BackgroundMeesmann epithelial corneal dystrophy (MECD) is an inherited eye disorder caused by dominant-negative mutations in either keratins K3 or K12, leading to mechanical fragility of the anterior corneal epithelium, the outermost covering of the eye. Typically, patients suffer from lifelong irritation of the eye and/or photophobia but rarely lose visual acuity; however, some individuals are severely affected, with corneal scarring requiring transplant surgery. At present no treatment exists which addresses the underlying pathology of corneal dystrophy. The aim of this study was to design and assess the efficacy and potency of an allele-specific siRNA approach as a future treatment for MECD.Methods and Findings We studied a family with a consistently severe phenotype where all affected persons were shown to carry heterozygous missense mutation Leu132Pro in the KRT12 gene. Using a cell-culture assay of keratin filament formation, mutation Leu132Pro was shown to be significantly more disruptive than the most common mutation, Arg135Thr, which is associated with typical, mild MECD. A siRNA sequence walk identified a number of potent inhibitors for the mutant allele, which had no appreciable effect on wild-type K12. The most specific and potent inhibitors were shown to completely block mutant K12 protein expression with negligible effect on wild-type K12 or other closely related keratins. Cells transfected with wild-type K12-EGFP construct show a predominantly normal keratin filament formation with only 5% aggregate formation, while transfection with mutant K12-EGFP construct resulted in a significantly higher percentage of keratin aggregates (41.75%; p<0.001 with 95% confidence limits). The lead siRNA inhibitor significantly rescued the ability to form keratin filaments (74.75% of the cells contained normal keratin filaments; p<0.001 with 95% confidence limits).ConclusionsThis study demonstrates that it is feasible to design highly potent siRNA against mutant alleles with single-nucleotide specificity for future treatment of MECD.

A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield.

Higher education is usually seen as serving the public good, especially when funded directly by the state, and because of the 'social benefit efficiency gains and potential equity effects on opportunity and reduced inequality' (McMahon, 2009, p. 255). Calhoun (2006, p. 19) argues that public support for higher education is only given and maintained according to its capacity, capability, and willingness, to 'educate citizens in general, to share knowledge, to distribute it as widely as possible in accord with publically articulated purposes'. So what is the public good and what defines it? Recent years have seen many governments adopt the format of a national strategy or development plan for higher education-setting out national objectives. Similarly, many governments (e.g. Ireland, Netherlands, Hong Kong, Finland, New Zealand) are adopting the policy tool of performance agreements or compacts to better align higher education institutions (HEIs) with the national objectives, involving identification of appropriate performance management and indicators (Benneworth, et al., 2011; de Boer, et al., 2015). The process by which national objectives are determined varies but may involve a group comprising national and international 'experts', sometimes using consultation mechanisms (open or limited). The concept of public good has played a significant role in (re)positioning higher education over recent years-especially in response to growing demands for greater accountability for all public organisations but also in response to specific concerns about growing higher education access/participation, costs/debt, graduate employability/unemployment, and social/economic impact. This paper takes a practical approach-both in relation to asking 'what is the public good' and 'who defines it'-by looking at how different countries are approaching the issue. The further expansion of higher education is inevitable and essential if we are to fulfil our aspirations as an innovative and knowledge-based economy, and we must ensure that this happens within a coherent policy environment that serves the advancement of knowledge, wider national development and the public good.

Science has always operated in a competitive environment, but the globalisation of knowledge and the rising popularity and use of global rankings have elevated this competition to a new level. The quality, performance and productivity of higher education and university-based research have become a national differentiator in the global knowledge economy. Global rankings essentially measure levels of wealth and investment in higher education, and they reflect the realisation that national pre-eminence is no longer sufficient. These developments also correspond with increased public scrutiny and calls for greater transparency, underpinned by growing necessity to demonstrate value, impact and benefit. Despite on-going criticism of methodologies, and scepticism about their overall role, rankings are informing and influencing policy-making, academic behaviour, stakeholder opinions-and our collective understanding of science. This article examines the inter-relationship and tensions between the national and the global in the context of the influences between higher education and global university rankings. It starts with a discussion of the globalisation of knowledge and the rise of rankings. It then moves on to consider rankings in the context of wider discourse relating to quality and measuring scholarly activity, both within academia and by governments. The next section examines the relationship and tensions between research assessment and rankings, in policy and practice. It concludes by discussing the broader implications for higher education and university-based research.

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