Electrostatically gated membrane permeability in inorganic protocells

Although several strategies are now available to produce functional microcompartments analogous to primitive cell-like structures, little progress has been made in generating protocell constructs with self-controlled membrane permeability. Here we describe the preparation of water-dispersible colloidosomes based on silica nanoparticles and delineated by a continuous semipermeable inorganic membrane capable of self-activated, electrostatically gated permeability. We use crosslinking and covalent grafting of a pH-responsive copolymer to generate an ultrathin elastic membrane that exhibits selective release and uptake of small molecules. This behaviour, which depends on the charge of the copolymer coronal layer, serves to trigger enzymatic dephosphorylation reactions specifically within the protocell aqueous interior. This system represents a step towards the design and construction of alternative types of artificial chemical cells and protocell models based on spontaneous processes of inorganic self-organization

Responsive, functional materials from self-stabilising and reactive branched addition co-polymers

A one-component emulsion templating strategy for the preparation of inorganic-organic encapsulated droplets and hollow capsules has been developed. The process exploits, and relies on, both branched addition co-polymer architectures and compositions, which provide simultaneous properties of emulsion droplet steric-stabilisation and cross-linking function. It was demonstrated that high yielding encapsulation of different hydrophobic actives was successful whilst retaining the structural integrity of the capsule compartments. Responsive capsule surfaces and shell/membrane properties with pre-determined complex functionalities were demonstrated. The incorporation of chemical functionality within the reactive branched addition co-polymer allowed higher order responsive structures to be formed. These materials have been shown to be highly useful in the preparation of large associated aggregates which can be loaded with numerous payloads. The encapsulation of both hydrophobic dyes and an oil-soluble polymer was illustrated. Protocell constructs with pH-mediated, electrostatically gated permeability were prepared by covalently grafting a multi-responsive functional terpolymer to the outer surface of a cross-linked membrane of silica nanoparticle-based colloidosomes. Terpolymer grafted membrane functionality-mediated uptake and release of small molecules from the colloidosomes was demonstrated.Open Acces

Radiation doses and associated risks from x-ray guided cardiac catheterization procedures in children and young adults

PhD ThesisCardiac catheterizations are an essential procedure in the management of patients with congenital and acquired heart conditions. However, associated radiation doses are often high, raising concerns over potentially increased cancer risks. Neither the radiation doses, nor the associated risks, have been adequately investigated in young people undergoing these procedures. A cohort was established of around 13,500 patients aged under 22 years who have undergone cardiac catheterizations in England. Organ doses were estimated based on a dosimetry system utilising data from Monte Carlo simulations. Doses were highest for the lungs (median: 17.6 millisieverts, mSv) and heart (13.6 mSv), while doses to bone marrow (2.6 mSv) and the thyroid (0.7 mSv) were relatively low. Radiation doses have fallen by a factor of up to ten during the study period. The results were compared to equivalent figures derived from physical measurements. Uncertainties in dose estimates were calculated. These were around ±30%, though were potentially much higher for breast dose. The risk of cancer in relation to estimated doses was calculated using BEIR VII risk models. For examinations conducted using modern equipment, these risks are around 1 in 1700. A small epidemiological analysis was performed, suggesting a nearly threefold increased risk of cancer in the cohort, compared to the general UK population. There are a number of reasons to suggest that this increase was primarily not related to radiation exposure, most notably the large impact of transplantation and likely associated immunosuppressant use. Despite the high cancer incidence, the overall survival in the cohort was high, at around 91% after 30 years. Conclusion: The study provides the first large scale estimation of organ doses from cardiac catheterizations among this age group. Rates of cancer among this patient group are high, although this is appears to be mostly due to factors other than radiation exposure.British Heart Foundatio

Molecular and genetic analysis of a new insertional mutation in the TgN(Imorpk)73Rpw line of mice that causes polycystic kidney disease.

