Determination of boron in serum, plasma and urine by inductively coupled plasma mass spectrometry (ICP-MS). Use of mannitol-ammonia as diluent and for eliminating memory effect

A rapid and accurate method has been developed for the determination of boron in serum, plasma and urine by inductively coupled plasma mass spectrometry. The memory effects of B were examined using different diluents/rinse solutions, including water, nitric acid, Triton X-100, ammonia and mannitol in water, in nitric acid and in ammonia. A combination of ammonia with mannitol, as both diluent and flush solution, gave the best precision, the minimum memory effect and the lowest background. A sample dilution of 20-fold was simply made for serum and plasma and 100-fold for urine for determination with a single calibration curve. Beryllium was employed as the internal standard to control matrix effects and to compensate for possible fluctuation and instrument drift. The isotope B-10(+) was utilised to avoid spectral overlap by the intense C-12(+) isotope. The final solution of blank, standards and samples contained 0.25% w/v mannitol, 0.1 M ammonia and 20 ng ml(-1) of Be. Six samples, including human and horse serum, human and horse plasma, and human urine, were analysed to test the reliability of the method. A limit of detection (3 sigma) of 0.015 ng ml(-1) was obtained and the recoveries of spiked boron (two spiking levels for each matrix) from the selected samples ranged from 98% to 104%. Much higher concentrations of B in urine (approximate to 1 mu g ml(-1)) were found compared to those in serum and plasma samples (32.8-61.1 ng ml(-1))

Lipid peptide nanocomplexes for gene delivery and magnetic resonance imaging in the brain.

Gadolinium-labelled nanocomplexes offer prospects for the development of real-time, non-invasive imaging strategies to visualise the location of gene delivery by MRI. In this study, targeted nanoparticle formulations were prepared comprising a cationic liposome (L) containing a Gd-chelated lipid at 10, 15 and 20% by weight of total lipid, a receptor-targeted, DNA-binding peptide (P) and plasmid DNA (D), which electrostatically self-assembled into LPD nanocomplexes. The LPD formulation containing the liposome with 15% Gd-chelated lipid displayed optimal peptide-targeted, transfection efficiency. MRI conspicuity peaked at 4h after incubation of the nanocomplexes with cells, suggesting enhancement by cellular uptake and trafficking. This was supported by time course confocal microscopy analysis of transfections with fluorescently-labelled LPD nanocomplexes. Gd-LPD nanocomplexes delivered to rat brains by convection-enhanced delivery were visible by MRI at 6 h, 24 h and 48 h after administration. Histological brain sections analysed by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) confirmed that the MRI signal was associated with the distribution of Gd(3+) moieties and differentiated MRI signals due to haemorrhage. The transfected brain cells near the injection site appeared to be mostly microglial. This study shows the potential of Gd-LPD nanocomplexes for simultaneous delivery of contrast agents and genes for real-time monitoring of gene therapy in the brain

Lambda and Antilambda polarization from deep inelastic muon scattering

We report results of the first measurements of Lambda and Antilambda polarization produced in deep inelastic polarized muon scattering on the nucleon. The results are consistent with an expected trend towards positive polarization with increasing x_F. The polarizations of Lambda and Antilambda appear to have opposite signs. A large negative polarization for Lambda at low positive x_F is observed and is not explained by existing models.A possible interpretation is presented.Comment: 9 pages, 2 figure

Vaccines against toxoplasma gondii : challenges and opportunities

Development of vaccines against Toxoplasma gondii infection in humans is of high priority, given the high burden of disease in some areas of the world like South America, and the lack of effective drugs with few adverse effects. Rodent models have been used in research on vaccines against T. gondii over the past decades. However, regardless of the vaccine construct, the vaccines have not been able to induce protective immunity when the organism is challenged with T. gondii, either directly or via a vector. Only a few live, attenuated T. gondii strains used for immunization have been able to confer protective immunity, which is measured by a lack of tissue cysts after challenge. Furthermore, challenge with low virulence strains, especially strains with genotype II, will probably be insufficient to provide protection against the more virulent T. gondii strains, such as those with genotypes I or II, or those genotypes from South America not belonging to genotype I, II or III. Future studies should use animal models besides rodents, and challenges should be performed with at least one genotype II T. gondii and one of the more virulent genotypes. Endpoints like maternal-foetal transmission and prevention of eye disease are important in addition to the traditional endpoint of survival or reduction in numbers of brain cysts after challenge

Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc1 complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30 nM) and cysts (IC50, 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc1 complex Qi site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites

Author Correction: New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

Correction to: Scientific Reports https://doi.org/10.1038/srep29179, published online 14 July 201

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

The curation of Mental Health Recovery Narrative Collections: systematic review and qualitative synthesis

Background: Mental health recovery narratives are first-person lived experience accounts of recovery from mental health problems, which refer to events or actions over a period of time. They are readily available, either individually, or in collections of recovery narratives published in books, health service booklets or online. Collection of recovery narratives have been used in a range of mental health interventions, and organisations or individuals who curate collections can therefore influence how mental health problems are seen and understood. No systematic review has been conducted of research into curatorial decision making. Objective: To produce a conceptual framework identifying and categorising decisions made in the curation of mental health recovery narrative collections. Methods: A conceptual framework was produced through a systematic review and qualitative evidence synthesis. Research articles were identified through searching of bibliographic databases (n=13), indexes of specific journals (n=3) and grey literature repositories (n=4). Informal documents presenting knowledge about curation was identified from editorial chapters of electronically-available books (n=50), public documents provided by online collections (n=50), and prefaces of health-service booklets identified through expert consultation (n=3). Narrative summaries of included research articles were produced. A qualitative evidence synthesis was conducted on all included documents through inductive thematic analysis. Sub-group analyses were conducted to identify differences in curatorial concerns between online and printed collections. The review protocol was pre-registered (PROSPERO CRD42018086997). Results: 5,410 documents were screened. 23 documents were included. These comprised 1 research publication and 22 informal documents. Nine higher level themes were identified, which considered the intended purpose and audience of the collection, how to support safety of narrators, recipients and third parties, the processes of collecting, selecting, organising and presenting recovery narratives, ethical and legal issues around collections, and the relationship to society of the collection. Online collections placed more emphasis on (1) providing benefits for narrators (2) safety for recipients. Printed collections placed more emphasis on the ordering of narrative within printed material, and the political context. Conclusions: Only one research article was identified, despite extensive searches, and hence this review has revealed a lack of peer-reviewed empirical research regarding the curation of recovery narrative collections. The conceptual framework can be used as a preliminary version of reporting guidelines for use when reporting on healthcare interventions which make use of narrative collections. It provides a theory base to inform the development of new narrative collections for use in complex mental health interventions. Collections can serve as a mechanism for supporting collective rather than individual discourses around mental health

Evaluation of a 'virtual' approach to commissioning health research

BACKGROUND: The objective of this study was to evaluate the implementation of a 'virtual' (computer-mediated) approach to health research commissioning. This had been introduced experimentally in a DOH programme – the 'Health of Londoners Programme' – in order to assess whether is could enhance the accessibility, transparency and effectiveness of commissioning health research. The study described here was commissioned to evaluate this novel approach, addressing these key questions. METHODS: A naturalistic-experimental approach was combined with principles of action research. The different commissioning groups within the programme were randomly allocated to either the traditional face-to-face mode or the novel 'virtual' mode. Mainly qualitative data were gathered including observation of all (virtual and face-to-face) commissioning meetings; semi-structured interviews with a purposive sample of participants (n = 32/66); structured questionnaires and interviews with lead researchers of early commissioned projects. All members of the commissioning groups were invited to participate in collaborative enquiry groups which participated actively in the analysis process. RESULTS: The virtual process functioned as intended, reaching timely and relatively transparent decisions that participants had confidence in. Despite the potential for greater access using a virtual approach, few differences were found in practice. Key advantages included physical access, a more flexible and extended time period for discussion, reflection and information gathering and a more transparent decision-making process. Key challenges were the reduction of social cues available in a computer-mediated medium that require novel ways of ensuring appropriate dialogue, feedback and interaction. However, in both modes, the process was influenced by a range of factors and was not technology driven. CONCLUSION: There is potential for using computer-mediated communication within the research commissioning process. This may enhance access, effectiveness and transparency of decision-making but further development is needed for this to be fully realised, including attention to process as well as the computer-mediated medium