A5083083639- Ubiquitin and proteasome pathways
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Peroxisome Proliferator-Activated Receptors
- RNA Interference and Gene Delivery
- Genomics and Chromatin Dynamics
- SARS-CoV-2 and COVID-19 Research
- Acute Myeloid Leukemia Research
- COVID-19 Clinical Research Studies
- Cancer Immunotherapy and Biomarkers
- RNA modifications and cancer
- Hormonal and reproductive studies
- Long-Term Effects of COVID-19
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Protein Tyrosine Phosphatases
- Autophagy in Disease and Therapy
- Congenital gastrointestinal and neural anomalies
- Endoplasmic Reticulum Stress and Disease
- Advertising and Communication Studies
- Business Strategies and Innovation
- Cholesterol and Lipid Metabolism
- NF-κB Signaling Pathways
- Child Nutrition and Feeding Issues
The Francis Crick Institute
2018-2022
Addenbrooke's Hospital
2012-2017
University of Cambridge
2007-2015
Yale University
2011
MRC Laboratory of Molecular Biology
2005-2008
St James's University Hospital
2007
University of Buenos Aires
2000-2006
Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The includes discrete changes in B myelomonocytic cell composition, profoundly altered T phenotypes, selective cytokine/chemokine upregulation SARS-CoV-2-specific...
The assembly of MHC class I molecules is governed by stringent endoplasmic reticulum (ER) quality control mechanisms. heavy chains that fail to achieve their native conformation in complex with β2-microglobulin (β2m) and peptide are targeted for ER-associated degradation. This requires ubiquitination the chain its dislocation from ER cytosol proteasome-mediated degradation, although cellular machinery involved this process unknown. Using an siRNA functional screen β2m-depleted cells, we...
A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01186-5
Abstract Person-to-person transmission of SARS-CoV-2 virus has triggered a global emergency because its potential to cause life-threatening Covid-19 disease. By comparison paucisymptomatic clearance by most individuals, been proposed reflect insufficient and/or pathologically exaggerated immune responses. Here we identify consensus peripheral blood signature across 63 hospital-treated patients who were otherwise highly heterogeneous. The core conspicuously blended adaptive B cell responses...
Non-coding RNAs and their interaction with RNA-binding proteins regulate mRNA levels in key cellular processes. This has intensified interest post-transcriptional regulation. Recent studies on the turnover of AU-rich cytokine mRNAs have linked metabolism ubiquitination. Ubiquitin is well recognized for its role protein regulation/degradation. In present paper, we describe a new group E3 ubiquitin ligases which are predicted to bind RNA stability. Although much effort been focused...
Abstract The regulation of protein and mRNA turnover is essential for many cellular processes. We recently showed that ubiquitin—traditionally linked to degradation—directly regulates the degradation mRNAs through action a newly identified family RNA-binding E3 ubiquitin ligases. How decay remains unclear. Here, we identify new role in regulating deadenylation, initial often rate-limiting step degradation. MEX-3C, canonical member this ligases, associates with cytoplasmic deadenylation...
Given the heterogeneous nature of antigens, major histocompatibility complex class I (MHC I) intracellular transport intersects with multiple degradation pathways for efficient peptide loading and presentation to cytotoxic T cells. MHC peptides in endoplasmic reticulum (ER) is a tightly regulated process, while post-ER considered occur by default, leading peptide-bearing delivery plasma membrane. We show here that traffic submitted previously uncharacterized sorting step at trans Golgi...
Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at cost broader cell repertoire disruption. We applied genomic DNA-based approach concurrently study the immunoglobulin-heavy (IGH) receptor (TCR) β δ chain loci 95 individuals. Our detected anticipated focusing for IGH repertoire, including expansions clusters related sequences temporally aligned with SARS-CoV-2–specific...
