Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: Development of a potent and CNS penetrant [3.1.0]-based lead

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]​-​based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclin. model of schizophrenia (prepulse inhibition)​.

Design and Development of a Film-based Intervention about Teenage Men and Unintended Pregnancy: Applying the Medical Research Council Framework in Practice

Following the UK Medical Research Council’s (MRC) guidelines for the development and evaluation of complex interventions, this study aimed to design, develop and optimise an educational intervention about young men and unintended teenage pregnancy based around an interactive film. The process involved identification of the relevant evidence base, development of a theoretical understanding of the phenomenon of unintended teenage pregnancy in relation to young men, and exploratory mixed methods research. The result was an evidence-based, theory-informed, user-endorsed intervention designed to meet the much neglected pregnancy education needs of teenage men and intended to increase both boys’ and girls’ intentions to avoid an unplanned pregnancy during adolescence. In prioritising the development phase, this paper addresses a gap in the literature on the processes of research-informed intervention design. It illustrates the application of the MRC guidelines in practice while offering a critique and additional guidance to programme developers on the MRC prescribed processes of developing interventions. Key lessons learned were: 1) know and engage the target population and engage gatekeepers in addressing contextual complexities; 2) know the targeted behaviours and model a process of change; and 3) look beyond development to evaluation and implementation.

Exploring molecular recognition pathways in one- and two-component gels formed by dendritic lysine-based gelators

This paper provides an integrated overview of the factors which control gelation in a family of dendritic gelators based on lysine building blocks. In particular, we establish that higher generation systems are more effective gelators, amide linkages in the dendron are better than carbamates, and long alkyl chain surface groups and a carboxylic acid at the focal point enhance gelation. The gels are best formed in relatively low polarity solvents with no hydrogen bond donor ability and limited hydrogen bond acceptor capacity. The dendrons with acid groups at the focal point can form two component gels with diaminododecane, and in this case, it is the lower generation dendrons which can avoid steric hindrance and form more effective gels. The stereochemistry of lysine is crucial in self-assembly, with opposite enantiomers disrupting each other's molecular recognition pathways. For the two-component system, stoichiometry is key, if too much diamine is present, dendron-stabilised microcrystals of the diamine begin to form. Interestingly, gelation still occurs in this case, and the systems with amides/alkyl chains are more effective gels, as a consequence of enhanced dendron-dendron intermolecular interactions allowing the microcrystals to form an interconnected network.

Development of Novel Activity-Based Probes for the Detection of Serine Proteases

Cystic Fibrosis (CF) is a genetic disease featuring a chronic cycle of inflammation and infection in the airways of sufferers. Mutations lead to altered ion transport, which in turn causes dehydrated airways and reduced mucociliary clearance which predisposes the patient to infection, resulting in a severe immune response and tissue destruction (1). Airway dehydration is primarily caused by the hyperabsorption of sodium by the epithelial sodium channel (ENaC) (2). ENaC is activated by the action of a number of predominantly trypsin-like Channel Activating Proteases (CAPs) including prostasin, matriptase and furin (3). Additional proteases known to activate ENaC include human airway trypsin (3), plasmin, neutrophil elastase and chymotrypsin (4).

Activity profiling is a valuable technique which involves the use of small inhibitory molecules called Activity-Based Probes (ABPs) which can be used to covalently label the active site of proteases and provide a range of information regarding its structure, catalytic mechanism, location and function within biological systems. The development of novel ABPs for CAPs, would enhance understanding of the role of these proteases in CF airways disease and in particular their role in ENaC activation and airway dehydration. This project investigates the application of a range of novel broad-spectrum ABPs targeting the various subclasses of serine proteases, to include those proteases involved in ENaC activation. Additionally, the application of more selective ABPs in detecting specific serine proteases is investigated.

