Synthesis and Evaluation of Novel PI3-K-Akt-mTOR Modulators

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 Effect of Information and Experience on Preference for Complexity

One area of research that has received a great deal of empirical and theoretical attention is preference for complexity. Two major conclusions may be drawn from a survey of the relevant literature in this area. First, there is a greater preference for the intermediate ranges of complexity than for the extreme levels, and secondly, preference for complexity is a function of the interaction of both stimulus and subject variables. The role of stimulus variables in preference for complexity has been repeatedly studied. This is also true of the subject variable experience, which is usually defined in terms of the subject\u27s age or amount of exposure to the stimuli. The present study attempted to define another subject variable as yet unreported in the literature. This variable was labeled a knowledge variable and was defined as the subject\u27s cognitive information with regard to the stimuli to be evaluated. The purpose of this study was to investigate the effects of, what has been defined as, knowledge and experience on preference for complexity. The subjects, 148 college students, were -randomly assigned to one of four groups and initial preference ratings for complexity were taken in each group. The stimuli rated were green and white random matrices or checkerboards varying in informational content. The complexity of these stimuli was defined by the number of bits of information each contained, and six levels of complexity were used. These stimuli were presented to the subjects in both the pretest and the posttest phases of the experiment in a paired comparison paradigm. From the obtained preference ratings, a score representing the total amount of information preferred (TIP) was computed for each subject and used as the basic data unit in the statistical analyses. The experience variable was administered using the repeated visual presentation of the individual matrices. Presentation of the knowledge variable consisted of a lecture in which subsuming concepts regarding the stimuli were given. A combination of the two subject variables was also given to a third group of subjects. The results indicate that any group receiving the knowledge variable showed significant increases in preference for complexity, while no significant increases were noted for the experience variable. The combination of the knowledge and experience variables produced significant increases in preference for complexity, but these increases were not significantly greater than those produced by the knowledge variable alone. It was concluded that the knowledge phase, in which subsuming concepts or advance organizers were given to the subjects rather than forcing them to develop their own cognitive organization as was done in the experience phase, was highly effective in increasing preference for complexity. The failure of the combination of the two subject variables to produce increases in preference significantly greater than the knowledge variable alone was attributed to the presence of a ceiling effect in this specific group. The value of individual differences in assessing preference was • noted and a brief description of the present data when sorted according to individual function is given. Some implications of the present study were discussed and the need for future research directed toward the replication of the specific findings along with the establishment of parameters for subject variables was indicated

Unbound Universe

Astronom

Double Reverse Play

When we were children, many of us went through a phase -- much to the dismay and embarrassment of our parents -- of reciting everything backward. Every so often, this practice would unearth a genuine reversal: live/evil, doom/mood, straw/warts. The following phrases define both words in a series of two word reversals; the length of each word is given in parenthesis. Be warned: some clues are straightforward, but others are obscure. Answers can be found at the end of this issue

Spatio-temporal influence of tundra snow properties on Ku-band (17.2 GHz) backscatter

During the 2010/11 boreal winter, a distributed set of backscatter measurements was collected using a ground-based Ku-band (17.2 GHz) scatterometer system at 26 open tundra sites. A standard snow-sampling procedure was completed after each scan to evaluate local variability in snow layering, depth, density and water equivalent (SWE) within the scatterometer field of view. The shallow depths and large basal depth hoar encountered presented an opportunity to evaluate backscatter under a set of previously untested conditions. Strong Ku-band response was found with increasing snow depth and snow water equivalent (SWE). In particular, co-polarized vertical backscatter increased by 0.82 dB for every 1 cm increase in SWE (R2 = 0.62). While the result indicated strong potential for Ku-band retrieval of shallow snow properties, it did not characterize the influence of sub-scan variability. An enhanced snow-sampling procedure was introduced to generate detailed characterizations of stratigraphy within the scatterometer field of view using near-infrared photography along the length of a 5m trench. Changes in snow properties along the trench were used to discuss variations in the collocated backscatter response. A pair of contrasting observation sites was used to highlight uncertainties in backscatter response related to short length scale spatial variability in the observed tundra environment

Predicting the movements of permanently installed electrodes on an active landslide using time-lapse geoelectrical resistivity data only

