837 research outputs found
Nuclear-armed submarines in Indo-Pacific Asia: stabiliser or menace?
No full textIn this Report, Lowy Institute Research Associate Brendan Thomas-Noone and Nonresident Fellow Professor Rory Medcalf examine the implications of sea-based nuclear weapons for strategic stability in the Indo-Pacific.
This paper is part of a wider research and outreach project on nuclear stability in a changing Indo-Pacific Asia, supported by a grant from the John D. and Catherine T. MacArthur Foundation.This report was commisioned by Lowy Institute for International Polic
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The spirit of England: selected essays of Stephen Medcalf
No full textStephen Medcalf (1936-2007) was an essayist, in the best traditional sense of that calling: a writer not of books but of substantial and justly celebrated essays, widely read in the Times Literary Supplement and elsewhere. Medcalf's abiding question to the world was the Psalmist's: 'What is man that thou art mindful of him?' His was a Blakean sense of Englishness, far from the chocolate-box painting or the television adaptation, and for him the strongest writers were those keenly aware of their roots in the classical, Anglo-Saxon or Celtic past. By gathering together Medcalf's most important work, this volume shows the coherence of his thinking, and of the elusive, complicated literary heritage he celebrated, one which acknowledges the Greco-Roman strain, the Christian strain, the down-to-earth humour and the gentle irony. Thirteen substantial essays cover Virgil, the Bible, the English translation of Alfred, Piers Plowman, the 'half-alien culture' of the high Middle Ages, Chaucer's contemporary Thomas Usk, Shakespeare's images of resurrection, Horace and Kipling juxtaposed, G. K. Chesterton, T. S. Eliot's use of Ovid, P. G. Wodehouse, William Golding, John Betjeman, Geoffrey Hill and other writers. The book concludes with perhaps Medcalf's most personal article of all: his account of finding a baby in a phone box on a cold winter's night, which first appeared in the Guardian Christmas Supplement in 2002
Fixing Australia’s incredible defence policy
No full textAustralia’s new government must make tough decisions in defence policy. Australia’s broad national interests and the challenging strategic environment in Indo-Pacific Asia make it essential to modernise the Australian Defence Force. The nation’s defence capabilities remain underfunded and its strategic edge in the region is eroding. The gap between the nation’s interests and capabilities is widening, and it is getting harder to meet the demands of the US alliance. Australia’s new government needs to restore focus and funding to defence.Key findings: The Australian government will need a first-principles review to identify the military strategy and force structure required to protect and advance the nation’s interests. The Australian government must increase defence funding in order to modernise the Australian Defence Force\u27s capabilities. Otherwise it will need to make drastic cuts to planned defence capability. The government must also think deeply about the role of the US alliance in Australia\u27s security, and take the initiative in shaping that alliance in Australia’s interests
Nuclear-armed submarines in Indo-Pacific Asia: stabiliser or menace?
No full textThis report examines the implications of sea-based nuclear weapons for strategic stability in the Indo-Pacific.
This paper is part of a wider research and outreach project on nuclear stability in a changing Indo-Pacific Asia, supported by a grant from the John D. and Catherine T. MacArthur Foundation.
Key findings
India and China, rising powers in the Indo-Pacific, are moving from the test and design phase of sea-based nuclear weapon platforms to active deployment.
In the long-term, these new ballistic missile-carrying nuclear submarines could lead to greater strategic stability in the region. But only once systems that ensure their safe and credible operation are put in place.
The deployment of these weapons will also exacerbate existing regional tensions over the South China Sea and the Bay of Bengal, and drive the deployment of ballistic missile defence systems and enhanced anti-submarine warfare capabilities in the region
Studies into the interaction between the plasminogen activating system and the blood-brain barrier
No full textThe serine protease tissue-type plasminogen activator (t-PA) is best recognised for its role in haemostasis, where it is converts the zymogen plasminogen into plasmin – a potent and broad-spectrum protease responsible for degradation of fibrin and removal of blood clots. Next to their vascular roles, t-PA and plasmin also possess endogenous functions in the brain, both as modulators of neuronal activity and t-PA also as a regulator of the blood-brain barrier (BBB). While the action of t-PA and plasmin is associated with normal brain function, it often contributes deleteriously to a variety of brain-related pathophysiological or pathological conditions. This basic fibrinolytic function of t-PA has led to its development for treatment of ischaemic stroke. Since 1995, t-PA is the only FDA-approved therapy for this acute condition; however, t-PA can only be administered within 3-4.5h post stroke onset, as later use has reduced clinical benefits. Unfortunately, t-PA treatment is accompanied by an increased risk for development of symptomatic intracerebral haemorrhage (sICH), a life-threatening complication which impairs the safety of the treatment and prevents any attempts for its implementation in longer therapeutic windows. In recent years, it was postulated that the elevated incidence of sICH associated with t-PA-induced thrombolysis may be directly linked to the ability of t-PA to modulate the BBB and enhance its permeability. According to this rationale, blockade of direct interactions between t-PA and the BBB may reduce the haemorrhagic side-effects of t-PA treatment without affecting its capacity to restore blood-flow. My PhD project examined this concept in vitro and aimed to uncover central mechanisms linking t-PA to BBB modulation with the hope that their antagonism may ultimately improve the safety of t-PA-induced