CD25 expression distinguishes functionally distinct alloreactive CD4+ CD134+ (OX40+) T-cell subsets in acute graft-versus-host disease

AbstractCD134 (OX40) is expressed on activated CD4+ donor T cells in allogeneic stem cell transplant recipients with acute graft-versus-host disease. The data presented here reveal that differential expression of CD25 by CD4+ CD134+ T cells allows separation of these activated cells into 2 phenotypically and functionally distinct alloreactive T-cell subsets. These subsets exhibit distinct tissue associations, with CD4+ CD134+ CD25− T cells preferentially found in lymphoid tissues and CD4+ CD134+ CD25+ T cells located in lymphoid tissues and inflamed extralymphoid tissues. The CD25− T-cell subset exhibited potent proliferative responses to both concanavalin A and allogeneic host leukocytes. By contrast, the CD25+ T-cell subset proliferated minimally in response to either treatment and inhibited alloantigen-induced proliferation of the CD25− subset. Proliferative unresponsiveness associated with the CD25+ T-cell subset did not extend to cytokine secretion. When stimulated with alloantigen, both CD4+ CD134+ T-cell subsets responded by secreting interferon-γ and interleukin (IL)-10, and neither T-cell subset produced detectable levels of IL-2 or IL-4. Three-day treatment of the CD25+ T-cell subset with IL-2 restored the proliferative responsiveness of these cells to host alloantigens, suggesting that the proliferative unresponsiveness associated with this T-cell subset reflected a requirement for IL-2. The preferential tissue associations and distinct functional properties associated with these separable alloreactive CD4+ CD134+ T-cell subsets suggest that they participate differentially in clinical graft-versus-host disease

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Reframing water governance praxis: does reflection on metaphors have a role?

Action for adaptation is needed in the face of anthropogenic climate change. The record of adaptation in the field of freshwater governance is poor to date, as it is apparently constrained by operational frameworks. Analyses based on the Contemporary Theory of Metaphor can reveal underlying, often institutionally reified, operational frameworks. We present a desktop metaphor mapping study of one UK and one Australian water management planning document. This mapping demonstrates the potential of metaphor analysis, with further methodological and praxis development, to support the new ways of thinking and acting that are needed to challenge deeply held social and cultural norms of linear, rather than systemic, causality. We suggest that metaphor has the potential to help practitioners expose and examine reified operational frameworks and practices, and to change those that hinder adaptive and systemic praxis

\u27Slowing down When You Should\u27: Initiators and Influences of the Transition from the Routine to the Effortful

BACKGROUND: \u27Slowing down when you should\u27 has been described as marking the transition from \u27automatic\u27 to \u27effortful\u27 functioning in professional practice. The ability to \u27slow down\u27 is hypothesized as an important factor in expert judgment. This study explored the nature of the \u27slowing down\u27 phenomenon intraoperatively and its link to surgical judgment. METHODS: Twenty-eight surgeons across different surgical specialties were interviewed from four hospitals affiliated with a large urban university. In grounded theory tradition, data were collected and analyzed in an iterative design, using a constant comparative approach. Emergent themes were identified and a conceptual framework was developed. RESULTS: Surgeons recognized the \u27slowing down\u27 phenomenon acknowledging its link to judgment and described two main initiators. Proactively planned \u27slowing down\u27 moments were anticipated preoperatively from operation-specific (tying superior thyroid vessels) or patient-specific (imaging abnormality) factors. Surgeons also described situationally responsive \u27slowing down\u27 moments to unexpected events (encountering an adherent tumor). Surgeons described several influencing factors on the slowing down phenomenon (fatigue, confidence). CONCLUSIONS: This framework for \u27slowing down\u27 assists in making tangible the previously elusive construct of surgical judgment, providing a vocabulary for considering the events surrounding these critical moments in surgery, essential for teaching, self-reflection, and patient safety