Nitrogen containing derivatives of diacetyl and their use as ligands

The main objective of this thesis is to synthesise and examine the chelating properties of substituted dihydrazones of diacetyl, CH3C(0)C(0)CH3. The synthesis, structures, spectroscopic and electrochemical properties of the substituted dihydrazones and their metal complexes are described. Chapter I provides a general introduction to the chemistry of substituted dihydrazones and describes the advantages of their use as coordinating ligands over more commonly studied ligands such as 2,2-bipyridine (bipy). A review of previously reported metal complexes of substituted dihydrazones of diacetyl and their applications is described. The synthesis and characterisation of a series of substituted mono- and dihydrazones of diacetyl including the preparation of some novel asymmetric dihydrazones are described in chapter II. The development of a new synthetic route for the preparation of azine oligomers of discrete sizes, H2N-[-N=C(CH3)-C(CH3)=N-]n-NH2 (for n = 1 to 5), where n is the number of repeat units, has been developed. A HPLC method is used to assign the number of repeat units of the oligomers. In chapter III, an introduction to the properties of [Ru(bipy)3 ]CI2 is given. [Ru(bipy)3 ]CI2 has the disadvantage of being photolabile which has led to considerable interest in a search for a complex which has more suitable properties. Dihydrazone and dihydrazone derivatives of diacetyl have been bound to [Ru(bipy)2Cl2 ] to give complexes [Ru(bipy)2(LL)](PF6)2, (where LL = diacetyldi(phenylhydrazone), diacetyldi(methylphenylhydrazone), diacetyldi- (o-tolylhydrazone), diacetyldi(dimethylhydrazone), diacetyldihydrazone, diacetyldi(benzilazine)). Some of the complexes were found to be photostable whereas other complexes decompose when irradiated by white light. Two features of interest of the complexes investigated include lack of emission and unusual highfield aromatic proton shifts in the 1H NMR spectra. Electrochemical analysis indicates that the hydrazone ligands are stronger n-acceptors than bipy. Excitation of the complexes is located on the hydrazone ligands and it is thought that these ligands do not emit. The highfield aromatic proton resonances are caused by the phenyl rings being positioned directly over the bipyridyl groups resulting in deshielding. To examine the contribution of the hydrazone ligands to the lack of emission, complexes of the type [Ru(bipy)2(LL)](PF6)2, (LL = 2-acetylpyridinephenylhydrazone, 2-acetylpyridinehydrazone), were prepared. The ligands LL are effectively a "half" bipy, half "hydrazone ligand" having both a hydrazone group and a pyridine ring. Both complexes display emission but are not photostable, indicating that it is possible to have an emitting complex containing a hydrazone ligand. Variable temperature 1H NMR analysis of the complexes was carried out. With the aid of single crystal X-ray diffraction study of the complex [Ru(bipy)2(ddph)](PF6)2, various rotational isomeric structures arising from rotation about the N-N bond of the hydrazone ligand within the complexes in solution at various temperatures were proposed. The polyazine oligomers which contain a repeating diimine unit, in the presence of high metal concentrations, were found to coordinate transition metals including zinc(ll) to form stable metal complexes, described in chapter IV. To assist in the elucidation of the structures of transition metal polyazine complexes, the X-ray crystal structure of [Zn(ddh)Cl2 ], (ddh = diacetyldihydrazone) was obtained. Using the crystal structure of [ZniddhJCIJ together with the shape of N-H stretching frequency bands in the infrared spectra of the complexes, coordination modes for the polyazine ligands around the metal centres are proposed. In dilute metal containing solutions, an unusual coupling reaction of the dihydrazone oligomers occurs, catalysed by various transition metals. The reaction most likely involves the coordination of two polyazine molecules around the metal, which orientates the terminal amino groups close enough together to react, resulting in disproportionation of the azine oligomers. Endcapping the dihydrazone oligomers with a phenyl group as in PhHN-[-N=C(CH3)-C(CH3)=N-]n-NHPh for (n = 1 to 4), produces a more stable oligomer, which also bind to metals

Delineation of RAID1, the RACK1 interaction domain located within the unique N-terminal region of the cAMP-specific phosphodiesterase, PDE4D5

