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Understanding p53 in Cancer: The characteristics of uncommon TP53 missense mutations
No full textp53 (TP53) is the most commonly mutated tumor suppressor in cancer. How mutant forms of p53 can contribute to disease progression to influence patient outcomes is important to understand. Previous in-vitro and in-vivo data have shown p53 mutants can drive hyperproliferation, resistance to cell death, and promote drug resistance. However, most of the literature has focused on a small subset of frequently occurring missense mutations in p53, namely hotspot mutations. With the advent of next-generation sequencing technology, many additional mutations in p53 have been identified. Therefore, to improve our understanding of p53 mutants in cancer, we studied the association of uncommon p53 mutants on patient outcomes. To characterise the biological impact of these mutants, we also created experimental tools to test in-vitro.
An analysis of the TCGA Pan-Cancer dataset was used to explore uncommon mutations in p53 present in >50 tumors compared to a hotspot mutation. Kaplan-Meier survival analyses were used to explore whether patients with tumors expressing uncommon TP53 mutations influence disease free survival (DFS). Site-directed mutagenesis was conducted to produce DNA constructs expressing two uncommon p53 missense mutations in H179, associated with poor DFS. Using isogenic in-vitro cell lines, H1299 lung carcinoma cells stably expressing mutant p53 (H179R, H179Y, and R175H) or no p53 (Empty) were created. SYBR-GreenTM assay was carried out on the created stable cell lines, to investigate whether one of these uncommon mutants (H179R/Y) was more efficient at promoting cell proliferation compared to the hotspot mutant (R175H) or p53 null (Empty).
Of the 8 uncommon p53 mutations included in this study, only zinc-binding mutations at C176 and H179 were associated with poorer DFS. Site-directed mutagenesis was effective at creating one hotspot mutant and two uncommon mutations in the pCMV- Neo-Bam-wtp53 plasmid. Restriction digest was used to remove the TP53 insert from the pCMV-Neo-Bam-wtp53 plasmid to generate pCMV-Empty. These plasmids were transfected in H1299 cells to confirm that the plasmids either expressed either no p53 (Empty) or mutant p53. After confirmation, H1299 cells stably expressing these plasmids were created via antibiotic selection. Interestingly, 2/3 cell proliferation replicates, suggests that H179R and H179Y missense mutations in p53 can drive hyperproliferation, compared to cells with no p53 expression and cells with a hotspot mutant. Cell survival, apoptosis, DNA damage assays, and RNA-sequencing will be carried out in the future to characterise these mutations, enabling a deeper understanding of the biological pathways associated with aggressive disease leading to poor patient outcomes
Promoting oral health in pregnancy. Exploring the needs of lead maternity care midwives
No full textAims: To identify the educational needs of practising lead maternity care (LMC) midwives to facilitate their provision of evidence-based oral health advice and promotion to their clients during pregnancy. To identify the enablers and barriers LMC midwives face in providing evidence-based oral health advice and promotion to their clients during pregnancy. Additionally, to inform future development of resources to support the provision of evidence-based oral health advice and promotion by LMC midwives to New Zealand women
Methods: LMC midwives in New Zealand were invited to participate in a mixed- methods study comprising a web-based survey and semi-structured interviews.
Results: One hundred and eleven LMC midwives returned completed surveys, six participated in a semi-structured interview. There was no evidence to suggest the demographic characteristics of our survey sample were significantly different to the New Zealand midwifery workforce. More than three quarters (76.6%, 95% CI 67.6-84.1) provided oral health advice and promotion to clients, despite four fifths (81.1%, 95% CI 72.6-87.4) having no exposure to education regarding oral health in pregnancy. Nearly all (99%, 95% CI 93.8-99.9) LMC midwives believe oral health care is safe during pregnancy, and almost two thirds (65.8%, 95% CI 56.4- 74.1) believe maintaining good oral health is ‘very important’ to pregnancy wellbeing. Eighty percent identified two or more barriers to the provision of oral health advice and promotion. Crucial barriers identified by interviewees include burdening of midwives and women with respect to antenatal information volume, and accessing oral health care in the context of systemic barriers to oral health services in New Zealand. Crucial facilitators include enhancing internal motivation; holistic care; partnership; and driving change from within the midwifery workforce. Four out of five LMC midwives surveyed (81.1%, 95%CI 72.6-87.4) would like more education regarding oral health in pregnancy, with over half (58.6%, 95% CI 49.1-67.4) believing this should be included in undergraduate midwifery training. The belief that good oral health is ‘very important’ to pregnancy wellbeing was associated with a significantly increased likelihood of providing oral health promotion, OR 3.68 (95% CI 1.47-9.16). Midwives with 11 or more years of practising experience were significantly more likely to provide oral health advice and promotion to their clients, OR 6.16 (95% CI 2.31-16.44) than those with less experience.
