1,861 research outputs found
Receptor Proteins for Nongenomic Actions of Thyroid Hormone.
No full textGenomic actions of thyroid hormone require the intranuclear binding by nuclear thyroid hormone receptors (TRs) of 3,5,3’-triiodo-L-thyronine (T3). Nongenomic actions of the hormone have been described that are initiated at the plasma membrane, in cytoplasm or in the mitochondrion. These are complex processes associated with maintenance of the cytoskeleton, control of cell respiration, cell proliferation—including tumor cell proliferation and angiogenesis—and nervous system function. We briefly review here the nature of the proteins which are now appreciated to initiate nongenomic actions of the hormone when they bind T3 or L-thyroxine (T4). These receptor proteins for nongenomic effects include truncated isoforms of TRalpha, cytoplasmic intact TRbeta, certain cytoplasmic enzymes and a structural protein of the plasma membrane, integrin alphaVbeta3
Nongenomic regulation by thyroid hormone of plasma membrane ion and small molecule pumps
No full textThe sodium/proton (Na/H) exchanger, Na,K-ATPase, and Ca2+-ATPase are membrane ion pumps whose basal activities may be regulated by local nongenomic actions of thyroid hormone and hormone analogues via a hormone receptor on plasma membrane integrin αvβ3. System A amino acid transport and the activity of P-glycoprotein (P-gp; ABCB1), a multidrug efflux pump, are also modulated by thyroid hormone and αvβ3. Where signal transduction has been studied, the presence of the hormone at the receptor is transduced by mitogen-activated protein kinase (MAPK) isoforms (ERK1/2; p38) or phosphatidylinositol 3-kinase into local actions. The existence of the cell surface receptor offers opportunities to pharmacologically modify actions of these important transport functions with nanoparticulate formulations of T4 and T3 that do not enter the cell. Such formulations may reverse complex intracellular accumulations of H+, Na+, and Ca2+ that occur in clinical settings such as ischemia. In addition, nanoparticulate tetraiodothyroacetic acid (tetrac), a thyroid hormone analogue that inhibits binding of T4 and T3 to integrin αvβ3 as well as certain other functions of the integrin, may reverse P-gp-dependent resistance to anti-cancer drugs in tumor cells
The role of Umkhonto we Sizwe (MK) in the national liberation struggle in South Africa with reference to the rural far northern Transvaal, 1976-1990
No full textIncludes bibliographical references (leaves 250-275)
Experiencing the armed struggle : the Soweto generation and after
No full textIncludes bibliographical references (p. 354-369).This study explores the experiences of the rank-and-file soldiers of Umkhonto we Sizwe and the Azanian People's Liberation Anny. Extensive interviews by the author and other researchers reveal the voices of the soldiers themselves. The African National Congress and Pan African Congress archives at the University of the Western Cape and the University of Fort Hare supplement and verify these oral testimonies, as do some published sources. Most previously published materials about the armed struggle against apartheid have already focused on diplomacy, strategy and tactics, operations, leadership, and human rights abuses to the neglect of the soldiers' actual experiences. This study complements these with significant new oral history materials from the Soweto generation of soldiers and their successors. When dealing with MK, many authors have documented issues of the camp structure in Angola, and operations inside South Africa, so much of this detail is only addressed briefly, leaving space to explore the soldiers' experiences. In the case of APLA, very little has been written on its history, and more detail is provided on these subjects. This study therefore deals with the soldiers' politicisation and motivation for joining the armed struggle, their experiences in leaving South Africa and training in exile, the crises in exile which limited their effectiveness for a time, their return to fight in South Africa, and their difficulties in the "new" South Africa. These materials reveal that vast problems remain facing these veterans of the struggle against apartheid, and that they have the potential, if properly supported and employed, to contribute substantially to the development of present day South Africa. Conversely, if their neglect continues, they also have the potential to bring vast harm to the country. Further use of the investigative tools of oral history, especially if extended to the former soldiers' vernacular languages, is necessary to augment the history of South Africa, and these soldiers' contributions
