The development and application of organocatalytic asymmetric epoxidation

Epoxides are widely encountered within organic and biological chemistry, being present in many secondary metabolites and pharmaceuticals. In addition, the unique functionality of the epoxide has been exploited to facilitate the synthesis of many organic molecules. A particularly attractive way to stereoselectively epoxidise a substrate is to employ an organocatalytic system. Our group has been actively pursuing research in this area for over a decade and we have developed several catalytic systems capable of excellent stereocontrol in the epoxidation of alkene substrates. In considering possible refinements to catalyst structure, we targeted two development paths: i) variation of the dihedral angle Φ within the atropos azepinium systems - shown by Lacour to strongly influence the levels of stereoinduction,1 and ii) introduction of a substituent α- to the iminium nitrogen, which we envisaged would also influence the stereochemical outcome of any process occurring at the catalytically active centre. The application of the combined optimisations to existing catalyst frameworks allowed us to create a second generation of catalyst that was capable of furnishing epoxides in ees of up to 97% for tri-substituted unfunctionalised alkenes. We observed a tangible improvement upon the previous generation, and, in explanation, we offer an in-depth discussion on the influence of α-substitution on the ratio of sp2N-sp3C rotamers, and the importance of that ratio on the improved enantiocontrol. As part of an extended research program within our group, we also report the emergence of atropisomerism of the traditionally tropos sp2C-sp2C axis contained within biphenyl systems, presumably caused by efficient stereochemical relays mediated by the α-substituent. Lastly, we were able to successfully apply our methodology in the enantioselective total synthesis of (+)-scuteflorin A.2,3 The key epoxidation step proceeded in 99% ee and 99% yield, as part of a 7-step sequence that was completed with a 14.3% overall yield. 1. R. Novikov, G. Bernardinelli, J. Lacour, Adv. Synth. Catal., 2009, 351, 596. 2. J. Li, Y. Ding, X. –C. Li, D. Ferreira, S. Khan, T. Smillie, I. A. Khan, J. Nat. Prod., 2009, 72, 983 3. C. J. Bartlett, D. Day, Y. Chan, S. M. Allin, M. J. McKenzie, A. M. Z. Slawin, P. C. B. Page, J. Org. Chem., 2012, 77, 772

The Biological Significance of BRG1 Mutations

Eukaryotic organisms package DNA into chromatin for compact storage in the cell nucleus, but this packaging process results in transcriptional repression of genes. Chromatin remodeling complexes have evolved to overcome the transcriptional repression caused by chromatin packaging of DNA into nucleosomes by histones. One example of a chromatin remodeling complex is the SWI/SNF complex in yeast which uses ATP to drive the chromatin apart and make DNA accessible to transcription factors. The yeast SWI2 protein was discovered as the catalytic subunit of the yeast SWI/SNF chromatin remodeling complex and is required for the complex to counteract the repressive nature of chromatin. BRG1 and BRM, SWI2 homologs, are part of human chromatin remodeling complexes and have been shown to play a redundant role in the regulation of certain cell cycle and cellular adhesion genes, as well as cellular pathways. Recent studies showing loss of BRG1 in human tumor cell lines and primary tissue samples, BRG1 mutations in human tumor cell lines, a requirement for BRG1 in Rb mediated arrest, and development of apocrine like tumors by BRG1 heterozygous mice, have implicated a role for BRG1 in cancer development. However, little is known about BRG1's role in the cell and the subsequent mechanistic changes cells experience after loss of BRG1 function. To better understand the role of BRG1 in cancer development we studied previously characterized human tumor cell lines with BRG1 point mutations. We found that the mutations in BRG1 resulted in the loss of CD44 and E-cadherin gene regulation by the complex and disruption of Rb mediated arrest. We next wanted to investigate the mechanism by which loss of BRG1 function effected gene regulation and Rb mediated arrest. We observed that reintroduction of BRG1 into the cells, or treatment with 5-azacytidine, demethylated bases in the CD44 and E-cadherin promoter, leading to re-expression of the genes. Loss of functional BRG1 may lead to aberrant methylation of target gene promoters and cancer development and/or progression through silencing of tumor suppressor genes.Doctor of Philosoph

Pathological or physiological erosion—is there a relationship to age?

This conventional literature review discusses whether pathological tooth wear is age dependant. It briefly reviews the components of tooth wear and the prevalence of tooth wear in children, adolescents and adults. The emphasis on terminology relating to tooth wear varies. In some countries, the role of erosion is considered the most important, whereas others consider the process to be a combination of erosion, attrition and abrasion often with one being more dominant. The importance of tooth wear or erosion indices in the assessment and the evidence for progression within subject and within lesions is described. The data from the few studies reporting pathological levels of wear reported in children and adults are discussed, in particular its relationship with age. There is little evidence to support the concept that pathological levels of erosion or wear are age dependant. There is, however, some evidence to suggest that normal levels of erosion or wear are age dependant

