Mastering the canonical loop of serine protease inhibitors : enhancing potency by optimising the internal hydrogen bond network

Background Canonical serine protease inhibitors commonly bind to their targets through a rigid loop stabilised by an internal hydrogen bond network and disulfide bond(s). The smallest of these is sunflower trypsin inhibitor (SFTI-1), a potent and broad-range protease inhibitor. Recently, we re-engineered the contact β-sheet of SFTI-1 to produce a selective inhibitor of kallikrein-related peptidase 4 (KLK4), a protease associated with prostate cancer progression. However, modifications in the binding loop to achieve specificity may compromise structural rigidity and prevent re-engineered inhibitors from reaching optimal binding affinity. Methodology/Principal Findings In this study, the effect of amino acid substitutions on the internal hydrogen bonding network of SFTI were investigated using an in silico screen of inhibitor variants in complex with KLK4 or trypsin. Substitutions favouring internal hydrogen bond formation directly correlated with increased potency of inhibition in vitro. This produced a second generation inhibitor (SFTI-FCQR Asn14) which displayed both a 125-fold increased capacity to inhibit KLK4 (Ki = 0.0386±0.0060 nM) and enhanced selectivity over off-target serine proteases. Further, SFTI-FCQR Asn14 was stable in cell culture and bioavailable in mice when administered by intraperitoneal perfusion. Conclusion/Significance These findings highlight the importance of conserving structural rigidity of the binding loop in addition to optimising protease/inhibitor contacts when re-engineering canonical serine protease inhibitors.

Communications materials on methods of development of revenue and cost estimates to non-technical audiences

This CDROM includes PDFs of presentations on the following topics: "TXDOT Revenue and Expenditure Trends;" "Examine Highway Fund Diversions, & Benchmark Texas Vehicle Registration Fees;" "Evaluation of the JACK Model;" "Future highway construction cost trends;" "Fuel Efficiency Trends and Revenue Impact"

Archimedes, aid/watch, constitutional levers and where we now stand

Significant reform of the laws regulating charities is under way in Australia. The reforms cover almost every facet of the relationship between charities and government and the process has brought to the surface different assumptions about the role of charities in society, their entitlement to fiscal and other privileges and the scope and nature of regulation that can or should be imposed on the charities. This paper explores these broader issues in the context of the Aid/Watch case, involving an organisation used by citizens to challenge the State. Such organisations occupy contested space as to what does and does not constitute a charity. Accordingly the case provides a useful perspective from which to consider the broader issues in the relationship between government and charity. This paper seeks to build on the contribution made by other academics, by exploring the constitutional significance of political purposes and drawing from philosophy to provide context and meaning to potentially significant aspects of the judgment that might be missed when it is analysed only in terms of legal precedent through the narrow lens of the existing four heads of charity. Revenue implications for taxation of charities and political parties are also considered and it is suggested that in practice, if not in theory, the fence between them has come down.

Law student psychological distress, ADR and sweet-minded, sweet-eyed hope

Empirical studies conducted by both Australian and American researchers have established law school’s causative role in increasing law student psychological distress. The purpose of this article is to highlight the role that law school curriculum might play in addressing this problem. By utilising lessons from the field of positive psychology (and in particular hope theory) a first-year law subject at the Queensland University of Technology has been specifically designed to promote law student well-being. Traditional legal education and pedagogy do not hold the answers for addressing this social phenomenon. A first-year curriculum that introduces students to alternative dispute resolution, non-adversarial justice, resilience and the positive role of lawyers in society may go some way to addressing the law student well-being challenge.

The role of the rule of law in virtual communities

Please see the updated published version of this work at http://eprints.qut.edu.au/37850/ There is a severe tendency in cyberlaw theory to delegitimize state intervention in the governance of virtual communities. Much of the existing theory makes one of two fundamental flawed assumptions: that communities will always be best governed without the intervention of the state; or that the territorial state can best encourage the development of communities by creating enforceable property rights and allowing the market to resolve any disputes. These assumptions do not ascribe sufficient weight to the value-laden support that the territorial state always provides to private governance regimes, the inefficiencies that will tend to limit the development utopian communities, and the continued role of the territorial state in limiting autonomy in accordance with communal values...

Family law issues and schools : guidance for Australian educators

A substantial number of Australian children are now living in separated families, with many moving between their parents’ homes. This has led to educators being confronted with an increasing number of family law issues. This article discusses the key aspects of family law that involve children. It highlights the need for schools to be aware of all family law orders that relate to children in their care, including family court, domestic violence and child protection orders. It also provides guidance in relation to how schools can adopt child focused approaches in some common scenarios, where parents are in dispute. In particular, we will recommend that educators take a child-focused approach, consistent with the principal provision of the Family Law Act 1975 (Cth) that ‘the best interests of the child’ be the paramount consideration. We will highlight how this contrasts starkly with what can be described as a ‘parental rights’ interpretation, which has unfortunately been taken by some since the 2006 amendments to the Family Law Act, and is, in our view, directly at odds with the intention of the legislation.

Sport and the law implications for the nonprofit corporation

Sports associations constitute a large portion of the nonprofit sector. The past 15 years have witnessed substantial changes in the overall legal environment in which they operate. This paper will examine selected aspects of those changes with a view to identifying considerations which may be relevant to the way in which nonprofit corporations in sport ought to be regulated