Compounds were synthesised by Solid-Phase Peptide Synthesis (SPPS) using a standard Fmoc/tBu strategy. Kinetic evaluation of synthesised ABPs against various serine proteases was determined by fluorogenic steady-state enzyme assays. Furthermore, application of ABPs and confirmation of irreversible nature of the compounds was carried out through SDS-PAGE and electroblotting techniques.

Synthesised compounds showed potent irreversible inhibition of serine proteases within their respective targeting class (NAP855 vs Trypsin k3/Ki = 2.60 x 106 M-1 min-1, NFP849 vs Chymotrypsin k3/Ki = 1.28 x 106 M-1 min-1 and NVP800 vs Neutrophil Elastase k3/Ki = 6.41 x 104 M-1 min-1). Furthermore ABPs showed little to no cross-reactivity between classes and so display selectivity between classes. The irreversible nature of compounds was further demonstrated through labelling of proteases, followed by separation and detection via SDS-PAGE and electroblotting techniques. Targeted labelling of active proteases only, was demonstrated by failure of ABPs to detect previously inactivated proteases. Extension of the substrate recognition site within probes resulted in an increased potency and selectivity in the detection of the target proteases. Successful detection of neutrophil elastase from CF sputum samples by NVP800, demonstrated the application of compounds within biological samples and their potential use in identifying further proteases involved in ENaC activation and airway dehydration in CF patients.

Development of a Polymer-carbon Nanotubes based Economic Solar Collector

A low cost solar collector was developed by using polymeric components as opposed to metal and glass components of traditional solar collectors. In order to utilize polymers for the absorber of the solar collector, Carbon Nanotubes (CNT) has been added as a filler to improve the thermal conductivity and the solar absorptivity of polymers. The solar collector was designed as a multi-layer construction with considering the economic manufacturing. Through the mathematical heat transfer analysis, the performance and characteristics of the designed solar collector have been estimated. Furthermore, the prototypes of the proposed system were built and tested at a state-of-the-art solar simulator facility to evaluate the actual performance of the developed solar collector. The cost-effective polymer-CNT solar collector, which achieved efficiency as much as that of a conventional glazed flat plate solar panel, has been successfully developed.

RNA interference in adult Ascaris suum - an opportunity for the development of a functional genomics platform that supports organism-, tissue- and cell-based biology in a nematode parasite

The sustainable control of animal parasitic nematodes requires the development of efficient functional genomics platforms to facilitate target validation and enhance anthelmintic discovery. Unfortunately, the utility of RNA interference (RNAi) for the validation of novel drug targets in nematode parasites remains problematic. Ascaris suum is an important veterinary parasite and a zoonotic pathogen. Here we show that adult A. suum is RNAi competent, and highlight the induction, spread and consistency of RNAi across multiple tissue types. This platform provides a new opportunity to undertake whole organism-, tissue- and cell-level gene function studies to enhance target validation processes for nematode parasites of veterinary/medical significance.

Synchrophasor-Based Islanding Detection for Distributed Generation Systems Using Systematic Principal Component Analysis Approaches

Systematic principal component analysis (PCA) methods are presented in this paper for reliable islanding detection for power systems with significant penetration of distributed generations (DGs), where synchrophasors recorded by Phasor Measurement Units (PMUs) are used for system monitoring. Existing islanding detection methods such as Rate-of-change-of frequency (ROCOF) and Vector Shift are fast for processing local information, however with the growth in installed capacity of DGs, they suffer from several drawbacks. Incumbent genset islanding detection cannot distinguish a system wide disturbance from an islanding event, leading to mal-operation. The problem is even more significant when the grid does not have sufficient inertia to limit frequency divergences in the system fault/stress due to the high penetration of DGs. To tackle such problems, this paper introduces PCA methods for islanding detection. Simple control chart is established for intuitive visualization of the transients. A Recursive PCA (RPCA) scheme is proposed as a reliable extension of the PCA method to reduce the false alarms for time-varying process. To further reduce the computational burden, the approximate linear dependence condition (ALDC) errors are calculated to update the associated PCA model. The proposed PCA and RPCA methods are verified by detecting abnormal transients occurring in the UK utility network.