ERA: On-the-fly networking for collaborative geology fieldwork

BACKGROUND Field-based activities are regarded as essential to the development of a range of professional and personal skills for undergraduate students within geography, earth and environmental sciences. Students are taught investigative skills to enable them to interpret features within the landscape, establish technical skills such as sketching and the use of field equipment, and learn to collaborate with peers. Students enjoy field activities, and these improve deeper learning and understanding. However, due to issues such as cost and access some have little opportunity to participate in field-based studies. The ERA (Enabling Remote Activity) project is investigating how mobile and communication technologies might enhance field learning experiences for all participants. We identify two ways in which supporting technologies can enable greater participation and add value to existing fieldwork: remote access and collaborative groupwork. METHODS In 2006 we enabled a single mobility impaired student to direct a remote geologist in the field, supporting remote access. A rapidly deployable, lightweight, battery powered wireless network was built (which we refer to as an ‘on-the fly network’) to enable the transmission of video, audio, and high resolution still images from the field to the student. In 2007 we supported three groups of volunteers undertaking remote collaboration, with half the participants in a university laboratory and the others in the field location. Each group was carrying out a separate specific geological investigation; graphic logging, paleontology, or mineralogy and paleocurrents. A network infrastructure supported communication and data transmission between the groups. Field and laboratory participants had their own distinct, significant roles and the trials explored how technology enhanced collaboration may be used to improve student learning. CONTRIBUTION ERA has tested highly mobile, easily configurable low cost network tools to explore how on-the-fly networking can support geology field studies at undergraduate level in remote locations. We have explored two differing configurations, developed through a collaborative design process undertaken between technology developers and course managers. EVALUATION AND REFLECTION A range of evaluation tools were used to enable analysis of the trials. Field journals were kept by all participants, which found ready acceptance with the geologists as an extension of their standard practice of keeping field notes. A wiki was used by the technical team to capture lessons learnt during the development and trial periods. Participants were gathered together for post-trial debrief sessions. In the second trial, participants’ responses were collected through written questionnaires and focus group discussions (audio recorded). Participants’ activities were also captured on video camera and this was analysed to capture critical incidents. Key findings underline the importance of co-designing technology and pedagogy, orchestration of multiple groups, on-site testing, and planning for graceful degradation of technologies and learning activities. In 2008 we will be looking to move the system from a development prototype to a production model that could be could be replicated by geology departments across the UK without intensive technical support, and the proving of specific technical enhancements including VOIP (Voice Over Internet Protocol) communication and the use of wireless digital cameras

Influence of Riding Experience on Glance Behavior, Brake Response Time and Deceleration Rates by Drivers and Motorcyclists

The focus of the research was to address the crash avoidance behaviors of drivers versus motorcyclists. Avoidance tasks include, attention maintenance and hazard anticipation measured with glance behaviors, and hazard mitigation measured with response times and deceleration. Specifically, where might the driver behavior be similar or different than that of a motorcyclist? The performances of 23participants were analyzed while they drove a car and rode a motorcycle over the same low-volume, open roads. Participants wore eye-tracking equipment used to record eye-glance information while the motorcycle and car were instrumented with an on-board accelerometer and GPS apparatus. Operators also responded by braking quickly to a stop when an LED, mounted in front of them, was illuminated. Motorcyclists spent less time glancing toward the road ahead and made fewer last-glances toward the direction of most threatening traffic before turning when riding the motorcycle, as opposed to when driving a car. Additionally, motorcyclists’ response times were similar to those when driving, yet motorcyclists decelerated less sharply compared to drivers. These results suggest that riders may be exposing themselves to unnecessary risk. Specifically, motorcyclists frequently failed to make proper glances and practice optimal riding techniques. The implication of these results relative to a training curriculum is discussed

Linear mixed models for replication data to efficiently allow for covariate measurement error

It is well known that measurement error in the covariates of regression models generally causes bias in parameter estimates. Correction for such biases requires information concerning the measurement error, which is often in the form of internal validation or replication data. Regression calibration (RC) is a popular approach to correct for covariate measurement error, which involves predicting the true covariate using error-prone measurements. Likelihood methods have previously been proposed as an alternative approach to estimate the parameters in models affected by measurement error, but have been relatively infrequently employed in medical statistics and epidemiology, partly because of computational complexity and concerns regarding robustness to distributional assumptions. We show how a standard random-intercepts model can be used to obtain maximum likelihood (ML) estimates when the outcome model is linear or logistic regression under certain normality assumptions, when internal error-prone replicate measurements are available. Through simulations we show that for linear regression, ML gives more efficient estimates than RC, although the gain is typically small. Furthermore, we show that RC and ML estimates remain consistent even when the normality assumptions are violated. For logistic regression, our implementation of ML is consistent if the true covariate is conditionally normal given the outcome, in contrast to RC. In simulations, this ML estimator showed less bias in situations where RC gives non-negligible biases. Our proposal makes the ML approach to dealing with covariate measurement error more accessible to researchers, which we hope will improve its viability as a useful alternative to methods such as RC