Music and conflict transformation in Bosnia: constructing and reconstructing the normal

Theme issue on music and arts in conflict transformationCan music play a role in positive conflict transformation? Having developed a theoretical basis from a previous examination of the contrasting musical conflict transformation projects of the West-Eastern Divan Orchestra and Hip Hop, I have collected data on an inter-religious choir in Sarajevo, Bosnia-Hercegovina with an explicit conflict transformation remit. Data was collected using ethnographic interviews and participant/observations with fifteen of the choristers in an attempt to answer this question. There was no direct access to audience data and any references to audience reception are from the choir members’ points of view. This detail highlights the issue of application of cultural findings within the choir to the wider social context. For the purposes of this paper therefore any discussions of wider social context are assumed to be mediated through the choristers themselves as members of the choir and the larger Sarajevo and Bosnian society. This data is compared with the previously developed theories and emerging themes are discussed. The fieldwork is ongoing and this article is a summary of findings thus far. The data conflicts with many of the original theories and this highlights the importance of a grounded theoretical approach. The emerging themes include questions of Bosnian and musical identities; what is ‘normal’; ‘knowing one’s place’ in a formal musical environment; and the difference between the choir’s ‘mission’ of conflict transformation and the motivations of the choir members. The findings so far indicate that this particular music conflict transformation project has had some success but it is limited to the types of people who become involved as choristers or audiences (all current data on audiences is from recall from the choristers, as no data collection directly from the audiences was possible). Data also indicates that music projects themselves should be reflexive as conflict situations are not static

On defects in affine Toda field theory

This thesis outlines methods for generating new integrable defects in affine Toda field theory. These methods are grounded in the hypothesis that defects have a particle-like classification with as many species of fundamental defect existing in a particular affine Toda theory as there are species of soliton. The methods employed are: 1. Defect fusing rules, linking different species of defect in the same theory. Defect fusing rules are used in this thesis to find transmission matrices for a new, species 2, defect in a^(1)_3. 2. Folding, linking defects in simply laced theories to defects in non-simply laced theories. Folding is used in this thesis to find defects in the c^(1)_n, d^(2)_n and a^(2)_2n affine Toda field theories

Development of a novel MRI technique for imaging the ischaemic penumbra in experimental stroke

