Type I but Not Type II Calreticulin Mutations Activate the IRE1α/XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms

Approximately 20% of patients with myeloproliferative neoplasms (MPN) harbor mutations in the gene calreticulin (CALR), with 80% of those mutations classified as either type I or type II. While type II CALR-mutant proteins retain many of the Ca2+ binding sites present in the wild-type protein, type I CALR-mutant proteins lose these residues. The functional consequences of this differential loss of Ca2+ binding sites remain unexplored. Here, we show that the loss of Ca2+ binding residues in the type I mutant CALR protein directly impairs its Ca2+ binding ability, which in turn leads to depleted endoplasmic reticulum (ER) Ca2+ and subsequent activation of the IRE1α/XBP1 pathway of the unfolded protein response. Genetic or pharmacologic inhibition of IRE1α/XBP1 signaling induces cell death in type I mutant but not type II mutant or wild-type CALR-expressing cells, and abrogates type I mutant CALR-driven MPN disease progression in vivo. Significance: Current targeted therapies for CALR-mutated MPNs are not curative and fail to differentiate between type I- versus type II-driven disease. To improve treatment strategies, it is critical to identify CALR mutation type-specific vulnerabilities. Here we show that IRE1α/XBP1 represents a unique, targetable dependency specific to type I CALR-mutated MPNs

Making a Difference in ICT Research: Feminist Theorization of Sociomateriality and the Diffraction Methodology

Part 3: Hybrid Agency and the Performativity of TechnologyInternational audienceOver the last decade, sociomateriality appeared as a theme in IS research that has been interrogated with a variety of theoretical lenses. However, researchers have since raised methodological concerns regarding its application. This paper argues that a research methodology cannot be separated from either the theoretical lens that the research adopts or from its overarching purpose. Considering the broad range of theoretical lenses through which sociomateriality could be examined, this paper focuses on Barad’s theory of agential realism [25]. The paper provides a brief history of agential realism to shed light on the reasons behind IS researchers methodological difficulty and offers a diffraction methodology as a possible methodological guide to IS research adopting this lens. Implication for research is discussed

Opening the Black Box of CSR Decision Making:A Policy-Capturing Study of Charitable Donation Decisions in China

This policy-capturing study, conducted in China, investigated the cognitive basis of managerial decisions to make a corporate charitable donation, a global issue in the context of corporate social responsibility (CSR) research and practice. Participants (N = 376) responded to a series of scenarios manipulating pressure from the five stakeholders (government, customers, competitors, employees, and shareholders) most commonly addressed by CSR research. The independent variables examined included organizational factors (industry, ownership, previous company donation, firm size, firm age, and perceived CEO attitudes toward charity) and the participants’ personal values. Results indicate a large positive effect of shareholder and governmental pressure on the decision with lesser positive effects from customers and competitors. Surprisingly, employee pressure had a negative effect on the decision to make a charitable donation. Further, personal values and perceived CEO attitudes toward charity were significantly related to the decisions participants made. In line with our theorizing, the findings indicate that a combination of personal, organizational, and institutional factors was salient in the minds of decision makers

The organizational environment with its measures, antecedents, and consequences: A review and research agenda

The organizational environment is a focal element of multifaceted managerial decisions. Consequently, research has shown a long lasting and still growing interest in investigating the organizational environment and understanding its impact on a firm. Because it is widely assumed that the business environment will become more dynamic, changes in the organizational environment have drawn the particular attention of many scholars. While the extant research has established valuable knowledge, its fragmentation due to differing definitions and contradictory findings calls for a broad review to establish a foundation for future research. By analyzing 279 studies that have investigated different aspects of the organizational environment between 1958 and mid-2017, we contribute to various research streams that involve this environmental factor. We use a comprehensive research framework to categorize and review the previous work. In particular, we distinguish between studies that define or measure the organizational environment, as well as studies that investigate antecedents, outcomes, and moderating effects of the organizational environments. Among those categories, we discuss our findings, before subsequently synthesizing existing works and deriving an agenda for future research