Towards a model of non-equilibrium binding of a metal ion in a biological system

We have used a systems biology approach to address the hitherto insoluble problem of the quantitative analysis of non-equilibrium binding of aqueous metal ions by competitive ligands in heterogeneous media. To-date, the relative proportions of different metal complexes in aqueous media have only been modelled at chemical equilibrium and there are no quantitative analyses of the approach to equilibrium1. While these models have improved our understanding of how metals are used in biological systems they cannot account for the influence of kinetic factors in metal binding, transport and fate2. Here we have modelled the binding of aluminium in blood serum by the iron transport protein transferrin (Tf) as it is widely accepted that the biological fate of this non-essential metal is not adequately described by experiments, in vitro and in silico, which have consistently demonstrated that at equilibrium 90% of serum Al(III) is bound by Tf3-5. We have coined this paradox 'the blood-aluminium problem'6 and herein applied a systems biology approach which utilised well-found assumptions to pare away the complexities of the problem such that it was defined by a comparatively simple set of computational rules and, importantly, its solution assumed significant predictive capabilities. Here we show that our novel computational model successfully described the binding of Al(III) by Tf both at equilibrium and as equilibrium for AlTf was approached. The model provided an explanation of why the distribution of Al(III) in the body cannot be adequately described by its binding and transport by Tf and it highlighted the significance of kinetic in addition to thermodynamic constraints in defining the fate of metal ions in biological systems. This is the first model of non-equilibrium metal binding in a biological system and it should prove to be a valuable predictive tool in furthering our understanding of the bioinorganic chemistry of metals

Amelioration of aluminium toxicity in Atlantic salmon, Salmo salar L., with particular reference to aluminium/silicon interactions

The aim of the research was to examine amelioration strategies for aluminium and in particular the potential of silicon to ameliorate the acute toxicity of A1 in Atlantic Salmo salar, fry in a dilute acid water. Methods were developed for the analysis of A1 and Si using graphite furnace atomic absorption spectrometry. This technique was then combined with carefully defined pre-treatment procedures to investigate simple A1 speciation and solubility in dilute aqueous milieu. Research than examined the potential of Ca(OH)2(s)CaCO3(s) and CaO/SiO2(2)to ameliorate acute A1 toxicity. A field study highlighted the inadequacies of Ca (OH)(2)(s)as an effective agent to ameliorate A1 toxicity and laboratory studies, whilst substantiating these inadequacies for both Ca(0H)2(s) and CaCO3(s) highlighted the potential of Ca0/Si02(s), and in particular silicic acid, as a potential detoxification agent for A1 in acid waters. Detailed laboratory studios of the interactions between A1 and silicic acid in dilute aqueous environments demonstrated the formation of aluminosilicates, the stabilities of which were dependent on the pH and the silicic acid concentration. Stable, occasionally charged aluminosilicate species were formed at silicic acid concentrations above 1000/ugl-1 probably through the interaction of silicic acid with the aluminate anion. Al(OH)4(aq) Those species were slow to come out of solution and increased Al solubility with respect to amorphous in the short-term, (168h). A flow-through toxicity system was developed to assess the results of these Al/Si interactions on the acute toxicity of Al to Atlantic salmon fry at pH 5.0. Acute Al toxicity was found to be abolished by a critical concentration of silicic acid, (•* 7S0^X^ "2400 /ugl~^). The silicic acid rendered the Al biologically unavailable, Al neither being taken up by the fish nor associating with the gill surface, and this observation has outlined a potential and not previously considered role of silicon in biology

An interaction of β-amyloid with aluminium in vitro

AbstractWe have used circular dichroism spectroscopy to confirm that, in a membrane-mimicking solvent, AβP(1–40) adopts a partially helical conformation and we have demonstrated the loss of this structure in the presence of physiologically relevant concentrations of aluminium. This is the first evidence of a direct biochemical interaction between aluminium and β-amyloid and may have important implications for the pathogenesis of Alzheimer's disease

Introducing high-cost health care to patients: dentists' accounts of offering dental implant treatment

Objectives: The decision-making process within health care has been widely researched, with shared decision-making, where both patients and clinicians share technical and personal information, often being cited as the ideal model. To date, much of this research has focused on systems where patients receive their care and treatment free at the point of contact (either in government-funded schemes or in insurance-based schemes). Oral health care often involves patients making direct payments for their care and treatment, and less is known about how this payment affects the decision-making process. It is clear that patient characteristics influence decision-making, but previous evidence suggests that clinicians may assume characteristics rather than eliciting them directly. The aim was to explore the influences on how dentists' engaged in the decision-making process surrounding a high-cost item of health care, dental implant treatments (DITs). Methods: A qualitative study using semi-structured interviews was undertaken using a purposive sample of primary care dentists (n = 25). Thematic analysis was undertaken to reveal emerging key themes. Results: There were differences in how dentists discussed and offered implants. Dentists made decisions about whether to offer implants based on business factors, professional and legal obligations and whether they perceived the patient to be motivated to have treatment and their ability to pay. There was evidence that assessment of these characteristics was often based on assumptions derived from elements such as the appearance of the patient, the state of the patient's mouth and demographic details. The data suggest that there is a conflict between three elements of acting as a healthcare professional: minimizing provision of unneeded treatment, trying to fully involve patients in shared decisions and acting as a business person with the potential for financial gain. Conclusions: It might be expected that in the context of a high-cost healthcare intervention for which patients pay the bill themselves, that decision-making would be closer to an informed than a paternalistic model. Our research suggests that paternalistic decision-making is still practised and is influenced by assumptions about patient characteristics. Better tools and training may be required to support clinicians in this area of practice