A novel radial basis function neural network principal component analysis scheme for PMU-based wide-area power system monitoring

A novel model-based principal component analysis (PCA) method is proposed in this paper for wide-area power system monitoring, aiming to tackle one of the critical drawbacks of the conventional PCA, i.e. the incapability to handle non-Gaussian distributed variables. It is a significant extension of the original PCA method which has already shown to outperform traditional methods like rate-of-change-of-frequency (ROCOF). The ROCOF method is quick for processing local information, but its threshold is difficult to determine and nuisance tripping may easily occur. The proposed model-based PCA method uses a radial basis function neural network (RBFNN) model to handle the nonlinearity in the data set to solve the no-Gaussian issue, before the PCA method is used for islanding detection. To build an effective RBFNN model, this paper first uses a fast input selection method to remove insignificant neural inputs. Next, a heuristic optimization technique namely Teaching-Learning-Based-Optimization (TLBO) is adopted to tune the nonlinear parameters in the RBF neurons to build the optimized model. The novel RBFNN based PCA monitoring scheme is then employed for wide-area monitoring using the residuals between the model outputs and the real PMU measurements. Experimental results confirm the efficiency and effectiveness of the proposed method in monitoring a suite of process variables with different distribution characteristics, showing that the proposed RBFNN PCA method is a reliable scheme as an effective extension to the linear PCA method.

Solubility parameter based screening methods for early stage formulation development of itraconazole amorphous solid dispersions

Objectives: This article uses conventional and newly extended solubility parameter (δ) methods to identify polymeric materials capable of forming amorphous dispersions with itraconazole (itz). Methods: Combinations of itz and Soluplus, Eudragit E PO (EPO), Kollidon 17PF (17PF) or Kollidon VA64 (VA64) were prepared as amorphous solid dispersions using quench cooling and hot melt extrusion. Storage stability was evaluated under a range of conditions using differential scanning calorimetry and powder X-ray diffraction. Key findings: The rank order of itz miscibility with polymers using both conventional and novel δ-based approaches was 17PF > VA64 > Soluplus > EPO, and the application of the Flory–Huggins lattice model to itz–excipient binary systems corroborated the findings. The solid-state characterisation analyses of the formulations manufactured by melt extrusion correlated well with pre-formulation screening. Long-term storage studies showed that the physical stability of 17PF/vitamin E TPGS–itz was poor compared with Soluplus and VA64 formulations, and for EPO/itz systems variation in stability may be observed depending on the preparation method. Conclusion: Results have demonstrated that although δ-based screening may be useful in predicting the initial state of amorphous solid dispersions, assessment of the physical behaviour of the formulations at relevant temperatures may be more appropriate for the successful development of commercially acceptable amorphous drug products.

Finance, social economics and community development

The last three decades have seen social enterprises in the United Kingdom pushed to the forefront of welfare delivery, workfare and area-based regeneration. For critics, this is repositioning the sector around a neoliberal politics that privileges marketization, state roll-back and disciplining community groups to become more self-reliant. Successive governments have developed bespoke products, fiscal instruments and intermediaries to enable and extend the social finance market. Such assemblages are critical to roll-out tactics, but they are also necessary and useful for more reformist understandings of economic alterity. The issue is not social finance itself but how it is used, which inevitably entangles social enterprises in a form of legitimation crises between the need to satisfy financial returns and at the same time keep community interests on board. This paper argues that social finance, how it is used, politically domesticated and achieves re-distributional outcomes is a necessary component of counter-hegemonic strategies. Such assemblages are as important to radical community development as they are to neoliberalism and the analysis concludes by highlighting the need to develop a better understanding of finance, the ethics of its use and tactical compromises in scaling it as an alternative to public and private markets.