SummaryCereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4CRBN. T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4CRBN substrates responsible for T cell co-stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros (IKZF1, encoded by the IKZF1 gene) and Aiolos (IKZF3, encoded by the IKZF3 gene) with CRL4CRBN is induced by lenalidomide or pomalidomide. Each agent promotes Aiolos and Ikaros binding to CRL4CRBN with enhanced ubiquitination leading to cereblon-dependent proteosomal degradation in T lymphocytes. We confirm that Aiolos and Ikaros are transcriptional repressors of interleukin-2 expression. The findings link lenalidomide- or pomalidomide-induced degradation of these transcriptional suppressors to well documented T cell activation. Importantly, Aiolos could serve as a proximal pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human subjects administered lenalidomide demonstrated Aiolos degradation in their peripheral T cells. In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4CRBN, leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.

No abstract

What is the meaning of our work? How do we find the work that is ours, work that is worth doing for us as individuals? This study attempted to answer these questions in understanding the experience of discovering one’s calling. It was undertaken with a group of professionals who work in areas serving the natural environment and used phenomenology to penetrate and apprehend the six themes of their experience. This article helps understand the meaning of their calling in its experiential components and offers support for its relevance in organizational life. Pseudonyms have been employed in this writing.

This article reviews andragogy as the philosophy resident in the broad arena of experience-based learning. Beneath the umbrella of experience-based learning lie the specific classroom orientations of student-centered learning, problem-based learning, and classrooms as organizations. These orientations contribute to the creation of autonomy-supportive classrooms that focus more fully on student experience as a means to greater learning. The exhaustive review of the literature on student experience in teaching environments is the foundation for claims to fuller integration of this approach and discussion that focuses on the student as the original reason for the existence of the classroom. The article closes with a call for more student-focused andragogy, its relevance for Millennial learners, and recommendations for educators.

No abstract