• The Role of Intangible Human Factors in Business Success in South Asian Ethnic Minority Small Businesses

      Harding, Nancy H.; Williams, Jannine; Cornelius, Nelarine; Wallace, James; Haq, Muhibul (University of BradfordFaculty of Management and Law, 2016)
      Extant scholarship has paid considerable attention to exploring the impact of people-dependent intangible resources on business success but in large organisations only. Research about the role of these resources in small businesses, in general, and in ethnic minority small businesses, in particular, is scarce. The current study attempts to narrow this gap. Since it is impossible to study all the ethnic minority small businesses, this study uses a case study strategy that focuses on South Asian ethnic minority small businesses that deal in fashion. The study adopts a qualitative research methodology, it uses the semi-structured in-depth interview method to collect data, and it espouses an inductive thematic technique for coding/analysis of the data. Five overarching themes emerged from the interview data. These are: business success; compassionate customer service; relationships; knowledge, experience, training and education; and ethnic culture and the wider economic and political environment. Discussion of these themes leads to the formation of the culture-induced entrepreneurship model. According to this model, the continued success of these businesses is driven by the ethnic culture, while the existence of these businesses helps to maintain the culture in return. However, overdependence on the coethnic base might risk the future success of these businesses. This thesis concludes by highlighting its theoretical contributions to the culturalist view and the mixed embeddedness model of ethnic minority entrepreneurship and small business literature. The implications of this study for researchers, practitioners, and policy-makers, as well as its limitations and the possible future research paths, are also discussed.
    • The Role of Interleukin-10 Family Members in Inflammatory Skin Diseases. Understanding the mechanism of action of interferon lambda and interleukin-22 on human primary keratinocytes and dermal fibroblasts with a focus on healing responses in inflammatory skin diseases

      Wittmann, Miriam; Tobin, Desmond J.; Alase, Adewonuola A. (University of BradfordCentre for Skin Sciences, School of Medical Sciences, Faculty of Life Sciences, 2015)
      Cutaneous lupus erythematosus (CLE) is an autoimmune disease that resolves with or without permanent scars depending on the subtype. Interferons (IFNs), including the skin specific IFNλ mainly activate STAT1, which results in inflammation in CLE and may play a significant role in scar formation in chronic discoid CLE. IL-22 activates STAT3 and it is emerging as a mediator with significant impact on normal wound repair, epidermal hyperproliferation and prevention of fibrosis. This work focussed on understanding the regulation and functional impact of IL-22 and IFNλ on skin cells. The counter-regulatory effect of IL-22 on the activities of IFNλ was assessed through downstream interferon stimulated genes (ISGs) expression in healthy and CLE keratinocytes. Cell proliferation and gap closure were investigated in skin resident cells using cell trace dye and scratch assay. Dermal fibroblasts were assessed for the presence of IFNλR1 and IL-22R1, downstream activities of the receptors. Results showed that IL-22 accelerated “scratch” closure in keratinocytes while IFNλ caused a delay in closure. IL-22 significantly downregulated IFNλ-induced chemokines expression in healthy, but not CLE keratinocytes. Reduced IL-22R1 expression and “STAT3 signature genes” was observed in CLE keratinocytes. A key finding of this project is that dermal fibroblasts respond to both IFNλ and IL-22. This work shows that IL-22 can reduce the damaging effect of IFNs in inflamed skin and also identifies dermal fibroblasts as important cells in skin immune responses. In conclusion, IL-10 family members can have both beneficial and destructive effects on the skin organ depending on the micro milieu and cell-type involved. Manipulating the balance of IL-10 family members in the skin may offer new therapeutic approach for both psoriasis and CLE.
    • The role of iron in oxidative stress accelerated endothelial dysfunction in chronic kidney disease

      Graham, Anne M.; Hadeiba, Tareg Hadi Ahmed (University of BradfordFaculty of Life Sciences, 2015)
      Chronic kidney disease (CKD) is growing global public health problem affecting 1 in 10 adults in developed countries and recognised as an important risk factor for cardiovascular disease (CVD) development. CVD is the main cause of death among CKD patients. Endothelial injury and dysfunction are critical steps in atherosclerosis, a major CVD. Oxidative stress (increased level of reactive oxygen species, ROS) has been associated with CVD development. Intravenous (IV) iron preparations are widely used in the management of CKD mediated anaemia, and have been associated with increased oxidative stress and cellular dysfunction. This study examined the effect of pharmacologically-relevant concentrations of IV Venofer (iron sucrose) or IV Ferinject (Ferric carboxymaltose, FCM) on primary human umbilical vein endothelial cell (HUVEC) activation/damage and on intracellular ROS generation as well as studying the potential mechanisms responsible. Data from TUNEL assay and Annexin V-FITC/PI staining showed that, IV FCM had no effect, but IV iron sucrose increased HUVEC apoptosis at 24hr. IV iron sucrose inhibited cell proliferation and reduced cell viability. Both compounds induced EC activation through sustained activation of p38 MAPK and up-regulation of ICAM-1 and VCAM-1. Additionally, the compounds induced significant increase in total ROS and superoxide anion production, which was attenuated by the anti-oxidant N-acetylcysteine (NAC). P38 MAPK showed up-regulation of pro-apoptotic protein Bax and down-regulation of antiapoptotic Bcl-2 protein in HUVEC treated with IV iron sucrose and p38 inhibition reversed these effects. In summary, these results suggest that IV iron sucrose causes more severe EC injury than IV FCM. However, both IV iron preparations induced intracellular ROS and superoxide anion generation in HUVEC leading to EC activation/dysfunction, providing a potential explanation for vascular damage in CKD patients.
    • Role of magnesium ions in the excitation of vascular smooth muscle. Effects of hypermagnesaemia and hypomagnesaemia on drug-induced contractions of mammalian arteries with special reference to the involvement of changed tissue calcium ion concentration or distribution in the observed responses.

