Spin-enhanced nanodiamond biosensing for ultrasensitive diagnostics

The quantum spin properties of nitrogen-vacancy defects in diamond enable diverse applications in quantum computing and communications. However, fluorescent nanodiamonds also have attractive properties for in vitro biosensing, including brightness, low cost and selective manipulation of their emission. Nanoparticle-based biosensors are essential for the early detection of disease, but they often lack the required sensitivity. Here we investigate fluorescent nanodiamonds as an ultrasensitive label for in vitro diagnostics, using a microwave field to modulate emission intensity and frequency-domain analysis to separate the signal from background autofluorescence, which typically limits sensitivity. Focusing on the widely used, low-cost lateral flow format as an exemplar, we achieve a detection limit of 8.2 × 10−19 molar for a biotin–avidin model, 105 times more sensitive than that obtained using gold nanoparticles. Single-copy detection of HIV-1 RNA can be achieved with the addition of a 10-minute isothermal amplification step, and is further demonstrated using a clinical plasma sample with an extraction step. This ultrasensitive quantum diagnostics platform is applicable to numerous diagnostic test formats and diseases, and has the potential to transform early diagnosis of disease for the benefit of patients and populations

Continuous flow synthesis of ultrasmall gold nanoparticles in a microreactor using trisodium citrate and their SERS performance

Ultrasmall gold nanoparticles were synthesized without strong capping agents by using a capillary-based continuous flow system. A mixture of gold(III) chloride trihydrate and trisodium citrate flowed through capillaries at elevated temperature. The effect of capillary material (polytetrafluoroethylene, fluorinated ethylene propylene, polyetheretherketone, fused silica), surface-to-volume ratio (capillary internal diameter 0.3–1 mm), average residence time (1.5–30 min) and temperature (70–100 °C) were investigated. At a flow rate of 0.006 ml/min (residence time 30 min), 100 °C, 275 kPa back pressure, citrate/gold molar ratio 3.15 and using PTFE capillary tubing with an inner diameter of 0.3 mm, very small (1.9 ± 0.2 nm) nanoparticles were obtained. For comparison, experiments were also performed under the same experimental conditions, but in slug flow using octane as segmenting fluid, thus isolating the reactants from the tubing wall. The synthesized particles were 17.4 ± 1.4 nm for segmented flow, demonstrating the important effect of the capillary wall surface. The performance of these citrate-capped gold nanoparticles was tested for Surface-Enhanced Raman Scattering (SERS). The average enhancement factor (AEF) of 2 nm gold nanoparticles capped by citrate from our work (AEF = 1.54 × 108) was nearly double when compared to 2 nm phosphate-capped commercial gold nanoparticles (AEF = 7.34 × 107). The adsorption of analyte molecules onto citrate-capped gold surface was easier due to the weaker binding strength of the carboxylate ligand and more hotspots formed with narrower gaps between neighbouring particles, giving rise to improved enhancement. This work has been selected by the Editors as a Featured Cover Article for this issue

Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric aggregates

The presence of oligomeric aggregates, which is often observed during the process of amyloid formation, has recently attracted much attention since it has been associated with neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. We provide a description of a sequence-indepedent mechanism by which polypeptide chains aggregate by forming metastable oligomeric intermediate states prior to converting into fibrillar structures. Our results illustrate how the formation of ordered arrays of hydrogen bonds drives the formation of beta-sheets within the disordered oligomeric aggregates that form early under the effect of hydrophobic forces. Initially individual beta-sheets form with random orientations, which subsequently tend to align into protofilaments as their lengths increases. Our results suggest that amyloid aggregation represents an example of the Ostwald step rule of first order phase transitions by showing that ordered cross-beta structures emerge preferentially from disordered compact dynamical intermediate assemblies.Comment: 14 pages, 4 figure

Co-opetition models for governing professional football

In recent years, models for co-creating value in a business-to-business context have often been examined with the aim of studying the strategies implemented by and among organisations for competitive and co-operative purposes. The traditional concepts of competition and co-operation between businesses have now evolved, both in terms of the sector in which the businesses operate and in terms of the type of goods they produce. Many researchers have, in recent times, investigated the determinants that can influence the way in which the model of co-opetition can be applied to the football world. Research interest lies in the particular features of what makes a good football. In this paper, the aim is to conduct an analysis of the rules governing the “football system”, while also looking at the determinants of the demand function within football entertainment. This entails applying to football match management the co-opetition model, a recognised model that combines competition and co-operation with the view of creating and distributing value. It can, therefore, be said that, for a spectator, watching sport is an experience of high suspense, and this suspense, in turn, depends upon the degree of uncertainty in the outcome. It follows that the rules ensuring that both these elements can be satisfied are a fertile ground for co-operation between clubs, as it is in the interest of all stakeholders to offer increasingly more attractive football, in comparison with other competing products. Our end purpose is to understand how co-opetition can be achieved within professional football

A Condensation-Ordering Mechanism in Nanoparticle-Catalyzed Peptide Aggregation

Nanoparticles introduced in living cells are capable of strongly promoting the aggregation of peptides and proteins. We use here molecular dynamics simulations to characterise in detail the process by which nanoparticle surfaces catalyse the self- assembly of peptides into fibrillar structures. The simulation of a system of hundreds of peptides over the millisecond timescale enables us to show that the mechanism of aggregation involves a first phase in which small structurally disordered oligomers assemble onto the nanoparticle and a second phase in which they evolve into highly ordered beta-sheets as their size increases

Plasma proteins predict conversion to dementia from prodromal disease.

PublishedJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tBACKGROUND: The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia. METHODS: Three multicenter cohorts of cognitively healthy elderly, mild cognitive impairment (MCI), and AD participants with standardized clinical assessments and structural neuroimaging measures were used. Twenty-six candidate proteins were quantified in 1148 subjects using multiplex (xMAP) assays. RESULTS: Sixteen proteins correlated with disease severity and cognitive decline. Strongest associations were in the MCI group with a panel of 10 proteins predicting progression to AD (accuracy 87%, sensitivity 85%, and specificity 88%). CONCLUSIONS: We have identified 10 plasma proteins strongly associated with disease severity and disease progression. Such markers may be useful for patient selection for clinical trials and assessment of patients with predisease subjective memory complaints.Medical Research Council (MRC)Alzheimer’s Research UKThe National Institute for Health Research (NIHR) Biomedical Research CentreBiomedical Research Unit for DementiaAddNeuroMed through the EU FP6 programInnovative Medicines Initiative Joint Undertaking under an EMIF grantEuropean Union’s Seventh Framework Programme (FP7/2007-2013

Low-risk persistent gestational trophoblastic disease treated with low-dose methotrexate: efficacy, acute and long-term effects

The aim of this study was to evaluate the efficacy and toxicity of low-dose methotrexate with folinic acid rescue in a large series of consecutively treated patients with low-risk persistent gestational trophoblastic disease. Between January 1987 and December 2000, 250 patients were treated with intramuscular methotrexate (50 mg on alternate days 1, 3, 5, 7) with folinic acid (7.5 mg orally on alternate days 2, 4, 6, 8) rescue. The overall complete response rate without recurrence was 72% for first-line treatment and 95% for those who required second-line chemotherapy. Eight women (3.2%) had recurrence following remission and two (0.8%) had new moles. Two women (0.8%) died of their disease giving an overall cure of 99%. Only 10 women (4%) experienced grade III/IV toxicity during the first course of treatment and 13 women (5.2%) subsequently. Toxicity included mucositis and stomatitis, pleuritic chest pain, thrombocytopenia, uterine bleeding, abdominal pain, liver function changes, rash and pericardial effusion. A total of 59 women (23.6%) required second-line chemotherapy; 48 women had methotrexate resistance, eight had methotrexate toxicity and an empirical decision to change therapy was made in three. In all, 11 women (4.4%) had a hysterectomy before, during or after treatment; 141 women (56.4%) became pregnant following treatment: in 128 (90.7%), the outcome was successful. Methotrexate with folinic acid rescue is an effective treatment for low-risk persistent trophoblastic disease. It has minimal severe toxicity, excellent cure rates and does not appear to affect fertility

Finite Size Effects in Simulations of Protein Aggregation

It is becoming increasingly clear that the soluble protofibrillar species that proceed amyloid fibril formation are associated with a range of neurodegenerative disorders such as Alzheimer's and Parkinson diseases. Computer simulations of the processes that lead to the formation of these oligomeric species are starting to make significant contributions to our understanding of the determinants of protein aggregation. We simulate different systems at constant concentration but with a different number of peptides and we study the how the finite number of proteins affects the underlying free energy of the system and therefore the relative stability of the species involved in the process. If not taken into account, this finite size effect can undermine the validity of theoretical predictions regarding the relative stability of the species involved and the rates of conversion from one to the other. We discuss the reasons that give rise to this finite size effect form both a probabilistic and energy fluctuations point of view and also how this problem can be dealt by a finite size scaling analysis

Inversion of the balance between hydrophobic and hydrogen bonding interactions in protein folding and aggregation.

Identifying the forces that drive proteins to misfold and aggregate, rather than to fold into their functional states, is fundamental to our understanding of living systems and to our ability to combat protein deposition disorders such as Alzheimer's disease and the spongiform encephalopathies. We report here the finding that the balance between hydrophobic and hydrogen bonding interactions is different for proteins in the processes of folding to their native states and misfolding to the alternative amyloid structures. We find that the minima of the protein free energy landscape for folding and misfolding tend to be respectively dominated by hydrophobic and by hydrogen bonding interactions. These results characterise the nature of the interactions that determine the competition between folding and misfolding of proteins by revealing that the stability of native proteins is primarily determined by hydrophobic interactions between side-chains, while the stability of amyloid fibrils depends more on backbone intermolecular hydrogen bonding interactions