A combined empirical and theoretical characterisation approach was taken in order to investigate the activity distribution and inventory in the Dounreay Fast Reactor (DFR) vault, so as to aid with ...the decommissioning and waste management strategy of the cooling circuits located within the shielded vault. The DFR vault is a no-man access, shielded void, which surrounds the reactor core and the graphite shield.
Empirical data was collected through various Non-Destructive Assay methods, utilising all available accesses into the reactor vault. This collection of information was then used to make a first assumption about the activity distribution within the vault; this was then included into a MCNP model of the vault as the source terms.
The model was run and a dose rate map of the vault obtained, and compared to the empirical dose rate data previously gathered in the accessible penetrations in the vault; the model was altered until a satisfactory agreement was obtained between theoretical and measured data.
Once this was obtained then, the model was used to provide an estimate of the activity inventory within the vault, and specifically within the various reactor components.
Preliminary SAR based on compound E1 was performed, and molecular probes designed and synthesized for applications in studies to identify the target of compound E1.
Analogues of the novel inhibitor ...of the PI3-K/PKB pathway, 2-5-(2-chloroethyl)-2-acetoxy-benzyl-4-(2-chloroethyl)-phenyl acetate (E1), have been prepared and preliminary SAR performed. This established that at least one of the chloroethyl para-substituents could be removed or modified and the ability to inhibit PKB/Akt activation retained. Synthetic methodologies were then developed to methylene-linked aryl acetates for use as molecular probes to identify the target of compound E1.
Screening a compound library of compound 48/80 analogues, we identified 2-5-(2-chloroethyl)-2-acetoxy-benzyl-4-(2-chloroethyl)-phenyl acetate (E1) as a novel inhibitor of the phosphoinositide ...3-kinase/Akt pathway. In order to determine the mechanism of action of E1, we analysed the effect of E1 on components of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. E1 demonstrated dose-dependent and time-dependent repression of Akt and mTOR activity in prostate and breast cancer cell lines, PC-3 and MCF-7, respectively. Inhibition of Akt and mTOR activity by E1 also coincided with increased c-Jun NH2-terminal kinase (JNK) phosphorylation. However, the mode of action of E1 is different from that of the mTOR inhibitor rapamycin. Proliferation and cell cycle analysis revealed that E1 induced cell cycle arrest and cell death in PC-3 and MCF-7 cells. Moreover, pretreatment of cancer cells with the JNK inhibitor SP600125 abolished the repression of Akt and mTOR activity by E1, indicating that the inhibition of Akt and mTOR by E1 is mediated through JNK activation. Consistently, E1 repressed Akt and mTOR activity in wild-type and p38-null mouse embryonic fibroblasts (MEFs), but not in MEFs lacking JNK1/2, and JNK-null MEFs were less sensitive to the antiproliferative effects of E1. We further showed that E1 can function cooperatively with suboptimal concentrations of paclitaxel to induce cell death in PC-3 and MCF-7 cells. Taken together, these data suggest that E1 induces cancer cell death through the JNK-dependent repression of Akt and mTOR activity and may provide a valuable compound for further development and research.
This review describes the progress that has been made in understanding the PI3-K-PKB-mTOR signalling pathway by using small molecules as pharmacological probes. It briefly covers the structural ...characteristics, regulation of and downstream effects of several key regulators of PI3-K-PKB-mTOR signalling, then highlights the use of small molecules (by structural type) to selectively modulate specific components of the pathway.
Holloway, La Boétie, Hegel Gunn, Richard; Wilding, Adrian
Journal of classical sociology : JCS,
05/2012, Letnik:
12, Številka:
2
Journal Article
Recenzirano
The article presents a comradely critique of John Holloway’s Crack Capitalism, one which endorses Holloway’s notion of grassroots revolution but which raises questions about his discussion’s ...conceptual basis. In particular, Holloway’s reliance on Étienne de La Boétie’s Discourse on Voluntary Servitude is found wanting, whereas strands of thought concerning ‘contradiction’ in Hegel’s Phenomenology of Spirit are held to provide a more adequate foundation. Hegel, it is argued, not merely accounts for the possibility and necessity of revolutionary transformation; his account of the French Revolution in relation to the theme of ‘recognition’ indicates how revolution may be understood in a ground-up or grassroots sense.
How might an open Marxist school of thought be developed? The authors of the present chapter are keen readers of Hegel (1770–1831) and of ‘German Idealism’ more generally. It strikes us that themes ...highlighted by open Marxism echo a strand of thought in Hegel’s Phenomenology of Spirit (1807).¹ In pointing to this strand, which is central to our recent work, we underline a continuity between Hegel and Marx. Stated differently, we attempt to renew what is referred to as ‘Left’ or ‘Young’ Hegelianism – which has become all but moribund in neoliberal years.
Marxism has traditionally aimed at emancipation – or,
The phosphoinositide 3-kinase / Akt / mammalian target of rapamycin (PI3-K-AktmTOR) signalling pathway is a regulator of critical cellular functions including apoptosis, metabolism and survival. Its ...deregulation is involved in numerous human diseases. This thesis describes the synthesis and biological evaluation of a series of analogues of the PI3-K-Akt-mTOR inhibitor E1, a homo-dimeric diarylmethane. Several structurally diverse hetero-dimeric E1 derivatives were discovered that inhibited PI3-K-Akt-mTOR signalling in human cancer cells. Chapter 1 provides an overview of the PI3-K-Akt-mTOR signalling pathway and its biological significance. Chapter 2 discusses the use of small molecules for the investigation of PI3-K-Akt-mTOR signalling, with examples given by structural class. It concludes with a profile of lead compound E1. Chapter 3 outlines the proposed approach to analogue synthesis by the coupling of functionalised building blocks, and describes the development of building block compounds via the orthofunctionalisation of phenol derivatives. Chapter 4 describes efforts towards the derivatisation of E1 with a linker group in order to allow the conjugation of biotin for affinity chromatography, or the incorporation of other groups useful for biological characterisation. In Chapter 5, the coupling of building blocks via C-C, C-O, C-N and N-S bond-forming reactions to generate homo- and hetero-dimeric E1 derivatives is discussed. Several of these compounds were capable of inducing cellular Akt inhibition. Chapter 6 focuses on the synthesis of hetero-dimeric analogues based on these new lead compounds. The biological evaluation of E1 derivatives in a cellular assay is described in Chapter 7. Finally, detailed experimental procedures are described in Chapter 8.
The phosphoinositide 3-kinase / Akt / mammalian target of rapamycin (PI3-K-AktmTOR) signalling pathway is a regulator of critical cellular functions including apoptosis, metabolism and survival. Its ...deregulation is involved in numerous human diseases. This thesis describes the synthesis and biological evaluation of a series of analogues of the PI3-K-Akt-mTOR inhibitor E1, a homo-dimeric diarylmethane. Several structurally diverse hetero-dimeric E1 derivatives were discovered that inhibited PI3-K-Akt-mTOR signalling in human cancer cells. Chapter 1 provides an overview of the PI3-K-Akt-mTOR signalling pathway and its biological significance. Chapter 2 discusses the use of small molecules for the investigation of PI3-K-Akt-mTOR signalling, with examples given by structural class. It concludes with a profile of lead compound E1. Chapter 3 outlines the proposed approach to analogue synthesis by the coupling of functionalised building blocks, and describes the development of building block compounds via the orthofunctionalisation of phenol derivatives. Chapter 4 describes efforts towards the derivatisation of E1 with a linker group in order to allow the conjugation of biotin for affinity chromatography, or the incorporation of other groups useful for biological characterisation. In Chapter 5, the coupling of building blocks via C-C, C-O, C-N and N-S bond-forming reactions to generate homo- and hetero-dimeric E1 derivatives is discussed. Several of these compounds were capable of inducing cellular Akt inhibition. Chapter 6 focuses on the synthesis of hetero-dimeric analogues based on these new lead compounds. The biological evaluation of E1 derivatives in a cellular assay is described in Chapter 7. Finally, detailed experimental procedures are described in Chapter 8.
We study the Hamiltonian dynamics for a system of two colliding point particles coupled to (2+1)-dimensional gravity with a negative cosmological constant by anchoring the dynamics of the system to ...its spatial infinity. We reduce the Chern-Simons formulation of the gravitational action, finding the reduced Hamiltonian for three special cases of the particle masses, in a phase space chart coordinatised by the geodesic distance between the two particles and its conjugate momentum. The dimension of the reduced phase space is two. At the threshold of black hole formation, the black hole mass depends linearly on the momentum, in agreement with previous analysis in a holonomy-based phase space chart. We use the reduced action to compute the semiclassical probability amplitude of two particles to tunnel out of the black hole, finding that the imaginary part of the action is equal to the Bekenstein-Hawking entropy of the hole. We also study the form that conformal field theory (CFT) correlation functions take in coset spaces of (2, C). We realise the (2, C) twistor space T in two distinct but equivalent ways, deriving some important facts about this space, and we also give one representation of another coset space B. We examine the form of CFT correlation functions in T, B and two other related spaces using techniques from representation theory and make a number of comments on the twistor transform for T.
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