      McCurrie, Janice R.; Irving, G.; Asmawi, Mohd. Z. (University of BradfordPostgraduate School of Studies in Pharmacology, 2009-11-26)
      Studies on the perfused rabbit ear artery preparation showed that withdrawal of Mg 2+ from extracellular fluid potentiated the responses to histamine and ATP but not to catecholamines. Similar results were obtained in [2xCa2+] Krebs solution. Increases in [Mg 2+] decreased responses to the three agonists to a similar extent. In subsequent experiments attempts were made to alter the availability of calcium for contraction induced by these agonists either by changing the [Ca 2+] of the Krebs solution or by using Ca 2+ influx inhibitors, ouabain and ryanodine. The effects of these agonists were compared to those observed when Mg2+ was altered. In general, the results obtained in perfused rabbit ear artery supported the hypothesis that changes in extracellular [Mg2+] affect the availability of calcium for contraction but were not consistent with the suggestion that Mg2+ alters Ca2+ influx. In a second type of preparation tension responses of superfused rings of ear artery were studied. Responses to changes in extracellular [Ca2+] and[ Mg2+] were found to differ slightly from those obtained in the perfused artery. A simultaneously perfused and superfused arterial preparation showed that responses to changes in [ Mg2+] and[Ca2+] were different if the agonist was administered to the adventitial surface of the vessel rather than via the intimal surface. The effects of alterations in extracellular [Mg 2+] were studied in mesenteric arteries from weight matched normotensive and spontaneously hypertensive rats (SHR). No differences in response to NA or ATP when extracellular [Mg 2+ ] was either increased or reduced were observed in the SHR compared to the normotensive animal. However, a difference in calcium dependence was demonstrated between the two types of vessels to NA. In contrast to mesenteric arteries, experiments on aortae from normotensive rats and SHR showed no differences in the calcium dependence of NA responses between normotensive and SHR vessels, whereas, [4xMg2+ ] Krebs solution reduced the responses of normotensive aorta to NA more than SHR. These results in the rat were not consistent with the hypothesis that alteration in [Mg 2+] can be explained in terms of altered calcium availability. Attempts to increase intracellular cyclic AMP with theophylline showed that the response to ED50 NA in both mesenteric arteries and aortae from normotensive were reduced more than SHR. It is concluded that the effect of changes in extracellular [Mg2+] on the reactivity of vascular muscle varies depending on the type of vessel and species of animal from which the vessel is taken. In addition when all the experimental results are considered, it is not possible to explain all the actions of altered [ Mg2+ ] simply in terms of changed calcium availability.
    • The role of MMP10 in non-small cell Lung cancer, and pharmacological evaluation of its potential as a target for therapeutic intervention. Investigation of the role of MMP10 in the tumour microenvironment of non-small cell lung cancer using gene, protein and mass spectrometry approaches to determine MMP10’s potential in drug development strategies

      Shnyder, Steven D.; Loadman, Paul M.; Patterson, Laurence H.; Gill, Jason H.; Bin Saeedan, Abdulaziz S.A. (University of BradfordInstitute of Cancer Therapeutics, 2014)
      Non-Small Cell Lung Cancer (NSCLC), which accounts for 80% of all lung cancer cases, is associated with resistance to chemotherapy and poor prognosis. Exploitation of NSCLC-upregulated pathways that can either be targeted by novel therapeutics or used to improve the tumour-delivery of current chemotherapeutics are required. Among the matrix metalloproteinases (MMPs) that are essential for tumour development, MMP10 is a potential candidate as a therapeutic target based on its expression and contribution to NSCLC development. This research aims to explore the expression and functions of MMP10 in the tumour microenvironment of NSCLC and evaluate the potential of MMP10 as a target for therapeutic intervention. Herein, MMP10 expression at gene and protein levels were analysed in a panel of NSCLC cell lines using RT-PCR and Western blotting analysis. To determine MMP10 functional relevance, an in vitro angiogenesis assay using cell conditioned media was carried out. To identify specific peptide sequences for the design of prodrugs rationalised to be MMP10 activated, in vitro substrate cleavage studies were performed using a mass spectrometry approach to differentiate between MMP10 and the structurally similar MMP3. This study demonstrates that MMP10 is highly expressed in NSCLC and that high levels of MMP10 are associated with induction of angiogenesis, a crucial process supporting tumour growth. In addition to the achievement of having been able to differentiate between closely similar MMP3 and MMP10 through carefully monitoring the hydrolysis rate of compound 444259 (a known MMP substrate), data generated herein provides the basis for further studies to exploit MMP10 as a prodrug-activator.
    • The role of moisture profiling towards understanding pharmaceutical solid state functionality. Validation and the application of a moisture profiling analytical tool for investigation into the characterisation of and prediction of the effects of compaction and storage on different lactose physical forms

