2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2.

Cytosolic phospholipase A2 (GIVA cPLA2) is the only PLA2 that exhibits a marked preference for hydrolysis of arachidonic acid containing phospholipid substrates releasing free arachidonic acid and lysophospholipids and giving rise to the generation of diverse lipid mediators involved in inflammatory conditions. Thus, the development of potent and selective GIVA cPLA2 inhibitors is of great importance. We have developed a novel class of such inhibitors based on the 2-oxoester functionality. This functionality in combination with a long aliphatic chain or a chain carrying an appropriate aromatic system, such as the biphenyl system, and a free carboxyl group leads to highly potent and selective GIVA cPLA2 inhibitors (X I(50) values 0.00007-0.00008) and docking studies aid in understanding this selectivity. A methyl 2-oxoester, with a short chain carrying a naphthalene ring, was found to preferentially inhibit the other major intracellular PLA2, the calcium-independent PLA2. In RAW264.7 macrophages, treatment with the most potent 2-oxoester GIVA cPLA2 inhibitor resulted in over 50% decrease in KLA-elicited prostaglandin D2 production. The novel, highly potent and selective GIVA cPLA2 inhibitors provide excellent tools for the study of the role of the enzyme and could contribute to the development of novel therapeutic agents for the treatment of inflammatory diseases

False-negative results using Neisseria gonorrhoeae porA pseudogene PCR - a clinical gonococcal isolate with an N. meningitidis porA sequence, Australia, March 2011

The gonococcal porA pseudogene is a popular target for in-house Neisseria gonorrhoeae PCR methods. With this study we present two novel findings: the first case of an N. gonorrhoeae porA pseudogene PCR false-negative result caused by sequence variation, and in the same organism, the first description of a clinical N. gonorrhoeae strain harbouring an N. meningitidis porA sequence

Pathwise Sensitivity Analysis in Transient Regimes

The instantaneous relative entropy (IRE) and the corresponding instanta- neous Fisher information matrix (IFIM) for transient stochastic processes are pre- sented in this paper. These novel tools for sensitivity analysis of stochastic models serve as an extension of the well known relative entropy rate (RER) and the corre- sponding Fisher information matrix (FIM) that apply to stationary processes. Three cases are studied here, discrete-time Markov chains, continuous-time Markov chains and stochastic differential equations. A biological reaction network is presented as a demonstration numerical example

A differential equation for a class of discrete lifetime distributions with an application in reliability: A demonstration of the utility of computer algebra

YesIt is shown that the probability generating function of a lifetime random variable T on a finite lattice with polynomial failure rate satisfies a certain differential equation. The interrelationship with Markov chain theory is highlighted. The differential equation gives rise to a system of differential equations which, when inverted, can be used in the limit to express the polynomial coefficients in terms of the factorial moments of T. This then can be used to estimate the polynomial coefficients. Some special cases are worked through symbolically using Computer Algebra. A simulation study is used to validate the approach and to explore its potential in the reliability context

Dorsal-Ventral Differences in Retinal Structure in the Pigmented Royal College of Surgeons Model of Retinal Degeneration

Retinitis pigmentosa is a family of inherited retinal degenerations associated with gradual loss of photoreceptors, that ultimately leads to irreversible vision loss. The Royal College of Surgeon's (RCS) rat carries a recessive mutation affecting mer proto-oncogene tyrosine kinase (merTK), that models autosomal recessive disease. The aim of this study was to understand the glial, microglial, and photoreceptor changes that occur in different retinal locations with advancing disease. Pigmented RCS rats (RCS-p+/LAV) and age-matched isogenic control rdy (RCS-rdy +p +/LAV) rats aged postnatal day 18 to 6 months were evaluated for in vivo retinal structure and function using optical coherence tomography and electroretinography. Retinal tissues were assessed using high resolution immunohistochemistry to evaluate changes in photoreceptors, glia and microglia in the dorsal, and ventral retina. Photoreceptor dysfunction and death occurred from 1 month of age. There was a striking difference in loss of photoreceptors between the dorsal and ventral retina, with a greater number of photoreceptors surviving in the dorsal retina, despite being adjacent a layer of photoreceptor debris within the subretinal space. Loss of photoreceptors in the ventral retina was associated with fragmentation of the outer limiting membrane, extension of glial processes into the subretinal space that was accompanied by possible adhesion and migration of mononuclear phagocytes in the subretinal space. Overall, these findings highlight that breakdown of the outer limiting membrane could play an important role in exacerbating photoreceptor loss in the ventral retina. Our results also highlight the value of using the RCS rat to model sectorial retinitis pigmentosa, a disease known to predominantly effect the inferior retina

An integrated environmental and fairtrade labelling scheme for product supply chains

Environmental initiatives such as carbon labelling have been suggested as a driver for achieving sustainable production systems of product supply chains. The paper therefore presents a systematic process of developing an environmental labelling framework as an extension of carbon labelling using the fairtrade certification as a platform to facilitate the process. Using the general theoretical constructs of lifecycle assessments, the framework presented provides insight into the formulation of multi-regional supply chains which has been specifically characterised in this paper for the UK-India-Rest of the World supply chain. The environmental labelling process presented in this paper is based on two key principles; Quantitative Principle in Eco-labelling and the Principle of Whole Lifecycle Perspective and it is used to inform two key stakeholder groups in the supply chain: consumers and supply chain partners. For consumers, a consistent way of presenting the environmental label information is presented highlighting the supply chain impacts across the indicators of CO2-eq emissions, water consumption and land use in addition to regional contributions to these impacts from a global supply chain perspective. Additionally, communicating the environmental impacts to supply chain partners provides a decision support to take actions to reduce the overall impacts by identifying processes within the global supply chain that needed prioritization. Given that fairtrade partnership is based on participatory development and a strict guidelines and standardization process, it is envisaged that synergies can be derived by integrating environmental labelling with the fairtrade scheme to enhance the environmental sustainability of product supply chains

Female Language in Popular Science

Fewer women than men are involved in STEM (Science, Technology, Engineering, and Mathematics) fields and one of the reasons might be a lack of exposure to familiar linguistic structures in reading materials designed to spark interest and to recruit new scientists. Popular science, as a multifaceted genre, creates an accessible kind of exposure to the scientific world that can potentially lead to a career in that field. Considering this potential of the genre and keeping in mind that most popular science is written by men, the present study examined fifteen articles (five written by men, five by women, and five co-written by authors of both genders) for the presence of female language. Female language was differentiated from gendered language (which is tied to female stereotypes) and identified based on the frequency of certain linguistic markers found in texts produced by women. The results demonstrate that women and teams of authors that include women write differently than men do, thus confirming previous investigations into differences in linguistic production between men and women. The study suggests that exposing young women considering a career in science to popular science written by females might be beneficial in cementing their aspirations, as language has a strong connection to self-perceived gender identity