LONG-TERM VARIATIONS IN THE HIGH-LATITUDE PLASMA FLOWS INFERRED FROM SUPERDARN RADAR DATA

ABSTRACT This Thesis investigates ionospheric plasma flows (commonly referred to as “convection”) at high latitudes with the objectives to assess seasonal and solar cycle variations in the shape of the flow patterns and the flow intensity in terms of external drivers of the flow, first of all the magnitude and orientation of the interplanetary magnetic field (IMF). Multi-year (2001-1011) line-of-sight Doppler velocity data collected by the Super Dual Auroral Network (SuperDARN) HF radars are considered. Two approaches are used: 1) analysis of monthly-averaged 2-dimentional patterns inferred from data of all SuperDARN radars operated and 2) analysis of near magnetic noon data from only two SuperDARN radars, Rankin Inlet and Inuvik monitoring meridional component of the flow in the near North Pole areas (polar cap). We show and discuss seasonal and solar cycle variations of three characteristics of the flows: magnetic latitudes of the region where plasma flow direction changes from toward the noon to away from the noon (convection reversal boundary), the magnetic local time location of the near noon region with stagnated flow (throat region) and, finally, the magnitude of the flow. All three parameters show trends, although not strong and consistent all the time, which agrees with previous publications where different analysis approaches and more limited data sets were used. For two specific points, one at the magnetic latitude of 72 degrees, representing the auroral oval latitudes (region where optical arcs occur most frequently) and the other one at 82 degrees, representing the polar cap latitudes we demonstrate that the average flow magnitude increases with the IMF intensity, and the effect is much stronger for the negative vertical component of the IMF Bz. In our second approach we demonstrate that the flow velocity increases almost linearly with an increase of the reconnection electric fields characterizing processes of interaction between the solar wind/IMF and the Earth`s magnetic dipole. Saturation effect is seen for strongest electric field. More clear seasonal effects are noticeable in these data; the velocity response to the reconnection electric field enhancement is stronger summer (winter) time for positive (negative) IMF Bz. The data are consistent with previous reports, where highly smoothed velocity data were considered

Crucial involvement of xanthine oxidase in the intracellular signalling networks associated with human myeloid cell function

Xanthine oxidase (XOD) is an enzyme which plays a central role in purine catabolism by converting hypoxanthine into xanthine and then further into uric acid. Here we report that XOD is activated in THP-1 human myeloid cells in response to pro-inflammatory and growth factor stimulation. This effect occurred following stimulation of THP-1 cells with ligands of plasma membrane associated TLRs 2 and 4, endosomal TLRs 7 and 8 as well as stem cell growth factor (SCF). Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) transcription complexes were found to be responsible for XOD upregulation. Importantly, the mammalian target of rapamycin (mTOR), a major myeloid cell translation regulator, was also found to be essential for XOD activation. Specific inhibition of XOD by allopurinol and sodium tungstate led to an increase in intracellular AMP levels triggering downregulation of mTOR activation by phosphorylation of its T2446 residue. Taken together, our results demonstrate for the first time that XOD is not only activated by pro-inflammatory stimuli or SCF but also plays an important role in maintaining mTOR-dependent translational control during the biological responses of human myeloid cells

Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity

Correction of human myeloid cell function is crucial for the prevention of inflammatory and allergic reactions as well as leukaemia progression. Caffeine, a naturally occurring food component, is known to display anti-inflammatory effects which have previously been ascribed largely to its inhibitory actions on phosphodiesterase. However, more recent studies suggest an additional role in affecting the activity of the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways, although detailed molecular events underlying its mode of action have not been elucidated. Here, we report the cellular uptake of caffeine, without metabolisation, by healthy and malignant hematopoietic myeloid cells including monocytes, basophils and primary acute myeloid leukaemia mononuclear blasts. Unmodified caffeine downregulated mTOR signalling, which affected glycolysis and the release of pro-inflammatory/pro-angiogenic cytokines as well as other inflammatory mediators. In monocytes, the effects of caffeine were potentiated by its ability to inhibit xanthine oxidase, an enzyme which plays a central role in human purine catabolism by generating uric acid. In basophils, caffeine also increased intracellular cyclic adenosine monophosphate (cAMP) levels which further enhanced its inhibitory action on mTOR. These results demonstrate an important mode of pharmacological action of caffeine with potentially wide-ranging therapeutic impact for treating non-infectious disorders of the human immune system, where it could be applied directly to inflammatory cells

Activation of immune evasion machinery is a part of the process of malignant transformation of human cells.

