A5037395026- Manufacturing Process and Optimization
- CRISPR and Genetic Engineering
- Advanced Manufacturing and Logistics Optimization
- Scheduling and Optimization Algorithms
- Advanced Measurement and Metrology Techniques
- Assembly Line Balancing Optimization
- Pluripotent Stem Cells Research
- Advanced machining processes and optimization
- Pancreatic function and diabetes
- Flexible and Reconfigurable Manufacturing Systems
- Animal Genetics and Reproduction
- Amyotrophic Lateral Sclerosis Research
- Receptor Mechanisms and Signaling
- Cardiomyopathy and Myosin Studies
- DNA Repair Mechanisms
- Advanced Surface Polishing Techniques
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- BIM and Construction Integration
- Advanced Numerical Analysis Techniques
- Iron Metabolism and Disorders
- Engineering Technology and Methodologies
- Cancer, Hypoxia, and Metabolism
- Renal and related cancers
- Congenital heart defects research
Centre for Human Genetics
2016-2025
University of Oxford
2016-2025
The Francis Crick Institute
2023-2025
UPMC Health System
2023
University of Pittsburgh Medical Center
2023
John Radcliffe Hospital
2022
Loughborough University
1992-2020
University of Regensburg
2018
University of Leeds
2002-2017
Ludwig Cancer Research
2016
LEOPARD syndrome (LS) is an autosomal dominant “RASopathy” that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene encodes SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components RAS/MAPK pathway, yet it remains unclear how PTPN11 alter cellular signaling to produce phenotypes. We therefore generated knockin mice harboring Ptpn11...
Significance The iron-exporting protein ferroportin is recognized as central to systemic iron regulation, but its role in tissues other than those involved handling unknown. This study shows that expression cardiomyocytes essential intracellular homeostasis and normal cardiac function. It also demonstrates the site of accumulation iron-overloaded heart depends on whether expressed cardiomyocytes. further functional significance overload highly dependent upon accumulation. These findings...
Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from liver, it inhibits exporter ferroportin in gut and spleen, sites absorption recycling respectively. Recently, we demonstrated that also found cardiomyocytes, its cardiac-specific deletion leads to fatal cardiac overload. expressed where function remains unknown. To define cardiomyocyte hepcidin, generated mice with cardiomyocyte-specific or knock-in hepcidin-resistant ferroportin. We find while both models...
In this study we identified prognostic factors for survival and validated the accuracy of Fournier's gangrene severity index in patients with gangrene.We retrospectively reviewed medical records diagnosed between 1996 2006. scores were assessed using a receiver operating characteristic curve. Using an outcome variable inpatient mortality, univariate analyses performed Mann-Whitney U, chi-square Fisher exact tests.A total 68 (79.4% male, mean age 55.8 +/- 15.2 years) met criteria review. The...
Oxidative stress is a common etiological feature of neurological disorders, although the pathways that govern defence against reactive oxygen species (ROS) in neurodegeneration remain unclear. We have identified role oxidation resistance 1 (Oxr1) as vital protein controls sensitivity neuronal cells to oxidative stress; mice lacking Oxr1 display cerebellar neurodegeneration, and neurons are less susceptible exogenous when gene over-expressed. A conserved short isoform also sufficient confer...
The mechanisms by which arterial fate is established and maintained are not clearly understood. Although a number of signaling pathways transcriptional regulators have been implicated in arterio-venous differentiation, none essential for formation, the manner widely expressed factors may achieve arterial-specific gene regulation unclear. Using both mouse zebrafish models, we demonstrate here that specification regulated combinatorially Notch SoxF transcription factors, via direct activation....
The activities of nine ubiquitous promoters (ROSA26, CAG, CMV, CMVd1, UbC, EF1α, PGK, chicken β-actin and MC1) have been quantified compared in mouse embryonic stem cells. To avoid the high variation transgene expression which results from uncontrolled copy number chromosomal position effects when using random insertion based transgenic approaches, we adopted a PhiC31 integrase mediated cassette exchange method for efficient transgenes at single within defined well characterized position,...
Sequencing and the single sperm During meiosis, homologous chromosomes undergo doublestrand breaks in DNA that can cross over, shuffling genetic material. However, not every double-strand break resolves a crossover event. Hinch et al. wanted to determine rules governing recombination. They developed method sequence individual mouse applied it mice carrying two different alleles of protein involved mammalian crossovers. A high-resolution map revealed relationships between distribution...
Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic (ALS) mouse it is clear that dosage-sensitive and effects arise from overexpression per se transgenic strains. Novel models required maintain physiological levels expression recapitulate the human disease-with progressive loss motor neurons heterozygous animals. Here, we describe new humanized FUS-ALS frameshift mutation, which fulfils both criteria:...
Abstract During meiotic recombination, homologue-templated repair of programmed DNA double-strand breaks (DSBs) produces relatively few crossovers and many difficult-to-detect non-crossovers. By intercrossing two diverged mouse subspecies over five generations deep-sequencing 119 offspring, we detect thousands crossover non-crossover events genome-wide with unprecedented power spatial resolution. We find that both non-crossovers are strongly depleted at DSB hotspots where the DSB-positioning...
Abstract Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated dipeptide knock-in mouse models characterized by expression 400 codon-optimized polyGR or polyPR repeats, and heterozygous reduction. (GR)400 (PR)400 mice recapitulate key features C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal...
Human epididymal protein 6 (HE6; also known as GPR64) is an orphan member of the LNB-7TM (B(2)) subfamily G-protein-coupled receptors. Family members are characterized by dual presence a secretin-like (type II) seven-transmembrane (7TM) domain and long cell adhesion-like extracellular domain. HE6 specifically expressed within efferent ductules initial segment epididymis, ductal systems involved in spermatozoon maturation. Here, we report that targeted deletion 7TM murine gene results male...
Abstract Background Phage-encoded serine integrases, such as φC31 integrase, are widely used for genome engineering. Fifteen integrases have been described but their utility engineering has not compared in uniform assays. Results We fifteen DNA manipulations mammalian cells after first demonstrating that all were functional E. coli . Chromosomal recombination reporters to show seven active on chromosomally integrated human fibroblasts and mouse embryonic stem cells. Five of the remaining...
Adhesion-GPCRs provide essential cell-cell and cell-matrix interactions in development, have been implicated inherited human diseases like Usher Syndrome bilateral frontoparietal polymicrogyria. They are the second largest subfamily of seven-transmembrane spanning proteins vertebrates, but function most these receptors is still not understood. The orphan Adhesion-GPCR GPR126 has recently shown to play an role myelination peripheral nerves zebrafish. In parallel, whole-genome association...
The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between dysregulation and cancer. Mutations the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, cancers, though respective pathogenic roles mitochondrial cytosolic FH isoforms remain undefined. On basis comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells tissues exhibit defects urea cycle/arginine...
Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin β4 (Tβ4) myocardial infarction (MI) by reactivating a fetal gene programme promote neovascularization cardiomyogenesis. The mechanism for epicardial (re-)activation remains elusive. Here we reveal that BRG1, the essential ATPase subunit of SWI/SNF chromatin-remodelling complex, is required expression Wilms' tumour 1 (Wt1), EPDC activation subsequent differentiation...
There is a major medical need for developing novel and effective approaches repairing non-union critical-sized bone defects. Although the mechanisms remain to be determined, it known that inflammation plays crucial role in initiating repair regeneration. This study investigated effect of short-term (3 days) preconditioning with tumor necrosis factor-alpha (TNF-α) on proliferation, mobilization, differentiation adipose tissue-derived mesenchymal stem cells (ASCs). We demonstrated TNF-α...