A line of transgenic mice has been generated that contains an insertional mutation causing a phenotype similar to human autosomal recessive polycystic kidney disease. TgN737Rpw homozygotes display a complex phenotype that includes bilateral polycystic kidneys and an unusual liver lesion. The mutant locus was cloned and characterized through use of the transgene as a molecular marker. A deletion of no more than 2.77 kb, and the insertion of 21.0 kb of genomic mouse DNA that stably cointegrated with the transgene, occurred at the integration site. An extended physical analysis of the mutant locus, which included pulsed field gel electrophoresis (PFGE), detected no additional rearrangements beyond the insertion site. A candidate polycystic kidney disease (PKD) gene was identified whose structure and expression is directly associated with the mutant locus. A cDNA derived from this gene predicted a peptide containing multiple repeats of a degenerate 34-amino acid motif that defines members of the tetratricopeptide repeat (TPR) gene family, which are often involved in cell cycle control. The TgN737RpwcDNA hybridizes to multiple transcripts during embryogenesis and in all wild-type adult tissues examined, and a cDNA isolated from embryonic day 14.5 may represent an alternatively-spliced form of the TgN737Rpw gene. Physical mapping data and the gene\u27s expression pattern suggest that the mutant phenotype in TgN73 7Rpw mice is due to the disruption of a single, ubiquitously-expressed gene that functions during embryonic development and into adulthood. The TgN737Rpw mutation is the first candidate gene accessed at the molecular level in any PKD model, and does not appear to be allelic with existing mouse models of PKD. The TgN737Rpw gene also represents the first in vivo TPR mutation in vertebrates. Moreover, the identification of the homologous human gene will permit a thorough molecular study of whether this gene is directly associated with any of the various forms of PKD in humans

Responsive feeding: establishing healthy eating behaviour early on in life

Responsive feeding (RF) refers to a reciprocal relationship between an infant or child and his or her caregiver that is characterised by the child communicating feelings of hunger and satiety through verbal or nonverbal cues, followed by an immediate response from the caregiver. The response includes the provision of appropriate and nutritious food in a supportive manner, while maintaining an appropriate feeding environment. The literature indicates that RF is the foundation for the development of healthy eating behaviour and optimal skills for self-regulation and self-control of food intake. Therefore, practising RF is associated with ideal growth standards, optimal nutrient intake and long-term regulation of weight. On the other hand, nonresponsive feeding (NRF) practices are associated with feeding problems and the development of under- or overnutrition. Different types of NRF behaviour have been described, where the caregiver is either uninvolved during meals, too restrictive or controlling, or allows the child to control mealtimes. Consequently, mealtimes may become cumbersome, characterised by inconsistent, nonresponsive interaction, and may result in a relationship that is lacking in trust. The effects of RF and NRF are reviewed in this article and the practical guideline to “Feed slowly and patiently, and encourage your baby to eat, but do not force them” is suggested as appropriate for inclusion in the proposed South African paediatric Food Based Dietary Guidelines. It is also acknowledged that RF practices are best established when mothers choose to breastfeed on demand, as they are less controlling and moreresponsive to their infants’ internal hunger and satiety cues

A simple Bayesian linear excess relative risk model

A new Bayesian Poisson relative risk model is proposed for displaying the excess relative risk associated to a unique exposure as a probability distribution in a closed form. The background risk can be modelled by a unique two levels factor, e.g. gender or smoking status.Cancer Research U

Accelerated Model Checking of Parametric Markov Chains

Parametric Markov chains occur quite naturally in various applications: they can be used for a conservative analysis of probabilistic systems (no matter how the parameter is chosen, the system works to specification); they can be used to find optimal settings for a parameter; they can be used to visualise the influence of system parameters; and they can be used to make it easy to adjust the analysis for the case that parameters change. Unfortunately, these advancements come at a cost: parametric model checking is---or rather was---often slow. To make the analysis of parametric Markov models scale, we need three ingredients: clever algorithms, the right data structure, and good engineering. Clever algorithms are often the main (or sole) selling point; and we face the trouble that this paper focuses on -- the latter ingredients to efficient model checking. Consequently, our easiest claim to fame is in the speed-up we have often realised when comparing to the state of the art

Anonymising Clinical Data for Secondary Use

Secondary use of data already collected in clinical studies has become more and more popular in recent years, with the commitment of the pharmaceutical industry and many academic institutions in Europe and the US to provide access to their clinical trial data. Whilst this clearly provides societal benefit in helping to progress medical research, this has to be balanced against protection of subjects' privacy. There are two main scenarios for sharing subject data: within Clinical Study Reports and Individual Patient Level Data, and these scenarios have different associated risks and generally require different approaches. In any data sharing scenario, there is a trade-off between data utility and the risk of subject re-identification, and achieving this balance is key. Quantitative metrics can guide the amount of de-identification required and new technologies may also start to provide alternative ways to achieve the risk-utility balance.Comment: 25 page