Three-dimensional (3D) cancer models are used as preclinical systems to mimic physiologic drug responses. We provide evidence for strong changes of proliferation and metabolic capacity in three dimensions by systematically analyzing spheroids of colon cancer cell lines. Spheroids showed relative lower activities in the AKT, mammalian target of rapamycin (mTOR) and S6K (also known as RPS6KB1) signaling pathway compared to cells cultured in two dimensions. We identified spatial alterations in signaling, as the level of phosphorylated RPS6 decreased from the spheroid surface towards the center, which closely coordinated with the tumor areas around vessels in vivo. These 3D models displayed augmented antitumor responses to AKT-mTOR-S6K or mitogen-activated protein kinase (MAPK) pathway inhibition compared to those in 2D models. Inhibition of AKT-mTOR-S6K resulted in elevated ERK phosphorylation in 2D culture, whereas under these conditions, ERK signaling was reduced in spheroids. Inhibition of MEK1 (also known as MAP2K1) led to decreased AKT-mTOR-S6K signaling in 3D but not in 2D culture. These data indicate a distinct rewiring of signaling in 3D culture and during treatment. Detached tumor-cell clusters in vessels, in addition to circulating single tumor cells, play a putative role in metastasis in human cancers. Hence, the understanding of signaling in spheroids and the responses in the 3D models upon drug treatment might be beneficial for anti-cancer therapies.

The Eurozone crisis constitutes a grave challenge to European integration. This essay presents an overview of the causes of the crisis, and analyzes why has it been so difficult to resolve. It focuses on how responses to the crisis were shaped by distributive conflicts both among and within countries. On the international level, debtor and creditor countries have fought over the distribution of responsibility for the accumulated debt; countries with current account surpluses and deficits have fought over who should implement the policies necessary to reduce the current account imbalances. Within countries, interest groups have fought to shift the costs of crisis resolution away from themselves. The essay emphasizes that the Eurozone crisis shares many features of previous debt and balance-of-payments crises. However, the Eurozone's predicament is unique because it is set within a monetary union that strongly constrains the policy options available to policymakers, and vastly increases the interdependence of the euro crisis countries on each other. The outcome of the crisis has been highly unusual, because the costs of resolving the crisis have been borne almost exclusively by the debtor countries and taxpayers in the Eurozone.2

Does globalization affect the demand-side of politics, and if so, how? This paper builds on new developments in trade theory to argue that globalization matters, but that its effects on individuals’ perceptions of labor market risk and policy preferences are more heterogenous than previous research has acknowledged. Globalization exposure increases risk perceptions and demands for social protection among low-skilled individuals, but decreases them among high-skilled individuals. This conditional effect is observationally distinct from classic trade models as well as arguments that deindustrialization or ideology predominantly drive such perceptions and preferences. Analyzing cross-national survey data from 16 European countries and focusing both on trade and offshoring, the empirical analyses support the prediction that exposure to globalization affects high- and low-skilled individuals differently, leading to variation in labor market risk perceptions and policy preferences.

This article introduces the special issue on the political economy of the Euro crisis, which aims to improve our understanding of the causes, consequences, and implications of the highly unusual nature of this crisis: a financial crisis among developed countries within a supranational monetary union. The article provides a brief chronology of the crisis, discusses its underlying causes, and reviews the ways in which comparative and international political economy can help us understand the crisis. The article then discusses the individual and collective contributions of the articles in the special issue and discusses possible future research paths on the political economy of the Euro crisis. We conclude with a brief discussion of how a political economy perspective informs our understanding of the long-term prospects for the Eurozone and European integration.

In an approaching scenario of soil nutrient depletion, root association with soil microorganisms can be key for plant health and sustainability [1-3]. Symbiotic arbuscular mycorrhizal (AM) fungi are major players in helping plants growing under nutrient starvation conditions. They provide plants with minerals like phosphate and, furthermore, act as modulators of plant growth altering the root developmental program [4, 5]. However, the precise mechanisms involved in this latter process are not well understood. Here, we show that AM fungi are able to modulate root cortex development in Medicago truncatula by activating a novel GRAS-domain transcription factor, MIG1, that determines the size of cortical root cells. MIG1 expression peaks in arbuscule-containing cells, suggesting a role in cell remodeling during fungal accommodation. Roots ectopically expressing MIG1 become thicker due to an increase in the number and width of cortical cells. This phenotype is fully counteracted by gibberellin (GA) and phenocopied with a GA biosynthesis inhibitor or by expression of a dominant DELLA (Δ18DELLA1) protein. MIG1 downregulation leads to malformed arbuscules, a phenotype rescued by Δ18DELLA1, suggesting that MIG1 intersects with the GA signaling to control cell morphogenesis through DELLA1. DELLA1 was shown to be a central node controlling arbuscule branching [6-8]. Now we provide evidence that, together with MIG1, DELLA1 is responsible for radial cortical cell expansion during arbuscule development. Our data point toward DELLA proteins being not only longitudinal root growth repressors [9] but also positive regulators of cortical radial cell expansion, extending the knowledge of how DELLAs control root growth.

In recent years, the world has seen a rising backlash against globalization. This article reviews the nature, causes, and consequences of the globalization backlash. It shows that, contrary to a popular narrative, the backlash is not associated with a large swing in public opinion against globalization but is rather a result of its politicization. The increasing influence of globalization-skeptic actors has resulted in more protectionist, isolationist, and nationalist policies, some of which fundamentally threaten pillars of the contemporary international order. Both material and nonmaterial causes drive the globalization backlash, and these causes interact and mediate each other. The consequences are shaped by the responses of societal actors, national governments, and international policy makers. These responses can either yield to and reinforce the global backlash or push back against it. Understanding these dynamics will be an important task for future research. Expected final online publication date for the Annual Review of Political Science, Volume 24 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Background: During the COVID-19 pandemic, the Working Group "Prevention and Integrative Oncology" (PRIO) in the German Cancer Society has initiated flash interviews and surveys. One of these stated increasing rates of fears and mental stress of tumor patients. Now we aimed to analyze whether tumor patients did perceive changes in their attitudes and behaviors related to their relationships, awareness of nature and quietness, interest in spiritual issues, or feelings of worries and isolation. A further point of interest was how these perceived changes could be predicted, either by meaning in life, spirituality as a resource to cope, perceived fears and worries, or particularly by their wellbeing. Materials and Methods: Online survey with standardized questionnaires (i.e., WHO-Five Well-being Index (WHO5), Meaning in Life Questionnaire (MLQ), Spiritual and Religious Attitudes to cope with illness (SpREUK-15), Gratitude/Awe scale (GrAw-7)) among 292 tumor patients (72% men; mean age 66.7 ± 10.8 years; 25% < 60 years, 33% 60-70 years, 41% > 70 years) from Germany between May 6 to June 10, 2020. Results: Patients´wellbeing (WHO5) scores were in the lower range (14.7 ± 6.0); 35% scored < 13, indicating depressive states. Wellbeing was significantly higher in older persons and lower in younger ones (F=11.1, p<.0001). Most were irritated by different statements about the danger and the course of the corona infection in the public media (60%), and 57% were worrying to be infected and to have a complicated course of disease. Because of the restrictions, patients noticed changes in their attitudes and behaviors (measured with the 12-item Perceptions of Change Scale): 1) Perception of nature and silence (Cronbach´s alpha = .82), 2) Worrying reflections and loneliness (Cronbach´s alpha = .80), 3) Interest in spirituality (Cronbach´s alpha = .91), 4) Intense relationships (Cronbach´s alpha = .64). These perceptions of change were similar in women and men, age groups and also with respect to tumor stages. Regression analyses

When popular referendums fail to ratify new international agreements or succeed in reversing existing ones, it not only affects domestic voters but also creates negative spillovers for the other parties to such agreements. We explore how voters respond to this strategic environment. We use original survey data from a poll fielded just one day before the 2015 Greek bailout referendum—a referendum in which the stakes for other countries were particularly high—to investigate how expectations about the likely foreign response to a noncooperative referendum outcome influence voting behavior and to what extent foreign policymakers can influence those expectations. Our analysis of the Greek referendum shows that such expectations had a powerful effect on voting behavior: voters expecting that a noncooperative referendum outcome would force Greece to leave the eurozone were substantially more likely to vote cooperatively than those believing that it would result in renewed negotiations with the country's creditors. Leveraging the bank closure that took place right before the vote, we also show that costly signals by foreign actors made voters more pessimistic about the consequences of a noncooperative vote and substantially increased the share of cooperative votes.