Conclusions: LMC midwives recognised the importance of oral health to pregnancy wellbeing, were receptive to oral health education, and promoting oral health as part of maternity care. LMC midwives require support through evidence- based midwifery-led education; development of culturally appropriate, fit-for- purpose resources; and interprofessional collaboration to address the systemic barriers to oral health services access for New Zealand women during pregnancy
Biomimetic remineralisation: A comparative evaluation of the enamel remineralisation potential of a short, medium, and long chain self-assembling peptide.
No full textDental caries is a dynamic noncommunicable disease which is multifactorial and dependent on the biological oral environment, human behaviour, and the social determinants of health. The World Health Organisation (WHO) identifies dental caries as the most prevalent and consequential oral disease affecting all age groups on a global scale, leading to large economic costs and lost productivity.
The clinical management of dental caries can be challenging for paediatric dental patients and dental practitioners. Dental caries remains the most common chronic disease in children resulting in six hundred million children with untreated dental caries worldwide in the year 2010 alone. According to the 2009 New Zealand Oral Health Survey, Māori and Pacific children and adolescents residing in higher socio-economic deprivation areas had the worse oral health outcomes.
The dental biofilm is a bacterial pellicle harbouring cariogenic mutans streptococci and lactobacilli which contribute to the microbial fermentation of residual foods leading to acid production and consequently leading to mineral loss from the tooth structure. Demineralisation is the loss of minerals from the tooth structure while remineralisation is the net mineral gain in demineralised tissue. When the caries activity is high and the oral environment favours the demineralisation cascade, an early enamel caries lesion initiates which is usually non-cavitated and white in appearance (white spot lesion).
Early enamel caries lesions (EECLs) describe the stage of the caries severity and not caries lesion activity. Minimal intervention dentistry (MID) is the minimal operative procedure that is rendered for the holistic management of the EECLs with the aim to preserve dental tissue. There is ongoing advocacy for early treatment of dental caries before cavity formation. Home care and professionally applied fluoride gels and varnishes have been the mainstay topical agents in promoting EECL remineralisation while newer strategies are being developed. Self-assembling peptides (SAPs) have shown potential in remineralisation of EECLs.
SAPs act as biological molecules and based on the self-assembling property of amelogenin and leucine rich amelogenin peptide (LRAP). SAPs claim stabilisation of the mineral due to the presence of the peptides and greater depth of remineralisation in EECLs. However, there is little evidence from standardized in-vitro and in-vivo research to support such claims. The aim of this laboratory-based research was to compare the remineralisation efficacy of a short (Curodont Repair ® (P11-4)), medium (P26), and long (LRAP) chain SAP with the standard 5% NaF varnish (Duraphat®) on EECLs.
Relevant research ethics approval obtained for collection of 25 sound premolar teeth. Enamel specimens were prepared according to the research protocols. Demineralising solution (DS) was used to create artificial EECLs in polished human dental enamel specimens, which were randomly allocated to the following treatment groups (n=10): Group 1: P11-4; Group 2: P26 solution; Group 3: LRAP solution; Group 4: 5% NaF varnish and Group 5: Deionised water (DIW). Following the treatment as per prescribed protocols, each specimen was subjected to eight days of pH cycling. Specimens from each test group were subjected to Micro-CT scans and nanomechanical testing to assess the mineral density (MD), hardness (H) and the elastic modulus (EM) properties of the sound, demineralised and treated enamel.