Background The cyclic AMP specific phosphodiesterase, PDE4D5 interacts with the β-propeller protein RACK1 to form a signaling scaffold complex in cells. Two-hybrid analysis of truncation and mutant constructs of the unique N-terminal region of the cAMP-specific phosphodiesterase, PDE4D5 were used to define a domain conferring interaction with the signaling scaffold protein, RACK1. Results Truncation and mutagenesis approaches showed that the RACK1-interacting domain on PDE4D5 comprised a cluster of residues provided by Asn-22/Pro-23/Trp-24/Asn-26 together with a series of hydrophobic amino acids, namely Leu-29, Val-30, Leu-33, Leu-37 and Leu-38 in a 'Leu-Xaa-Xaa-Xaa-Leu' repeat. This was done by 2-hybrid analyses and then confirmed in biochemical pull down analyses using GST-RACK1 and mutant PDE4D5 forms expressed in COS cells. Mutation of Arg-34, to alanine, in PDE4D5 attenuated its interaction with RACK1 both in 2-hybrid screens and in pull down analyses. A 38-mer peptide, whose sequence reflected residues 12 through 49 of PDE4D5, bound to RACK1 with similar affinity to native PDE4D5 itself (Ka circa 6 nM). Conclusions The RACK1 Interaction Domain on PDE4D5, that we here call RAID1, is proposed to form an amphipathic helical structure that we suggest may interact with the C-terminal β-propeller blades of RACK1 in a manner akin to the interaction of the helical G-γ signal transducing protein with the β-propeller protein, G-β

The ‘values journey’ of nursing and midwifery students selected using multiple mini interviews; Year One findings

Aim: to explore how adult, child and mental health nursing and midwifery students, selected using multiple mini interviews, describe their ‘values journey’ following exposure to the clinical practice environment. Background: Values based recruitment incorporates assessment of healthcare students’ personal values using approaches like multiple mini interviews. Students’ experience of adjustment to their values during their programme is conceptualised as a ‘values journey’. The impact of VBR in alleviating erosion of personal values is unclear. Design A cross-professional longitudinal cohort study was commenced at one university in England in 2016 with data collection points at the end of years one, two and three. Non-probability consecutive sampling resulted in 42 healthcare students (8 adult, 8 child and 9 mental health nursing and 17 midwifery students) taking part. Methods: Six semi-structured focus groups were conducted at the end of participants’ Year One (DC1). Data analysis incorporated inductive and deductive approaches in a hybrid synthesis. Findings: Participants described a ‘values journey’ where their values, particularly communication, courage and wanting to make a difference, were both challenged and retained. Participants personal journeys also acknowledged the: ‘courage it takes to use values’; ‘reality of values in practice’ and ‘need for self-reflection on values’. Conclusion: A ‘values journey’ may begin early in healthcare student’s education programme. This is important to recognise so that appropriate measures are implemented to support students across higher education and clinical practice. Consideration should also be given to the values incorporated in values based recruitment to ensure their fitness for purpose

The reliability and validity of multiple mini interviews (MMIs) in values based recruitment to nursing, midwifery and paramedic practice: Findings from an evaluation study

Background: Universities in the United Kingdom (UK) are required to incorporate values based recruitment (VBR) into their healthcare student selection processes. This reflects an international drive to strengthen the quality of healthcare service provision. This paper presents novel findings in relation to the reliability and predictive validity of multiple mini interviews (MMIs); one approach to VBR widely being employed by universities. Objectives: To examine the reliability (internal consistency) and predictive validity of MMIs using end of Year One practice outcomes of under-graduate pre-registration adult, child, mental health nursing, midwifery and paramedic practice students. Design: Cross-discipline evaluation study. Setting: One university in the United Kingdom. Participants: Data were collected in two streams: applicants to A) The September 2014 and 2015 Midwifery Studies programmes; B) September 2015 adult; Child and Mental Health Nursing and Paramedic Practice programmes. Fifty-seven midwifery students commenced their programme in 2014 and 69 in 2015; 47 and 54 agreed to participate and completed Year One respectively. 333 healthcare students commenced their programmes in September 2015. Of these, 281 agreed to participate and completed their first year (180 adult, 33 child and 34 mental health nursing and 34 paramedic practice students). Methods: Stream A featured a seven station four-minute model with one interviewer at each station and in Stream B a six station model was employed. Cronbach’s alpha was used to assess MMI station internal consistency and Pearson’s moment correlation co-efficient to explore associations between participants’ admission MMI score and end of Year one clinical practice outcomes (OSCE and mentor grading). Results: Stream A: Significant correlations are reported between midwifery applicant’s MMI scores and end of Year One practice outcomes. A multivariate linear regression model demonstrated that MMI score significantly predicted end of Year One practice outcomes controlling for age and academic entry level: coefficients 0.195 (p = 0.002) and 0.116 (p = 0.002) for OSCE and mentor grading respectively. In Stream B no significant correlations were found between MMI score and practice outcomes measured by mentor grading. Internal consistency for each MMI station was ‘excellent’ with values ranging from 0.966–0.974 across Streams A and B. Conclusion: This novel, cross-discipline study shows that MMIs are reliable VBR tools which have predictive validity when a seven station model is used. These data are important given the current international use of different MMI models in healthcare student selection processes

