A5091621309- Alzheimer's disease research and treatments
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Immune Cell Function and Interaction
- Immune Response and Inflammation
- Ubiquitin and proteasome pathways
- Cancer, Hypoxia, and Metabolism
- Virus-based gene therapy research
- Viral-associated cancers and disorders
- Enzyme Structure and Function
- Cytomegalovirus and herpesvirus research
- Cellular transport and secretion
- Herpesvirus Infections and Treatments
- Galectins and Cancer Biology
- Inflammation biomarkers and pathways
- Studies on Chitinases and Chitosanases
- Trauma, Hemostasis, Coagulopathy, Resuscitation
- Blood donation and transfusion practices
- Toxoplasma gondii Research Studies
- Peptidase Inhibition and Analysis
- Polyomavirus and related diseases
- Protein Kinase Regulation and GTPase Signaling
AstraZeneca (United Kingdom)
2020-2025
AstraZeneca (Brazil)
2022-2024
AstraZeneca (United States)
2021
Institute for Medical Research
2020
University of Cambridge
2006-2017
National Institute for Health Research
2015
Addenbrooke's Hospital
2004-2014
Wellcome Trust
2004-2014
Institute of Cancer Research
2011-2013
American Red Cross
2003-2004
The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS FTD remain controversial. We propose a model low-complexity (LC) domains of drive its physiologically reversible assembly into membrane-free, liquid droplet hydrogel-like structures. ALS/FTD LC or non-LC induce further phase transition poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary sufficient for neurotoxicity C. elegans FUS-dependent neurodegeneration....
Research Article30 August 2017Open Access Source DataTransparent process TREM2 shedding by cleavage at the H157-S158 bond is accelerated for Alzheimer's disease-associated H157Y variant Peter Thornton Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Granta Park, Cambridge, UK Search more papers this author Jean Sevalle Tanz Centre in Neurodegenerative Diseases, University of Toronto, ON, Canada Michael J Deery Cambridge Proteomics, UKCorrection added on 2 October 2017...
Hypoxia-inducible transcription factors (HIFs) control adaptation to low oxygen environments by activating genes involved in metabolism, angiogenesis, and redox homeostasis. The finding that HIFs are also regulated small molecule metabolites highlights the need understand complexity of their cellular regulation. Here we use a forward genetic screen near-haploid human cells identify stabilize under aerobic conditions. We two mitochondrial genes, oxoglutarate dehydrogenase (OGDH) lipoic acid...
Background Epithelial damage, repair and remodelling are critical features of chronic airway diseases including obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation IL-33 to a non-ST2-binding form (IL-33 ox ) is thought limit activity. We investigated whether has functional activities that independent ST2 in the epithelium. Methods In vitro epithelial damage assays...
Protein modules related to the C-type carbohydrate-recognition domains of animal lectins are found in at least 125 proteins encoded Caenorhabditis elegans genome. Within these proteins, 183 lectin-like (CTLDs) have been identified. The classified based on overall arrangement within polypeptides and sequence similarity between CTLDs. C.elegans generally different domain organization from known mammalian containing Most CTLDs divergent those proteins. However, 19 show conservation most amino...
TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids Aβ inducing an innate immune response. Missense mutations (e.g., R47H) of increase risk Alzheimer's disease (AD). The soluble ectodomain wild-type (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that oligomers bind cellular TREM2, shedding sTREM2 domain. Wild-type bound (measured by single-molecule imaging, dot blots, Bio-Layer...
RING domains are found in a large number of eukaryotic proteins. Most function as E3 ubiquitin-protein ligases, catalyzing the terminal step ubiquitination process. Structurally, these have been characterized binding two zinc ions stable cross-brace motif. The tumorigenic human γ-herpesvirus Kaposi's sarcoma-associated herpesvirus encodes ligase termed K3, which functions an immune evasion molecule by ubiquitinating major histocompatibility complex class I. K3 possesses at its N terminus...
Highlights•The head contains nicastrin ectodomain and overhangs a solute-accessible cavity in base•The base has central channel lateral cleft (putative substrate docking site)•Inhibitors close the rotate head, blocking accessSummaryPresenilin-mediated endoproteolysis of transmembrane proteins plays key role physiological signaling pathogenesis Alzheimer disease some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used...
Mannose-binding protein (MBP; mannose-binding lectin) forms part of the innate immune system. By binding directly to carbohydrates on surfaces potential microbial pathogens, MBP and MBP-associated serine proteases (MASPs) can replace antibodies complement components C1q, C1r, C1s classical pathway. In order investigate mechanisms MASP activation by MBP, cDNAs rat MASP-1 -2 have been isolated, portions encompassing N-terminal CUB epidermal growth factor-like domains expressed purified....
Abstract Elevated expression of folate receptor alpha (FRα) in various cancers, including epithelial ovarian cancer (EOC), highlights FRα as a potential target for the development novel therapeutics to treat FRα-expressing tumor types. AZD5335, an FRα-targeting antibody conjugated topoisomerase 1 inhibitor (TOP1i) payload, is currently being investigated FONTANA Phase I/IIa clinical trial (NCT#05797168), either single agent or combination with PARP1-selective (saruparib). Using EOC xenograft...
Chemical inducer of dimerization (CID) modules can be used effectively as molecular switches to control biological processes, and thus there is significant interest within the synthetic biology community in identifying novel CID systems. To date, have been primarily engineering cells for vitro applications. broaden their utility clinical setting, including potential cell gene therapies, identification should consider factors such safety pharmacokinetic profile small molecule inducer,...
Computational free energy-based methods have the potential to significantly improve throughput and decrease costs of protein design efforts. Such must reach a high level reliability, accuracy, automation be effectively deployed in practical industrial settings way that impacts projects. Here, we present benchmark study for calculation relative changes protein-protein binding affinity single point mutations across variety systems from literature, using energy perturbation (FEP+) calculations....
Abstract Folate receptor alpha (FRα) is a cell surface GPI-anchored protein overexpressed in several solid tumors with highest prevalence ovarian cancer and lung adenocarcinoma but restricted expression normal tissues. An antibody drug conjugate (ADC) microtubule inhibitor (MTI) payload recently received accelerated approval from the FDA for FRα-expressing platinum-resistant cancer. We describe first time preclinical activity of AZD5335, an FRα-targeting conjugated to AZ’s proprietary...
Abstract Background Signal peptide peptidase (SPP), a member of the presenilin-like intra-membrane cleaving aspartyl protease family, migrates on Blue Native (BN) gels as 100 kDa, 200 kDa and 450 species. SPP has recently been implicated in other non-proteolytic functions such retro-translocation MHC Class I molecules binding misfolded proteins endoplasmic reticulum (ER). These high molecular weight complexes might contain additional that regulate proteolytic activity or support its...
BACKGROUND: In January 2003, blood center person‐nel in the American Red Cross, Southern Region Atlanta, noticed whitish particulate material (WPM) that had not been observed previously several units of red cells (RBCs). An expert panel was formed to evaluate studies and make appropriate recommendations STUDY DESIGN AND METHODS: The reviewed information provided by investigations organizations. This included: background informa‐tion, experiences relating WPM; WPM composi‐tion; factors...