      Forbes, Robert T.; Hulse, W.L.; Seymour, Louise (University of BradfordSchool of Pharmacy, Faculty of Life Sciences, 2015)
      The majority of therapeutic pharmaceutical formulations are presented in the solid form. Moisture is able to play an important role in the functional performance of pharmaceutical solids. Moisture profiling is able to provide novel information with regards to the behaviour of moisture within materials using equilibrium relative humidity as a measurement. The hypothesis investigated explores the changes in equilibrium relative humidity of pharmaceutical material induced by physical, chemical or storage conditions, these are able to be monitored using the innovative moisture profiler system. The aims within this were to primarily validate the moisture profiler and secondly evaluate the effects of moisture on physical forms and with respect to effects of compaction, finally this was compared to conventional characterisation methods. Preliminary explorations were conducted in order to assess the validity of the moisture profiler, from this lactose was selected as a suitable pharmaceutical material for further work. Processing effects were then examined, firstly storage at elevated relative humidity of different forms of lactose were explored, and this was carried out with supplementary analysis. Secondly the effects of tabletting were explored, different compaction forces were investigated to observe if this had any notable effects on equilibrium relative humidity of the different lactose forms. Finally subsequent storage of the compacts were examined in order to explore if there were any changes in the equilibrium relative humidity.
    • The Role of Organisational Culture in Digital Government Implementation. Exploring the Relationship between Public Sector Organisational Culture and the Implementation of Digital Government in Oman

      Cullen, Andrea J.; Tassabehji, Rana; Almamari, Mohammed R.H. (University of BradfordFaculty of Engineering and Informatics, 2016)
      Organisational culture plays an important role in the success of the adoption of technology and the development of the organisation; therefore, it is very important to understand how organisational culture impacts the process of implementing technology, either positively or negatively. The aim of this study is to explore the role of organisational culture in digital government implementation in Omani public sector organisations. This study used mixed methods as a research methodology. In the qualitative phase, semi-structured interviews were conducted with top and middle management and at operational levels in the Omani public sector organisations. In the quantitative phase, a survey was distributed to employees within the public sector organisations to build on the findings of the first stage and develop an understanding of the relationship between organisational culture and implementation of digital government in Oman. This study found that there is a relationship between organisational culture and digital government implementation. It was found that the type of organisational culture has some impact on the digital government implementation as it was found that the organisations with the clan culture type had low levels of implementation of digital government whereas, organisations with the hierarchy culture type had high levels of implementation. Moreover, the study found that middle managers in public sector organisations in Oman had a critical impact on the digital government implementation.
    • The role of peripheral visual cues in planning and controlling movement :|ban investigation of which cues provided by different parts of the visual field influence the execution of movement and how they work to control upper and lower limb motion.

      Bloj, Marina; Graci, Valentina (University of BradfordBradford School of Optometry and Vision Science, 2013-11-22)
      Visual cues have previously been classified as visual exproprioceptive, when defining the relative position of the body within the environment and are continuously updated while moving (online), and visual exteroceptive when describing static features of the environment which are typically elaborated offline (feedforward). However peripheral visual cues involved in the control of movement have not previously been clearly defined using this classification. Hence the role played by peripheral visual cues in the planning and/or online control of movement remains unclear. The aim of this thesis was to provide a systematic understanding of the importance of peripheral visual cues in several types of movement, namely overground locomotion, adaptive gait, postural stability and reaching and grasping. 3D motion capture techniques were used to collect limb and whole body kinematics during such movements. Visual peripheral cues were manipulated by visual field occlusion conditions or by the employment of point-lights in a dark room. Results showed that the visual cues provided by different parts of the peripheral visual field are mainly used for online fine tuning of limb trajectory towards a target (either a floor-based obstacle or an object to grasp). The absence of peripheral visual cues while moving disrupted the spatio-temporal dynamic relationship between subject and target and resulted in increased margins of safety between body and target and increased time and variability of several dependent measures. These findings argue in favour of the classification of peripheral visual cues as visual exproprioceptive.
    • Role of pharmacists in adverse drug reaction reporting in Holy City of Makkah, Saudi Arabia. Characterisation of models for evaluating Pharmacovigilance in the Holy City of Makkah and attitude and awareness of pharmacists towards Adverse Drug Reaction Reporting.