How does priority setting for resource allocation happen in commissioning dental services in a nationally led, regionally delivered system: a qualitative study using semistructured interviews with NHS England dental commissioners

Objectives: To understand approaches to priority setting for healthcare service resource allocation at an operational level in a nationally commissioned but regionally delivered service. Design: Qualitative study using semistructured interviews and a Framework analysis. Setting: National Health Service dentistry commissioning teams within subregional offices in England. Participants: All 31 individuals holding the relevant role (dental lead commissioner in subregional offices) were approached directly and from this 14 participants were recruited, with 12 interviews completed. Both male and female genders and all regions were represented in the final sample. Results: Three major themes arose. First, 'Methods of priority setting and barriers to explicit approaches' was a common theme, specifically identifying the main methods as: perpetuating historical allocations, pressure from politicians and clinicians and use of needs assessments while barriers were time and skill deficits, a lack of national guidance and an inflexible contracting arrangements stopping resource allocation. Second, 'Relationships with key stakeholders and advisors' were discussed, showing the important nature of relationships with clinical advisors but variation in the quality of these relationships was noted. Finally, 'Tensions between national and local responsibilities' were illustrated, where there was confusion about where power and autonomy lay. Conclusions: Commissioners recognised a need for resource allocation but relied on clinical advice and needs assessment in order to set priorities. More explicit priority setting was prevented by structure of the commissioning system and standard national contracts with providers. Further research is required to embed and simplify adoption of tools to aid priority setting

Aluminum's preferential binding site in proteins: sidechain of amino acids versus backbone interactions

The interaction of aluminum ion Al(III) with polypeptides is a subject of paramount importance, since it is a central feature to understand its deleterious effects in biological systems. Various drastic effects have been attributed to aluminum in its interaction with polypeptides and proteins. These interactions are thought to be established mainly through the binding of aluminum to phosphorylated and non-phosphorylated amino acid sidechains. However, a new structural paradigm has recently been proposed, in which aluminum interacts directly with the backbone of the proteins, provoking drastic changes in their secondary structure and leading ultimately to their denaturation. In the present paper, we use computational methods to discuss the possibility of aluminum to interact with the backbone of peptides and compare it with the known ability of aluminum to interact with amino acid sidechains. To do so, we compare the thermodynamics of formation of prototype aluminum-backbone structures with prototype aluminum-sidechain structures, and compare these results with previous data generated in our group in which aluminum interacts with various types of polypeptides and known aluminum biochelators. Our results clearly points to a preference of aluminum towards amino acid sidechains, rather than towards the peptide backbone. Thus, structures in which aluminum is interacting with the carbonyl group are only slightly exothermic, and they become even less favorable if the interaction implies additionally the peptide nitrogen. However, structures in which aluminum is interacting with negatively-charged sidechains like aspartic acid, or phosphorylated serines are highly favored thermodynamically.Technical and human support was provided by SGI/IZO (SGIker) of UPV/EHU and European funding (ERDF and ESF). Financial support comes from UPV/EHU (PES14/35), Eusko Jaurlaritza (IT588-13) and the Spanish Ministerio de Ciencia e Innovación (MINECO/FEDER) (CTQ2015-67608-P). GdT thanks the European Union for a Ph.D. grant inside the ITN-TCCM-642294 program

BRIEF OBSERVATION Aluminum in Tobacco and Cannabis and Smoking-Related Disease

ABSTRACT PURPOSE: The study aimed to confirm the very high content of aluminum in tobacco and cannabis and to provide for the first time evidence that such aluminum could be biologically available. METHODS: Complete digestion of tobacco and cannabis was achieved using a 50:50 mixture of 14 M HNO 3 and 0.1 M NaF. Total Al in digests was measured by graphite furnace atomic absorption spectrometry. A bespoke cigarette smoking apparatus was used to determine if aluminum in active or passive tobacco/cannabis smoke would be trapped by a surrogate lung fluid. RESULTS: The aluminum content of tobacco and cannabis was confirmed to be high, as much as 0.37% and 0.4% by weight respectively. Aluminum in tobacco and cannabis smoke, whether actively (drawn) or passively inhaled, was shown to accumulate significantly in surrogate lung fluids, thus demonstrating its potential biological availability. CONCLUSIONS: Active and passive smoking of tobacco or cannabis will increase the body burden of aluminum and thereby contribute to respiratory, neurological and other smoking-related disease