Malignant transformation of human cells is associated with their re-programming which results in uncontrolled proliferation and in the same time biochemical activation of immunosuppressive pathways which form cancer immune evasion machinery. However, there is no conceptual understanding of whether immune evasion machinery pathways and expression of immune checkpoint proteins form a part of the process of malignant transformation or if they are triggered by T lymphocytes and natural killers (NK) attempting to attack cells which are undergoing or already underwent malignant transformation. To address this fundamental question, we performed experimental malignant transformation of BEAS-2B human bronchial epithelium cells and RC-124 non-malignant human kidney epithelial cells using bracken extracts containing carcinogenic alkaloid called ptaquiloside. This transformation led to a significant upregulation of cell proliferation velocity and in the same time led to a significant upregulation in expression of key immune checkpoint proteins - galectin-9, programmed death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO1). Their increased expression levels were in line with upregulation of the levels and activities of HIF-1 transcription complex and transforming growth factor beta type 1 (TGF-β)-Smad3 signalling pathway. When co-cultured with T cells, transformed epithelial cells displayed much higher and more efficient immune evasion activity compared to original non-transformed cells. Therefore, this work resolved a very important scientific and clinical question and suggested that cancer immune evasion machinery is activated during malignant transformation of human cells regardless the presence of immune cells in microenvironment

Dose-dependent effects of Allopurinol on human foreskin fibroblast cell and human umbilical vein endothelial cell under hypoxia

Allopurinol, an inhibitor of xanthine oxidase, has been used in clinical trials of patients with cardiovascular and chronic kidney disease. These are two pathologies with extensive links to hypoxia and activation of the transcription factor hypoxia inducible factor (HIF) family. Here we analysed the effects of allopurinol treatment in two different cellular models, and their response to hypoxia. We explored the dose-dependent effect of allopurinol on Human Foreskin Fibroblasts (HFF) and Human Umbilical Vein Endothelial Cells (HUVEC) under hypoxia and normoxia. Under normoxia and hypoxia, high dose allopurinol reduced the accumulation of HIF-1α protein in HFF and HUVEC cells. Allopurinol had only marginal effects on HIF-1α mRNA level in both cellular systems. Interestingly, allopurinol effects over the HIF system were independent of prolyl-hydroxylase activity. Finally, allopurinol treatment reduced angiogenesis traits in HUVEC cells in an in vitro model. Taken together these results indicate that high doses of allopurinol inhibits the HIF system and pro-angiogenic traits in cells

The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

Human cancer cells operate a variety of effective molecular and signaling mechanisms which allow them to escape host immune surveillance and thus progress the disease. We have recently reported that the immune receptor Tim-3 and its natural ligand galectin-9 are involved in the immune escape of human acute myeloid leukemia (AML) cells. These cells use the neuronal receptor latrophilin 1 (LPHN1) and its ligand fibronectin leucine rich transmembrane protein 3 (FLRT3, and possibly other ligands) to trigger the pathway. We hypothesized that the Tim-3-galectin-9 pathway may be involved in the immune escape of cancer cells of different origins. We found that studied breast tumors expressed significantly higher levels of both galectin-9 and Tim-3 compared to healthy breast tissues of the same patients and that these proteins were co-localized. Increased levels of LPHN2 and expressions of LPHN3 as well as FLRT3 were also detected in breast tumor cells. Activation of this pathway facilitated the translocation of galectin-9 onto the tumor cell surface, however no secretion of galectin-9 by tumor cells was observed. Surface-based galectin-9 was able to protect breast carcinoma cells against cytotoxic T cell-induced death. Furthermore, we found that cell lines from brain, colorectal, kidney, blood/mast cell, liver, prostate, lung, and skin cancers expressed detectable amounts of both Tim-3 and galectin-9 proteins. The majority of cell lines expressed one of the LPHN isoforms and FLRT3. We conclude that the Tim-3-galectin-9 pathway is operated by a wide range of human cancer cells and is possibly involved in prevention of anti-tumor immunity

The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells

Acutemyeloid leukemia (AML) is a severe and often fatal systemicmalignancy. Malignant cells are capable of escaping host immune surveillance by inactivating cytotoxic lymphoid cells. In this work we discovered a fundamental molecular pathway, which includes ligand-dependent activation of ectopically expressed latrophilin 1 and possibly other G-protein coupled receptors leading to increased translation and exocytosis of the immune receptor Tim-3 and its ligand galectin-9. This occurs in a protein kinase C and mTOR (mammalian target of rapamycin)-dependent manner. Tim-3 participates in galectin-9 secretion and is also released in a free soluble form. Galectin-9 impairs the anti-cancer activity of cytotoxic lymphoid cells including natural killer (NK) cells. Soluble Tim-3 prevents secretion of interleukin-2 (IL-2) required for the activation of cytotoxic lymphoid cells. These results were validated in ex vivo experiments using primary samples from AML patients. This pathway provides reliable targets for both highly specific diagnosis and immune therapy of AML

Influence of feed moisture and hammer mill operating factors on bagasse particle size distributions

Physical properties of ground bagasse could be important for processes such as densification. Bagasse chops into 20–25 cm slice at three moisture content 8, 12 and 16% (wb) were ground using a hammer mill (0.5 hp) with three screen sizes of 1, 2.5 and 4 mm at two hammer mill speeds 1400 and 2000 rpm. Physical properties of grinds such as geometric mean diameter of grind particles, particle size distribution were determined. The highest specific energy consumption was 750 KjKg-1 for the sample that has highest moisture content, using smallest screen size and at 2000 rpm hammer mill speed. And least specific energy consumption was 11 Kj­Kg-1for the sample that has least moisture content, using largest screen size (4 mm) and at 1400 rpm speed. Four distributions were examined. For 1, 2.5 and 4 mm screen sizes normal, Generalized Extreme Value and log-normal distribution has best performance, respectively

