the world including in Europe, the United States, and Australia. They are often portrayed as a market-based solution to a “market failure.” This chapter highlights the many challenges – technical, economic, and social – of such “designer” markets that attempt to commodify energy savings, with key problems they face including measurement and additionality. However, there are broader challenges in the complex interaction between technologies and behaviors inherent in energy use and in the financialization of such complex, interacting, uncertain outcomes, making potential imputed “savings” even more problematic. It is concluded that considerable care is required with such approaches to energy efficiency policy lest governments’ merely add yet another market failure to those already existing for energy efficiency. More importantly, policymakers will need to move beyond framing energy efficiency within conventional economic terms of market failure, and address the broader challenge of engaging energy users on their unsustainable behaviors including, notably, the constant fuelling of the desire for further energy services.

Photovoltaics research and development in Australia

Australia has had an active photovoltaic device research and development program for the past 30 years, with more sporadic interest shown in photovoltaic systems, components and markets. Exciting new developments continue to come out of Australian research laboratories, yet many are commercialized elsewhere and local deployment now lags behind that of many other countries. This paper examines past achievements, current research activities, research support and the potential for PV to contribute to future energy supply in Australia. It also examines some of the institutional and energy policy issues which provide the framework for continued development and increased deployment of photovoltaics in Australia.

Impact of Distributed Photovoltaic Systems on Zone Substation Peak Demand

Australia has likely the worlds highest residential photovoltaic (PV) system penetration. In this paper, the impact of distributed PV on peak demand at different distribution network zone substations (ZSs) is assessed by upscaling 15 min PV generation data from 270 distributed PV systems across Sydney, Australia, and comparing it with load data from 138 ZS serving the Sydney region. Gross load (load had there been no PV) was estimated, allowing the impact of current and higher PV penetrations on the value and time of peak at the different ZSs to be assessed. A probabilistic assessment of the impact of PV on ZSs is conducted, based on the availability of PV during the peak demand periods. To better understand the impact of PV on peak demand, K-means clustering is used to group ZSs based on PV generation during peak periods as the clustering features. Mapping of PV availability across percentage of peak times for all ZSs highlights the interannual variability of peak reductions and the potential impact of short-term load shifting. The impact of different penetration levels of distributed PV on the peak demand of the entire distribution network is also assessed by aggregating the ZS loads.