thrombolysis in stroke. During the project both human and mouse in vitro BBB models were developed to serve as authentic research tools (chapter 4). Our human BBB system was established based on immortalised human astrocytes and high-passaged human brain endothelial cells (BECs) co-cultured in contact conditions, allowing rapid accumulation of human-relevant information. To confirm these data and assist in mechanistic determination we also generated mouse primary cultures of well-differentiated astrocytes and BECs and used them for assembly of a non-contact mouse BBB model. Together, our human and mouse in vitro BBB models provided us with potent tools to reliably examine the effect of t-PA and plasminogen on the neurovascular unit. The effect of t-PA, without or with plasminogen, was then tested in the intact BBB models (chapter 5). t-PA caused a concentration-dependent increase in permeability which relied on its proteolytic activity. This effect was fully dependent on plasmin formation and was strongly potentiated in the presence of plasminogen. Strikingly, solution-applied plasmin or other plasminogen activators (PAs; reteplase, desmoteplase but most importantly urokinase (u-PA), with or without plasminogen) could not substitute for in situ t-PA-dependent plasminogen activation, while the close t-PA derivative tenecteplase was only partially effective. Of particular interest was the effect of u-PA, which in fact reduced plasminogen-dependent increase in BBB permeability, possibly by competition with endogenous t-PA over plasminogen. Inhibition of matrix metalloproteinases (MMPs) and receptor tyrosine kinases by broad-spectrum inhibitors (GM6001 and imatinib, respectively) was ineffective at blocking the effect of t-PA, while t-PA:PAI-1 complex could not open the BBB, suggesting that other known mechanisms for BBB opening by t-PA are less likely to play a role in our system. Finally, when t-PA and plasminogen were employed together, the BBB opening effect occurred, and was even potentiated, under oxygen-glucose deprivation (OGD), indicating the applicability of the primary event also during brain ischaemia. Surprisingly, the sensitivity of the BBB to high levels of t-PA alone was diminished under OGD, suggesting that the overall response of the BBB to t-PA during stroke may be of much greater complexity. Collectively, these observations implied that a unique action of t-PA, by localisation and activation of plasminogen at selective sites on the surface of the BBB, synergised with plasmin to create a t-PA-specific opening of the BBB. Lastly, to better understand the mechanism underlying this effect, we stimulated isolated cultures of BECs and astrocytes with t-PA and plasminogen and followed morphological, signalling and functional aspects associated with this stimulation (chapter 6). Both BECs and astrocytes dramatically reacted by morphology changes to t-PA-generated, cell-surface-associated plasmin. The response of BECs to t-PA/plasmin seemed rather complex. It did not involve LDLRs, but potentially included proteolysis of tight junctions and basement membrane as well as initiation of Rho/Rho-kinase (ROCK) signalling, promoting together morphological changes, loss of adhesion and barrier compromise. In astrocytes, morphological changes exerted by t-PA and plasmin fully mirrored the proteases action on the in vitro BBB, strongly suggesting that they played a functional role in BBB opening. The principal event triggered by t-PA, via plasmin, in astrocytes was activation of the Rho/ROCK signalling pathway; changes in astrocyte morphology coincided with increased formation of actin stress-fibres, enlargement of focal adhesion size and induction of phosphorylated myosin and actomyosin-dependent contractility, all being hallmarks of Rho/ROCK activation. Inhibition of ROCK with selective ROCK inhibitors, and especially with the clinically-utilised HA1077 (fasudil), blocked the astrocytic morphology changes and importantly reduced t-PA/plasminogen-mediated increases in permeability both in the human and the mouse BBB models. We conclude that during t-PA-driven thrombolysis in acute ischaemic stroke substantial levels of plasmin, selectively generated by t-PA in situ, may indeed interact with both ischaemic and healthy brain microvessels, leading to alterations in the function of BEC but especially to modulation of the astrocytic cytoskeleton by ROCK activation. The subsequent changes in astrocyte morphology increase the permeability of the BBB, potentially contributing to formation of sICH. Blockade of the Rho/ROCK pathway in astrocytes may effectively antagonise t-PA-induced BBB opening during thrombolysis, reducing the incidence of sICH and increasing the safety of the treatment without affecting its fibrinolytic capacity. Rock inhibition could thus have beneficial consequences during thrombolytic therapy in patients with ischaemic stroke
t-PA activity and mRNA levels are increased in spinal cord extracts of T4+ mice.
No full textA: Spinal cord extracts prepared from naïve T4 control and T4+ mice were evaluated for t-PA dependent plasminogen activation using an amidolytic assay (see methods). T4+ mice (n = 4) displayed a 14.58 ± 1.78 fold increase in plasminogen activation rates relative to their littermate T4control mice (n = 3). Data presented as Mean±SEM. *p(B): A ~4-fold increase in t-PA mRNA is also observed in spinal cord extracts from naïve T4control and T4+ mice (p(C): T4control mice immunized with the MOG35-55 peptide also displayed a ~4-fold increase in t-PA mRNA levels (assessed at clinical severity score of 3); p<0.01. Data presented as Mean±SEM.</p
t-PA<sup>-/-</sup> mice develop a more severe form of EAE.
No full text(A): Wild-type (WT, n = 16) and t-PA-/- mice (n = 9) were immunized with the MOG35-55 peptide to induce EAE. Disease severity was evaluated daily using a neurological severity score scale (see methods). As shown, t-PA-/- mice developed EAE symptoms at a greater rate than WT mice. Data presented as Mean±SEM. *p-/- mice displayed less symptom-free survival (p<0.001) and significantly reduced survival rates (p<0.01) following EAE compared to wild-type control mice. (Gehan-Breslow-Wilcoxin test).</p
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