L-Thyroxine vs 3,5,3'-Triodo-L-Thyronine and cell proliferation: Activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase
No full textTriiodo-L-thyronine (T(3)), but not L-thyroxine (T(4)), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an alpha(v)beta(3) integrin receptor on human glioblastoma U-87 MG cells. Although both T(3) and T(4) stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T(3)-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T(3) and T(4). Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T(3)-treated U-87 MG cells. T(3) and T(4) both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Small-interfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T(3) on U-87 MG cells. PI3-kinase-dependent actions of T(3) in these cells included shuttling of nuclear thyroid hormone receptor-alpha (TR alpha) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1 alpha mRNA; LY-294002 inhibited these actions. Results of studies involving alpha(v)beta(3) receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T(3) from the integrin by unlabeled T(3) and by unlabeled T(4), are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T(3) exclusively, activates PI3-kinase via Src kinase, and stimulates TR alpha trafficking and HIF-1 alpha gene expression. Tetrac and RGD peptide both inhibit T(3) action at this site. The second site binds T(4) and T(3), and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T(3) action here is inhibited by tetrac alone, but the effect of T(4) is blocked by both tetrac and the RGD peptide
Nanotetrac targets integrin αvβ3 on tumor cells to disorder cell defense pathways and block angiogenesis.
No full textThe extracellular domain of integrin αvβ3 contains a receptor for thyroid hormone and hormone analogs. The integrin is amply expressed by tumor cells and dividing blood vessel cells. The proangiogenic properties of thyroid hormone and the capacity of the hormone to promote cancer cell proliferation are functions regulated nongenomically by the hormone receptor on αvβ3. An L-thyroxine (T4) analog, tetraiodothyroacetic acid (tetrac), blocks binding of T4 and 3,5,3'-triiodo-L-thyronine (T3) by αvβ3 and inhibits angiogenic activity of thyroid hormone. Covalently bound to a 200 nm nanoparticle that limits its activity to the cell exterior, tetrac reformulated as Nanotetrac has additional effects mediated by αvβ3 beyond the inhibition of binding of T4 and T3 to the integrin. These actions of Nanotetrac include disruption of transcription of cell survival pathway genes, promotion of apoptosis by multiple mechanisms, and interruption of repair of double-strand deoxyribonucleic acid breaks caused by irradiation of cells. Among the genes whose expression is suppressed by Nanotetrac are EGFR, VEGFA, multiple cyclins, catenins, and multiple cytokines. Nanotetrac has been effective as a chemotherapeutic agent in preclinical studies of human cancer xenografts. The low concentrations of αvβ3 on the surface of quiescent nonmalignant cells have minimized toxicity of the agent in animal studies
Dawn Aerospace Mk-III Spaceplane Aerothermodynamic Analysis
No full textDawn Aerospace is developing a horizontal take-off and landing two stage to orbit partially-reusable launcher concept. The re-usable first stage spaceplane operates on a return to launch site trajectory and integrates into the existing airspace, flying as an UAV. For any re-entry vehicle the design needs to account for aerothermodynamic behaviour around the vehicle, to ensure the structure can survive the re-entry temperatures. The unique mission of the Mk-III means the thermal design considerations are unique and provide a new engineering challenge and research topic. This thesis investigates the aerothermodynamic behaviour of the Mk-III flow and structure. A loosely coupled model was created for this purpose, which couples engineering methods to predict the aerothermodynamics and the thermal behaviour of the structure. The coupling is done by transferring the external skin temperature and convective heat flux between the two simulations. The primary research question for this thesis is “What thermal protection systems have potential to be implemented on the Dawn Aerospace Mk-III spaceplane for a range of different design trajectories.” Two thermal protection systems (TPS) and material choices have been identified as potential solutions. The first is a fully titanium structure, which can handle the temperature experienced by the Mk-III for all trajectories at every point along the vehicle. The second is a combined titanium and BMI CF structure with an insulation layer on the BMI CF. The titanium is required for the temperatures experienced on the vehicle’s leading edges, while the BMI CF has been identified as suitable in areas away from the leading edge if protected by an insulation TPS. A benefit this option produces is that the insulation layer can be changed in thickness to lighten the vehicle for lower design trajectories, therefore creating different vehicles for different trajectories. However, combining a metal with a composite could pose manufacturing issues such as cost for different manufacturing processes and joining problems. This thesis could not properly trade-off between these two options due to it being outside the scope of this thesis and due to limitations in detailed structural knowledge. These two material choices were chosen from four materials analysed in the thesis and four different TPS. Other TPS were not suitable at decreasing the structural temperature for the Mk-III mission or had an unjustifiable weight penalty. The other material choices would have been suitable in certain situations but were heavier than the current proposed options and might have required a TPS. This thesis provides valuable insight in what suitable material and TPS choices could be for the Mk-III mission. It also shows that for any future material and TPS choice to be made, a comprehensive structural analysis is required. Mass is a key trade-off parameter between the two proposed solutions and a better structural analysis is required for any further trade-off.Aerospace Engineerin
On the determinant of Up on Mk(p,χ)
No full textIn this work, for p a prime, we compute the absolute value of the determinant of the UpUp-operator on the vector space Mk(p,χ)Mk(p,χ) of holomorphic modular forms of weight k and level Γ0(p)Γ0(p) with character χχ. As an implication, we confirm a number of conjectures of the second author
Changing dogma regarding the conformation of electron transferring menaquinone (MK)
Get PDF2017 Spring.Includes bibliographical references.Menaquinone-9 (MK-9) is the natural substrate containing a naphthoquinone and an isoprenyl side-chain with nine isoprene units that carry out the electron transfer for the Mycobacterium tuberculosis. We present studies aiming to understand the chemical and biochemical properties of hydrophobic MK molecules. Specifically, we are investigating the MK derivative with two isoprene units, MK-2, because it provides us with the base structure containing the naphthoquinone unit and the isoprene side-chain. Its synthesis is relatively simple because the precursors are commercially available, which allows for large scale preparation and detailed characterization of the molecular structure under different conditions. Using 1D and 2D 1H NMR studies we are establishing that MKs have different conformations depending on the specific environmental conditions. Similarly, we show using 1H-1H 2D NOESY NMR studies that the association of MK with the surfactant- water interface of reverse micelles, which is a model membrane system, modify the conformation of the menaquinone derivative. Finally, the redox potentials of MK-2 was measured in the three different solvents (DMSO, CH3CN and pyridine). We hypothesize that the redox potential is correlated to the conformational of the MK. We observed that the redox potentials varied with solvent. The observed folded structures of MK derivatives stand in contrast to the linear conformation shown in life science text books
Mitigating the autogenous shrinkage of alkali-activated slag by metakaolin
No full textThis study investigates the effectiveness of metakaolin (MK)in mitigating the autogenous shrinkage of alkali-activated slag (AAS). It is found that the autogenous shrinkage of AAS paste can be reduced by 40% and 50% when replacing 10% and 20% slag with MK, respectively. By providing additional Si and Al, and decreasing the pH of the pore solution, the incorporation of MK retards the formation of aluminium-modified calcium silicate hydrate (CASH)gels, the main reaction products in the studied pastes. The chemical shrinkage and pore refinement are consequently mitigated, resulting in a substantial reduction in the pore pressure. Meanwhile, the elastic modulus of AAS paste is only slightly influenced after MK addition. As a result, the autogenous shrinkage of AAS is significantly mitigated by incorporating MK. In addition, the introduction of MK would extend the setting time, slightly decrease the compressive strength, but greatly increase the flexural strength of AAS.Accepted Author ManuscriptMaterials and Environmen
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