John Radcliffe Hospital

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.

Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo.

Abstract: Timely elimination of damaged mitochondria is essential to protect cells from the potential harm of disordered mitochondrial metabolism and release of proapoptotic proteins In mammalian red blood cells, the expulsion of the nucleus followed by the removal of other organelles, such as mitochondria, are necessary differentiation steps Mitochondrial sequestration by autophagosomes, followed by delivery to the lysosomal compartment for degradation (mitophagy), is a major mechanism of mitochondrial turnover Here we show that mice lacking the essential autophagy gene Atg7 in the hematopoietic system develop severe anemia Atg7−/− erythrocytes accumulate damaged mitochondria with altered membrane potential leading to cell death We find that mitochondrial loss is initiated in the bone marrow at the Ter119+/CD71High stage Proteomic analysis of erythrocyte ghosts suggests that in the absence of autophagy other cellular degradation mechanisms are induced Importantly, neither the removal of endoplasmic reticulum nor ribosomes is affected by the lack of Atg7 Atg7 deficiency also led to severe lymphopenia as a result of mitochondrial damage followed by apoptosis in mature T lymphocytes Ex vivo short-lived hematopoietic cells such as monocytes and dendritic cells were not affected by the loss of Atg7 In summary, we show that the selective removal of mitochondria by autophagy, but not other organelles, during erythropoeisis is essential and that this is a necessary developmental step in erythroid cells

Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS.

Abstract: The authors have previously shown that acute lung injury (ALI) produces a wide spectrum of pathological processes in patients who die of severe acute respiratory syndrome (SARS) and that the SARS coronavirus (SARS-CoV) nucleoprotein is detectable in the lungs, and other organs and tissues, in these patients. In the present study, immunohistochemistry (IHC) and in situ hybridization (ISH) assays were used to analyse the expression of angiotensin-converting enzyme 2 (ACE2), SARS-CoV spike (S) protein, and some pro-inflammatory cytokines (PICs) including MCP-1, TGF-beta1, TNF-alpha, IL-1beta, and IL-6 in autopsy tissues from four patients who died of SARS. SARS-CoV S protein and its RNA were only detected in ACE2+ cells in the lungs and other organs, indicating that ACE2-expressing cells are the primary targets for SARS-CoV infection in vivo in humans. High levels of PICs were expressed in the SARS-CoV-infected ACE2+ cells, but not in the uninfected cells. These results suggest that cells infected by SARS-CoV produce elevated levels of PICs which may cause immuno-mediated damage to the lungs and other organs, resulting in ALI and, subsequently, multi-organ dysfunction. Therefore application of PIC antagonists may reduce the severity and mortality of SARS.

Characterization of encapsulated and noncapsulated Haemophilus influenzae and determination of phylogenetic relationships by multilocus sequence typing.

Abstract: A multilocus sequence typing (MLST) scheme has been developed for the unambiguous characterization of encapsulated and noncapsulated Haemophilus influenzae isolates The sequences of internal fragments of seven housekeeping genes were determined for 131 isolates, comprising a diverse set of 104 serotype a, b, c, d, e, and f isolates and 27 noncapsulated isolates Many of the encapsulated isolates had previously been characterized by multilocus enzyme electrophoresis (MLEE), and the validity of the MLST scheme was established by the very similar clustering of isolates obtained by these methods Isolates of serotypes c, d, e, and f formed monophyletic groups on a dendrogram constructed from the differences in the allelic profiles of the isolates, whereas there were highly divergent lineages of both serotype a and b isolates Noncapsulated isolates were distinct from encapsulated isolates and, with one exception, were within two highly divergent clusters The relationships between the major lineages of encapsulated H influenzae inferred from MLEE data could not be discerned on a dendrogram constructed from differences in the allelic profiles, but were apparent on a tree reconstructed from the concatenated nucleotide sequences Recombination has not therefore completely eliminated phylogenetic signal, and in support of this, for encapsulated isolates, there was significant congruence between many of the trees reconstructed from the sequences of the seven individual loci Congruence was less apparent for noncapsulated isolates, suggesting that the impact of recombination is greater among noncapsulated than encapsulated isolates The H influenzae MLST scheme is available at wwwmlstnet, it allows any isolate to be compared with those in the MLST database, and (for encapsulated isolates) it assigns isolates to their phylogenetic lineage, via the Internet