A5049363617- Parkinson's Disease Mechanisms and Treatments
- Peroxisome Proliferator-Activated Receptors
- Nuclear and radioactivity studies
- Monoclonal and Polyclonal Antibodies Research
- Graphite, nuclear technology, radiation studies
- Adenosine and Purinergic Signaling
- Advanced Glycation End Products research
- Nuclear Receptors and Signaling
- Neuroinflammation and Neurodegeneration Mechanisms
- Radioactive element chemistry and processing
- Viral Infectious Diseases and Gene Expression in Insects
- S100 Proteins and Annexins
- Herpesvirus Infections and Treatments
- Adipose Tissue and Metabolism
- Chemical Synthesis and Analysis
- Toxoplasma gondii Research Studies
- Glycosylation and Glycoproteins Research
- Click Chemistry and Applications
- Circular RNAs in diseases
- MicroRNA in disease regulation
- Peptidase Inhibition and Analysis
- Genetic Neurodegenerative Diseases
- Neurological disorders and treatments
- Carbohydrate Chemistry and Synthesis
- Ubiquitin and proteasome pathways
University of Leeds
2012-2024
St James's University Hospital
2013-2023
Oklahoma State University
2019
University of Aberdeen
2009-2016
Wellcome Trust
2015
University of Pennsylvania
2014
Cancer Research Institute
2014
University of Maine
2013
Institute of Medical Sciences
2012
University of Maryland, Baltimore
2011
The highly prevalent parasite Toxoplasma gondii manipulates its host's behavior. In infected rodents, the behavioral changes increase likelihood that will be transmitted back to definitive cat host, an essential step in completion of parasite's life cycle. mechanism(s) responsible for host is unknown but two lines published evidence suggest alters neurotransmitter signal transduction: disruption parasite-induced with medications used treat psychiatric disease (specifically dopamine...
Molecular recognition reagents are key tools for understanding biological processes and used universally by scientists to study protein expression, localisation interactions. Antibodies remain the most widely of such many show excellent performance, although some poorly characterised or have stability batch variability issues, supporting use alternative binding proteins as complementary applications. Here we report on Affimer research reagents. We selected 12 diverse molecular targets...
Parkinson's disease is a neurodegenerative disorder that can, at least partly, be mimicked by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. S100B calcium-binding protein expressed in, and secreted by, astrocytes. There increasing evidence acts as cytokine or damage-associated molecular pattern not only in inflammatory but also diseases. In this study, we show levels were higher post-mortem substantia nigra of patients with compared control tissue, cerebrospinal fluid large...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. Recent work in rodent models ALS has shown that insulin-like growth factor-1 (IGF-1) slows progression when delivered at onset. However, IGF-1's mechanism action along neuromuscular axis remains unclear. In this study, symptomatic mice received IGF-1 through stereotaxic injection an IGF-1-expressing viral vector to deep cerebellar nuclei (DCN), region cerebellum with extensive brain stem and spinal...
High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that released during tissue damage from immune non-immune cells — including microglia neurons. HMGB1 can contribute to progression of numerous chronic inflammatory autoimmune diseases which mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There increasing evidence vitro studies may link two main pathophysiological components Parkinson's disease (PD), i.e. progressive dopaminergic...
Abstract Inhibition of protein–protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α‐Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed “proteomimetics”, which can assembled modular manner reproduce the vectoral presentation key side chains found on helical motif from one partner within PPI. In this work, it is demonstrated that by library N‐alkylated aromatic oligoamide helix mimetics, potent mimetics their...
Infection by the neurotropic agent Toxoplasma gondii alters rodent behavior and can result in neuropsychiatric symptoms humans. Little is understood regarding effects of infection on host neural processes but alterations to dopaminergic neurotransmission are implicated. We have previously reported elevated levels dopamine (DA) infected cells however involvement enzymes fate produced DA were not defined. In order clarify biosynthetic packaging we examined enzyme activity accumulation release...
Parkinson's disease (PD) is a common neurodegenerative disorder of unknown pathogenesis characterized by the loss nigrostriatal dopaminergic neurons. Oxidative stress, microglial activation and inflammatory responses seem to contribute pathogenesis. The receptor for advanced glycation endproducts (RAGE) multiligand immunoglobulin superfamily cell surface molecules. formation end products (AGEs), first ligand RAGE identified, requires complex series reactions including nonenzymatic free...
