A5067478490- Advanced biosensing and bioanalysis techniques
- Muscle Physiology and Disorders
- Monoclonal and Polyclonal Antibodies Research
- Signaling Pathways in Disease
- Nanowire Synthesis and Applications
- Cytokine Signaling Pathways and Interactions
- Analytical Chemistry and Sensors
- RNA Interference and Gene Delivery
- Regulation of Appetite and Obesity
- Advanced Biosensing Techniques and Applications
- Biochemical Analysis and Sensing Techniques
- RNA and protein synthesis mechanisms
- Cardiomyopathy and Myosin Studies
- Diabetes and associated disorders
- Extracellular vesicles in disease
- Clinical practice guidelines implementation
- Glycosylation and Glycoproteins Research
- Analog and Mixed-Signal Circuit Design
- Congenital heart defects research
- Pancreatic function and diabetes
- Axon Guidance and Neuronal Signaling
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Enzyme Production and Characterization
- Adipose Tissue and Metabolism
- Hypothalamic control of reproductive hormones
University of Cambridge
2010-2023
Addenbrooke's Hospital
2017-2023
NHS Blood and Transplant
2023
Wellcome Trust
2010-2020
Wellcome/MRC Institute of Metabolic Science
2017-2020
MRC Laboratory of Molecular Biology
2015
St James's University Hospital
2010-2011
Rutherford Appleton Laboratory
2010
University of Oxford
2010
University of Birmingham
2007-2009
Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to development these circuits. In genetic studies, found 40 rare variants SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) 573 severely obese individuals; disrupted secretion and/or through multiple molecular mechanisms. Rare this set genes were significantly enriched 982 cases compared 4,449 controls. zebrafish mutagenesis screen, deletion 7 pathway...
Abstract Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion SRC-1 in mice attenuates their depolarization by leptin, decreases expression increases leading high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants found severely...
Abstract Brain-derived neurotrophic factor (BDNF) signals through its high affinity receptor Tropomyosin kinase-B (TrkB) to regulate neuronal development, synapse formation and plasticity. In rodents, genetic disruption of Bdnf TrkB leads weight gain a spectrum neurobehavioural phenotypes. Here, we functionally characterised de novo missense variant in BDNF seven rare variants identified large cohort people with severe, childhood-onset obesity. cells, the E183K resulted impaired processing...
Examination of embryonic myogenesis two distinct, but functionally related, skeletal muscle dystrophy mutants (mdx and cav-3(-/-)) establishes for the first time that key elements pathology Duchenne muscular (DMD) limb-girdle type 1C (LGMD-1c) originate in disruption cardiac patterning processes. Disruption occurs earlier mdx mutants, which lack a functional form dystrophin, than cav-3(-/-) Cav3 gene encodes protein caveolin-3; this finding is consistent with milder phenotype LGMD-1c,...
Proteins mediate the bulk of biological activity and are powerfully assayed in diagnosis diseases. Protein detection relies largely on antibodies, which have significant technical limitations especially when immobilized two-dimensional surfaces. Here, we report integration peptide aptamers with extended gate metal-oxide-semiconductor field-effect transistors (MOSFETs) to achieve label-free sub-picomolar target protein detection. Specifically, that recognize highly related partners...
Constrained binding peptides (peptide aptamers) may serve as tools to explore protein conformations and disrupt protein−protein interactions. The quality of the scaffold, by which peptide is constrained presented, crucial importance. SQT (Stefin A Quadruple Mutant—Tracy) our most recent development in Stefin A-derived scaffold series. naturally uses three surfaces interact with its targets. tolerates insertions at all positions. Peptide aptamers can be expressed bacterial, yeast human cells,...
Macrocyclic peptides are potentially a source of powerful drugs, but their de novo discovery remains challenging. Here we describe the high-affinity (Kd = 10 nM) peptide macrocycle (M21) against human tumor necrosis factor-alpha (hTNFα), key drug target in treatment inflammatory disorders, directly from diverse semi-synthetic phage repertoires. The bicyclic M21 (ACPPCLWQVLC) comprises two loops covalently anchored to 2,4,6-trimethyl-mesitylene core and upon binding induces disassembly...
Disruption of the adaptor protein SH2B1 (SH2-B, PSM) is associated with severe obesity, insulin resistance, and neurobehavioral abnormalities in mice humans. Here, we identify 15 variants severely obese children. Four obesity-associated human lie Pleckstrin homology (PH) domain, suggesting that PH domain essential for SH2B1’s function. We generated a mouse model variant this (P322S). P322S/P322S exhibited substantial prenatal lethality. Examination P322S/+ metabolic phenotype revealed...
Non-antibody scaffold proteins are used for a range of applications, especially the assessment protein–protein interactions within human cells. The search versatile, robust and biologically neutral previously led us to design STM (stefin A triple mutant), derived from intracellular protease inhibitor stefin A. Here, we describe five new STM-based that contain modifications designed further improve versatility our scaffold. In step-by-step approach, introduced restriction sites in open...
Abstract Background Fibre type specification is a poorly understood process beginning in embryogenesis which skeletal muscle myotubes switch myosin-type to establish fast, slow and mixed fibre groups with distinct function. Growth factors are required fibres; it unknown how fast twitch fibres specified. Igf-2 an embryonically expressed growth factor established vitro roles muscle. Its localisation role embryonic differentiation had not been established. Results Between E11.5 E15.5 Myosin...
In the near future, personalised medicine and phase-0 trials will require that clinical practitioners move from "one biomarker per disease" paradigm to use of molecular signatures disease for diagnosis prediction a patient's response treatment. These be composed biomarkers specific disease, include over-expression normal protein gene does not carry mutation; loss expression an essential protein; mutant gene; metabolites whose levels are altered in disease. Surrogates expression, such as...
The B-cell CLL/lymphoma-2 (Bcl-2) family of proteins are important regulators the intrinsic pathway apoptosis, and their interactions, driven by Bcl-2 homology (BH) domains, great interest in cancer research. Particularly, BH3 domain is clinical relevance, as it promotes apoptosis through activation Bcl-2-associated x protein (Bax) antagonist killer (Bak), well antagonising anti-apoptotic members. Although investigated extensively vitro, study alone inside cells more problematic because...
then moved to the UK further her clinical training in general medicine, gastroenterology and hepatology