Selective expansion of viral variants following experimental transmission of a reconstituted feline immunodeficiency virus quasispecies

Following long-term infection with virus derived from the pathogenic GL8 molecular clone of feline immunodeficiency virus (FIV), a range of viral variants emerged with distinct modes of interaction with the viral receptors CD134 and CXCR4, and sensitivities to neutralizing antibodies. In order to assess whether this viral diversity would be maintained following subsequent transmission, a synthetic quasispecies was reconstituted comprising molecular clones bearing envs from six viral variants and its replicative capacity compared in vivo with a clonal preparation of the parent virus. Infection with either clonal (Group 1) or diverse (Group 2) challenge viruses, resulted in a reduction in CD4+ lymphocytes and an increase in CD8+ lymphocytes. Proviral loads were similar in both study groups, peaking by 10 weeks post-infection, a higher plateau (set-point) being achieved and maintained in study Group 1. Marked differences in the ability of individual viral variants to replicate were noted in Group 2; those most similar to GL8 achieved higher viral loads while variants such as the chimaeras bearing the B14 and B28 Envs grew less well. The defective replication of these variants was not due to suppression by the humoral immune response as virus neutralising antibodies were not elicited within the study period. Similarly, although potent cellular immune responses were detected against determinants in Env, no qualitative differences were revealed between animals infected with either the clonal or the diverse inocula. However, in vitro studies indicated that the reduced replicative capacity of variants B14 and B28 in vivo was associated with altered interactions between the viruses and the viral receptor and co-receptor. The data suggest that viral variants with GL8-like characteristics have an early, replicative advantage and should provide the focus for future vaccine development

Modulation of the virus-receptor interaction by mutations in the V5 loop of feline immunodeficiency virus (FIV) following in vivo escape from neutralising antibody

<b>BACKGROUND:</b> In the acute phase of infection with feline immunodeficiency virus (FIV), the virus targets activated CD4+ T cells by utilising CD134 (OX40) as a primary attachment receptor and CXCR4 as a co-receptor. The nature of the virus-receptor interaction varies between isolates; strains such as GL8 and CPGammer recognise a "complex" determinant on CD134 formed by cysteine-rich domains (CRDs) 1 and 2 of the molecule while strains such as PPR and B2542 require a more "simple" determinant comprising CRD1 only for infection. These differences in receptor recognition manifest as variations in sensitivity to receptor antagonists. In this study, we ask whether the nature of the virus-receptor interaction evolves in vivo.<p></p> <b>RESULTS:</b> Following infection with a homogeneous viral population derived from a pathogenic molecular clone, a quasispecies emerged comprising variants with distinct sensitivities to neutralising antibody and displaying evidence of conversion from a "complex" to a "simple" interaction with CD134. Escape from neutralising antibody was mediated primarily by length and sequence polymorphisms in the V5 region of Env, and these alterations in V5 modulated the virus-receptor interaction as indicated by altered sensitivities to antagonism by both anti-CD134 antibody and soluble CD134.<p></p> <b>CONCLUSIONS:</b> The FIV-receptor interaction evolves under the selective pressure of the host humoral immune response, and the V5 loop contributes to the virus-receptor interaction. Our data are consistent with a model whereby viruses with distinct biological properties are present in early versus late infection and with a shift from a "complex" to a "simple" interaction with CD134 with time post-infection.<p></p&gt

Enhancement of outflow facility in the murine eye by targeting selected tight-junctions of Schlemm's canal endothelia

The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm’s canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system

How Common is Common Human Reason?:The Plurality of Moral Perspectives and Kant’s Ethics

In his practical philosophy, Kant aims to systematize and ground a conception of morality that every human being already in some form is supposedly committed to in virtue of her common human reason. While Kantians especially in the last few years have explicitly acknowledged the central role of common human reason for a correct understanding of Kant’s ethics, there has been very little detailed critical discussion of the very notion of a common human reason as Kant envisages it. Sticker critically discusses in what ways Kant is committed to the notion that there are certain rational insights and rational capacities that all humans share, and thus investigates critically how Kant thinks moral normativity appears to the common human being, the rational agent who did not enjoy special education or philosophical training

Action 3:30R: Process evaluation of a cluster randomised feasibility study of a revised teaching assistant-led extracurricular physical activity intervention for 8 to 10 year olds