If electrodes move during geoelectrical resistivity monitoring and their new positions are not incorporated in the inversion, then the resulting tomographic images exhibit artefacts that can obscure genuine time-lapse resistivity changes in the subsurface. The effects of electrode movements on time-lapse resistivity tomography are investigated using a simple analytical model and real data. The correspondence between the model and the data is sufficiently good to be able to predict the effects of electrode movements with reasonable accuracy. For the linear electrode arrays and 2D inversions under consideration, the data are much more sensitive to longitudinal than transverse or vertical movements. Consequently the model can be used to invert the longitudinal offsets of the electrodes from their known baseline positions using only the time-lapse ratios of the apparent resistivity data. The example datasets are taken from a permanently installed electrode array on an active lobe of a landslide. Using two sets with different levels of noise and subsurface resistivity changes, it is found that the electrode positions can be recovered to an accuracy of 4 % of the baseline electrode spacing. This is sufficient to correct the artefacts in the resistivity images, and provides for the possibility of monitoring the movement of the landslide and its internal hydraulic processes simultaneously using electrical resistivity tomography only

Topics in 2 + 1 gravity and conformal field theory

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

A world shared - a world apart: the experience of families after the death of a significant other late in life

Aims: The aim of this study was to investigate the impact of the death of an older member on families. Background: The death of a significant other in later life is a dramatic moment. Research has demonstrated that some older persons face negative consequences for their well-being. A majority, however, exhibit resilience in the wake of loss. Nonetheless, the relational process through which older persons come to terms with the loss in interaction with their families is little understood, but vital to support bereaved families. Design: Heideggerian hermeneutic phenomenology. Methods: A purposive sample of ten older persons with their families, represented by children, grandchildren and in-laws (n = 30) were interviewed several times in 2013, alone (n = 16) and in family groups (n = 21), 6-23 months after their significant other's death (mean age 81 years). Data collection and thematic analysis was informed by van Manen's and Benner's analytical strategies. Findings: Three family themes were discerned. First, through meaning-making, bereaved families weaved the death into their family narrative. Second, through sharing-not sharing their feelings and daily moments, family members lived with the loss both together and alone. Third, some families faced upheaval in their family life, which required them to re-create their everyday life, whereas other families continued with little change. Conclusions: Findings demonstrate that families hold an inherent capacity to make meaning of the death and enact family thereafter. Family relations arose as interplay of different, contradicting forces. Nurses should facilitate families’ meaning-making of the death, attend to their converging and diverging sense of loss and strengthen family caring

Constraining Large Scale Structure Theories with the Cosmic Background Radiation

We review the relevant 10+ parameters associated with inflation and matter content; the relation between LSS and primary and secondary CMB anisotropy probes; COBE constraints on energy injection; current anisotropy band-powers which strongly support the gravitational instability theory and suggest the universe could not have reionized too early. We use Bayesian analysis methods to determine what current CMB and CMB+LSS data imply for inflation-based Gaussian fluctuations in tilted $\Lambda$CDM, $\Lambda$hCDM and oCDM model sequences with age 11-15 Gyr, consisting of mixtures of baryons, cold (and possibly hot) dark matter, vacuum energy, and curvature energy in open cosmologies. For example, we find the slope of the initial spectrum is within about 5% of the (preferred) scale invariant form when just the CMB data is used, and for $\Lambda$CDM when LSS data is combined with CMB; with both, a nonzero value of $\Omega_\Lambda$ is strongly preferred ($\approx 2/3$ for a 13 Gyr sequence, similar to the value from SNIa). The $o$CDM sequence prefers $\Omega_{tot}<1$, but is overall much less likely than the flat $\Omega_\Lambda \ne 0$ sequence with CMB+LSS. We also review the rosy forecasts of angular power spectra and parameter estimates from future balloon and satellite experiments when foreground and systematic effects are ignored.Comment: 20 pages, LaTeX, 5 figures, 2 tables, uses rspublic.sty To appear in Philosophical Transactions of the Royal Society of London A, 1998. "Discussion Meeting on Large Scale Structure in the Universe," Royal Society, London, March 1998. Text and colour figures also available at ftp://ftp.cita.utoronto.ca/bond/roysoc9