      Naylor, Ian; Al-Alhazmi, Naif N.N. (University of BradfordUniversity of BradfordSchool of Pharmacy, 2014-04-29)
      Health care systems in Saudi Arabia and elsewhere play a significant role in the lives of individuals as well as society at large. Although healthcare aims at enhancing the quality of life it can sometimes happen that treatment itself can lead to a diminution of the quality of life due to unexpected adverse effects. These problems may cause therapeutic failures or even drug-related morbidity and mortality. Consequently there is a need to have in place a system, conventionally known as Pharmacovigilance. The aims of Pharmacovigilance are to identify, quantify and continuously monitor all drug use through a system which would enable all health care professionals such as physicians, pharmacists, dentists and nurses to contribute. This thesis investigated the present knowledge of and use of, the Pharmacovigilance system in Makkah, in the Kingdom of Saudi Arabia. A mixed method yielded data that provided depth and breadth to the findings of this study. A questionnaire was designed for 170 community pharmacists and 310 respondents drawn from different medical roles across the seven hospitals in Makkah yielded some useful results. Resistance to change was identified in some groups but it was of interest to discover that 72% of respondents who admitted that their knowledge was insufficient were, nevertheless, agreed about its importance. Key issues from the analysis of the questionnaire were used to design the second phase of the sequential mixed method which involved semi structured interviews with seven senior pharmacists, one from each of the seven hospitals. Analysis yielded three overarching categories: Technology, Internalisation and Motivation. A follow up feedback survey at the end of a lecture, of a group of pharmacy students enhanced the overall findings of the study and revealed a very high degree of interest and acceptance of Pharmacovigilance reporting systems and an expressed desire for its inclusion as a subject in its own right in their training programme. Conflicting epistemological positions inherent in a mixed method are candidly admitted and no attempt is made to circumvent this difficulty. Rather, the enhanced nature of the findings is highlighted despite the opposing knowledge claims of both approaches. A key finding was that 59% of the respondents were unaware of the Saudi National Pharmacovigilance centre (NPC) and reporting arrangements. The problems of lack of internet access and of suitable reporting forms were important contributory reasons for the under-usage of the system. There is a need to raise awareness of all pharmacists of the importance of the knowledge and practice of Pharmacovigilance. Technological solutions should be implemented to facilitate reporting at all levels. Continuing professional development should include Pharmacovigilance. Resistance to change can be addressed by identifying the motivational factors that can lead to a more wholehearted acceptance of the importance of Pharmacovigilance for patient care and well-being. Indeed, these could well be the focus of future studies.
    • The role of photoreceptors in human skin physiology; potential targets for light-based wound healing treatments. Identification of opsins and cryptochromes and the effect of photobiomodulation on human skin and in cultured primary epidermal keratinocytes and dermal fibroblasts

      Thornton, M. Julie; Botchkarev, Vladimir A.; Castellano-Pellicena, Irene (University of BradfordCentre for Skin Sciences, Faculty of Life Sciences, 2017)
      The positive effect of photobiomodulation in wound healing has previously been reported, however there is a considerable lack of knowledge regarding the molecular mechanisms involved, and no consensus on light parameters. Cytochrome c oxidase (CCO) is established as the main photoreceptor in cells, but light also induces nitric oxide (NO), production of reactive oxygen species (ROS) and activation of ion channels. Emerging new molecular targets include the GPCRs opsins (OPNs) and the circadian clock transcription factors, cryptochromes (CRYs). Localisation of OPN1-SW, OPN3, OPN5, CRY1 and CRY2 was seen in female facial and abdominal human skin. Furthermore, expression of these photoreceptors was retained in primary epidermal keratinocytes and dermal fibroblasts in culture; both cell types expressed OPN1-SW, OPN3, CRY1 and CRY2, at the mRNA and protein level. OPN2 was only expressed in cultured dermal fibroblasts, while in line with in situ expression, OPN5 was only expressed in cultured keratinocytes. The photoreceptor-expressing cultured epidermal keratinocytes demonstrated a dose- and wavelength- dependent response in both metabolic activity and cell migration in a scratch-wound assay. Specifically, low dose (2 J/cm2) blue light (447 nm) increased metabolic activity, but it did not impact keratinocyte migration. In contrast, high dose (30 J/cm2) blue light had no effect on metabolism, but inhibited migration of epidermal keratinocytes. Red light (655 nm) at 30 J/cm2 stimulated metabolic activity but did not modulate migration, while a higher dose of 60 J/cm2 had no effect on keratinocyte metabolic activity. In order to study OPN3 and CRY1 function, they were silenced in keratinocytes using siRNA; additionally 8 μM KL001 was used to stabilize CRY1. KL001 inhibited migration, and induced KRT1 and KRT10, an effect which was abrogated by knockdown of OPN3. Interestingly, knockdown of OPN3 upregulated CRY1 expression, while KL001 upregulated OPN3 expression, indicating a regulation by OPN3 of the molecular epidermal clock. Low levels of blue light increased early differentiation of epidermal keratinocytes, which was mediated by OPN3 and circadian clock mechanisms. However, low levels of blue light decreased keratinocyte DNA synthesis, which was mediated by circadian clock independently of OPN3. Translation of parameters ex vivo showed increasing re-epithelialisation and induction of OPN3 and CRY1 expression following exposure to 2 J/cm2 of blue light; however high doses of blue light inhibited re-epithelialisation. Red light, also increased re-epithelialisation, but had no effect on OPN3 or CRY1 expression. In conclusion, photoreceptors are expressed in human skin and they mediate DNA synthesis, migration and differentiation of epidermal keratinocytes. Furthermore, low dose of blue light interacts with OPN3 to induce epidermal differentiation, through the regulation of the circadian clock. A better understanding of the molecular mechanisms behind the photobiomodulation response in vitro will help to develop light based therapies for human wound healing. Interestingly, selected light parameters translated to human ex vivo skin showed a beneficial effect of low doses of blue (2 J/cm2) and red (30 J/cm2) light in re-epithelialisation.
    • The Role of Polycomb Repressive Complex 2 in Epidermal Homeostasis and Hair Growth