The mean MD percentage gain was highest in the P26 and P11-4 groups, followed by the LRAP, 5% NaF varnish and DIW groups. There was statistically significant difference between the four treatment and the negative control groups. In the outer layer of the artificial EECLs, the EM and H were highest amongst the P26, P11-4, followed by the LRAP and Duraphat. In the inner layer, the EM and H were highest amongst P11-4 and P26 groups, indicative of enhanced penetration and remineralisation of the deeper parts of the EECLs.
Self-assembling peptides P26 and P11-4 are more effective than 5% NaF varnish in remineralising the surface and deeper parts of the EECLs. The synergistic effect of SAPs and other homecare and professionally applied topical agents should be investigated. Although further research is warranted, it is expected that the integration of SAPs into the clinical management of EECLs will lead to favourable clinical outcomes. This supports the new paradigm of minimally invasive procedures for atraumatic experiences and improved quality of life for paediatric dental patents and their families
Investigating the decline and future of the threatened bladderwort Utricularia australis in New Zealand
Get PDFAround the globe biodiversity has been at threat due to changes in ecosystems, of which most are anthropogenic in origin. One area of biodiversity that has been impacted gravely is the flora and fauna of small lakes and wetlands, as these areas have suffered large amounts of historical modification, and are at threat from further being modified negatively in the future, by agriculture, forestry and invasive species. Utricularia australis is a species of free floating aquatic bladderwort that inhabits such areas and has therefor suffered a significant decline of
greater than 70% in the last 10 years making this species now nationally critical in threat status.
In Northland of 22 lakes it used to inhabit that are regularly surveyed it now only persists in 3. To protect species like U. australis we must understand how these changes to the environment are effecting the species, what factors are the most influential and at what level of interaction
may they cause harm or loss. The protection of this species in New Zealand and globally is also shadowed by taxonomic uncertainty and recruitment issues.
This thesis investigates firstly the phylogenetic relationship between New Zealand populations of U. australis and those in Australia as well as Europe. Using ITS markers from samples taken in New Zealand and sequences provided from other countries it was possible to determine that
New Zealand populations of U. australis were indeed within that taxon which had been historically disputed.
Using historical records of lake vegetation and water quality, analysis were carried out to determine the relative importance of each water quality factor on the presence or absence of U. australis in Northland lakes. This investigation was made difficult by the rapid loss of U. australis from study lakes, however, a negative relationship between Trophic Level Index and the presence of U. australis was observed despite no factors showing significant impacts alone.
Relationships between land use and presence were significant with U. australis now only found in lakes with indigenous or native forested catchments. Aerial images matched with time also highlighted the risk between sedimentation from logging events and loss of U. australis in lake
Te Kahika. A threat that needs to be further investigated an mitigated in the future. Species distribution modelling techniques allowed the prediction of the total range of the invasive Utricularia gibba could inhabit in New Zealand based of climate information from its Australian range. A greater range was predicted that what is currently inhabited including populations of U. australis that have been unaffected by the species. Modelling of future climate showed the species to have a small increase in potential range suitability in areas with increased temperature.
