A5018474916- Epigenetics and DNA Methylation
- SARS-CoV-2 and COVID-19 Research
- CRISPR and Genetic Engineering
- CAR-T cell therapy research
- Digestive system and related health
- Genomics and Chromatin Dynamics
- interferon and immune responses
- Polyamine Metabolism and Applications
- Biochemical and Molecular Research
- COVID-19 Clinical Research Studies
- Immunotherapy and Immune Responses
- Amino Acid Enzymes and Metabolism
- Immune cells in cancer
- Viral Infections and Vectors
- Clusterin in disease pathology
- vaccines and immunoinformatics approaches
- RNA Research and Splicing
- Immune Cell Function and Interaction
- Wnt/β-catenin signaling in development and cancer
- Peroxisome Proliferator-Activated Receptors
- Phagocytosis and Immune Regulation
- RNA modifications and cancer
- Cancer-related gene regulation
- Receptor Mechanisms and Signaling
- Alzheimer's disease research and treatments
Evotec (Germany)
2023-2024
MRC Weatherall Institute of Molecular Medicine
2016-2023
University of Oxford
2016-2023
John Radcliffe Hospital
2017-2023
Evotec (United Kingdom)
2023
AstraZeneca (United Kingdom)
2022
Medical Research Council
2018-2020
MRC Human Immunology Unit
2020
European Molecular Biology Laboratory
2011-2019
Friedrich Miescher Institute
2009
Neutrophils are critical and short-lived mediators of innate immunity that require constant replenishment. Their differentiation in the bone marrow requires extensive cytoplasmic nuclear remodeling, but processes governing these energy-consuming changes unknown. While previous studies show autophagy is required for other blood cell lineages, its function during granulopoiesis has remained elusive. Here, we have shown metabolism developmentally programmed essential neutrophil vivo....
Abstract NP 105–113 -B*07:02-specific CD8 + T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis clones and single-cell sequencing were performed concurrently, functional avidity antiviral efficacy assessed using an vitro SARS-CoV-2 infection system, correlated receptor usage, transcriptome signature disease severity (acute n = 77, convalescent 52). demonstrated a beneficial cells...
Abstract Zika virus (ZIKV) is a major public health concern in the Americas. We report that ZIKV infection and RNA extracted from infected cells potently activated induction of type I interferons (IFNs). This effect was fully dependent on mitochondrial antiviral signaling protein (MAVS), implicating RIG‐I‐like receptors (RLRs) as upstream sensors viral RNA. Indeed, RIG‐I related sensor MDA5 contributed to IFN response cells. found NS5 recent Brazilian isolate blocked downstream RLRs also...
The CRISPR system is widely used in genome editing for biomedical research. Here, using either dual paired Cas9D10A nickases or Cas9 nuclease we characterize unintended larger deletions at on-target sites that frequently evade common genotyping practices. We found are prevalent multiple distinct loci on different chromosomes, cultured cells and mouse embryos alike. observed a high frequency of microhomologies deletion breakpoint junctions, suggesting the involvement microhomology-mediated...
β-Thalassemia is one of the most common inherited anemias, with no effective cure for patients. The pathophysiology reflects an imbalance between α- and β-globin chains excess free α-globin causing ineffective erythropoiesis hemolysis. When α-thalassemia co-inherited β-thalassemia, are reduced significantly ameliorating clinical severity. Here we demonstrate use CRISPR/Cas9 genome editing primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes...
Progress in the somatosensory field has been restricted by limited number of genetic tools available to study gene function peripheral sensory neurons. Here we generated a Cre-driver mouse line that expresses Cre-recombinase from locus neuron specific Advillin. These mice displayed almost exclusive Cre-mediated recombination all As such, Advillin-Cre-driver will be powerful tool for targeting neurons future investigations.
Acetylation of α-tubulin at lysine 40 (K40) is a well-conserved posttranslational modification that marks long-lived microtubules but has poorly understood functional significance. Recently, αTAT1, member the Gcn5-related N-acetyltransferase superfamily, been identified as an acetyltransferase in ciliated organisms. Here, we explored function αTAT1 with aim understanding consequences αTAT1-mediated microtubule acetylation. We demonstrate major target also acetylates itself regulatory...
Interferon-induced transmembrane 3 (IFITM3) is known to restrict the entry of a range enveloped viruses. The single nucleotide polymorphism rs12252-C within IFITM3 has been shown be associated with severe influenza A virus infection. It suggested that results in expression truncated protein lacking first 21 amino acids. By performing high-throughput RNA sequencing on primary dendritic cells and peripheral blood mononuclear isolated from pandemic H1N1 human immunodeficiency virus-1 (HIV-1)...
