Dysregulated RasGRP1 Responds to Cytokine Receptor Input in T Cell Leukemogenesis

Enhanced signaling by the small guanosine triphosphatase Ras is common in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), but the underlying mechanisms are unclear. We identified the guanine nucleotide exchange factor RasGRP1 (Rasgrp1 in mice) as a Ras activator that contributes to leukemogenesis. We found increased RasGRP1 expression in many pediatric T-ALL patients, which is not observed in rare early T cell precursor T-ALL patients with KRAS and NRAS mutations, such as K-Ras[superscript G12D]. Leukemia screens in wild-type mice, but not in mice expressing the mutant K-Ras[superscript G12D] that encodes a constitutively active Ras, yielded frequent retroviral insertions that led to increased Rasgrp1 expression. Rasgrp1 and oncogenic K-Ras[superscript G12D] promoted T-ALL through distinct mechanisms. In K-Ras[superscript G12D] T-ALLs, enhanced Ras activation had to be uncoupled from cell cycle arrest to promote cell proliferation. In mouse T-ALL cells with increased Rasgrp1 expression, we found that Rasgrp1 contributed to a previously uncharacterized cytokine receptor–activated Ras pathway that stimulated the proliferation of T-ALL cells in vivo, which was accompanied by dynamic patterns of activation of effector kinases downstream of Ras in individual T-ALLs. Reduction of Rasgrp1 abundance reduced cytokine-stimulated Ras signaling and decreased the proliferation of T-ALL in vivo. The position of RasGRP1 downstream of cytokine receptors as well as the different clinical outcomes that we observed as a function of RasGRP1 abundance make RasGRP1 an attractive future stratification marker for T-ALL.National Institutes of Health (U.S.). Pioneer AwardNational Cancer Institute (U.S.). Physical Sciences-Oncology Center (U54CA143874)National Institutes of Health (U.S.). (P01 AI091580

Power sharing, conflict resolution, and the logic of pre-emptive defection

Conclusions about the potential for peace via power-sharing are mixed. For some, power-sharing does little to overcome the commitment problem characterizing a transition from conflict, while others argue that such concessions provide signals of parties’ willingness to incur costs. This article develops and tests a new theory, aiming to shed light on the mechanisms through which power-sharing bargains help to overcome the commitment problem. I argue that government parties tend to hold an electoral and military advantage, which heightens incentives for rebel leaders to defect from a settlement prior to conceding their capacity to use violence. Where settlements provide discrete guarantees that offset the risks of electoral defeat and the co-optation of forces, these incentives for pre-emptive defection should be mitigated. I offer a novel disaggregation of provisional power-sharing subtypes, distinguishing between long-term and short-term arrangements. The analysis rests on an original, cross-national dataset of government-and-rebel dyads to negotiated settlements signed between 1975 and 2015 (N = 168). The logistic regression results clearly indicate that power-sharing settlements stipulating ‘consociational’-style reforms are significantly more likely to resolve conflict between settlement dyads, all else equal. Meanwhile, standard conceptualizations of power-sharing, which include transitional coalitions and troop integration, appear unlikely to secure rebel commitment beyond the transition period, which helps to explain the contradictory findings in existing research

Cardiac Myosin-Binding Protein C Modulates the Tuning of the Molecular Motor in the Heart

Cardiac myosin binding protein C (cMyBP-C) is an important regulator of cardiac contractility. Its precise effect on myosin cross-bridges (CBs) remains unclear. Using a cMyBP-C−/− mouse model, we determined how cMyBP-C modulates the cyclic interaction of CBs with actin. From papillary muscle mechanics, CB characteristics were provided using A. F. Huxley's equations. The probability of myosin being weakly bound to actin was higher in cMyBP-C−/− than in cMyBP-C+/+. However, the number of CBs in strongly bound, high-force generated state and the force generated per CB were lower in cMyBP-C−/−. Overall CB cycling and the velocity of CB tilting were accelerated in cMyBP-C−/−. Taking advantage of the presence of cMyBP-C in cMyBP-C+/+ myosin solution but not in cMyBP-C−/−, we also analyzed the effects of cMyBP-C on the myosin-based sliding velocity of actin filaments. At baseline, sliding velocity and the relative isometric CB force, as determined by the amount of α-actinin required to arrest thin filament motility, were lower in cMyBP-C−/− than in cMyBP-C+/+. cAMP-dependent protein kinase-mediated cMyBP-C phosphorylation further increased the force produced by CBs. We conclude that cMyBP-C prevents inefficient, weak binding of the myosin CB to actin and has a critical effect on the power-stroke step of the myosin molecular motor