Summarising the information in the prior chapters conservation recommendations have been made to prevent further decline or loss of the species, as well as the environments they live in. These include further research into potential low genetic diversity and genetic caused
recruitment failure, the interactions between U. gibba and U. australis, and he management of land around lakes to prevent degradation. Further recommendations include, strategic riparian areas to protect lakes and staggered logging to prevent mass sedimentation events that may
cause loss. The information presented is a useful beginning into understanding this unique species in New Zealand and trying to protect it before it is lost
Long-Term Neurochemical Changes within the Cochlear Nucleus and the Auditory Cortex in Acoustic Trauma-Induced Tinnitus Rats
No full textTinnitus is a debilitating auditory disorder commonly described as a ringing in the ears in the absence of a physical external sound source. Although a variety of risk factors has been reported to be related to the perception of tinnitus, sound overexposure is considered the main cause. Neuronal hyperactivity is one of the potential mechanisms for the genesis of tinnitus and has been found within major regions in the central auditory system, including the cochlear nucleus (CN) and the auditory cortex (AC). The hyperactivity of neurons has been correlated to the imbalance of excitation and inhibition caused by neurotransmitter alterations, amino acids in particular. However, there is no study that directly correlated acoustic trauma and/or tinnitus with extracellular levels of amino acids, which are more accurate measurements in reflecting the functions of those neurochemicals. Theref ore, the present study aimed to investigate how the extracellular amino acid levels altered in the CN and the AC in rats with tinnitus using the in vivo microdialysis technique. The effects of sound stimulation on amino acid changes in the two regions were also examined. In addition, the effect of age on neurochemical changes associated with tinnitus was also examined, owing to the 2-month age gap caused by the COVID-19 lockdown. The animals were exposed to 1-h unilateral acoustic trauma at 16 kHz, 110 dB SPL under anaesthesia and hearing levels were measured before, immediately and about 5 months after acoustic trauma. The animals were tested 5 weeks post-exposure to confirm the development of tinnitus using the conditioned lick-suppression paradigm. Following the confirmation of tinnitus, in vivo microdialysis was combined with high-performance liquid chromatography (HPLC) to measure the extracellular concentrations of amino acids. An immediate hearing loss was evident in the exposed ear of rats following acoustic trauma (P ≤ 0.001) and 70% of exposed rats were confirmed to exhibit tinnitus-like behaviour at 5 weeks after acoustic trauma. The hearing levels were tested again at 5 months after acoustic trauma and they were completely recovered in all of the old rats and 7 out of the 10 young rats. However, hearing levels were partially recovered in 3 out of the 10 young rats. There was no significant difference on either the basal amino acid levels or the sound stimulation evoked amino acid changes between sham and exposed rats or between sham and tinnitus rats in the CN and the AC. It was found that amino acid levels between sound stimulation and silent periods varied significantly for threonine, taurine and alanine in the CN and glutamine, serine and taurine in the AC. Furthermore, there were also age-related changes in the basal and/or sound-evoked amino acid levels for glutamate, threonine and serine. These results suggest that acoustic trauma and/or tinnitus did not cause long-term changes in the extracellular concentrations of amino acids, which provided a new line of evidence for a better understanding of the neurochemical mechanisms of tinnitus. The study also demonstrated that extracellular concentrations of amino acids could be altered by age and sound stimulations, which provided some preliminary evidence for further investigation into the neurochemical shaping of neuronal response to sound or aging
Alterations in myofilament calcium sensitivity and calcium regulation in type 2 diabetic rat heart
No full textDiabetes induces specific cardiac dysfunction in the absence of heart disease, including impairment of cardiac β-adrenergic responsiveness. The underlying mechanisms of cardiac dysfunction induced by diabetes are unclear. Recent studies suggest that diabetes-induced cardiac dysfunction cannot be fully explained by changes in calcium (Ca²⁺) regulation through sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) alone. Another potential, but almost unexplored cause might be alterations in myofilament Ca²⁺ sensitivity. Myofilament Ca²⁺ sensitivity is regulated by post-translational modification through phosphorylation of cardiac troponin I (cTnI) at Ser23/24. However, it is unclear how diabetes affects phosphorylation of cTnI. Moreover, the effects of diabetes on myofilament Ca²⁺ sensitivity and SERCA activity in response to adrenergic stimulation have not been explored. Therefore, this thesis aimed (1) to compare myofilament Ca²⁺ sensitivity, expression of Ca²⁺-handling proteins and SERCA activity in type 2 diabetic heart, and (2) to investigate whether alteration in myofilament Ca²⁺ sensitivity and/or Ca²⁺ handling contributes to reduced adrenergic responsiveness in type 2 diabetic heart.
