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In both thrombosis and haemostasis, two distinct populations of activated platelets form, pro-aggregatory and pro-coagulant platelets. Pro-aggregatory platelets have active integrins and aggregate together via fibrinogen to form the haemostatic plug which prevents bleeding. Pro-coagulant platelets expose phosphatidylserine (PS) which acts as a surface for binding of the tenase (FIXa/VIIIa) and prothrombinase (FXa/Va) complexes that generate a burst of thrombin production responsible for occlusive clot formation. All current anti-platelet drugs are associated with bleeding side effects since they inhibit pro-aggregatory platelet activity. No drug exists which selectively targets the pro-coagulant platelet population, though this could be an alternative anti-thrombotic approach associated with fewer bleeding side effects if pro-aggregatory activity remains. In order to test such an approach, a selective inhibitor of pro-coagulant platelet activity must be developed. Critical to platelet PS exposure is activity of the main platelet scramblase, TMEM16F. This thesis aimed to develop inhibitors of TMEM16F and platelet scramblase activity. R5421 was the only previously described inhibitor of platelet scramblase activity. R5421, however, is shown to be a non-selective inhibitor of platelet scramblase activity, also affecting platelet pro-aggregatory activity by inhibiting ��IIb��3 integrin activation, ��-granule release and cytosolic Ca2+ signalling in response to a range of agonists. Ligand-based in silico methods were applied to identify new inhibitors of platelet scramblase activity. The pesticide thiodicarb was identified as a novel inhibitor of platelet scramblase activity but also acts non-selectively. Since R5421 has wide ranging off-target effects and attempts to improve its selectivity were unsuccessful, other lead compounds were pursued. The polyphenolic compounds tannic acid and epigallocatechin gallate (EGCG���) inhibit TMEM16F activity when over-expressed in cell lines. Both tannic acid and EGCG��� are shown to inhibit platelet scramblase activity. An empirical screen of polyphenolic compounds defined an emerging pharmacophore for inhibition of platelet scramblase activity. All catechin gallate compounds inhibited platelet scramblase activity non-selectively. Structure-based in silico methods were applied to identify new inhibitors of platelet scramblase activity, first using the fungal nhTMEM16 structure and later the mTMEM16F structure. These screens identified novel inhibitors of platelet scramblase activity which do not affect platelet ��IIb��3 integrin activation, ��-granule release or cytosolic Ca2+ signalling. Further work is required to confirm whether these compounds act directly on TMEM16F or inhibit platelet scramblase activity through a different mechanism., British Heart Foundation 4 Year PhD studentship under Grant FS/15/62/32032

Supplemental material, Appendix_I_Interview_and_Focus_Group_Guide for Influencers on deprescribing practice of primary healthcare providers in Nova Scotia: An examination using behavior change frameworks by Natalie Kennie-Kaulbach, Rachel Cormier, Olga Kits, Emily Reeve, Anne Marie Whelan, Ruth Martin-Misener, Fred Burge, Sarah Burgess and Jennifer E. Isenor in Medicine Access @ Point of Care

Scott Syndrome is a very rare inhibited bleeding disorder characterised by an isolated deficit in procoagulant activity in platelets and other blood cells, caused by a lack of phosphatidylserine (PS) exposure following activation.[1,2] It results from mutations in ANO6, which encodes the phospholipid scramblase protein, TMEM16F.[3]

© 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Green infrastructure is an essential component of health and sustainable places. The quality of green infrastructure often represents a missed opportunity to achieve this. This paper presents a review examining how built environment assessment systems evaluate the quality of green infrastructure. This was used to develop proposals for a new benchmark, which were examined by experts in terms of the demand, scope and operation. The findings suggest that current systems are not providing a robust assessment of green infrastructure and that a benchmark for green infrastructure would overcome some of the challenges associated with its planning, design and delivery.

