Synthesis and Application of Light-Activated Molecular Systems

PhD ThesisRuthenium complexes and BODIPY dyes are two very typical types of light-activated molecular systems which are useful in various chemistry and biology applications such as photodynamic therapy, chemical sensors, biological labelling and imaging. But correspondingly, these applications can face problems like cytotoxicity, poor analyte selectivity and a weak signal-to-noise ratio (SNR). This thesis is concerned with work focusing on the design and preparation of several novel ruthenium polypyridyl complexes and BODIPY-based compounds for applications in photodynamic therapy and the fluorescent sensing area. Their photochemistry behaviours are investigated via a range of optical techniques and methods. We hoped to discover compounds with excellent features like low toxicity, high selectivity, good optical signal response and stable performance. The ideas are presented in six chapters within the thesis. Chapter 1 outlines the research directions based on ruthenium complexes and BODIPY-based light-activated molecular systems. The literature review generally introduces the previous discoveries of these two types of compounds, their structural feature, principles of synthetic considerations, chemistry and some applications. A review of photochemistry principles which are related to their structures for development in the other chapters are also reviewed as the basis of this chapter. Chapter 2 describes the common instrumentations, general experimental set ups, data collection and analysis methods which are applicable for the prepared samples and some preliminary structural characterization. Chapter 3 talks about the design of a new class of PDT agents using light-activated small molecules like ruthenium complexes to block biological functioning, especially targeting mitochondria and how they may interfere with critical redox reactions under light activation. Based on our concepts the complex [Ru(bipy)2(1-hydroxyanthra-9,10 quinone)]Cl (RU1) was prepared and studied to understand the preliminary reaction mechanisms and its excited state behaviour through a series of stability tests, electrochemistry, UV-Visible kinetic and femtosecond transient absorption spectroscopy experiments. Under light in the presence of H2O2 two different reactions (fast and slow) appear to take place. The complex loses the quinone-based ligand and a resulting Ru(III) or Ru(V) species is produced. The complex RU1 shows good potential to consume H2O2 from the one carbon metabolism in mitochondria, and hence may cut the energy cycle pathway of tumour cells. Chapter 4 explored a new a julolidine-based BODIPY compound to selectively detect sulfite in a real wine sample. A non-oxidised julolidine-based BODIPY compound (JUL) was reacted with silver (I) ions in the presence of white light and produced its oxidised julolidine version (OXJUL) which contains a quaternary nitrogen. This type of oxidation reaction is highly unusual and there were no reports about it previously. With the addition of a small amount of Na2SO3 in an aqueous solution, the fluorescence maxima of OXJUL blue shifted from 648 nm to 608 nm over several minutes. In the presence of a large excess of sulfite, a further slower reaction occurred accompanied by a blue-shift of the emission to 544 nm. These series of changes are the basis of a real-time fluorescent ratiometric sensor for the detection of sulfite in real wine samples. Chapter 5 successfully developed a new low molecular weight BODIPY based voltage sensitive dye (AJBD) to image and detect voltage changes in giant unilamellar vesicles (GUVs) according to lifetime changes. Julolidine was mono substituted in the α-position of a BODIPY core to form a neutral and lipophilic VSD with a charge transfer feature. With the ON-OFF voltage change on the GUVs, the fluorescence lifetime distribution ratio of AJBD showed a zigzag pattern alongside the ON-OFF voltage changes. When the GUVs were subjected to a ramping voltage, the lifetime distribution ratio showed a linear change in line with the voltage change. These observations were the evidence to indicate the voltage sensitive character of AJBD. Chapter 6 briefly concludes the previous work and highlights the development of the project in the future. For RU1 and RU2, we are aiming to apply it in mitochondria and investigate its behaviour in interrupting the metabolism pathway under the light in Newcastle University Medical School. For OXJUL and AJBD, the targets will be following tested in cells labelling and imaging using fluorescence lifetime imaging microscopy (FLIM) in collaboration with Central Laser Facility (CLF) in the future

Age-related modulation of the nitrogen resorption efficiency response to growth requirements and soil nitrogen availability in a temperate pine plantation