In my first study, I investigated the effects of diabetes on myofilament Ca²⁺ sensitivity, expression of Ca²⁺-handling proteins, and SERCA activity in type 2 diabetic heart. Left ventricular tissues were obtained from 20-week-old male Zucker type 2 diabetic fatty (ZDF) rats (n = 5) and age-matched non-diabetic control rats (n = 5). Cardiomyocytes isolated from the diabetic and non-diabetic rat tissues were chemically “skinned” to permeabilise and remove all membrane-bound structures. This allowed direct determination of the myofilament properties by manipulating the external environment and activation with buffer solutions containing different Ca²⁺ concentrations. Myofilament Ca²⁺ sensitivity was greater in diabetic cardiomyocytes as indicated by a greater pCa50 when compared to non-diabetic cardiomyocytes. Western blots showed that phosphorylation of cTnI at Ser23/24 was lower in the diabetic heart. SERCA to phospholamban (PLB) ratio and phosphorylation of PLB at Ser16 were lower in the diabetic hearts, but SERCA Ca²⁺ uptake activity was not different between groups. These findings suggest that increased myofilament Ca²⁺ sensitivity, but not SERCA activity is most likely contributing to cardiac dysfunction in type 2 diabetes.
In my second study, I investigated the mechanism of reduced adrenergic responsiveness in the diabetic heart with regard to myofilament Ca²⁺ sensitivity and SERCA activity. Langendorff perfused hearts isolated from 20-week-old male type 2 diabetic ZDF rats and non-diabetic rats were randomised to noradrenaline stimulation or to a time-control group (n = 8/ group). When paced at equal rates (6Hz), the left ventricular developed pressure (LVDP), maximal rate of contraction (+dP/dtmax), and maximal rate of relaxation (-dP/dtmax) were lower by 33.8%, 40.1%, and 39.4%, respectively in the diabetic hearts when compared to the non-diabetic hearts. LVDP, +dP/dtmax and -dP/dtmax increased less across all concentrations of noradrenaline in the diabetic hearts. At the end of the isolated heart experiments, the left ventricular tissues were snap frozen in liquid nitrogen and stored at -80˚C for myofilament Ca²⁺ sensitivity measurement, western blot and SERCA Ca²⁺ uptake activity assay. Noradrenaline stimulation increased phosphorylation of cTnI at Ser23/24, and reduced myofilament Ca²⁺ sensitivity in both groups to a similar extent. SERCA activity was not different between the diabetic and non-diabetic hearts. Noradrenaline stimulation had no effect on SERCA and PLB expression, and increased SERCA activity to a similar extent, in the diabetic and non-diabetic hearts. Interestingly, noradrenaline stimulation increased NCX expression in the diabetic hearts. These findings suggest that impaired adrenergic responsiveness in the diabetic heart was not caused by changes in myofilament Ca²⁺ sensitivity or SERCA activity.
These studies show that cardiac function is impaired in the type 2 diabetic heart. Increased myofilament Ca²⁺ sensitivity, but not changes in SERCA activity may cause cardiac dysfunction in type 2 diabetes. These findings also show depressed cardiac function during adrenergic stimulation in the diabetic heart, but this impairment is not caused by changes in myofilament Ca²⁺ sensitivity or SERCA activity. Increased NCX expression by noradrenaline stimulation suggests that changes in intracellular Ca²⁺ transient during adrenergic stimulation may underlie impaired diabetic heart function. The findings from my thesis highlight the important role of cardiac myofilament in diabetic heart dysfunction, suggesting that the myofilament could potentially be a new therapeutic target for specific cardiac dysfunction induced by diabetes. My thesis did not support the hypothesis that changes in myofilament Ca²⁺ sensitivity or SERCA activity underlie impaired adrenergic responsiveness in the type 2 diabetic heart. Importantly, to our knowledge, this is the first study that found upregulated NCX expression with adrenergic stimulation in the diabetic heart. This provides a new mechanistic insight into the pathophysiological mechanism of diabetic heart dysfunction
The study on Chinese SMEs' internationalization speed
Get PDFEnterprise internationalization, as one of the key strategies for companies to increase business opportunities and expand their business territory, is not only the core driving factor of economic globalization, but also a key link for SMEs to make strategic decisions to enter the international market. However, the speed of enterprise internationalization and market performance will show huge differences under different environmental factors. In particular, the current academic research is more focused on the internationalization speed and market performance of large enterprises, the trajectory and influence mechanism of how SMEs are going international and how to proceed quickly are rarely known. On the other hand, the internationalization speed of SMEs is often accompanied by many limitations, such as lack of resources, etc. Thereby, if