On Morals, Markets, and Climate Change: Exploring Pope Francis’ Challenge

The relation between Culture and Business has caught researchers’ attention long ago; itis not hard to find studies relating to these topics. According to Hofstede et al. (2010, p.18), Hampden-Turner and Trompenaars (2012, p. 8), and Erez and Gati (2004, p. 5),culture can be defined in many levels, for example, organizational culture, and national culture. The field of Business also contains several disciplines, for example, International Business Management, Project Management, and Project Governance. However, not somany studies can be found studying the relation between National Culture and Project Governance; therefore, this study is focused on this relation.This study is designed following a qualitative approach in order to clarify the relation between National Culture and Project Governance Principles. Case studies are used targeting the IT industry of three countries, Spain, Sweden, and Taiwan. These cases also contain the classical theory of cultural dimensions from Hofstede. Hofstede’s dimensionsare Power Distance (PDI), Individualism vs. Collectivism (IDV), Uncertainty Avoidance(UAI), Masculinity vs. Femininity (MAS), Long-term Orientation (LTO), and Indulgencevs. Restraint (IDU). They are applied in this study for distinguishing the differences between countries. This study is also based on the definition of Project GovernancePrinciples from Garland (2009), Klakegg (2008), and Müller et al. (2013). ProjectGovernance Principles are split into two categories as well, hard/ structural principles andsoft/ behaviour principles.In order to clarify the link between National Culture and Project Governance Principles,this thesis’ authors interviewed 19 people, including 10 project managers and 9 experts.All of them have a long experience dealing with Project Management in the three selected countries. Their answers are based on the knowledge and experience of Project Management and Project Governance, as well as their opinions about their own national culture. After analysing the interviews, the authors consider that differences between these three countries in Project Governance and Project Governance Principles do exist. On the other hand, there are also some similar parts, for example, the influence ofcustomers’ orientation and preference. Moreover, respondents, Project Managers and Experts, all mentioned it is also necessary to be aware of the globalized environment, inother words, there is no influence of a single national culture in one country anymore.However, they all admit the importance of their own national culture as well. All these findings from this study encourage further and deeper study in the future

eIF4A inhibitors suppress cell-cycle feedback response and acquired resistance to CDK4/6 inhibition in cancer

CDK4/6 inhibitors are FDA-approved drugs for estrogen receptor-positive (ER+) breast cancer and are being evaluated to treat other tumor types, including KRAS-mutant non-small cell lung cancer (NSCLC). However, their clinical utility is often limited by drug resistance. Here, we sought to better understand the resistant mechanisms and help devise potential strategies to overcome this challenge. We show that treatment with CDK4/6 inhibitors in both ER+ breast cancer and KRAS-mutant NSCLC cells induces feedback upregulation of cyclin D1, CDK4, and cyclin E1, mediating drug resistance. We demonstrate that rocaglates, which preferentially target translation of key cell-cycle regulators, effectively suppress this feedback upregulation induced by CDK4/6 inhibition. Consequently, combination treatment of CDK4/6 inhibitor palbociclib with the eukaryotic initiation factor (eIF) 4A inhibitor, CR-1-31-B, is synergistic in suppressing the growth of these cancer cells in vitro and in vivo Furthermore, ER+ breast cancer and KRAS-mutant NSCLC cells that acquired resistance to palbociclib after chronic drug exposure are also highly sensitive to this combination treatment strategy. Our findings reveal a novel strategy using eIF4A inhibitors to suppress cell-cycle feedback response and to overcome resistance to CDK4/6 inhibition in cancer.Accepted manuscrip

