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Institution

John Radcliffe Hospital

HealthcareOxford, Oxfordshire, United Kingdom
About: John Radcliffe Hospital is a healthcare organization based out in Oxford, Oxfordshire, United Kingdom. It is known for research contribution in the topics: Population & Antigen. The organization has 14491 authors who have published 23670 publications receiving 1459015 citations.


Papers
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Journal ArticleDOI
TL;DR: It is shown that the gene expression programmes of the adapted cells partially reflected their aberrant karyotype, but also resulted from a failure in X-inactivation, emphasizing the importance in adaptation of karyotypically silent epigenetic changes.
Abstract: Human embryonic stem cell (HESC) lines vary in their characteristics and behaviour not only because they are derived from genetically outbred populations, but also because they may undergo progressive adaptation upon long-term culture in vitro. Such adaptation may reflect selection of variants with altered propensity for survival and retention of an undifferentiated phenotype. Elucidating the mechanisms involved will be important for understanding normal self-renewal and commitment to differentiation and for validating the safety of HESC-based therapy. We have investigated this process of adaptation at the cellular and molecular levels through a comparison of early passage (normal) and late passage (adapted) sublines of a single HESC line, H7. To account for spontaneous differentiation that occurs in HESC cultures, we sorted cells for SSEA3, which marks undifferentiated HESC. We show that the gene expression programmes of the adapted cells partially reflected their aberrant karyotype, but also resulted from a failure in X-inactivation, emphasizing the importance in adaptation of karyotypically silent epigenetic changes. On the basis of growth potential, ability to re-initiate ES cultures and global transcription profiles, we propose a cellular differentiation hierarchy for maintenance cultures of HESC: normal SSEA3+ cells represent pluripotent stem cells. Normal SSEA3- cells have exited this compartment, but retain multilineage differentiation potential. However, adapted SSEA3+ and SSEA3- cells co-segregate within the stem cell territory, implying that adaptation reflects an alteration in the balance between self-renewal and differentiation. As this balance is also an essential feature of cancer, the mechanisms of culture adaptation may mirror those of oncogenesis and tumour progression.

295 citations

Journal ArticleDOI
TL;DR: The experiments show that CD56bright NK cells accumulate in inflammatory lesions and, in the appropriate cytokine environment, can engage with CD14+ monocytes in a reciprocal activatory fashion, thereby amplifying the inflammatory response.
Abstract: Human NK cells may be divided into a CD56(dim) subset and a CD56(bright) subset. In peripheral blood, CD56(dim) NK cells dominate, whereas in lymph nodes, CD56(bright) NK cells are more common. In this study we show that CD56(bright) NK cells accumulate within inflammatory lesions in a wide variety of clinical diseases affecting several different anatomical sites. We demonstrate that when activated by the monokines IL-12, IL-15, and IL-18, these NK cells promote TNF-alpha production by CD14(+) monocytes in a manner that is dependent on cell:cell contact. Conversely, CD14(+) monocytes synergize with monokines to promote IFN-gamma production by these NK cells. Again, this interaction is dependent on cell:cell contact. The experiments show that CD56(bright) NK cells accumulate in inflammatory lesions and, in the appropriate cytokine environment, can engage with CD14(+) monocytes in a reciprocal activatory fashion, thereby amplifying the inflammatory response. Such a positive feedback loop is likely to be important in the pathogenesis of chronic inflammatory conditions such as rheumatoid arthritis.

295 citations

Journal ArticleDOI
TL;DR: It is suggested that ATP binding, not hydrolysis, drives the major conformational change associated with solute translocation in P‐glycoprotein, and biochemical data suggest that these rearrangements may involve rotation of transmembrane α‐helices.
Abstract: P‐glycoprotein (P‐gp) is an ABC (ATP‐binding cassette) transporter, which hydrolyses ATP and extrudes cytotoxic drugs from mammalian cells. P‐gp consists of two transmembrane domains (TMDs) that span the membrane multiple times, and two cytoplasmic nucleotide‐binding domains (NBDs). We have determined projection structures of P‐gp trapped at different steps of the transport cycle and correlated these structures with function. In the absence of nucleotide, an ∼10 A resolution structure was determined by electron cryo‐microscopy of two‐dimensional crystals. The TMDs form a chamber within the membrane that appears to be open to the extracellular milieu, and may also be accessible from the lipid phase at the interfaces between the two TMDs. Nucleotide binding causes a repacking of the TMDs and reduction in drug binding affinity. Thus, ATP binding, not hydrolysis, drives the major conformational change associated with solute translocation. A third distinct conformation of the protein was observed in the post‐hydrolytic transition state prior to release of ADP/P i . Biochemical data suggest that these rearrangements may involve rotation of transmembrane α‐helices. A mechanism for transport is suggested.

295 citations

Journal ArticleDOI
TL;DR: The carbonic anhydrases, CAIX and CAXII, are expressed in a wide variety of malignancies and appear to be tightly regulated by microenvironmental hypoxia, which may inhibit tumour growth and invasion, with consequent therapeutic potential.
Abstract: The carbonic anhydrases (CAs) comprise a family of evolutionarily ancient enzymes found ubiquitously in nature. They have important roles in facilitating transport of carbon dioxide and protons in the intracellular space, across biological membranes and in the unstirred layers of the extracellular space. The tumour-associated isoenzymes, CAIX and CAXII, are expressed in a wide variety of malignancies and appear to be tightly regulated by microenvironmental hypoxia. CAIX expression is linked to poor prognosis in a number of human tumours, and may be a marker of aggressive malignant phenotype and a mechanism of progression. Inhibitors of CA may inhibit tumour growth and invasion, with consequent therapeutic potential.

295 citations

Journal ArticleDOI
TL;DR: Analysis of deleted ARNT/HIF-1β genes indicated that the basic, helix-loop-helix, and PAS domains, but not the amino or carboxyl termini, were necessary for function in the response to hypoxia.

295 citations


Authors

Showing all 14542 results

NameH-indexPapersCitations
Douglas G. Altman2531001680344
Salim Yusuf2311439252912
David J. Hunter2131836207050
Mark I. McCarthy2001028187898
Stuart H. Orkin186715112182
Richard Peto183683231434
Ralph M. Steinman171453121518
Adrian L. Harris1701084120365
Rory Collins162489193407
Nicholas J. White1611352104539
David W. Johnson1602714140778
David Cella1561258106402
Edmund T. Rolls15361277928
Martin A. Nowak14859194394
Kypros H. Nicolaides147130287091
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
202311
202252
20211,048
20201,013
2019916
2018773