      Botchkareva, Natalia V.; Mardaryev, Andrei N.; Asamaowei, Inemo E. (University of BradfordFaculty of Life Sciences, 2017)
      Polycomb repressive complex 2 (PRC2) catalyses the methylation of ‘Lys-27’ of histone H3, leading to transcriptional repression of target genes through its catalytic subunit Enhancer of zeste homolog 1/2 (EZH1/2). PRC2 functions as a critical regulator of stem cells in mouse embryonic and adult tissues. However, the role of PRC2 in human skin remains largely unknown. This study investigated the role of PRC2 in human epidermal homeostasis and hair growth. The expression of EZH2 was elevated in differentiating suprabasal layers of the human epidermis. Consistently, EZH1/2 expression and enzymatic activity was upregulated in differentiating primary human keratinocytes (NHEKs) in vitro. Inhibition of EZH2 and Embryonic ectoderm development (EED) in NHEKs stimulated the expression of differentiation-associated genes, therefore leading to their premature differentiation; while inhibition of EZH1/2 reduced cell proliferation and promoted apoptosis. Silencing of EZH2 in NHEKs induced complex changes in gene expression programmes, including the upregulation of terminal differentiation genes, such as Filaggrin. EZH2 expression was downregulated in aged keratinocytes accompanied with upregulation of senescence-associated genes, p16INK4A and p19INK4D, suggesting EZH2 involvement in epidermal aging. In human anagen hair follicle (HF), EZH2 was detected in stem and progenitor cells; and hair matrix keratinocytes. Silencing EZH2 in HFs accelerated anagen-catagen transition and retarded hair growth accompanied by decreased proliferation and increased apoptosis. Silencing EZH2 in outer root sheath keratinocytes resulted in upregulation of p14ARF and K15, suggesting EZH2 involvement in regulating proliferation and stem cell activity. Thus, this study demonstrates that PRC2-mediated repression is crucial for epidermal homeostasis and hair growth. Modulating the activities of PRC2 in skin might offer a new therapeutic approach for disorders of epidermal differentiation and hair growth.
    • The Role of Self on Ethical Consumption in a Religious Culture: A Case of Consumers in Thailand

      Fukukawa, Kyoko; Maxwell, Rachael; Srisaracam, Nattida (University of BradfordFaculty of Management and Law, 2015)
      This thesis explores the role of the self-concept on ethical consumption behaviour within the Thai consumer context. Religiosity has an influence on a person’s self and morality as Thai people place high importance on religious values. Ten consumers are studied through in-depth, phenomenological interviews, focusing on ethical consumption experiences and meanings. The self-concept is viewed as an experiencer and a moral entity that is dynamic and contextual between internal and external values. The study has extended knowledge on the self-concept and self-image congruency in the context of ethical consumption. It found the existence of a self-ethics relationship through processes of internalisation and externalisation. Personal value, emotion, moral salience, religious beliefs and social values are internalised into the self-concept. On the other hand, externalisation allows consumers to express personal meanings onto society. Self-monitoring functions in these processes to control ethical behaviour. Ethical consumption helps consumers to construct and enhance moral identity, underpinned by the moral self. This thesis has found self-ethics congruency, where meanings of the self and ethical consumption are symbolised and encouraging ethical consumption. Moreover, the multidimensional self has emerged from the study. This finding offers insights on different aspects of the self-concept through ethical consumption. Consumers intuitively engage in ethical consumption when emotion is involved. The implications of this study suggest “who ethical consumers are” by looking at the consumer’s self. Organisations and marketers can use different selves and moral identity to segment and target potential ethical consumers while creating brand image corresponding to consumer’s self-image.
    • The role of sensory history and stimulus context in human time perception. Adaptive and integrative distortions of perceived duration

      Heron, James; Fulcher, Corinne (University of BradfordFaculty of Life Sciences, 2017)
      This thesis documents a series of experiments designed to investigate the mechanisms subserving sub-second duration processing in humans. Firstly, duration aftereffects were generated by adapting to consistent duration information. If duration aftereffects represent encoding by neurons selective for both stimulus duration and non-temporal stimulus features, adapt-test changes in these features should prevent duration aftereffect generation. Stimulus characteristics were chosen which selectively target differing stages of the visual processing hierarchy. The duration aftereffect showed robust interocular transfer and could be generated using a stimulus whose duration was defined by stimuli invisible to monocular mechanisms, ruling out a pre-cortical locus. The aftereffects transferred across luminance-defined visual orientation and facial identity. Conversely, the duration encoding mechanism was selective for changes in the contrast-defined envelope size of a Gabor and showed broad spatial selectivity which scaled proportionally with adapting stimulus size. These findings are consistent with a second stage visual spatial mechanism that pools input across proportionally smaller, spatially abutting filters. A final series of experiments investigated the pattern of interaction between concurrently presented cross-modal durations. When duration discrepancies were small, multisensory judgements were biased towards the modality with higher precision. However, when duration discrepancies were large, perceived duration was compressed by both longer and shorter durations from the opposite modality, irrespective of unimodal temporal reliability. Taken together, these experiments provide support for a duration encoding mechanism that is tied to mid-level visual spatial processing. Following this localised encoding, supramodal mechanisms then dictate the combination of duration information across the senses.
    • Role of the bone morphogenetic protein signalling in skin carcinogenesis. Effect of transgenic overexpression of BMP antognist Noggin on skin tumour development; molecular mechanisms underlying tumour suppressive role of the BMP signalling in skin.