Regulation of Egf Receptor Dynamics by Protein Tyrosine Phosphatases

The phosphorylated epidermal growth factor receptor (EGFR) initiates intracellular signaling processes that regulate cell growth, survival, and migration, and disregulated EGFR-mediated signaling occurs in many cancers. While the processes that lead to EGFR activation and phosphorylation have been studied in detail, quantitative aspects of the spatiotemporal regulation of EGFR by protein tyrosines phosphatases (PTPs) are not well understood. To begin to address this, we developed a new compartmentalized mechanistic model of EGFR phosphorylation dynamics and used it to interpret quantitative biochemical measurements to show that EGFR is dephosphorylated at the plasma membrane and in the cell interior with a time scale that is small compared to the time scales for EGFR internalization. By expanding our computational model and experimental data set, we went on to demonstrate that EGFR dephosphorylation at the plasma membrane surprisingly does not affect phosphorylation-dependent EGFR internalization because a separation of phospho-dependent time scales enables EGFR to enter clathrin-coated pits prior to being acted upon by PTPs. This same separation of time scales does, however, allow PTPs to control EGFR association with adapter proteins that regulate downstream signaling. Thus, our model provides new quantitative understanding of how EGFR participates in a number of simultaneous processes that compete for EGFR C-terminal phosphotyrosines. We went on to apply this new quantitative understanding of EGFR regulation by PTPs by developing predictive models to understand how such regulation might differentially impact the efficacy of antibodies and kinase inhibitors targeting EGFR. We also developed new computational models to quantitatively predict how receptor dephosphorylation kinetics as rapid as we found for EGFR might differentially control signaling initiated by receptor tyrosine kinases that dimerize in structurally distinct ways observed naturally among the family of receptor tyrosine kinases (RTKs). Ultimately, the new quantitative understanding of EGFR regulation by PTPs developed in this thesis significantly refines our understanding of the dynamics of EGFR-mediated signaling, provides a number of additional testable predictions related to fundamental aspects of EGFR signaling complex nucleation and efficacy of EGFR-targeted therapeutics, and offers a basic quantitative framework for exploring the regulation of other receptor tyrosine kinases by PTPs

From Top-Down to Bottom-Up Climate Policy: New Challenges in Carbon Market Design

This Article explores the shift from top-down to bottom-up approaches to carbon market design, focusing on three strategies that have emerged since 2009: the California Cap-and-Trade Program, the Clean Power Plan, and the UNFCCC process. The Article then examines the prospects for broad multilateral markets to emerge under a bottom-up approach and identifies three pathways to streamline market design choices: a coordinated approach; a dominant actor approach; and a common elements approach

The Ends and Means of Decarbonization: The Green New Deal in Context

Disputes about climate policy involve much more than whether or not to reduce greenhouse gas emissions. There is general agreement among proponents of climate policy that strategies should be cost effective, address distributional impacts, and incentivize investments in low-carbon technologies. Yet disagreements abound regarding additional goals of climate policy design. Decarbonizing the economy means changing the sources of energy we use, how we transport people and products, how we produce food, and which resources we consume. Yet even among proponents of federal climate legislation there is strong disagreement regarding policy instruments. Recent proposals for a revenue-neutral carbon tax and a Green New Deal (GND) frame the opposite ends of the debate. On one end, the GND framework treats climate policy as an opportunity to steer the trajectory of the U.S. economy while also correcting social and environmental injustices. Proponents of the most expansive iterations of a GND argue that it is not possible to separate justice and economic considerations from environmental policy. At the other end of the spectrum, revenue-neutral carbon tax proposals reject the creation of new government programs and focus on controlling greenhouse gas emissions rather than the economic and social impacts of the policy. This Essay identifies core disputes about the non-emission goals in state and federal climate policy debates that create barriers to legislative consensus. The Essay begins with a comparison of recent proposals to mitigate climate change, including pricing carbon via a carbon market or carbon tax, regulatory measures such as the Obama-era Clean Power Plan, state-based policies, and the GND. It then identifies three conflicts, the resolution of which will shape future climate policy developments: the role of decarbonization as technology policy, social justice policy, and fiscal policy. Deploying low carbon technologies is a critical piece of the climate mitigation puzzle, but stakeholders disagree whether decarbonization strategies should prioritize renewable energy or include technologies such as nuclear or carbon capture. Each policy discussed in this Essay considers some range of social impacts (at minimum, cost increases), but differ significantly about which social impacts to address and the how to address them. The policies also adopt different approaches to the link between fiscal policy and climate policy, with some generating revenue to fund new government programs, some returning revenue to U.S. citizens, and some not addressing the issue. The Essay concludes with comments about the early impacts of the GND on the domestic policy debate and opportunities to resolve it

Ratemaking as Climate Adaptation Governance

Electric utilities are directly affected by, and in some cases are a source of, many pressing climate adaptation challenges: wildfires, vulnerable infrastructure, extreme storms, and drought. The state Public Utilities Commission (PUC) is one of the most consequential government agencies guiding the electricity sector’s response to climate change. Rate-regulated utilities may not charge ratepayers for new capital investments without PUC approval. When PUCs decide which costs are eligible for rate recovery, they also define which risks utilities seek to manage and which hedging strategies they use to do so. This Article argues that the foundational principles of ratemaking allow the state PUC tomanagemany aspects of electricity sector adaptation planning, coordination, and implementation. The Article begins with an overview of ratemaking for electric utilities and identifies how the process is an exercise in risk management. The Article then explains how a risk governance perspective can position the PUC to explicitly incorporate climate adaptation into ratemaking procedures as well as help coordinate adaptation policy across multiple agencies