Space, Gaze and Femineity: Representation of Women in Architectural Spaces in Persian Miniature Painting (Timurid to Safavid eras)

Architecture can be compared with the veil (or hijab) in terms of its visual and spatial functions. While the veil may overtly conceal, it may also define the woman it clothes in the same way that architecture may simultaneously support and represent its function. Both can deny or direct vision, and mediate space. However, whilst the veil has often been invoked in critiques of the cultural construction of women, the agential role of architecture has largely been overlooked. Using architecture as a lens, this art-historical thesis examines the representation of female figures in Persian miniature paintings as a tactic to reveal and interpret the changing place and power of women in pre-modern Persian society and culture. Architectures of many descriptions, from mobile tents to monumental mosques and palaces, are among the most consistent and recognisable elements with which Persian miniature paintings are composed, and within which the female figures depicted are literally framed. Through a historical comparison of the architectural framing of the female figure in Persian miniature paintings, produced during the transformation of cultural traditions from the Turko-Mongol practices of the Timurid dynasty to the Irano-Islamic cultural norms and pratcices associated with the Safavid dynasty, the research examines how women were placed and defined in these spaces – sedentary and mobile, and public as well as private – to better understand the changes in social status and mobility that they were experiencing over this same period. Although previous scholars have recognised Persian miniature paintings as a potentially rich alternative source of primary historical evidence where written sources are lacking or silent, the conceptual distance and visual ambiguity of that medium relative to present day artistic practice and perceptual conventions have presented persistent obstacles to interpretation and understanding. Independently, both the representation of Women, and the representation of Architecture in Persian miniature paintings have been the focus of valuable but unconnected and differently oriented studies by previous scholars. What has not been studied so closely and methodically before is the spatial structure and arrangement of women in relation to the architecture in (and of) these images, and how a rigorous analysis of that relationship might enhance current understanding of women in the socio-historical contexts depicted in Persian miniature paintings. Methodological experimentation undertaken in this study has sought to enhance how the multifocal perspective characteristic of architectural elements and spaces depicted in Persian miniature paintings could be better understood. This has resulted in a significant extension and refinement of an analytical method suggested by previous scholars, but evidently never developed and applied so thoroughly before. The particular folding and pop-up technique developed here produces three-dimensional paper projections of Persian miniature paintings through which the spatial arrangement and structure of the architectural elements depicted can be decoded. Using this spatially expanded architecture as a lens and apparatus to view and to site the figures of women in these paintings more accurately, the study then examines the vision and visibility of these women and how this mediated their power within physical and social space. Historically and culturally specific theories of vision and the gaze are engaged in the analysis in two ways: first, with respect to specific ways of seeing reflected in the conventions of Persian miniature painting and its visual representation of the outer world; and, second, in terms of the more universal concepts and acts of seeing in Islamic society, culture and religion, and the way these define codes of behaviour concerning veiling and the spatial polarisation of the sexes. Through this combination of visual and spatial tactics, this research advances the study of the past by enhancing the analytical depth at which we can interpret and better understand historically and culturally distant visual materials, enabling sharper and even novel observations that challenge certain assumptions about the place(s) of women in Islamic societies, cultures, and art. The study indicates further avenues for the extension of such spatially focused visual inquiry in the Art Historical field of Islamic visual arts and miniature painting studies in particular, and in gender and women’s studies more generally.Thesis (Ph.D.) -- University of Adelaide, School of Architecture and Built Environment, 202

Crucial involvement of xanthine oxidoreductase in the biological responses of myeloid hematopoietic cells

Xanthine oxidoreductase (XOR) is one of the main purine catabolising enzymes which converts hypoxanthine into xanthine and further into uric acid. The enzyme has a homodimeric structure and contains two FeS centres, one FAD molecule and one molybdenum atom per monomer. Recent evidence clearly demonstrated that XOR activity is highly increased in human hematopoietic cells of myeloid lineage during their pathogen-induced and endogenously generated biological responses. The integrative signalling role and especially involvement of XOR in cross-talk of metabolic and signalling machinery of human leukocytes remains poorly understood. We have demonstrated that XOD is activated in human myeloid cells in response to pro-inflammatory and growth factor stimulation. Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP1) transcription complexes were found responsible for maintaining XOR catalytic activity and protein levels. Importantly, the mammalian target of rapamycin (mTOR), a major myeloid cell translation regulator, appeared to be essential for XOR activation. Specific inhibition of XOR led to an increase in intracellular AMP levels triggering downregulation of mTOR activation. Taken together, these results show that XOD is not only activated by pro-inflammatory stimuli or SCF (growth factors), but also plays a crucial role in maintaining mTOR-dependent translational control during the biological responses of hematopoietic cells of myeloid lineage. Findings reported in this thesis open a new field in human myeloid cell research and translational medicine. XOR is an easily accessible therapeutic target, which could be pharmacologically corrected using non-toxic drugs