      Botchkarev, Vladimir A.; Botchkareva, Natalia V.; Mardaryev, Andrei N. (University of BradfordCentre for Skin Sciences, Division of Biomedical Sciences, School of Life Sciences, 2010-06-01)
      Bone morphogenetic protein (BMP) signalling plays key roles in skin development and also possesses a potent anti-tumour activity in postnatal skin. To study mechanisms of the tumour-suppressive role of BMPs in the skin, a transgenic (TG) mouse model was utilized, in which a transgenic expression of the BMP antagonist Noggin was targeted to the epidermis and hair follicles (HFs) via Keratin 14 promoter. K14-Noggin mice developed spontaneous HF-derived tumours, which resembled human trichofolliculoma. Initiation of the tumours was associated with a marked increase in cell proliferation and an expansion of the hair follicle stem/early progenitor cells. In addition, the TG mice showed hyperplastic changes in the sebaceous glands and the interfollicular epidermis. The epidermal hyperplasia was associated with an increase in the susceptibility to chemically-induced carcinogenesis and earlier malignant transformation of chemically-induced papillomas. Global gene expression profiling revealed that development of the trichofolliculomas was associated with an increase in the expression of the components of several pro-oncogenic signalling pathways (Wnt, Shh, PDGF, Ras, etc.). Specifically, expression of the Wnt ligands and (¿-catenin/Lef1 markedly increased at the initiation stage of tumour formation. In contrast, expression of components of the Shh pathway was markedly increased in the fully developed tumours, compared to the tumour placodes. Pharmacological treatment of the TG mice with the Wnt and Shh antagonists resulted in the stage-dependent inhibition of the tumour initiation and progression, respectively. Further studies revealed that BMP signalling antagonizes the activity of the Wnt and Shh pathways via distinct mechanisms, which include direct regulation of the expression of the tumour suppressor Wnt inhibitory factor 1 (Wif1) and indirect effects on the Shh expression. Thus, tumour suppressor activity of the BMPs in skin epithelium depends on the local concentrations of Noggin and is mediated, at least in part, via stage-dependent antagonizing of the Wnt and Shh signalling pathways.
    • The role of the SWI/SNF ATP dependent chromatin remodelling complex in the regulation of the human hair follicle cell proliferation and control of the human cutaneous wound healing

      Fessing, Michael Y.; Botchkareva, Natalia V.; Kellett, Carl W. (University of BradfordFaculty of Life sciences, 2018)
      Epigenetic regulation of gene expression occurs at a number of levels including covalent DNA and histone modifications, nucleosome positioning and ATP-dependent chromatin remodelling as well as higher order chromatin folding and 3D genome organisation. ATP-dependent chromatin remodelling complexes modulate nucleosome structure, positioning and chromatin de-compaction and are involved in gene activation and repression. SWI/SNF ATP-dependent chromatin remodelling complexes contain either BRG1 or BRM as the core ATPase together with other common and variable subunits. BRG1 is required for terminal epidermal differentiation in mice and humans and for hair follicle stem cell activation during mouse hair follicle regeneration and cutaneous wound healing. However, the role of SWI/SNF complexes in human hair growth and wound healing remain unknown. Here it is demonstrated that genes encoding SWI/SNF complex subunits are expressed in human hair follicles. It also highlights that siRNA mediated suppression of SWI/SNF complexes in hair follicle culture has no effect on hair growth, or anagen-catagen transition in the short term, but a significant increase in proliferation of the outer root sheath keratinocytes was seen. The data also documents the expression of several SWI/SNF subunits in human epidermis and that siRNA mediated SMARCA4 gene suppression in primary human keratinocyte monolayers defined the requirements of BRG1 for wound closure through control of cell migration, but not proliferation. In summary, this data revealed a diverse SWI/SNF complex subunit composition in human epidermis and hair follicle, and an essential role of the core complex ATPase BRG1 in keratinocyte migration during wound closure and re-epithelisation.
    • The Role of vision and refractive correction changes in dizziness

      Elliott, David B.; Alderson, Alison J.; Armstrong, Deborah (University of BradfordBradford School of Optometry and Vision Science, 2018)
      Dizziness is a common, multifactorial problem that causes reductions in quality of life and is a major risk factor for falls, but the role of vision is a very under-researched area. This study aimed to investigate any link between dizziness and vision and to establish if changes in spectacle lens correction could elicit dizziness symptoms. A link between dizziness and self-reported poor vision was indicated in the epidemiological literature as shown by a systematic review, provided lightheadedness was not included in the definition of dizziness. Cases of individuals who reported vision-related dizziness were investigated to determine potential areas of research for this thesis and subsequently two studies investigated the effects of refractive correction changes on dizziness status. The first study was limited by logistical problems, although it highlighted limitations in the short form of the Dizziness Handicap Inventory that was used to quantify dizziness. Results of an optometry practice recheck study found that oblique cylindrical changes were significantly more likely to be associated with dizziness symptoms than other spectacle lens changes. It also highlighted that optometrists do not ask/record about dizziness symptoms with only 4% of records including “dizziness” as a problem when 38% of patients reported dizziness symptoms when directly asked. All studies highlighted a need for a patient-reported outcome measure to be designed to assess vision-related dizziness. Literature review, interviews with experts and patients and focus groups led to the development of a pilot questionnaire and subsequently a 25-item Vision-Related Dizziness instrument, the VRD-25. This was validated using responses from 223 respondents, with 79 participants completing the questionnaire a second time to provide test-retest data. Two subscales of VRD-12-frequency (VRD-12f) and VRD-13-severity (VRD-13s) were shown to be unidimensional and had good psychometric properties, convergent validity and test-retest repeatability. The VRD-25 is the only patient-reported outcome measure developed to date to assess vision related dizziness and will hopefully provide the platform to further grow this under-researched area that seems likely to provide important clinical information.
    • The roles of exotic and native tree species in preventing desertification and enhancing degraded land restoration in the north east of Libya. Reciprocal effects of environmental factors and plantation forestry on each other, assessed by observations on growth and reproductive success of relevant tree species, and environmental factors analysed using multivariate statistics.

