The Human Minor Histocompatibility Antigen1 Is a RhoGAP

The human minor Histocompatibility Antigen HMHA-1 is a major target of immune responses after allogeneic stem cell transplantation applied for the treatment of leukemia and solid tumors. The restriction of its expression to hematopoietic cells and many solid tumors raised questions regarding its cellular functions. Sequence analysis of the HMHA-1 encoding HMHA1 protein revealed the presence of a possible C-terminal RhoGTPase Activating Protein (GAP) domain and an N-terminal BAR domain. Rho-family GTPases, including Rac1, Cdc42, and RhoA are key regulators of the actin cytoskeleton and control cell spreading and migration. RhoGTPase activity is under tight control as aberrant signaling can lead to pathology, including inflammation and cancer. Whereas Guanine nucleotide Exchange Factors (GEFs) mediate the exchange of GDP for GTP resulting in RhoGTPase activation, GAPs catalyze the low intrinsic GTPase activity of active RhoGTPases, resulting in inactivation. Here we identify the HMHA1 protein as a novel RhoGAP. We show that HMHA1 constructs, lacking the N-terminal region, negatively regulate the actin cytoskeleton as well as cell spreading. Furthermore, we show that HMHA1 regulates RhoGTPase activity in vitro and in vivo. Finally, we demonstrate that the HMHA1 N-terminal BAR domain is auto-inhibitory as HMHA1 mutants lacking this region, but not full-length HMHA1, showed GAP activity towards RhoGTPases. In conclusion, this study shows that HMHA1 acts as a RhoGAP to regulate GTPase activity, cytoskeletal remodeling and cell spreading, which are crucial functions in normal hematopoietic and cancer cells

Knowledge ‘Translation’ as Social Learning: Negotiating the Uptake of Research-Based Knowledge in Practice

BACKGROUND: Knowledge translation and evidence-based practice have relied on research derived from clinical trials, which are considered to be methodologically rigorous. The result is practice recommendations based on a narrow view of evidence. We discuss how, within a practice environment, in fact individuals adopt and apply new evidence derived from multiple sources through ongoing, iterative learning cycles. DISCUSSION: The discussion is presented in four sections. After elaborating on the multiple forms of evidence used in practice, in section 2 we argue that the practitioner derives contextualized knowledge through reflective practice. Then, in section 3, the focus shifts from the individual to the team with consideration of social learning and theories of practice. In section 4 we discuss the implications of integrative and negotiated knowledge exchange and generation within the practice environment. Namely, how can we promote the use of research within a team-based, contextualized knowledge environment? We suggest support for: 1) collaborative learning environments for active learning and reflection, 2) engaged scholarship approaches so that practice can inform research in a collaborative manner and 3) leveraging authoritative opinion leaders for their clinical expertise during the shared negotiation of knowledge and research. Our approach also points to implications for studying evidence-informed practice: the identification of practice change (as an outcome) ought to be supplemented with understandings of how and when social negotiation processes occur to achieve integrated knowledge. SUMMARY: This article discusses practice knowledge as dependent on the practice context and on social learning processes, and suggests how research knowledge uptake might be supported from this vantage point

Organisationskultur. Eine Konkretisierung aus systemtheoretischer Perspektive

Kühl S. Organisationskultur. Eine Konkretisierung aus systemtheoretischer Perspektive. Managementforschung. 2018;28(1):7-35.Die Bestimmung des Verhältnisses von Informalität und Organisationskultur bereitet in der Organisationstheorie Schwierigkeiten. Das liegt daran, dass der Begriff Informalität häufig stillschweigend durch den Begriff der Organisationskultur ersetzt wurde, ohne dass dafür eine präzise, abgrenzungsscharfe Definition vorgenommen worden wäre. Unter Rückgriff auf Überlegungen von Dario Rodríguez argumentiert dieser Artikel, dass die beiden Begriffe Organisationskultur und Informalität das gleiche Phänomen bezeichnen: die nichtentschiedenen Entscheidungsprämissen einer Organisation. Dabei wird systematisch zwischen „unentscheidbaren Entscheidungsprämissen“ und „prinzipiell entscheidbaren, aber nicht entschiedenen Entscheidungsprämissen“ unterschieden. Es wird gezeigt, wie sich mit einer präzisen Bestimmung über das Konzept der Entscheidungsprämissen Ordnung in die „wilden Merkmallisten“ der Literatur sowohl über Informalität als auch Organisationskultur bringen lässt und empirische Phänomene genauer erfasst werden können