In Scotland, stroke is the third most common cause of death behind heart disease and cancer. However, most strokes are not fatal and can cause severe disability, with one third of survivors still functionally dependent after one year. The advent of recombinant tissue plasminogen activator (rT-PA) as a thrombolytic modality revolutionised the treatment for ischaemic stroke, providing a treatment aimed to promptly restore nutritional blood flow to the ischaemic penumbra, a transient tissue state which is amenable to salvage. Crucially, patient ineligibility from a multitude of factors (including the narrow time window for benefit and the risk of intracranial haemorrhage) means that fewer than 10% of all stroke patients are thrombolysed. Positive identification of penumbra is not employed in the current intravenous rT-PA administration strategy, which is instead based on two main prerequisites: stroke patients in whom intracerebral haemorrhage has been excluded with non-contrast computed tomography (CT) and who also present within 4.5 hours of symptom onset. The technical impracticalities and limited availability of the gold standard penumbral imaging modality, multitracer 15O positron emission tomography (PET), and the lack of standardised thresholds to identify penumbra using non-contrast CT have hindered the development and inclusion of routine brain imaging in the management of acute stroke patients. An alternative research tool which may potentially be used in clinical practice is magnetic resonance imaging (MRI) which defines penumbra on the basis of diffusion-perfusion (DWI/PWI) mismatch. However, this provides an imprecise measure of penumbra and fails to identify tissue viability. Current PET-derived definitions of penumbra use metabolic indices such as oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2), which are not fully incorporated into MR definitions. This thesis presents an alternative MRI method for identifying the metabolic penumbra in a rodent model of focal cerebral ischaemia. This utilises an MRI sequence similar to that used in functional MRI (fMRI) techniques, and uses 100% oxygen inhalation as a biotracer to detect penumbral tissue. Specifically, by using a blood oxygen level dependent (BOLD) T2*-weighted sequence in which changes in the deoxyhaemoglobin:oxyhaemoglobin ratio are detected - in conjunction with a transient hyperoxic challenge (Oxygen Challenge (OC) paradigm: 5 minutes breathing air followed by 5 minutes breathing 100% oxygen) - penumbral tissue can be distinguished from adjacent ischaemic core and benign oligaemia (Santosh et al, 2008). Changes in CBF, cerebral blood volume (CBV), tissue oxygenation, and oxidative metabolism can all influence the T2* signal (Ramsay et al, 1993; Corfield et al, 2001), so it was important to evaluate the possibility that factors other than tissue metabolism were influencing the signal change during OC. An initial study was performed which showed that baseline CBF did not influence T2* signal response to OC, whilst a greater increase in the percentage change in arterial oxygen saturation following OC caused an increased magnitude in T2* percentage signal change in contralateral tissue and penumbra, but not in ischaemic core. Arterial oxygen levels (PaO2) affect the magnitude of the T2* signal change to OC, with lower baseline PaO2 levels amplifying the T2* signal response in metabolically active regions, implying that careful control of physiological variables may optimise the T2*OC technique. The first validation study used [14C] 2-deoxyglucose autoradiography to determine the metabolic status of penumbra defined by T2*OC MRI. The results confirmed that glucose metabolism in the T2*OC-defined penumbra was comparable to contralateral values, whereas markedly different levels of glucose metabolism were evident in the ADC-derived ischaemic core and an adjacent region of increased 2DG phosphorylation. From this, it was concluded that metabolic information could be yielded from the ischaemic brain that may improve delineation of the penumbra using the OC technique. As penumbral tissue must fulfil the fundamental criteria of being potentially salvageable and responsive to therapy, the consequences of reperfusion on the T2*OC-defined penumbra was tested. This study confirmed that T2*OC-defined penumbra displayed a T2* signal change significantly higher than contralateral tissue during ischaemia which subsequently returned to contralateral levels following reperfusion and did not progress to infarction when assessed at day 7 following stroke. Finally, the spatiotemporal characteristics of the T2*OC-defined penumbra were investigated and compared with DWI/PWI mismatch-defined penumbra. Serial scanning demonstrated that T2*OC penumbra behaved in a similar manner to tissue defined by traditional mismatch criterion. The spatial location and tissue volumes of penumbra were similar with both methods, showing that, in animals where mismatch tissue volume reduced over time, T2*OC penumbra reduced similarly, and in animals where mismatch volume remained static over time, T2*OC-defined penumbra behaved similarly. Additionally, an interesting finding arose in the latter study which showed that ischaemic damage continues to progress beyond 4 hours following permanent MCAO, which may be relevant to the calculation of ADC and CBF thresholds used in defining DWI/PWI mismatch. Collectively, the preclinical data support the potential of T2*OC to discriminate tissue compartments in acute stroke based on metabolic status which thereby provides an alternative and improved means of defining the ischaemic penumbra

Paying for news: price-conscious consumers look for value amid cost-of-living crisis

This report uses survey data from 20 countries and qualitative research from the United Kingdom (UK), United States (US), and Germany to explore who is paying for news content online, which publications they pay for, how much they pay, and what motivations they have for subscribing or donating to news. We focus, in particular, on how the cost-of-living crisis is impacting willingness to pay for online news, through talking to those who have cancelled their subscriptions over the last 12 months as well as those who have maintained subscriptions during this period. We also look at the prospects for attracting new subscribers amid this economic downturn and ask what approaches, if any, might persuade these reluctant consumers to pay for online news in the future. Finally, we use insights from our research to explore ways in which the publishing industry could adapt current strategies around news payment