      Hale, William H.G.; Zatout, Masoud Moustafa Mohamed (University of BradfordDivision of Archaeological, Geographical and Environmental Sciences, 2013-11-22)
      Today's arid and semi-arid zones of the Mediterranean are affected by desertification, resulting from various factors, including climatic variations and human activities such as overcultivation, overgrazing and deforestation. Afforestation programs are one of the most effective means in preventing desertification. For many years Libya has had afforestation programs in order to restore degraded land and in response to rapid desert encroachment in the north east of Libya, in the area called the Jabal Akhdar (Green Mountain), which has been investigated in this study. The purpose of this research was to investigate the relative roles of exotic compared to native tree species in preventing desertification and enhancing degraded land restoration in the Jabal Akhdar. The effect of environmental factors on exotic compared to native tree species have been assessed by observations on growth and reproductive success of the species, including variables of stocking rate, trunk diameter, tree height, crown diameter, tree coverage, natural mortality, felling and seedling regeneration, as well as calculated variables, derived from these measurements. The effects of methods and age of afforestation on the promotion of biological diversity have been investigated using the Shannon-Wiener diversity index. The effects of tree species on soil depth have also been investigated. Multivariate statistical analyses of site, species and environmental data, using both cluster analyses and factor analyses have been performed, with the aim of determining what is influencing the species, crops or differentiating between the sites, based on soil depth, angle of slope, altitude, rainfall and air temperature values. Pinus halepensis showed success in its growth and regeneration, particularly at higher altitudes and steeper slopes. Cupressus sempervirens was successful in growth and regeneration in the mountains. The exotic Eucalyptus gomphocephala was very successful in its growth, but did not regenerate well, while the exotic Acacia cyanophylla trees had a failure of both growth and regeneration. E. gomphocephala species appeared to favour relativley the flatter (non-mountain) sites, while A. Cyanophylla appeared to favour relativly the mountain sites. All the species responded positively to greater rainfall and deep soil, but they differed in where they were most likely to be successful. Environmental factors such as climate, terrain and soil are the main determinants of species distribution in the study area, in addition to their impact on the growth of the main trees. There appeared not to be any relationship between biodiversity and whether the main trees were native or exotic, and only P. halepensis showed any negative effect on the abundance of shrubs. There was greater diversity of trees and shrubs generally at the younger sites than the old sites. The present study emphasises the current mismanagement of planted forests, particularly with overgrazing contributing to desertification, through preventing tree growth and eliminating most sapling regeneration. This study concludes by making recommendations for more effective choice of tree species to plant, and for subsequent management to improve afforestation programmes in the Jabal Akhdar area.
    • The roles of hepatocyte growth factor family members in androgen-regulation of human hair growth. A comparison of the expression of hepatocyte growth factor family members, HGF and MSP, and their receptors, c-Met and RON, in isolated hair follicles from normal and androgenetic alopecia (balding) scalp.

      Randall, Valerie A.; Al-Waleedi, Saeed A. (University of BradfordDepartment of Biomedical Sciences, 2010)
      Androgens are the main regulators of human hair growth stimulating larger, terminal hair development e.g. beard and causing scalp balding, androgenetic alopecia. Hair disorders cause psychological distress but are poorly controlled. Androgens probably act by altering regulatory paracrine factors produced by the mesenchyme-derived dermal papilla. This study aimed to investigate paracrine factors involved in androgen-regulated alopecia, particularly hepatocyte growth factor (HGF) family members, by investigating their in vivo status. Balding and non-balding scalp hair follicles and their component tissues were isolated and analysed by molecular biological methods (reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative PCR and DNA microarray analysis), cell culture and immunohistochemistry. Scalp follicles expressed a range of paracrine messenger genes. The dermal papilla, cultured dermal papilla cells and dermal sheath expressed several HGF family genes, while matrix cells only produced the receptor RON suggesting autocrine roles for HGF and MSP, but a paracrine route only for MSP. Comparing balding and non-balding follicles from the same individuals revealed the expected reduction in several keratin and keratin-related protein genes supporting this approach's validity. There were also significant differences in paracrine factors previously implicated in androgen action by in vitro studies. Several factors believed to increase during androgen stimulation of larger, darker follicles, e.g. IGF-I and SCF, were lowered in balding follicles, while putative inhibitory factors, e.g. TGFß-1, were increased. HGF and MSP and their receptors, c-Met and RON, were significantly reduced. These results increase our understanding of androgen action in human hair follicles; this could lead to better treatments for hair disorders.
    • The roles of regional organisations in international peace and security in the post-modern era. The case of the Organization for Security and Co-Operation in Europe with the Former Soviet Union Republic States.

