A5090102833- Complement system in diseases
- Monoclonal and Polyclonal Antibodies Research
- Erythrocyte Function and Pathophysiology
- Neuroinflammation and Neurodegeneration Mechanisms
- Blood groups and transfusion
- Renal Diseases and Glomerulopathies
- Glycosylation and Glycoproteins Research
- Peripheral Neuropathies and Disorders
- Systemic Lupus Erythematosus Research
- Multiple Sclerosis Research Studies
- Alzheimer's disease research and treatments
- Cell Adhesion Molecules Research
- Immune Cell Function and Interaction
- Cardiomyopathy and Myosin Studies
- Blood Coagulation and Thrombosis Mechanisms
- Bacterial Infections and Vaccines
- Retinal Diseases and Treatments
- Immunotherapy and Immune Responses
- Platelet Disorders and Treatments
- Reproductive System and Pregnancy
- RNA Interference and Gene Delivery
- Myasthenia Gravis and Thymoma
- T-cell and B-cell Immunology
- SARS-CoV-2 and COVID-19 Research
- Clusterin in disease pathology
Cardiff University
2016-2025
UK Dementia Research Institute
2017-2025
Cytokinetics (United States)
2016-2025
Iowa State University
2025
University Hospital of Wales
1986-2024
Institute of Infection and Immunity
2010-2023
Rutgers, The State University of New Jersey
2023
Nottingham University Hospitals NHS Trust
2023
Salisbury University
2022
Newcastle upon Tyne Hospitals NHS Foundation Trust
2020
In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues management these 2 diseases were considered by global panel experts. Areas addressed included renal pathology, clinical phenotype assessment, genetic drivers disease, acquired treatment strategies. order to help guide clinicians who...
C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors this document) in renal pathology, nephrology, complement biology, and therapeutics met to discuss first Glomerulopathy Meeting. The objectives were reach consensus on: glomerulopathy, appropriate investigations that should be...
Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, small-molecule, direct activator myosin. Here, show that it binds to the myosin catalytic domain and operates an allosteric mechanism transition rate into strongly actin-bound force-generating state. Paradoxically,...
Only around 80% of patients with generalized myasthenia gravis (MG) have serum antibodies to acetylcholine receptor [AChR; antibody positive (AChR-MG)] by the radioimmunoprecipitation assay used worldwide. Antibodies muscle specific kinase [MuSK; MuSK (MuSK-MG)] make up a variable proportion remaining 20%. The neither AChR nor are often called seronegative (seronegative MG, SNMG). There is accumulating evidence that SNMG similar AChR-MG in clinical features and thymic pathology. We...
Hemolytic uremic syndrome (HUS) is an important cause of acute renal failure in children. Mutations one or more genes encoding complement-regulatory proteins have been reported approximately one-third nondiarrheal, atypical HUS (aHUS) patients, suggesting a defect the protection cell surfaces against complement activation susceptible individuals. Here, we identified subgroup aHUS patients showing persistent alternative pathway and found within this two families with mutations gene factor B...
Abstract Twenty‐three plaques obtained at early autopsy from 2 patients with secondary‐progressive multiple sclerosis were examined immunohistochemically for microglia/macrophages, and immunoglobulins components of activated complement. Most the lesions in both cases exhibited evidence low‐grade active demyelination an unusual type (frustrated phagocytosis) periplaque white matter. This included linear groups microglia engaging short segments disrupted myelin that associated deposits C3d,...
The membrane attack complex of complement (MAC), apart from its classical role lysing cells, can also trigger a range non-lethal effects on acting as drive to inflammation. In the present study, we chose investigate these inflammasome activation. We found that, following sublytic MAC attack, there is increased cytosolic Ca(2+) concentration, at least partly through release endoplasmic reticulum lumen via inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine (RyR) channels. This increase...
The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the factor H-related ( CFHR ) locus. Elucidating mechanism underlying these associations has been hindered by lack of understanding biological role proteins. Here we present unique structural data demonstrating that three proteins contain shared dimerization motif this hitherto unrecognized property...
Abstract In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins form pores in lipid bilayers. MAC directly lyses pathogens by a ‘multi-hit’ mechanism; however, sublytic on host cells activate signalling pathways. Previous studies have described structures of individual components and subcomplexes; molecular details its assembly mechanism action remain unresolved. Here we report electron cryo-microscopy structure human at subnanometre...
Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes with disease, experimental data demonstrated proliferation as a component of the neuropathology. In this study, we tested efficacy selective CSF1R inhibitor JNJ-40346527 (JNJ-527) P301S mouse tauopathy model. We first anti-proliferative effects JNJ-527 on microglia ME7 prion model, its impact inflammatory...
Abstract Introduction Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a “Holy Grail” of AD research and intensively sought; however, there no well‐established plasma markers. Methods A hypothesis‐led biomarker search was conducted in the context international multicenter studies. The discovery phase measured 53 inflammatory proteins elderly control (CTL; 259), mild cognitive impairment (MCI; 199), (262) subjects from AddNeuroMed. Results Ten analytes showed...
Hypercontractility of the cardiac sarcomere may be essential for underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel myosin inhibitor that was discovered from optimization indoline compound 1. The important advancement discovery an Indane analogue (12) with less restrictive structure-activity relationship allowed rapid improvement drug-like properties. designed to provide predicted human half-life (t1/2) appropriate once...
Plasma biomarkers for Alzheimer's disease-related pathologies have undergone rapid developments during the past few years, and there are now well-validated blood tests amyloid tau pathology, as well neurodegeneration astrocytic activation. To define disease with rather than clinical assessment, we assessed prediction of research-diagnosed status using these tested genetic variants associated that may reflect more accurately risk biochemically defined instead dementia. In a cohort cases [n =...
BackgroundLong COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with SARS-CoV-2. The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is hallmark acute COVID-19 but has not been investigated as potential determinant long COVID.MethodsWe quantified series complement proteins, including markers activation regulation, in plasma...
Dysregulation of the initial, innate immune response to bacterial infection may lead septic shock and death. Toll-like receptors (TLRs) play a crucial role in this response, yet regulatory mechanisms controlling microbial-induced TLR triggering are still be fully understood. We have therefore sought specific that modulate signaling. In study, we tested for possible existence functionally active soluble form TLR2. demonstrated natural forms TLR2 (sTLR2), which show capable modulating cell...
Abstract Exosomes are secreted nanometer‐sized vesicles derived from antigen‐presenting cells, which have attracted recent interest as they likely play important roles in immune regulation, and their use cell‐free tools for immunotherapy has been proposed. Liposomes used clinically transport vehicles can activate the complement system, leading to rapid degradation significant inflammatory toxicity. The of isolated exosomes therapy, therefore, may also elicit activation, reducing potential...