We have described that, in adrenal and Leydig cells, the hormonal regulation of free arachidonic acid (AA) concentration is mediated by concerted action two enzymes: an acyl-CoA thioesterase (MTE-I or ARTISt) synthetase (ACS4). In this study we analyzed potential these proteins steroidogenic cells. demonstrated that ACS4 rapidly induced adrenocorticotropin (ACTH) cAMP Y1 adrenocortical The hormone its second messenger increased protein levels a time dependent way. Maximal ACTH (10 mIU/ml)...
Although the role of arachidonic acid (AA) in regulation steroidogenesis is well documented, mechanism for AA release not clear. Therefore, aim this study was to characterize an acyl-CoA thioesterase (ARTISt) and synthetase as members alternative pathway intracellular levels steroidogenesis. Purified recombinant ARTISt releases from arachidonoyl-CoA (AA-CoA) with a Km 2 micro m. Antibodies raised against recognize endogenous protein both adrenal tissue Y1 tumor cells by immunohistochemistry...
The isolation of haploid cell lines has recently allowed the power forward genetic screens to be applied mammalian cells. interest in applying this powerful approach a system is only tempered by limited utility these screens, if confined lethal phenotypes. Here we expand scope approaches beyond live/dead and show that selection for surface phenotype via fluorescence-activated sorting can identify key molecules an intracellular pathway, case MHC class I antigen presentation. Non-lethal are...
TPL-2 MAP 3-kinase promotes inflammation in numerous mouse disease models and is an attractive anti-inflammatory drug target. However, TPL-2-deficient (Map3k8 -/-) mice develop exacerbated allergic airway to house dust mite (HDM) compared with wild type controls. Here, we show that Map3k8D270A/D270A expressing kinase dead had unaltered response HDM, indicating the severe observed Map3k8 -/- not due blockade of signaling rather reflects a adaptor function. Severe was likely reduced levels...
Mouse models of human cancers are important for understanding determinants overt disease and "preclinical" development rational therapeutic strategies; instance, based on macrodrugs. Chromosomal translocations underlie many leukemias, sarcomas, epithelial tumors. We have developed three technologies homologous recombination in mouse ES cells to mimic chromosome translocations. The first, called the knockin method, allows creation fusion genes like those typical leukemias sarcomas. Two new...
An amendment to this paper has been published and can be accessed via a link at the top of paper.
AbstractIt has been well established that arachidonic acid (AA) and its metabolism to leukotrienes plays an obligatory role in steroid production. The release of AA is regulated by hormone stimulation protein phosphorylation. We have cloned a cDNA phosphoprotein with molecular mass 43 kDa (p43), purified from the cytosol stimulated adrenal glands. This acts as intermediary synthesis through release, found be member recently described acyl-CoA thioesterase family. In view mandatory this...
Although the role of arachidonic acid (AA) in trophic hormone‐stimulated steroid production various steroidogenic cells is well documented Citation, mechanism responsible for AA release remains unknown. We have previously shown evidence an alternative pathway generation tissues. Our results are consistent with hypothesis that, cells, released by action a mitochondrial acyl‐CoA thioesterase (MTE‐I). that recombinant MTE‐I hydrolyses arachidonoyl‐CoA to free AA. An synthetase specific AA, 4,...
The ACTH signaling pathway includes both PKA activation as well PKA-dependent tyrosine phosphatase activation. In addition, the action of this hormone also regulation intracellular levels arachidonic acid (AA) by concerted two enzymes: an acylCoA-thioesterase and acyl-CoA-synthetase (ACS4). This work describes production characterization a specific ACS4 antibody, which was used to analyze effect on protein level in Y1 adrenocortical cells putative relationship between phosphatases ACS4....
Abstract Mouse models of human cancer are a potential preclinical setting for drug testing and development methods delivery macromolecular drugs to tumors. We have assessed mouse model leukemia caused by Mll-Enl protein fusion as situation in which myeloid-lineage results from de novo occurrence chromosomal translocations between Mll Enl genes. Here, we show that the leukemias respond cytosine arabinoside, frontline treatment leukemia. The observations myeloid cells susceptible mice undergo...