      Not named; Nara, Takako (University of BradfordDepartment of Peace Studies, 2013-11-04)
      The thesis analyses the systems, dynamics and conditions of international cooperation/non-cooperation in the international community that is embodied through international/regional institutions and organisations. As Robert Cooper describes, the international community consists of the three worlds in which the differences between them may be confrontational in international cooperation. While the post-modern civilisation and values are introduced into the institutions and organisations for international peace and security, the state actors from the pre-modern and modern civilisations and values are vigorously defending the traditional version of state sovereignty. Then, all these are equally the member of the international community and, as Robert Axelrod¿s Prisoner Dilemma game sets, neither state actors nor structural actors of international relations can escape from it. Therefore, it is hoped that, as Axelrod¿s theory suggests, the closed community, in the end, produces cooperation and a positive peace for a better future for all. In the case studies, the OSCE faces a number of non-cooperative state actors, like Russia. An anti-OSCE civilisation exists and is resisting the organisational values, while it is staying in the framework. Thus, the organisation is suffering from defectors and free-riders. Knowing the limitation of the organisation, it still has a space for improvement and a useful function which is to provide a long term process to make a non-cooperate actor cooperative.
    • The roles of vitamin D in cutaneous wound healing: In vitro and ex vivo studies of the effect of 1,25(OH)2D3 and its precursors on human dermal fibroblasts and epidermal keratinocytes in cutaneous wound healing

      Thornton, M. Julie; Graham, Anne M.; Tay, Jing Q.
      In humans, the epidermis is the main site for the synthesis of Vitamin D3 (cholecalciferol) from 7-dehydrocholesterol. Cholecalciferol undergoes further hydroxylation in the liver and kidney to produce the active form of the circulating hormone 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). In target cells, 1,25(OH)2D3 interacts with the specific intracellular vitamin D receptor (VDR), a member of the nuclear receptor superfamily. However, epidermal keratinocytes, in addition to being target cells, have enzymes required for autocrine production of 1,25(OH)2D3. They can convert cholecalciferol to 1,25(OH)2D3 via 25-hydroxylase (CYP2R1) and 1α-hydroxylase (CYP27B1). Another enzyme, 24-hydroxylase (CYP24A1), regulates local levels by inactivating 1,25(OH)2D3. While recent studies have shown that absence of VDR or 1,25(OH)2D3 impairs formation of granulation tissue during wound healing in mice, little is known about the autocrine and paracrine regulation of biologically active vitamin D3 by human dermal fibroblasts during cutaneous wound healing. Primary cultures of human keratinocytes and fibroblasts expressed VDR and all the cytochrome enzymes necessary for autocrine production of vitamin D. The relative expression of VDR mRNA was higher in dermal fibroblasts than donor-matched keratinocytes. In contrast, epidermal keratinocytes had a higher mRNA expression of vitamin D3 metabolising enzymes. A scratch wound assay confirmed that 1,25(OH)2D3 stimulated keratinocyte migration, but paradoxically inhibited fibroblast migration as early as 4h, yet neither cholecalciferol nor 25-hydroxyvitamin D3 had any effect. VDR knockdown using small interfering RNA (siRNA) abolished the inhibitory effect of 1,25(OH)2D3 on fibroblast migration, demonstrating the requirement for the VDR in this response. Immunofluorescent staining revealed that 1,25(OH)2D3 increased nuclear VDR protein expression, without a corresponding increase in VDR mRNA transcription only in mechanically wounded dermal fibroblasts, indicating activation of the receptors. Incubation with either 1,25(OH)2D3, cholecalciferol or 25(OH)D3 up-regulated CYP24A1 transcription. This response was most pronounced with 1,25(OH)2D3, suggesting a tightly regulated feedback control on 1,25(OH)2D3 bioavailability within the dermis. In addition, cholecalciferol also increased CYP2R1 and CYP27B1 mRNA expression in scratched dermal fibroblasts, providing evidence for autocrine regulation of 1,25(OH)2D3 by dermal fibroblasts. Expression of α-SMA protein was up-regulated in cultured dermal fibroblasts following scratching, which was down-regulated in the presence of 1,25(OH)2D3. These observations suggest that 1,25(OH)2D3 may restrict differentiation of wounded dermal fibroblasts into pro-fibrotic myofibroblasts. 1,25(OH)2D3 also down-regulated MMP-2 secretion and collagen type I to III ratio in scratched dermal fibroblasts. Using a human ex vivo wound healing model, it was demonstrated that 1,25(OH)2D3, but not cholecalciferol, stimulated the rate of wound closure. In summary, this study has confirmed that human dermal fibroblasts express the transcriptional machinery for autocrine production of 1,25(OH)2D3, and a higher VDR expression suggests they are more responsive than keratinocytes. Changes in CYP and VDR expression in the presence of cholecalciferol, 25-hydroxyvitamin D3 or 1,25(OH)2D3 indicate fine-tuning of the bioavailability of vitamin D in the dermis after wounding. Down-regulation of α-SMA, MMP-2 secretion and the collagen type I to III ratio by 1,25(OH)2D3 highlight an important role for 1,25(OH)2D3 in modulating wound healing and the scarring process.