Visualization of membrane localization and the functional state of CBR pools using matched agonist and inverse agonist probe pairs.

The diversity of physiological roles of the endocannabinoid system has turned it into an attractive yet elusive therapeutic target. However, chemical probes with various functionalities could pave the way for a better understanding of the endocannabinoid system at the cellular level. Notably, inverse agonists of CBR - a key receptor of the endocannabinoid system - lagged behind despite the evidence regarding the therapeutic potential of its antagonism.

Krein support vector machine classification of antimicrobial peptides.

Antimicrobial peptides (AMPs) represent a potential solution to the growing problem of antimicrobial resistance, yet their identification through wet-lab experiments is a costly and time-consuming process. Accurate computational predictions would allow rapid screening of candidate AMPs, thereby accelerating the discovery process. Kernel methods are a class of machine learning algorithms that utilise a kernel function to transform input data into a new representation.

A mechanoresponsive nano-sized carrier achieves intracellular release of drug on external ultrasound stimulus.

Control over intracellular release of therapeutic compounds incorporated into nano-carriers will open new possibilities for targeted treatments of various diseases including cancer, and viral and bacterial infections. Here we report our study on mechanoresponsive nano-sized liposomes which, following internalization by cells, achieve intracellular delivery of encapsulated cargo on application of external ultrasound stimulus. This is demonstrated in a bespoke cell reporter system designed to assess free drug in cytoplasm.

Immune Modulation by Design: Using Topography to Control Human Monocyte Attachment and Macrophage Differentiation.

Macrophages play a central role in orchestrating immune responses to foreign materials, which are often responsible for the failure of implanted medical devices. Material topography is known to influence macrophage attachment and phenotype, providing opportunities for the rational design of "immune-instructive" topographies to modulate macrophage function and thus foreign body responses to biomaterials. However, no generalizable understanding of the inter-relationship between topography and cell response exists.

Ligand discrimination during virtual screening of the CB1 cannabinoid receptor crystal structures following cross-docking and microsecond molecular dynamics simulations.

The therapeutic potential of the CB1 cannabinoid receptor remains underexploited with only a few synthetic ligands on the market. The crystal structures of both the inactive and active-state CB1 receptor have recently been solved, allowing for unprecedented opportunities in structure-based drug discovery applications such as virtual screening. In this study, we have investigated the virtual screening performance of the active and inactive-state CB1 crystal structures and their ability to discriminate between agonist and inverse agonist/antagonist ligands.

Synthesis of novel (benzimidazolyl)isoquinolinols and evaluation as adenosine A1 receptor tools.

G protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors in eukaryotes. The adenosine A receptor (AAR) is a class A GPCR that is of interest as a therapeutic target particularly in the treatment of cardiovascular disease and neuropathic pain. Increased knowledge of the role AAR plays in mediating these pathophysiological processes will help realise the therapeutic potential of this receptor.

Use of a new proximity assay (NanoBRET) to investigate the ligand-binding characteristics of three fluorescent ligands to the human -adrenoceptor expressed in HEK-293 cells.

Previous research has indicated that allosteric interactions across the dimer interface of -adrenoceptors may be responsible for a secondary low affinity binding conformation. Here we have investigated the potential for probe dependence, in the determination of antagonist pK values at the human -adenoceptor, which may result from such allosterism interactions. Three fluorescent -adrenoceptor ligands were used to investigate this using bioluminescence energy transfer (BRET) between the receptor-bound fluorescent ligand and the N-terminal NanoLuc tag of a human -adrenoceptor expressed in HEK 293 cells (NanoBRET).

Cisplatin induced sensory neuropathy is prevented by vascular endothelial growth factor-A.

Increased patient survival is a mark of modern anti-cancer therapy success. Unfortunately treatment side-effects such as neurotoxicity are a major long term concern. Sensory neuropathy is one of the common toxicities that can arise during platinum based chemotherapy.

Using Fisher's method with PLINK 'LD clumped' output to compare SNP effects across Genome-wide Association Study (GWAS) datasets.

Unlabelled: As the number of publically available GWAS datasets continues to grow, bioinformatic tools which enable routine manipulation of data are becoming increasingly useful. Meta-analysis using multiple GWAS datasets has become essential to elucidate novel SNP associations which may not be readily discovered in each GWAS individually due to insufficient power. Replication of GWAS findings is critical and is the 'arbiter' of genuine SNP associations.

Expression of Cre recombinase during transient phage infection permits efficient marker removal in Streptomyces.

We report a system for the efficient removal of a marker flanked by two loxP sites in Streptomyces coelicolor, using a derivative of the temperate phage phiC31 that expresses Cre recombinase during a transient infection. As the test case for this recombinant phage (called Cre-phage), we present the construction of an in-frame deletion of a gene, pglW, required for phage growth limitation or Pgl in S.coelicolor.