Controlling the uncontrolled: Are there incidental experimenter effects on physiologic responding?

The degree to which experimenters shape participant behavior has long been of interest in experimental social science research. Here, we extend this question to the domain of peripheral psychophysiology, where experimenters often have direct, physical contact with participants, yet researchers do not consistently test for their influence. We describe analytic tools for examining experimenter effects in peripheral physiology. Using these tools, we investigate nine data sets totaling 1,341 participants and 160 experimenters across different roles (e.g., lead research assistants, evaluators, confederates) to demonstrate how researchers can test for experimenter effects in participant autonomic nervous system activity during baseline recordings and reactivity to study tasks. Our results showed (a) little to no significant variance in participants' physiological reactivity due to their experimenters, and (b) little to no evidence that three characteristics of experimenters that are well known to shape interpersonal interactions-status (using five studies with 682 total participants), gender (using two studies with 359 total participants), and race (in two studies with 554 total participants)-influenced participants' physiology. We highlight several reasons that experimenter effects in physiological data are still cause for concern, including the fact that experimenters in these studies were already restricted on a number of characteristics (e.g., age, education). We present recommendations for examining and reducing experimenter effects in physiological data and discuss implications for replication

Mitral Annular and Coronary Artery Calcification Are Associated with Mortality in HIV-Infected Individuals.

BackgroundHIV infection increases cardiovascular risk. Coronary artery calcification (CAC) and mitral annular calcification (MAC) identify patients at risk for cardiovascular disease (CVD). The purpose of this study was to examine the association between MAC, CAC and mortality in HIV-infected individuals.Methods and resultsWe studied 152 asymptomatic HIV-infected individuals with transthoracic echocardiography (TTE) and computed tomography (CT). MAC was identified on TTE using standardized criteria. Presence of CAC, CAC score and CAC percentiles were determined using the modified Agatston criteria. Mortality data was obtained from the Social Security and National Death Indices (SSDI/NDI). The median age was 49 years; 87% were male. The median duration of HIV was 16 years; 84% took antiretroviral therapy; 64% had an undetectable viral load. CVD risk factors included hypertension (35%), smoking (62%) and dyslipidemia (35%). Twenty-five percent of individuals had MAC, and 42% had CAC. Over a median follow-up of 8 years, 11 subjects died. Subjects with CAC had significantly higher mortality compared to those with MAC only or no MAC. The Harrell's C-statistic of CAC was 0.66 and increased to 0.75 when MAC was added (p = 0.05). MAC, prior CVD, age and HIV viral load were independently associated with higher age- and gender-adjusted CAC percentiles in an adjusted model (p < 0.05 for all).ConclusionIn HIV patients, the presence of MAC, traditional risk factors and HIV viral load were independently associated with CAC. Presence of CAC and MAC may be useful in identifying HIV-infected individuals at higher risk for death

Fluctuations in depression and well-being are associated with sexual risk episodes among HIV-positive men

Peer reviewedPostprin

SEASONALITY OF BIRD STRIKES: TOWARDS A BEHAVIOURAL EXPLANATION

It is well known that, at least in the Northern Hemisphere, there is a strong seasonal element in the annual pattern of bird strikes. This study undertakes a statistical analysis of an 11year data set collected at Dublin Airport, Ireland. It attempts to identify statistically significant trends in the seasonal trajectories of bird strikes, both in general and in respect of individual species and in comparison with seasonal trends in the abundance of birds generally and at Dublin Airport in particular. Hypotheses relating to the idea of “open” (i.e. intervals of through-put of naïve and young birds) and “closed” (i.e. intervals when throughput is declining or at a minimum) periods are tested. The results are discussed in the context of the probable ability of birds to learn to avoid aircraft. If birds possess a spatio-temporal memory then it is likely that this ability, or the lack of it, may explain some of the observed trends in the seasonal distribution of bird strikes