Institution
University of Liverpool
Education•Liverpool, United Kingdom•
About: University of Liverpool is a education organization based out in Liverpool, United Kingdom. It is known for research contribution in the topics: Population & Context (language use). The organization has 40406 authors who have published 94388 publications receiving 3188970 citations. The organization is also known as: Liverpool University & The University of Liverpool.
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TL;DR: Based on protein folding considerations, a pentapeptide ligand, CALNN, which converts citrate-stabilized gold nanoparticles into extremely stable, water-solublegold nanoparticles with some chemical properties analogous to those of proteins, has been designed.
Abstract: Based on protein folding considerations, a pentapeptide ligand, CALNN, which converts citrate-stabilized gold nanoparticles into extremely stable, water-soluble gold nanoparticles with some chemical properties analogous to those of proteins, has been designed. These peptide-capped gold nanoparticles can be freeze-dried and stored as powders that can be subsequently redissolved to yield stable aqueous dispersions. Filtration, size-exclusion chromatography, ion-exchange chromatography, electrophoresis, and centrifugation can be applied to these particles. The effect of 58 different peptide sequences on the electrolyte-induced aggregation of the nanoparticles was studied. The stabilities conferred by these peptide ligands depended on their length, hydrophobicity, and charge and in some cases resulted in further improved stability compared with CALNN, yielding detailed design criteria for peptide capping ligands. A simple strategy for the introduction of recognition groups is proposed and demonstrated with bi...
680 citations
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TL;DR: Results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.
Abstract: The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1β, IL-18 and high-mobility group box 1 (HMGB1). By studying HMGB1 release mechanisms, here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1β, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD) and pro-caspase-1 reconstitutes inflammasome activity. These results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.
679 citations
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TL;DR: Clinical predictors of severe disease include high temperature and lethargy, and lumbar puncture might reveal pleocytosis, and intravenous immunoglobulin seems to be beneficial in severe disease, perhaps through non-specific anti-inflammatory mechanisms, but has not been tested in any formal trials.
Abstract: Although poliomyelitis has been mostly eradicated worldwide, large outbreaks of the related enterovirus 71 have been seen in Asia-Pacific countries in the past 10 years. This virus mostly affects children, manifesting as hand, foot, and mouth disease, aseptic meningitis, poliomyelitis-like acute flaccid paralysis, brainstem encephalitis, and other severe systemic disorders, including especially pulmonary oedema and cardiorespiratory collapse. Clinical predictors of severe disease include high temperature and lethargy, and lumbar puncture might reveal pleocytosis. Many diagnostic tests are available, but PCR of throat swabs and vesicle fluid, if available, is among the most efficient. Features of inflammation, particularly in the anterior horns of the spinal cord, the dorsal pons, and the medulla can be clearly seen on MRI. No established antiviral treatment is available. Intravenous immunoglobulin seems to be beneficial in severe disease, perhaps through non-specific anti-inflammatory mechanisms, but has not been tested in any formal trials. Milrinone might be helpful in patients with cardiac dysfunction.
679 citations
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University College London1, French Institute of Health and Medical Research2, University of Liverpool3, University of Edinburgh4, Netherlands Cancer Institute5, University of Pennsylvania6, University of Melbourne7, University of Cambridge8, Western General Hospital9, University of St Andrews10, University of Aberdeen11, International Agency for Research on Cancer12, University of Utah13, Trinity College, Dublin14, Curie Institute15, St James's University Hospital16, Leiden University17
TL;DR: Key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCa2 genes are identified and this information may improve the classification of breast cancer in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.
Abstract: BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.
679 citations
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Wellcome Trust Sanger Institute1, Massachusetts Institute of Technology2, University of Cambridge3, University of Edinburgh4, National Research Council5, National Institutes of Health6, Liverpool School of Tropical Medicine7, University of Liverpool8, Harvard University9, University College London10
TL;DR: Data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
Abstract: The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses. Both the magnitude and breadth of the IFITM proteins' in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 'Spanish' influenza. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
678 citations
Authors
Showing all 40921 results
Name | H-index | Papers | Citations |
---|---|---|---|
Lei Jiang | 170 | 2244 | 135205 |
Gregory Y.H. Lip | 169 | 3159 | 171742 |
Ian J. Deary | 166 | 1795 | 114161 |
Nicholas J. White | 161 | 1352 | 104539 |
Tomas Hökfelt | 158 | 1033 | 95979 |
William J. Sutherland | 148 | 966 | 94423 |
Tommaso Dorigo | 141 | 1806 | 104276 |
Paul Jackson | 141 | 1372 | 93464 |
Andrew Askew | 140 | 1496 | 99635 |
Stephen Wimpenny | 138 | 1489 | 104084 |
Robin Erbacher | 138 | 1721 | 100252 |
Andrew Mehta | 137 | 1444 | 101810 |
Tim Jones | 135 | 1314 | 91422 |
Christophe Delaere | 135 | 1320 | 96742 |
Sinead Farrington | 133 | 1422 | 91099 |