SMEs want to realize the internationalization more quickly, they tend to rely on the entrepreneurial orientation, innovation capabilities, and a certain degree of adventurous spirit. This research will focus on how entrepreneurial orientation affects the speed of internationalization of private SMEs in China. It further explores the relationship between the institutional environment and different relationship networks on the impact of entrepreneurial orientation and the speed of corporate internationalization. We hypothesize that entrepreneurial orientation has a positive role in promoting the speed of enterprise internationalization, and this promotion relationship will be stronger in a more developed institutional environment. At the same time, we also believe that an established relationship network will have a positive impact on this facilitating role of entrepreneurial orientation. From a historical perspective, China, as an important part of the international market, has provided active institutional and environmental support for the internationalization of local enterprises. This research provides support for our hypothesis based on the survey research of 146 Chinese private enterprises. The results of this study not only bring theoretical enlightenment and support to the research of private SMEs, but also have practical significance of management practice
Food Sources of Energy by Socioeconomic Status in New Zealand Adolescents
Get PDFThe food environment and a person’s socioeconomic status are known to influence a person’s access to food and food choices. Socioeconomic status has been found to impact food sources of energy amongst adults and children; however limited research has been conducted investigating the relationship in adolescents (15-18 years old). The last New Zealand Adult Nutrition Survey was conducted over 10 years ago, and food patterns are thought to have changed since. The aim of the current study is to investigate the relationship between area-based socioeconomic status and food group consumption in adolescents, the type and amount of food they consume, and provide updated data on food sources of energy for adolescents living in New Zealand
The Role of Empathy and Parent Mental State Talk in Theory-of-Mind Development: A Longitudinal Investigation
Get PDFTheory of mind is an important aspect of social understanding and the development of this skill is of much interest. Theory of mind describes the ability to infer the mental states of others and apply this knowledge. Despite significant research into the roles that related constructs such as language and emotion understanding play in theory-of-mind development, the construct of empathy has received little attention. It is of interest to look at the association between empathy and theory of mind, in the context of known social correlates such as parent mental state talk. This longitudinal study aimed to investigate the relation between empathy and theory of mind, and to determine whether it was mediated by parent mental state talk.
The current study involved 55 children and their parents. These children were involved in a previous study by Aitken (2019) when they had an average age of 20.5 months. Aitken’s study assessed child prosociality, self-concept, empathy, and language ability, and parent’s use of mental state talk. The current study saw these children again when they were 4.6 years on average. Child false-belief understanding, empathy, emotion understanding, prosociality, and language ability was assessed, and parents’ mental state talk was assessed again.
Correlation and mediation analyses revealed three main findings. First, early empathy was not related to later theory of mind, second, empathy and theory of mind were not associated at age 4.6, and third, both empathy and theory of mind were associated with parent mental state talk at the later time point. Additionally, results showed that children’s later prosociality mediated the association between parents’ early references to child emotions and later child emotion understanding. Furthermore, within the later time point, the association between parents’ references to child cognitions and child false-belief understanding, was mediated by children’s general language ability
Spin crossover in iron(II) dinuclear helicates and tetranuclear cages
No full textAmongst the 151 discrete di- to poly-nuclear spin crossover (SCO) active assemblies of Fe(II) published before July 2020, only 19 are Fe(II) triply bridged dinuclear helicates (Fe2L3) and only 6 are edge bridged tetranuclear cages (Fe4L6). Brooker and coworkers have reported numerous examples of mononuclear SCO-active Fe(II) complexes of monotopic bidentate Rdpt (4-R-substituted-3,5-di(2-pyridinyl)-1,2,4-triazole) type ligands. This thesis builds on that foundation by developing new classes of ditopic Rdpt type ligands, for the self-assembly of new classes of SCO-active triply bridged dinuclear helicates (Fe2L3) and edge bridged tetranuclear tetrahedral cages (Fe4L6).
Chapter 1 starts with a brief introduction to SCO. Then the 151 SCO-active discrete di- to poly-nuclear Fe(II) architectures, from dinuclear Fe2L3 to octanuclear Fe8L12, and the ligand designs used to access them, reported before July 2020, are comprehensively reviewed, followed by selected examples of Rdpt type Fe(II) complexes from the literature. Finally, the new class of ditopic Rdpt type ligands, which feature bis-bidentate azine-triazole or azole-triazole binding pockets (Rat) and the corresponding iron(II) complexes that are targeted in this thesis, are introduced.
Chapter 2 presents the extension of our general protocol to the synthesis of the first generation of robust ditopic Rat ligands, which feature meta-phenylene linked (L2/4pym-meta) and para-phenylene linked (L2/4pym-para) bidentate azine-triazole binding pockets. The four ditopic Rat ligands enabled the assembly of two distinct supramolecular architectures, the structurally characterised pair of dinuclear helicates [FeII2Lnpym-meta3](BF4)4 and pair of tetranuclear tetrahedral cages [FeII4Lnpym-para6](BF4)8 (n = 2 and 4). Solution (UV-vis and Evans method 1H NMR spectroscopy) studies of all four complexes revealed that they remain low spin, confirming that coordination by three azine-triazole binding pockets imposes too strong a ligand field.
In order to reduce the ligand field strength, in Chapter 3, the first Rat ligands to feature azoles, not azines, in the binding pocket were accessed. A pair of monotopic azole-triazole Rat ligands (L4NMe/SIm) was synthesised by extension of our general protocol. In contrast to the low spin tris(azine-triazole) coordinated Fe(II) complexes, these new tris(azole-triazole) coordinated complexes, [Fe(L4NMeIm)3]2+ and [Fe(L4SIm)3]2+, are high spin and SCO-active, respectively, in both solid and solution. This confirmed the expected reduced ligand field strength of the azoles compared with the azine analogues.
Hence, in Chapters 4 and 5, these azole-triazole bidentate binding pockets were incorporated into a second generation of reduced ligand field ditopic Rat ligands, to enable the self-assembly of SCO-active dinuclear helicates (Chapter 4 meta-phenylene linker) and tetranuclear cages (Chapter 5 para-phenylene linker).
Specifically, in Chapter 4, five second generation ditopic bis-bidentate Rat ligands, Lazole-meta (azole: 2 and 4-imidazole, 1-methyl-4-imidazole, 4-oxazole and 4-thiazole), were prepared and shown to enable assembly of five structurally characterised SCO-active dinuclear helicates, [FeII2Lazole-meta3]4+. Variable temperature solution studies (UV-vis and Evans method NMR spectroscopy) and cyclic voltammetry studies in MeCN confirmed that all of the five helicates are SCO-active and that the choice of non-coordinated heteroatom influences the ligand field strength, SCO temperature and the redox potential of the Fe(II) centre. In general, the higher the high spin fraction present in the solution, the easier the Fe(II) centre was to oxidise. Furthermore, DOSY NMR spectroscopy was successfully used to characterise the dinuclear helicates regardless of the spin state.
Chapter 5 presents the first pair of second generation ditopic Rat ligands (L4NMeIm-para and L4SIm-para) and the self-assembly of a pair of edge-bridged tetranuclear cages, HS [FeII4L4NMeIm-para6]8+ and SCO-active [FeII4L4SIm-para6]8+. Comparison of the variable temperature solid state magnetic and MeCN solution (UV-vis and Evans method NMR spectroscopy) studies of the cages and the analogous helicates confirmed that the meta-phenylene linked ligands in the dinuclear helicates provide a stronger ligand field than the para-phenylene linked ligands do in the tetranuclear cages.
Finally, in Chapter 6, the key findings are summarised and some future directions are suggested