Policy Feedback and the Politics of the Affordable Care Act

There is a large body of literature devoted to how “policies create politics” and how feedback effects from existing policy legacies shape potential reforms in a particular area. Although much of this literature focuses on self‐reinforcing feedback effects that increase support for existing policies over time, Kent Weaver and his colleagues have recently drawn our attention to self‐undermining effects that can gradually weaken support for such policies. The following contribution explores both self‐reinforcing and self‐undermining policy feedback in relationship to the Affordable Care Act, the most important health‐care reform enacted in the United States since the mid‐1960s. More specifically, the paper draws on the concept of policy feedback to reflect on the political fate of the ACA since its adoption in 2010. We argue that, due in part to its sheer complexity and fragmentation, the ACA generates both self‐reinforcing and self‐undermining feedback effects that, depending of the aspect of the legislation at hand, can either facilitate or impede conservative retrenchment and restructuring. Simultaneously, through a discussion of partisan effects that shape Republican behavior in Congress, we acknowledge the limits of policy feedback in the explanation of policy stability and change

Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors

Pre–B cell receptor–mediated cell cycle arrest in Philadelphia chromosome–positive acute lymphoblastic leukemia requires IKAROS function

B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre–B cell receptor–dependent stages. The Philadelphia chromosome–positive (Ph+) subtype of ALL accounts for 25–30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre–B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph+ ALL cells. Pre–B cell receptor–mediated cell cycle arrest in Ph+ ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre–B cell receptor signaling pathway, even if expression of the pre–B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre–B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph+ ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre–B cell receptor–mediated tumor suppression

The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells

Bone marrow hematopoietic stem cells (HSCs) balance proliferation and differentiation by integrating complex transcriptional and post-translational mechanisms regulated by cell intrinsic and extrinsic factors. We found that transcripts of G0/G1 switch gene 2 (G0S2) are enriched in lineage− Sca-1+ c-kit+ (LSK) CD150+ CD48− CD41− cells, a population highly enriched for quiescent HSCs, whereas G0S2 expression is suppressed in dividing LSK CD150+ CD48− cells. Gain-of-function analyses using retroviral expression vectors in bone marrow cells showed that G0S2 localizes to the mitochondria, endoplasmic reticulum, and early endosomes in hematopoietic cells. Co-transplantation of bone marrow cells transduced with the control or G0S2 retrovirus led to increased chimerism of G0S2-overexpressing cells in femurs, although their contribution to the blood was reduced. This finding was correlated with increased quiescence in G0S2-overexpressing HSCs (LSK CD150+ CD48−) and progenitor cells (LS−K). Conversely, silencing of endogenous G0S2 expression in bone marrow cells increased blood chimerism upon transplantation and promoted HSC cell division, supporting an inhibitory role for G0S2 in HSC proliferation. A proteomic study revealed that the hydrophobic domain of G0S2 interacts with a domain of nucleolin that is rich in arginine-glycine-glycine repeats, which results in the retention of nucleolin in the cytosol. We showed that this cytosolic retention of nucleolin occurs in resting, but not proliferating, wild-type LSK CD150+ CD48− cells. Collectively, we propose a novel model of HSC quiescence in which elevated G0S2 expression can sequester nucleolin in the cytosol, precluding its pro-proliferation functions in the nucleolus

Views of democracy and society and support for political violence in the USA: findings from a nationally representative survey.

BACKGROUND: Current conditions in the USA suggest an increasing risk for political violence. Little is known about the prevalence of beliefs that might lead to political violence, about support for and personal willingness to engage in political violence, and about how those measures vary with individual characteristics, lethality of violence, political objectives that violence might advance, or specific populations as targets. METHODS: This cross-sectional US nationally representative survey was conducted on May 13 to June 2, 2022, of adult members of the Ipsos KnowledgePanel. Outcomes are weighted, population-representative proportions of respondents endorsing selected beliefs about American democracy and society and violence to advance political objectives. RESULTS: The analytic sample included 8620 respondents; 50.5% (95% confidence interval (CI) 49.3%, 51.7%) were female; and weighted mean (± standard deviation) age was 48.4 (± 18.0) years. Nearly 1 in 5 (18.9%, 95% CI 18.0%, 19.9%) agreed strongly or very strongly that having a strong leader for America is more important than having a democracy; 16.2% (95% CI 15.3%, 17.1%) agreed strongly or very strongly that in America, native-born white people are being replaced by immigrants, and 13.7% (95% CI 12.9%, 14.6%) agreed strongly or very strongly that in the next few years, there will be civil war in the United States. One-third of respondents (32.8%, 95% CI 31.7%, 33.9%) considered violence to be usually or always justified to advance at least 1 of 17 specific political objectives. Among all respondents, 7.7% (95% CI 7.0%, 8.4%) thought it very or extremely likely that within the next few years, in a situation where they believe political violence is justified, I will be armed with a gun; 1.1% (95% CI 0.9%, 1.4%) thought it very or extremely likely that I will shoot someone with a gun. Support for political violence and for the use of firearms in such violence frequently declined with increasing age, education, and income. CONCLUSIONS: Small but concerning proportions of the population consider violence, including lethal violence, to be usually or always justified to advance political objectives. Prevention efforts should proceed urgently based on the best evidence available

Views of democracy and society and support for political violence in the USA: findings from a nationally representative survey

Abstract Background Current conditions in the USA suggest an increasing risk for political violence. Little is known about the prevalence of beliefs that might lead to political violence, about support for and personal willingness to engage in political violence, and about how those measures vary with individual characteristics, lethality of violence, political objectives that violence might advance, or specific populations as targets. Methods This cross-sectional US nationally representative survey was conducted on May 13 to June 2, 2022, of adult members of the Ipsos KnowledgePanel. Outcomes are weighted, population-representative proportions of respondents endorsing selected beliefs about American democracy and society and violence to advance political objectives. Results The analytic sample included 8620 respondents; 50.5% (95% confidence interval (CI) 49.3%, 51.7%) were female; and weighted mean (± standard deviation) age was 48.4 (± 18.0) years. Nearly 1 in 5 (18.9%, 95% CI 18.0%, 19.9%) agreed strongly or very strongly that “having a strong leader for America is more important than having a democracy”; 16.2% (95% CI 15.3%, 17.1%) agreed strongly or very strongly that “in America, native-born white people are being replaced by immigrants,” and 13.7% (95% CI 12.9%, 14.6%) agreed strongly or very strongly that “in the next few years, there will be civil war in the United States.” One-third of respondents (32.8%, 95% CI 31.7%, 33.9%) considered violence to be usually or always justified to advance at least 1 of 17 specific political objectives. Among all respondents, 7.7% (95% CI 7.0%, 8.4%) thought it very or extremely likely that within the next few years, in a situation where they believe political violence is justified, “I will be armed with a gun”; 1.1% (95% CI 0.9%, 1.4%) thought it very or extremely likely that “I will shoot someone with a gun.” Support for political violence and for the use of firearms in such violence frequently declined with increasing age, education, and income. Conclusions Small but concerning proportions of the population consider violence, including lethal violence, to be usually or always justified to advance political objectives. Prevention efforts should proceed urgently based on the best evidence available