The design and synthesis of targeted BET inhibitors

Please note the confidentiality statement on each page of this thesis DOES NOT apply.Previously held under moratorium in Chemistry Department (GSK) from 15 June 2016 until 18 June 2021.The field of epigenetics is an exciting new area for drug discovery. In particular, modulating proteins at the level of gene expression has already been verified as a valuable tool in treating disease. Within this area, bromodomain containing proteins recognise the epigenetic code on histone proteins, modulating gene expression. The bromodomains contained within the BET family have been implicated in multiple disease indications, including cancer, inflammation and viral infections. Furthermore, the BET family of bromodomains have been widely disclosed as amenable to inhibition by small molecules. However, of the four bromodomain containing proteins within the BET family, three (Brd2, Brd3 and Brd4) are expressed ubiquitously. Therefore inhibition of BET bromodomain function has the potential to affect all cell types, not just those associated with disease. In this regard, a targeted drug delivery system could minimise the broader systemic effects of BET inhibition and potentially improve the therapeutic index associated with this pharmacology. To this end, this thesis will focus on the use of an esterase sensitive motif (ESM) pro-drug targeting strategy. The ESM, developed by Chroma Therapeutics, consists of an amino acid ester which is selectively hydrolysed by the tissue-specific esterase human carboxyesterase 1 (hCE-1), mainly localised in the immune cells, monocytes and macrophages. However, the incorporation of this targeting motif contributes around 200 molecular weight to a small molecule inhibitor. Therefore, a small, ligand efficient BET bromodomain inhibitor was identified to initiate the work described within this thesis. The first section of results within this thesis describes attempts made to further improve the ligand efficient fragment. While modifying the electronics of a phenyl ring contained within this fragment did not give an improved profile, replacement of this ring with a pyridyl group showed promise for the future physicochemical properties of this series. Subsequently, the ESM was successfully incorporated onto this template, with the hydrolysis of the ESM, within target cells, being demonstrated. However, the resulting acid, produced in large quantities within the target cell, was less potent in biochemical assays of BET inhibition than the parent ester. Additional investigation of the linker between the aryl and amino acid ester demonstrated, for the first time, the importance of linker length in the observed potency of the acid and in modulating hydrolysis rate of the ester at the site of action. In the second results section, the aim was to introduce selectivity over the wider bromodomains. To achieve this, while maintaining desirable physicochemical properties, the aim was to utilise saturated groups to interact with the WPF shelf region of the BET bromodomains. Optimisation was conducted through a number of iterations, making use of modern medicinal chemistry techniques including: structure-based design, small molecule X-ray data and computational modelling. Overall, work towards this thesis has taken a fragment molecule and optimised it towards a well-rounded lead molecule with excellent potency and physicochemical properties. The lead molecule has provided a platform to progress this series into lead optimisation within our laboratory with the aim of discovering a clinical candidate molecule to be evaluated in the treatment of rheumatoid arthritis. The human biological samples used within this thesis were sourced ethically and their research use was in accord with the terms of the informed consents. All animal studies discussed within this thesis were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals.The field of epigenetics is an exciting new area for drug discovery. In particular, modulating proteins at the level of gene expression has already been verified as a valuable tool in treating disease. Within this area, bromodomain containing proteins recognise the epigenetic code on histone proteins, modulating gene expression. The bromodomains contained within the BET family have been implicated in multiple disease indications, including cancer, inflammation and viral infections. Furthermore, the BET family of bromodomains have been widely disclosed as amenable to inhibition by small molecules. However, of the four bromodomain containing proteins within the BET family, three (Brd2, Brd3 and Brd4) are expressed ubiquitously. Therefore inhibition of BET bromodomain function has the potential to affect all cell types, not just those associated with disease. In this regard, a targeted drug delivery system could minimise the broader systemic effects of BET inhibition and potentially improve the therapeutic index associated with this pharmacology. To this end, this thesis will focus on the use of an esterase sensitive motif (ESM) pro-drug targeting strategy. The ESM, developed by Chroma Therapeutics, consists of an amino acid ester which is selectively hydrolysed by the tissue-specific esterase human carboxyesterase 1 (hCE-1), mainly localised in the immune cells, monocytes and macrophages. However, the incorporation of this targeting motif contributes around 200 molecular weight to a small molecule inhibitor. Therefore, a small, ligand efficient BET bromodomain inhibitor was identified to initiate the work described within this thesis. The first section of results within this thesis describes attempts made to further improve the ligand efficient fragment. While modifying the electronics of a phenyl ring contained within this fragment did not give an improved profile, replacement of this ring with a pyridyl group showed promise for the future physicochemical properties of this series. Subsequently, the ESM was successfully incorporated onto this template, with the hydrolysis of the ESM, within target cells, being demonstrated. However, the resulting acid, produced in large quantities within the target cell, was less potent in biochemical assays of BET inhibition than the parent ester. Additional investigation of the linker between the aryl and amino acid ester demonstrated, for the first time, the importance of linker length in the observed potency of the acid and in modulating hydrolysis rate of the ester at the site of action. In the second results section, the aim was to introduce selectivity over the wider bromodomains. To achieve this, while maintaining desirable physicochemical properties, the aim was to utilise saturated groups to interact with the WPF shelf region of the BET bromodomains. Optimisation was conducted through a number of iterations, making use of modern medicinal chemistry techniques including: structure-based design, small molecule X-ray data and computational modelling. Overall, work towards this thesis has taken a fragment molecule and optimised it towards a well-rounded lead molecule with excellent potency and physicochemical properties. The lead molecule has provided a platform to progress this series into lead optimisation within our laboratory with the aim of discovering a clinical candidate molecule to be evaluated in the treatment of rheumatoid arthritis. The human biological samples used within this thesis were sourced ethically and their research use was in accord with the terms of the informed consents. All animal studies discussed within this thesis were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals

Ex vivo testing of a novel, tissue-preserving technology for battlefield deployment and limb perfusion support technology that provides long-term circulatory support to systemically-isolated injured limbs

Objectives -- Limb injuries are the most common combat injuries, representing ~70% of injuries in the Iraq/Afghanistan conflicts, with 5-7% resulting in major limb amputation. Under battlefield conditions, the priority is to preserve life, often leading to irreversible limb damage/amputation. To reduce limb loss rate, we have developed limb salvage technology suitable for austere environments. The point of contact technology has two components, aimed at preserving limbs at injury site and during clearance/transportation. A dual, pneumatic tourniquet isolates the limb and controls haemorrhage, and a cooling sock reduces metabolic requirements and enhances viability. The third component (perfusion technology) is not field-deployed (used in field hospitals). Using our mini-integrated ECMO, coupled with automated control and encasement technology, our limb life support technology supports prolonged tissue metabolism and circulation, permitting staged surgical intervention. This technology chain was tested using disarticulated ovine hind limbs, mimicking the most extreme scenario–salvaging a fully disarticulated limb beyond 3hrs. Methods -- Freshly disarticulated limbs were collected (point of contact) and assessment of prolonged muscle viability performed under three conditions: Non-cooled, non-perfused (NC-NP, no intervention); perfused-cooled (NC-P), and; cooled-perfused (C-P) (n=3 per group). Cooled limbs placed in the cooling sock throughout transit/evacuation, and perfused limb groups placed on limb life support technology (arrival at military medical facility). Femoral artery and vein were cannulated and limb heated and oxygenated for 2hrs. Tissue viability assessment was at 1hr (baseline) and 3hr post-disarticulation, performed using nerve stimulation on intact muscle. Results -- Mean±SD deep tissue cooling after 1hr was 8.56 ±1oC for cooled groups. Limbs were perfused 77±17min post-disarticulation. For nerve stimulation (observable twitch threshold (in mA for 1s)), all groups displayed baseline muscle activity 1hr post-disarticulation; C-P 21±20.5; NC-P 85±18; NC-NP 33±26.5. At test endpoint, C-P and NC-P values were 50±69.3 and 22±13.5, respectively, and no muscle activity shown in non-intervention group. Discussions -- We sustained considerable muscle nerve activity in both perfused groups at 3hr post-disarticulation, whilst non-intervention limbs showed no activity. Our technology focuses on ultimately maximising functional recovery. The field-deployable system is suitable for frontline trauma care in austere environments, and designed to support tissue salvage and regeneration

Development of a dual-pneumatic tourniquet for haemorrhage control in austere military environments

Objectives Haemorrhage associated with traumatic extremity injuries remains one of the leading causes of preventable death on the battlefield. There has been a widespread reintroduction of emergency tourniquets on the battlefield and an associated improvement in casualty survival rates. Criticism towards the use of tourniquets largely centres around the potential for tissue damage. Moreover, in the battlefield, limited resources, stressful conditions, and the complex medical trauma associated with injuries arising from explosions and gunshot wounds, can result in tourniquet misapplication which has implications for the efficacy of subsequent procedures and increases risk of death by limb exsanguination. We sought to develop a device to address these concerns. Methods The device first measures the patient’s systolic pressure through oscillometry and then inflates to apply this pressure plus a user-defined overpressure at the first occlusion site. The pressure is maintained for a user-defined interval period, after which systolic pressure is again measured and the appropriate occlusive pressure is applied to the second site. This cyclical application of pressure crucially allows for reperfusion of downstream tissue and reduces the total occlusion time for any single site. This dual pneumatic tourniquet was tested using the Hapmed Tourniqet Trainer - an established testing platform for novel tourniquet systems, particularly within the defence sector. Results Results show that the dual-pneumatic tourniquet is able to quickly apply sufficient occlusive force to control haemorrhage. The magnitude of this force is tailored to the patient’s systolic pressure and is applied to two separate sites in order to minimise tissue damage. The system permits short periods of downstream reperfusion as scheduled by the user to maintain tissue viability. Discussions We have developed a dual pneumatic tourniquet capable of managing haemorrhage control in battlefield injuries with a view to minimise tissue damage. This device has the potential to improve casualty outcomes whilst reducing the burden on military medical personnel. Further investigations are planned. Conclusions We present a novel tourniquet system capable of addressing concerns with current haemorrhage control practices in military applications