Nitrogen (N) resorption is a key strategy for conserving N in forests, and is often affected by soil nutrient condition and N sink strength within the plant. However, our understanding of the age-related pattern of N resorption and how increasing N deposition will affect this pattern is limited. Here, we investigated N resorption along a chronosequence of stands ranging in age from 2 to 100 years old, and conducted a 4-year exogenous N input experiment in stands at age class 11, 20, and 45 in a Larix Principis-rupprechtii plantation in north China. We found a logarithmic increase in leaf N resorption efficiency (NRE) and green leaf N concentration, and a logarithmic decrease in senesced-leaf N concentration along the stand-age chronosequence. Leaf NRE was negatively correlated with plant-available N concentration. Stand-level N resorption was positively correlated with the annual N requirement for tree growth. N resorption contributed to 45, 62, and 68% of the annual N supply in the 11-, 20-, and 45-year-old stands, respectively. Our exogenous N input experiment showed that leaf NRE in the 11- and 20-year-old stands decreased 17 and 12% following a 50-kg N ha¯¹ y¯¹ input. However, leaf NRE was not affected in the 45-year-old stand. The increases in leaf NRE and the contribution of N resorption to annual N supply along stand ages suggested that, with stand development, tree growth depends more on N resorption to supply its N need. Furthermore, the leaf NRE of mature stand was not decreased under exogenous N input, suggesting that mature stands can be stronger sinks for N deposition than young stands due to their higher capacity to retain the deposited N within plants via internal cycle. Ignoring age-related N use strategies can lead to a bias in N cycle models when evaluating forest net primary production under increasing global N deposition

Safety of azithromycin in paediatrics: a systematic review protocol

Introduction: Azithromycin is widely used in children not only in the treatment of individual children with infectious diseases, but also as mass drug administration (MDA) within a community to eradicate or control specific tropical diseases. MDA has also been reported to have a beneficial effect on child mortality and morbidity. However, concerns have been raised about the safety of azithromycin, especially in young children. The aim of this review is to systematically identify the safety of azithromycin in children of all ages.Methods and analysis: MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, Embase, CINAHL, International Pharmaceutical Abstracts and adverse drug reaction (ADR) monitoring systems will be systematically searched for randomised controlled trials (RCTs), cohort studies, case–control studies, cross-sectional studies, case series and case reports evaluating the safety of azithromycin in children. The Cochrane risk of bias tool, Newcastle-Ottawa and quality assessment tools, and The Joanna Briggs Institute Critical Appraisal tools will be used for quality assessment. Meta-analyses will be conducted to the incidence of ADRs from RCTs if appropriate. Subgroup analyses will be performed in different age and azithromycin dosage groups

Exploring the curriculum development in content and language integrated learning: A systematic review

Content and language integrated learning (CLIL) is a booming innovation pervading many educational settings. The global spread of CLIL is being practiced in classrooms the world over. Nevertheless, there is still a lack of systematic curricula for CLIL, despite its widespread adoption. Furthermore, the majority of teachers are implementing CLIL without the support of suitable published materials or resource banks. To explore and explain the curriculum development in CLIL, 281 studies from 2009 to 2019 were reviewed systematically, focusing on peer-reviewed English-language journals. We identified studies through using 'Content and Language Integrated Learning' and CLIL as the search terms in the ProQuest Research Library and EBSCOhost databases. Selected articles were organized into five inquiry areas and analyzed thematically, inspired by the curriculum development model proposed by Pawlas and Oliva: 1) CLIL philosophy; 2) CLIL goals; 3) CLIL plan; 4) CLIL implementation; and 5) CLIL evaluation. Based on these themes, Boyer's scholarship of integration was introduced to propose a holistic model for CLIL curriculum development

Safety of ceftriaxone in paediatrics: a systematic review protocol

Introduction Ceftriaxone is widely used in children in the treatment of sepsis. However, concerns have been raised about the safety of ceftriaxone, especially in young children. The aim of this review is to systematically evaluate the safety of ceftriaxone in children of all age groups.Methods and analysis MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, International Pharmaceutical Abstracts and adverse drug reaction (ADR) monitoring systems will be systematically searched for randomised controlled trials (RCTs), cohort studies, case–control studies, cross-sectional studies, case series and case reports evaluating the safety of ceftriaxone in children. The Cochrane risk of bias tool, Newcastle-Ottawa and quality assessment tools developed by the National Institutes of Health will be used for quality assessment. Meta-analysis of the incidence of ADRs from RCTs and prospective studies will be done. Subgroup analyses will be performed for age and dosage regimen.Ethics and dissemination Formal ethical approval is not required as no primary data are collected. This systematic review will be disseminated through a peer-reviewed publication and at conference meetings