Background: Numerous interventions to increase children's physical activity levels are published, yet, few studies report indicators of external validity. Process evaluations are critical for assessing intervention implementation, sustainability and effectiveness. A mixed-methods process evaluation, using the RE-AIM framework, was conducted to evaluate the internal and external validity of Action 3:30R, a revised teaching assistant-led after-school intervention which aimed to increase physical activity in children aged 8-10 years and was underpinned by Self-determination Theory (SDT). Methods: Data were collected and reported in line with the five components of RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance). Quantitative measures included logbooks, registers and self-reported teaching-efficacy, autonomy support, child enjoyment and perceived exertion questionnaires. Questionnaire data were collected at three points throughout the 15-week intervention. Observations by trained researchers were also conducted to assess fidelity to the intervention manual and its underpinning theory. Post-intervention focus groups with pupils and interviews with teaching assistants (TAs), school staff and external stakeholders explored the implementation and potential sustainability of Action 3:30R from stakeholders' perspectives. Results: Action 3:30R appealed to a broad range of pupils, including girls and less-active pupils. The Action 3:30R TA training was implemented as intended and was perceived as valuable professional development. Releasing staff for training was a barrier in two of the six intervention schools, which were unable to deliver the intervention as a result. Pupils enjoyed the intervention, and the Action 3:30R core principles underpinned by SDT were implemented with high fidelity, as was the intervention itself. Scheduling conflicts with other clubs and lack of parental support were perceived as the main barriers to recruitment and attendance. Lack of space and season were cited as the main barriers affecting the quality of delivery. The study shows evidence of maintenance, as one intervention school decided to continue Action 3:30R beyond the study. Funding and continued TA training were suggested as factors which may affect the maintenance of Action 3:30R. Conclusions: Action 3:30R is an enjoyable, autonomy-supportive after-school programme, which engages a range of pupils and offers TAs valuable training. RE-AIM provided helpful structure and is recommended for intervention evaluations. Trial registration: ISRCTN34001941. Prospectively registered 01/12/2016

Effects of explaining on children's preference for simpler hypotheses

Research suggests that the process of explaining influences causal reasoning by prompting learners to favor hypotheses that offer "good" explanations. One feature of a good explanation is its simplicity. Here, we investigate whether prompting children to generate explanations for observed effects increases the extent to which they favor causal hypotheses that offer simpler explanations, and whether this changes over the course of development. Children aged 4, 5, and 6 years observed several outcomes that could be explained by appeal to a common cause (the simple hypothesis) or two independent causes (the complex hypothesis). We varied whether children were prompted to explain each observation or, in a control condition, to report it. Children were then asked to make additional inferences for which the competing hypotheses generated different predictions. The results revealed developmental differences in the extent to which children favored simpler hypotheses as a basis for further inference in this task: 4-year-olds did not favor the simpler hypothesis in either condition; 5-year-olds favored the simpler hypothesis only when prompted to explain; and 6-year-olds favored the simpler hypothesis whether or not they explained

Feline low-grade alimentary lymphoma: an emerging entity and a potential animal model for human disease

Background: Low-grade alimentary lymphoma (LGAL) is characterised by the infiltration of neoplastic T-lymphocytes, typically in the small intestine. The incidence of LGAL has increased over the last ten years and it is now the most frequent digestive neoplasia in cats and comprises 60 to 75% of gastrointestinal lymphoma cases. Given that LGAL shares common clinical, paraclinical and ultrasonographic features with inflammatory bowel diseases, establishing a diagnosis is challenging. A review was designed to summarise current knowledge of the pathogenesis, diagnosis, prognosis and treatment of feline LGAL. Electronic searches of PubMed and Science Direct were carried out without date or language restrictions. Results: A total of 176 peer-reviewed documents were identified and most of which were published in the last twenty years. 130 studies were found from the veterinary literature and 46 from the human medicine literature. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. The pathophysiology of feline LGAL still needs to be elucidated, not least the putative roles of infectious agents, environmental factors as well as genetic events. The most common therapeutic strategy is combination treatment with prednisolone and chlorambucil, and prolonged remission can often be achieved. Developments in immunohistochemical analysis and clonality testing have improved the confidence of clinicians in obtaining a correct diagnosis between LGAL and IBD. The condition shares similarities with some diseases in humans, especially human indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Conclusions: The pathophysiology of feline LGAL still needs to be elucidated and prospective studies as well as standardisation of therapeutic strategies are needed. A combination of conventional histopathology and immunohistochemistry remains the current gold-standard test, but clinicians should be cautious about reclassifying cats previously diagnosed with IBD to lymphoma on the basis of clonality testing. Importantly, feline LGAL could be considered to be a potential animal model for indolent digestive T-cell lymphoproliferative disorder, a rare condition in human medicine