Toxicity is a major cause of failure in drug discovery and development, whilst robust toxicological testing occurs, efficiency could be improved if compounds with cytotoxic characteristics were identified during primary compound screening. The use high-content imaging screening becoming more widespread, by utilising phenotypic approaches it should possible to incorporate cytotoxicity counter-screens into screens. Here we present novel assay that can used as counter-screen identify adverse...
Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to provide neuroprotection in a number of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. These protective effects are primarily considered result from the anti-inflammatory actions PPARγ, however, there is increasing evidence that anti-oxidant mechanisms may also contribute. This study explored impact PPARγ agonist rosiglitazone antagonist GW9662 MPP+/MPTP...
Parkinson's disease (PD) is the second most common neurodegenerative and results from loss of dopaminergic neurons nigrostriatal pathway. The pathogenesis PD poorly understood, but inflammatory processes have been implicated. Indeed increases in number major histocompatibility complex II (MHC II) reactive cells long recognised brains patients at post‐mortem. However whether expressing MHC play an active role has not delineated. This was addressed utilising a transgenic mouse null for...
Peroxisome proliferator-activated receptor (PPAR)-γ and PPARα have shown neuroprotective effects in models of Parkinson’s disease (PD). The role the third, more ubiquitous isoform PPARδ has not been fully explored. This study investigated PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model dopaminergic neurodegeneration PD. In vitro administration antagonist GSK0660 (1 μM) increased detrimental effect 1-methyl-4-phenylpyridinium iodide (MPP+) on cell viability, which was...
RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors RAS, as druggable pockets have proven difficult to identify. Here, we identify two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange downstream signaling pathways with distinct isoform mutant profiles. K6 binds in SI/SII pocket, whilst is non-covalent inhibitor SII region reveals conformer wild-type large, SII/α3...
Abstract Ecological risk assessments must increasingly consider the effects of chemical mixtures on environment as anthropogenic pollution continues to grow in complexity. Yet testing every possible mixture combination is impractical and unfeasible; thus, there an urgent need for models that can accurately predict toxicity from single‐compound data. Currently, two are frequently used data: Concentration addition independent action (IA). The accuracy predictions generated by these currently...
Abstract Inhibition of protein–protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α‐Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed “proteomimetics”, which can assembled modular manner reproduce the vectoral presentation key side chains found on helical motif from one partner within PPI. In this work, it is demonstrated that by library N‐alkylated aromatic oligoamide helix mimetics, potent mimetics their...
Behavioral barriers to gene flow often evolve faster than intrinsic incompatibilities and can eliminate the opportunity for hybridization between interfertile species. While acoustic signal divergence is a common driver of premating isolation in birds insects, its contribution speciation mammals less studied. Here we characterize incidence of, potential to, among three closely related species grasshopper mice (genus Onychomys). All use long-distance signals attract localize mates; Onychomys...
Kinases are important therapeutic targets, and their inhibitors classified according to mechanism of action, which range from blocking ATP binding covalent inhibition. Here, a inhibition is highlighted by capturing p21-activated kinase 5 (PAK5) in an intermediate state activation using Affimer reagent that binds the P+1 pocket. PAK5 was identified non-hypothesis-driven high-content imaging RNAi screen urothelial cancer cells. Silencing resulted reduced cell number, G1/S arrest, enlargement...
Abstract Despite SH2 domains, being pivotal in protein interactions linked to various diseases like cancer, we lack specific research tools for intracellular assays. Understanding SH2-mediated and creating effective inhibitors requires which target individual domains. Affimer reagents exhibit promise, yet their potential against the extensive domain family remains largely unexplored. Our study aimed bridge this gap by identifying that selectively bind 22 out of 41 These enabled a...
The tumor necrosis factor like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible 14 (Fn14), mediate inflammation neuronal in cerebral edema, ischemic stroke multiple sclerosis. downstream effectors pathways linked to TWEAK-Fn14 signaling are strongly implicated the pathology Parkinson's disease (PD), thus indicating a putative role for TWEAK/Fn14 PD neurodegeneration. Using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, we aimed...
Premature chromosome condensation (PCC) is a consequence of early mitotic entry, where mitosis begins before completion DNA replication. Previously we have identified mutations in MCPH1, damage response and potential tumor suppressor gene, as cause primary microcephaly PCC. Here describe high-throughput assay to identify modifiers Reverse transfection control siRNA followed by forward MCPH1 small interfering RNA (siRNA) was performed induce Condensin II subunits CAPG2 CAPH2 were validated...