Corticosteroids for the prevention of bronchopulmonary dysplasia in preterm infants: a network meta-analysis

Objective: To determine the comparative efficacy and safety of corticosteroids in the prevention of bronchopulmonary dysplasia (BPD) in preterm infants.  Study design: We systematically searched PubMed, EMBASE and the Cochrane Library. Two reviewers independently selected randomised controlled trials (RCTs) of postnatal corticosteroids in preterm infants. A Bayesian network meta-analysis and subgroup analyses were performed.  Results: We included 47 RCTs with 6747 participants. The use of dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.29, 95% credible interval (CrI) 0.14 to 0.52; OR 0.58, 95% CrI 0.39 to 0.76, respectively). High-dose dexamethasone was more effective than hydrocortisone, beclomethasone and low-dose dexamethasone. Early and long-term dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.11, 95% CrI 0.02 to 0.4; OR 0.37, 95% CrI 0.16 to 0.67, respectively). There were no statistically significant differences in the risk of cerebral palsy (CP) between different corticosteroids. However, high-dose and long-term dexamethasone ranked lower than placebo and other regimens in terms of CP. Subgroup analyses indicated budesonide was associated with a decreased risk of BPD in extremely preterm and extremely low birthweight infants (OR 0.60, 95% CrI 0.36 to 0.93).  Conclusions: Dexamethasone can reduce the risk of BPD in preterm infants. Of the different dexamethasone regimens, aggressive initiation seems beneficial, while a combination of high-dose and long-term use should be avoided because of the possible adverse neurodevelopmental outcome. Dexamethasone and inhaled corticosteroids need to be further evaluated in large-scale RCTs with long-term follow-ups

Recombinant mycobacterium tuberculosis fusion protein for diagnosis of mycobacterium tuberculosis infection: a short-term economic evaluation

ObjectivesRecombinant Mycobacterium tuberculosis fusion protein (EC) was anticipated to be used for the scale-up of clinical application for diagnosis of Mycobacterium tuberculosis infection in China, but it lacked a head-to-head economic evaluation based on the Chinese population. This study aimed to estimate the cost-utility and the cost-effectiveness of both EC and tuberculin pure protein derivative (TB-PPD) for diagnosis of Mycobacterium tuberculosis infection in the short term.MethodsFrom a Chinese societal perspective, both cost-utility analysis and cost-effectiveness analysis were performed to evaluate the economics of EC and TB-PPD for a one-year period based on clinical trials and decision tree model, with quality-adjusted life years (QALYs) as the utility-measured primary outcome and diagnostic performance (including the misdiagnosis rate, the omission diagnostic rate, the number of patients correctly classified, and the number of tuberculosis cases avoided) as the effective-measured secondary outcome. One-way and probabilistic sensitivity analyses were performed to validate the robustness of the base-case analysis, and a scenario analysis was conducted to evaluate the difference in the charging method between EC and TB-PPD.ResultsThe base-case analysis showed that, compared with TB-PPD, EC was the dominant strategy with an incremental cost-utility ratio (ICUR) of saving 192,043.60 CNY per QALY gained, and with an incremental cost-effectiveness ratio (ICER) of saving 7,263.53 CNY per misdiagnosis rate reduction. In addition, there was no statistical difference in terms of the omission diagnostic rate, the number of patients correctly classified, and the number of tuberculosis cases avoided, and EC was a similar cost-saving strategy with a lower test cost (98.00 CNY) than that of TB-PPD (136.78 CNY). The sensitivity analysis showed the robustness of cost-utility and cost-effectiveness analysis, and the scenario analysis indicated cost-utility in EC and cost-effectiveness in TB-PPD.ConclusionThis economic evaluation from a societal perspective showed that, compared to TB-PPD, EC was likely to be a cost-utility and cost-effective intervention in the short term in China