Identification of novel subgroup a variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

<b>BACKGROUND:</b> The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD) of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C.<p></p> <b>RESULTS:</b> Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C.<p></p> <b>CONCLUSIONS:</b> Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be predisposed towards enhanced replication in vivo and subsequent conversion to FeLV-C. The selection pressures in vivo that drive the emergence of FeLV-C in a proportion of infected cats remain to be established

Pat’s Petition

Pat’s Petition was originally an e-petition submitted on the UK Government’s website asking the Department for Work and Pensions to ‘stop and review the changes to benefits and services which are falling disproportionately on disabled people, their carers and families’. All e-petitions are submitted by an individual, in this case Pat Onions, and aim to reach 100,000 signatures for the possibility of debate in parliament.Pat’s Petition was a small group formed of volunteers, all with firsthand experience of the issue as disabled people and/or carers, who had no previous experience as a group or in reaching out online to a wider community for petition signatures. The petition reached over 62,600 signatures and ended on November 1st 2012. At the time, it was the 12th most successful petition out of the 10,294 closed petitions.While the group continues to press for change, it is helpful to reflect on the learning of their first year; specifically the development of the group and the use of e-petitions. This learning may be of use to other campaigners, to people thinking of online campaigning and also to those interested in online groups.This reflective account draws on the experiences of the individuals concerned and the private resource of communications between the group. It looks back on their experience from October 2011 to November 2012 when the petition closed, and reflects on the story of Pat’s Petition

Tumours derived from HTLV-I tax transgenic mice are characterized by enhanced levels of apoptosis and oncogene expression

In order to investigate the role that the human T‐lymphotropic virus type I (HTLV‐I) tax oncogene plays in apoptosis and transformation in vivo, four lines of HTLV‐I tax transgenic mice were generated under the regulatory control of the CD3‐ϵ promoter–enhancer sequence. These mice develop a variety of phenotypes including mesenchymal tumours, which develop at wound sites, and salivary and mammary adenomas. In situ DNA fragment labelling and immunocytochemical analysis of these tumours reveals that they display enhanced levels of apoptosis, which is associated with elevated levels of Myc, Fos, Jun, and p53 protein expression. Furthermore, double immunofluorescent staining shows that Tax expression and apoptosis co‐localize, indicating that Tax expression is closely associated with apoptosis in vivo

VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy

Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes–induced glomerular albumin solute permeability (Ps’alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps’alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy