The Asymmetric Synthesis of Several Fragrant Natural Products

The thesis covers the synthetic routes to the jasmonoids, in particular the methyl jasmonates. It is divided into several chapters. The initial chapter covers background on the jasmonates including the discovery, occurrence in nature and the biosynthesis of these compounds along with the more recent research into their biological activity as plant pheromones. This section also focuses in more detail, using selected examples from the chemical literature, on the various syntheses to methyl dihydrojasmonates (hedione), methyl frans-jasmonates and methyl epi-jasmonates together with the problems associated with these. Chapter 2 explores synthetic routes to the trans-jasmonoids in particular methyl dihydrojasmonate. A particular emphasis is placed upon the asymmetric conjugate addition reaction, using extended enolates of homochiral phospholidinone templates (derived from homochiral ephedrine), to afford methyl frans-dihydrojasmonates (hedione) in high enantioselectivity. This asymmetric conjugate reaction is further explored in Chapter 3 where we use this synthetic asymmetric methodology is used to prepare both enantiomers of methyl frans-jasmonates proceeding via a functionalised enone system. The synthesis of the intermediates required for the conjugate additions are also presented. In Chapter 4 a novel route to racemic epi-jasmonate is discussed. The synthetic routes concentrate on a Diels-Alder strategy. It includes our initial investigations comprising, the cycloaddition reactions of 2-cyclopenten-1-one with 2-methoxybutadiene and isoprene using various Lewis acids, together with a synthetic route to a racemic mixture epi-jasmonate using concentrated solutions of lithium perchlorate to catalyse the Diels-Alder reaction of 2- cyclopenten-1-one spiroketals with isoprene. This synthetic route was developed further by using chiral spiroketals of 2-cyclopenten-1-one derived from tartaric acid, in an attempt to introduce chirality during the cycloaddition. This work also provided an insight into the mechanism of this particular cycloaddition reaction. Chapter 5 highlights the two synthetic routes to the calythrone analogue (n-butyl-3,4- dimethylcyclopent-3-en-2,3-dione). The first route is based upon the rearrangement of a derivative of 2,3-dimethylmaleic anhydride. The latter comprises the Pauson-Khand reaction to establish the functionalised cyclopentendione skeleton. Finally a formal description of the experimental results and procedures is presented

Numerical investigation on the hydrodynamic characteristics of an autonomous underwater glider with different wing layouts

An autonomous underwater glider is a self-propelled underwater vehicle which is designed primarily for oceanography. It moves with low speed in saw-tooth pattern and has long endurance. The vertical motion of the glider is controlled by changing its buoyancy and its wings convert this vertical motion into horizontal motion. The hydrodynamic coefficients of glider will dictate its performance and possible applications. In this paper, the impact of rectangular and tapered wings on the hydrodynamics coefficient of a glider and the corresponding glide velocity was investigated using ANSYS Computational Fluid Dynamics (CFD) turbulence model and FLUENT flow solver. The lift force of a rectangular wing is higher with less drag force compared to tapered wings. A glider with tapered wings glider will have a larger glide angle and is therefore suitable of deep ocean applications

Effect of wing form on the hydrodynamic characteristics and dynamic stability of an underwater glider

We are developing a prototype underwater glider for subsea payload delivery. The idea is to use a glider to deliver payloads for subsea installations. In this type of application, the hydrodynamic forces and dynamic stability of the glider is of particular importance, as it has implications on the glider's endurance and operation. In this work, the effect of two different wing forms, rectangular and tapered, on the hydrodynamic characteristics and dynamic stability of the glider were investigated, to determine the optimal wing form. To determine the hydrodynamic characteristics, tow tank resistance tests were carried out using a model fitted alternately with a rectangular wing and tapered wing. Steady-state CFD analysis was conducted using the hydrodynamic coefficients obtained from the tests, to obtain the lift, drag and hydrodynamic derivatives at different angular velocities. The results show that the rectangular wing provides larger lift forces but with a reduced stability envelope. Conversely, the tapered wing exhibits lower lift force but improved dynamic stability

Effect of water current on underwater glider velocity and range

An autonomous underwater glider speed and range is influenced by water currents. This is compounded by a weak actuation system for controlling its movement. In this work, the effects of water currents on the speed and range of an underwater glider at steady state glide conditions are investigated. Extensive numerical simulations have been performed to determine the speed and range of a glider with and without water current at different net buoyancies. The results show that the effect of water current on the glider speed and range depends on the current relative motion and direction. In the presence of water current, for a given glide angle, glide speed can be increased by increasing the net buoyancy of the glider

Epidemiology of Alzheimer’s disease and other dementias: rising global burden and forecasted trends

Background: The burden associated with Alzheimer’s disease is recognized as one of the most pressing issues in healthcare. This study aimed to examine the global and regional burden of Alzheimer’s disease and related dementias. Methods: Epidemiological data from the latest Global Burden of Disease (GBD) dataset were analysed to determine the prevalence, incidence and mortality rates from 1990 to 2019 for 204 countries and world regions. This dataset derives estimates for health metrics by collating primary data from research studies, disease registries and government reports. Temporal forecasting was conducted using the GBD Foresight tool. Results: An estimated 0.7% of the global population has dementia, translating to 51.6 million people worldwide. The total number of persons affected has more than doubled from 1990 to 2019. Dementia metrics showed a continuous increase in prevalence, incidence, mortality, and disability adjusted life years (DALYs) rates worldwide during the last three decades. Japan has the highest prevalence (3,079 cases per 100,000), followed by Italy, Slovenia, Monaco, Greece and Germany. The prevalence is higher in high-income regions such as Western Europe compared to Asia and Africa. However, total number of affected individuals is substantial in South and East Asian regions, in particular China, Japan and India. Dementia related deaths are projected to increase from the current 2.4 million per year to 5.8 million by 2040. Women are more likely to be affected by dementia than men. Age-standardized rates have not changed indicating possible stability of risk factors. Conclusions: Alzheimer’s disease and other dementias are rising rapidly and will more than double in mortality burden over the next 20 years. The tremendous burden in high- and middle-income countries can potentially overwhelm communities and health systems. Urgent measures are needed to allocate funding and provide residential care for affected persons

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome.METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants.RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving.CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.</p