Platelet activation plays a key role in normal haemostasis and pathological thrombosis. Platelet activation is rapid; within minutes of stimulation, platelets generate bioactive phospholipids, secrete their granule contents, activate integrins and aggregate together to form a haemostatic plug. These events are dependent on ATP synthesis. Mitochondrial function in platelets from healthy volunteers and patients with a range of diseases indicate an important role for oxygen consumption in oxidative phosphorylation in normal and pathological function. Platelets also consume oxygen during oxidation reactions, such as cyclooxygenase-dependent thromboxane A2 synthesis. In this study, we used high-resolution respirometry to investigate rapid changes in oxygen consumption during platelet activation. We demonstrated a rapid, transient increase in oxygen consumption rate within minutes of platelet stimulation by the physiological activator, thrombin. This was partly inhibited by aspirin and by oligomycin. This shows that high resolution respirometry can provide information regarding rapid and dynamic changes in oxygen consumption during platelet activation.

The effects of environmental hypoxia on cardiac and skeletal muscle metabolism are dependent on the duration and severity of hypoxic exposure, though factors which dictate the nature of the metabolic response to hypoxia are poorly understood. We therefore set out to investigate the time-dependence of metabolic acclimatisation to hypoxia in rat cardiac and skeletal muscle. Rats were housed under normoxic conditions, or exposed to short-term (2 d) or sustained (14 d) hypoxia (10% O2), after which samples were obtained from the left ventricle of the heart and the soleus for assessment of metabolic regulation and mitochondrial function. Mass-corrected maximal oxidative phosphorylation was 20% lower in the left ventricle following sustained but not short-term hypoxia, though no change was observed in the soleus. After sustained hypoxia, the ratio of octanoyl carnitine- to pyruvate- supported respiration was 11% and 12% lower in the left ventricle and soleus, respectively, whilst hexokinase activity increased by 33% and 2.1-fold in these tissues. mRNA levels of PPARα targets fell after sustained hypoxia in both tissues, but those of PPARα remained unchanged. Despite decreased Ucp3 expression after short-term hypoxia, UCP3 protein levels and mitochondrial coupling remained unchanged. Protein carbonylation was 40% higher after short-term but not sustained hypoxic exposure in the left ventricle, but was unchanged in the soleus at both timepoints. Our findings therefore demonstrate that 14 days, but not 2 days, of hypoxia induces a loss of oxidative capacity in the left ventricle but not the soleus, and a substrate switch away from fatty acid oxidation in both tissues.

Across the years 1887 to 1926, at a time when the British Empire was at its height, nine governors and their wives took up vice-regal office in New Zealand. This study is concerned with the public enactment of the position of vice-regal wives' in New Zealand in these years. It explores what it meant for a woman to be a public figure with a prominent profile and at the same time a wife within a marriage during the late nineteenth and early twentieth centuries. In doing so, the thesis looks at three distinct aspects of vice-regal life, as played out in public: official vice-regal ceremony and social life; involvement in voluntary welfare and women's imperialist organisations; and the display of vice-regal life through governors' wives' appearance and the furnishing of Government House. Of key concern is the way in which these aspects of vice-regal life are conveyed to the public through newspapers, and so Judith Butler's theory of gender performativity is considered as a way to think about the position occupied by governors' wives. As women married to men in public office, governors' wives occupied a particular position and space within the British Empire in the late nineteenth and early twentieth centuries. The position was defined and created through marriage and through the enactment of the duties of vice-regal office. Governors' wives were present at vice-regal ceremonies and social events as both witnesses and wives; they involved themselves with voluntary welfare and imperialist organisations with a particular focus on women as mothers and contributors to Empire; and through their dress and the decoration of Government House governors' wives presented a display of their suitability for holding vice-regal office. The enactment of these duties over the period from 1887 to 1926 was remarkably consistent. Alongside this a degree of change occurred in the recognition afforded to governors' wives in the fulfilment of vice-regal office.