Down Regulation of Genes Involved in T Cell Polarity and Motility during the Induction of Heart Allograft Tolerance by Allochimeric MHC I

BACKGROUND:The allochimeric MHC class I molecule [alpha1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) epitopes displayed on recipient-type (ACI, RT1a) administered in conjunction with sub-therapeutic dose of cyclosporine (CsA) induces indefinite survival of heterotopic cardiac allografts in rat model. In vascularized transplantation models, the spleen contributes to graft rejection by generating alloantigen reactive T cells. The immune response in allograft rejection involves a cascade of molecular events leading to the formation of immunological synapses between T cells and the antigen-presenting cells. METHODOLOGY/PRINCIPAL FINDINGS:To elucidate the molecular pathways involved in the immunosuppressive function of allochimeric molecule we performed microarray and quantitative RTPCR analyses of gene expression profile of splenic T cells from untreated, CsA treated, and allochimeric molecule + subtherapeutic dose of CsA treated animals at day 1, 3 and 7 of post transplantation. Allochimeric molecule treatment caused down regulation of genes involved in actin filament polymerization (RhoA and Rac1), cell adhesion (Catna1, Vcam and CD9), vacuolar transport (RhoB, Cln8 and ATP6v1b2), and MAPK pathway (Spred1 and Dusp6) involved in tubulin cytoskeleton reorganization and interaction between actin and microtubule cytoskeleton. All these genes are involved in T cell polarity and motility, i.e., their ability to move, scan and to form functional immunological synapse with antigen presenting cells (APCs). CONCLUSIONS:These results indicate that the immunosuppressive function of allochimeric molecule may depend on the impairment of T cells' movement and scanning ability, and possibly also the formation of immunological synapse. We believe that these novel findings may have important clinical implications for organ transplantation

The need for education on health related-quality of life

<p>Abstract</p> <p>Background</p> <p>Health-related quality of life is increasingly recognised as an important outcome measure that complements existing measures of clinical effectiveness. The education available on this subject for different healthcare professionals is varied. This article describes the design, implementation and evaluation of a Special Study Module on Health-Related Quality of Life for undergraduate medical students at the University of Birmingham.</p> <p>Methods</p> <p>The course involves 10 hours of "guided discovery learning" covering core concepts of Health-Related Quality of Life assessment including methodological considerations, use in clinical trials, routine practice and in health policy followed by self-directed learning. The taught components aim to provide students with the skills and knowledge to enable them to explore and evaluate the use of quality of life assessments in a particular patient group, or setting, through self-directed learning supported by tutorials.</p> <p>Results</p> <p>The use of case studies, recent publications and research, and discussion with a research oncology nurse in task-based learning appeared to provide students with a stimulating environment in which to develop their ideas and was reflected in the diverse range of subjects chosen by students for self-directed study and the positive feedback on the module. Course evaluation and student assessment suggests that quality of life education appears to integrate well within the medical curriculum and allows students to develop and utilise skills of time-management and independent, self-directed learning that can be applied in any context.</p> <p>Conclusion</p> <p>We suggest that education and training initiatives in quality of life may improve the quality of studies, and help bridge the gap between research and clinical practice. Resources for curriculum development on health-related quality of life have been developed by the International Society for Quality of Life Research and may prove a useful tool to educators interested in this area.</p

Phylomemetics—Evolutionary Analysis beyond the Gene

Genes are propagated by error-prone copying, and the resulting variation provides the basis for phylogenetic reconstruction of evolutionary relationships. Horizontal gene transfer may be superimposed on a tree-like evolutionary pattern, with some relationships better depicted as networks. The copying of manuscripts by scribes is very similar to the replication of genes, and phylogenetic inference programs can be used directly for reconstructing the copying history of different versions of a manuscript text. Phylogenetic methods have also been used for some time to analyse the evolution of languages and the development of physical cultural artefacts. These studies can help to answer a range of anthropological questions. We propose the adoption of the term “phylomemetics” for phylogenetic analysis of reproducing non-genetic elements

Genomic reconstruction of the SARS-CoV-2 epidemic in England.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021

Friends disconnected: How mobile work transforms friendships through absence and presence

In this paper, we focus on friendship as a significant interpersonal relationship that has not prominently figured in geographic discussions of mobile work. Taking friendship as our object of analysis, we explore how wellbeing becomes compromised for mobile workers and their friends. Responding to concerns outlined by our research participants during semi‐structured Skype interviews, we acknowledge mobile working practices transform friendships that exist outside sites of paid labour. To consider the complexity of these transformations, we address how spatial relations of proximity and distance demarcate physical and metaphorical issues of absence and presence. These issues can lead mobile workers to become reclusive and focused on self‐directed activities. This oscillating absence and presence transforms friendships and highlights the relational interplay of mobility and immobility in mobile work

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease