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Phosphatidylinositol (PhoIns)-specific phospholipase C enzymes (PLCs) are central to the inositol lipid signalling pathways and contribute to intracellular Ca²⁺ release and protein kinase C activation in mammalian neurons. Six distinct classes of PhoIns-specific PLCs are known to exist in mammals (β, γ, δ, ε, ζ, and η), all of which are activated by distinct membrane receptor-mediated events. The Stewart lab previously revealed that expression of the PLC isozyme, PLC-η2 is essential for neurite growth, a process central to normal neuronal differentiation. A new study from the lab has gone a step further and shown that active PLC-η2 is needed for neurite growth to occur. Furthermore, the study also revealed that PLC-η2 interacts directly with LIM Domain Kinase 1, a key cytoskeletal regulatory protein previously implicated in this process. The new findings are published in the journal, Histochemistry and Cell Biology. Full text is available here: DOI 10.1007/s00418-015-1390-7.

Dr Alan Stewart has been appointed to the BBSRC Pool of Experts. The BBSRC is one of the 7 Research Councils that work together as Research Councils UK (RCUK). The BBSRC which funds world leading UK bioscience has an annual budget in excess of £500M. Pool members are appointed based upon an active involvement in high quality UK biological research, and are recruited from a range of scientific backgrounds to assist in the assessment of funding applications.

Dagmara Wiatrek was in attendance at the 29th European Macrophage and Dendritic Cell Society (EMDS) Meeting in Krakow, Poland. Dagmara presented a poster entitled “Alterations in zinc transporter expression during dendritic cell maturation”. Her trip was supported by a travel award from EMDS.

On 2^nd of September Dagmara took part in Life Sciences event for schools which took place at Perth High School. Her series of workshops on ELISA technique were attended by over 100 pupils aged 12-17.

A BHF-funded PhD studentship characterising zinc-dependent heparin neutralisation by fibrinogen and histidine-rich glycoprotein is available in the laboratories of Dr Alan Stewart And Dr Sam Pitt. Full details and instructions on how to apply are available here.

Dagmara Wiatrek has been awarded £400 from the European Macrophage and Dendritic Cell Society (EMDS) to attend their annual meeting in Krakow, Poland in September. Dagmara will present part of her PhD studies at the meeting relating to zinc transporter expression in dendritic cells .

The Stewart lab has an opening for a Research Assistant in Biochemical Ophthalomology for a period of 24 months. For details of the post and how to apply see the link.

A research grant of £110,951 has been awarded to Dr Alan Stewart and Dr Imre Lengyel (UCL Institute of Ophthalmology) from Fight for Sight to carry out a new 2-year study entitled “Identifying the hydroxyapatite interactome: clarifying the involvement of serum proteins in the formation of sub-retinal pigment epithelial (RPE) deposits”. A major feature of the ageing retina is the thickening of Bruch’s membrane and the formation of sub-retinal pigment epithelial (RPE) deposits that can block metabolic exchange between the choroidal blood circulation and the retina leading to sensory retinal degeneration and eventually to age-related macular degeneration (AMD), a major cause of visual impairment and blindess in older adults (>50 years). Recently, Thompson et al. reported the existence of small (0.5-20 μm diameter) protein-binding hydroxyapatite (HAP) spherules within sub-RPE deposits isolated from AMD-affected individuals (see link). This suggests that the spherules may provide nucleation sites for sub-RPE deposit formation, where the initiation, growth and retention of deposits are controlled by the binding of proteins present in the sub-RPE space to the spherules. In the funded study, HAP-binding proteins in the plasma of genotyped late-stage AMD patients will be isolated and quantitatively identified and biochemically characterised.

A research grant of £191,250 has been awarded to Dr Alan Stewart from the British Heart Foundation to carry out a new 3-year study entitled “Role of zinc in controlling histidine-rich glycoprotein (HRG) complex formation: Implications for the development of thrombotic complications”. This work will advance current knowledge of the structure and function of HRG, a key molecule involved in controlling coagulation, and its regulation of haemostasis in health and disease. In addition, the project will evaluate a potentially novel zinc-dependent haemopathological mechanism in diabetes patients stemming from elevated plasma FFA levels and modulation of HRG functioning. The study is a collaboration between investigators at the University of St Andrews (Dr Stewart, Dr Samantha Pitt and Prof. James Naismith) and the University of Leeds (Dr Ramzi Ajjan).

Histidine-rich glycoprotein (HRG) is a plasma protein that regulates a number of biological processes in the blood including coagulation, through its ability to bind and neutralize heparins. HRG contains a distinctive histidine-rich region that associates with zinc ions (Zn²⁺) to stimulate HRG-heparin complex formation. Under normal conditions the majority of Zn²⁺ in plasma associates with serum albumin. However, clinically high levels of free fatty acid (FFA) allosterically disrupt the major Zn²⁺-binding site on serum albumin and are associated with an increased risk of thrombotic complications. The Stewart group report in the Journal of Thrombosis and Haemostasis that increased levels of circulatory fatty acids are likely to increase the proportion of plasma Zn²⁺ associated with HRG. In this study the Zn²⁺-binding properties of HRG and the formation of HRG-heparin complexes in the presence of different Zn²⁺ concentrations were investigated. Furthermore, the binding of Zn²⁺ to serum albumin was examined in the presence of various concentrations of myristate by ITC. Speciation modeling of plasma Zn²⁺ based upon the data obtained from these experiments suggests that FFA-mediated displacement of Zn²⁺ from serum albumin is likely to contribute to the development of thrombotic complications in individuals with high plasma FFA levels – Full text is available online.