The Zika virus (ZIKV) has received much attention due to an alarming increase in cases of neurological disorders including congenital syndrome associated with infection. To date, there is no effective treatment available. An immediate response by the innate immune system crucial for control virus. Using CRISPR/Cas9-mediated knockouts A549 cells, we investigated individual contributions RIG-I-like receptors MDA5 and RIG-I ZIKV sensing this using a Brazilian strain. We show that main sensor...
Most transcriptional repression pathways depend on the targeted deacetylation of histone tails. In this report, we characterize NIR, a novel corepressor with inhibitor acetyltransferase (INHAT) activity. NIR (Novel INHAT Repressor) is ubiquitously expressed throughout embryonic development and adulthood. potent that not blocked by deacetylase inhibitors capable silencing both basal activator-driven transcription. directly binds to nucleosomes core histones prevents acetylation...
T cell function can be compromised during chronic infections or through continuous exposure to tumor antigens by the action of immune checkpoint receptors, such as programmed death protein 1 (PD-1). Systemic administration blocking antibodies against PD-1 pathway restore function, and has been approved for treatment several malignancies, although there is a risk adverse immune-related side-effects. We have developed method generating gene knockouts in human antigen (Ag)-specific cytotoxic...
During development, it is unclear if lineage-fated cells derive from multilineage-primed progenitors and whether active mechanisms operate to restrict cell fate. Here we investigate how mesoderm specifies into blood-fated cells. We document temporally restricted co-expression of blood (Scl/Tal1), cardiac (Mesp1) paraxial (Tbx6) lineage-affiliated transcription factors in single cells, at the onset specification, supporting existence common progenitors. At same time-restricted stage, absence...
Mutations within viral epitopes can result in escape from T cells, but the contribution of mutations flanking regions SARS-CoV-2 has not been investigated. Focusing on two nucleoprotein CD8+ epitopes, we investigated these to proteasomal processing and cell activation. We found decreased NP9-17-B*27:05 responses NP-Q7K mutation, likely due a lack efficient epitope production by proteasome, suggesting immune caused this mutation. In contrast, NP-P6L NP-D103 N/Y NP105-113-B*07:02 respectively,...
The orphan receptor germ cell nuclear factor (GCNF) is a member of the superfamily receptors. During development, GCNF exhibits restricted brain-specific expression pattern, whereas in adult specific. Therefore, may participate regulation neurogenesis and reproductive functions. No natural target gene has yet been identified, but recent data demonstrate specific high-affinity binding either to direct repeat DNA element AGGTCAAGGTCA (DR0) or extended half-sites, such as TCAAGGTCA. In this...
Salmonella enterica represent a major disease burden worldwide. S. serovar Typhi (S. Typhi) is responsible for potentially life-threatening Typhoid fever affecting 10.9 million people annually. While non-typhoidal (NTS) serovars usually trigger self-limiting diarrhoea, invasive NTS bacteraemia growing public health challenge. Dendritic cells (DCs) are key professional antigen presenting of the human immune system. The ability pathogenic bacteria to subvert DC functions and prevent T cell...
A dominant transcription factor mutation disrupting nuclear liquid phase separation causes human immunodeficiency.
Abstract The CD47-SIRPα axis is a critical checkpoint that prevents SIRPα-positive macrophages from phagocytosing CD47-expressing solid tumors. Several agents aiming to block this have recently entered early clinical trials including anti-CD47 and anti-SIRPα monoclonal antibodies (mAb). These inhibitors (CPI) aim modulate the phagocytotic activity of endogenous tumor associated (TAMs). However, adoptive transfer resistant CD47-based inhibition in microenvironment (TME) could also increase...
Abstract GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. The catalysis of BH4 biosynthesis tightly regulated physiological neurotransmission, inflammation, and vascular tone. Paradoxically, has emerged as an oncometabolite regulating tumor growth, but effects on development remain controversial. Here, we found that GCH1 potentiated growth triple-negative breast cancer (TNBC) HER2+ transformed nontumor epithelial cells. Independent production,...
ABSTRACT Genome-wide association studies (GWAS) have identified over 150,000 links between common genetic variants and human traits or complex diseases. Over 80% of these associations map to polymorphisms in non-coding DNA. Therefore, the challenge is identify disease-causing variants, genes they affect, cells which effects occur. We developed a platform using ATAC-seq, DNaseI footprints, NG Capture-C machine learning address this challenge. Applying approach red blood cell identifies...
Use of dual sgRNAs is a common CRISPR/Cas9-based strategy for the creation genetic deletions. The ease screening combined with rather high rate success makes this approach reliable genome engineering procedure. Recently, number studies using CRISPR/Cas9 have revealed unwanted large-scale rearrangements, duplications, inversions or larger-than-expected Strict quality control measures are required to validate model system, and crucially depends on knowing which potential experimental outcomes...