Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is ...also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.
Estrogen receptor-α (ER) is the driving transcription factor in most breast cancers, and its associated proteins can influence drug response, but direct methods for identifying interacting proteins ...have been limited. We purified endogenous ER using an approach termed RIME (rapid immunoprecipitation mass spectrometry of endogenous proteins) and discovered the interactome under agonist- and antagonist-liganded conditions in breast cancer cells, revealing transcriptional networks in breast cancer. The most estrogen-enriched ER interactor is GREB1, a potential clinical biomarker with no known function. GREB1 is shown to be a chromatin-bound ER coactivator and is essential for ER-mediated transcription, because it stabilizes interactions between ER and additional cofactors. We show a GREB1-ER interaction in three xenograft tumors, and using a directed protein-protein approach, we find GREB1-ER interactions in half of ER+ primary breast cancers. This finding is supported by histological expression of GREB1, which shows that GREB1 is expressed in half of ER+ cancers, and predicts good clinical outcome. These findings reveal an unexpected role for GREB1 as an estrogen-specific ER cofactor that is expressed in drug-sensitive contexts.
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► A proteomic method identifies protein-protein interaction in primary tumors ► GREB1 is the top estrogen-induced ER-interacting protein ► GREB1 is an essential ER cofactor recruited to chromatin ► GREB1 is an independent prognostic marker
Discovering endogenous protein-protein interactions has been limited by sensitivity and the requirement for large quantities of starting material. Carroll and colleagues establish a method called RIME that permits rapid and sensitive purification of associated proteins from limited starting material. They show that the most enriched estrogen receptor (ER)-associated factor in breast cancer cells is GREB1, a factor with no known function. GREB1 is shown to be an essential chromatin-bound regulatory protein, which contributes to ER-mediated gene expression.
Despite the steadily expanding woman player population, women face many barriers to entering the video game industry and player community, including historical design and advertising practices, ...gendered behavioral expectations, assumed lack of skill or interest, and harassment. Offline progress in understanding gender and gender identity, combined with unique multi-user online battle arenas (MOBAs) features, may create the needed catalyst for challenging these barriers and gender stereotypes. Through 55 interviews, this study identifies gendered stereotypes familiar to League of Legends players, examines implications of those stereotypes for both men and women, and discusses insights offered to challenging stereotypes within the gaming community.
This article explores the contextual nature of fragmentation and polarisation – subjects that have attracted significant concern in the age of social media. I investigate the media sharing practices ...of Scandinavian Twitter users discussing the 2020 American presidential election, an event that attracted international attention. Using links in tweets, I map the media networks of users in Sweden and Norway in their national languages and in English. This intranational approach provides a view into whether fragmentation and polarisation are characteristic of the audience or the media milieu. The findings show Scandinavian users exhibit low audience polarisation within their national languages, but they display polarisation similar to American users when engaging with English-language media. At the same time, media fragmentation is higher in the Norwegian language than in any other sphere. This article sheds light on the relationship between the sometimes-conflated concepts of fragmentation and polarisation and provides a discussion of the implications of political information sharing on transnational digital platforms.
Objective
In this narrative review, we summarize experimental and clinical evidence demonstrating mechanistic connections between POTS and migraine.
Background
Migraine is the most common comorbidity ...in patients with POTS, a heterogenous disorder of the autonomic nervous system characterized by orthostatic intolerance and positional tachycardia. POTS is a debilitating illness with few effective treatments. We aim for this narrative review to increase awareness of the mechanistic connections between POTS and migraine providing foundational information that optimizes clinical care and advances the development of pathophysiologic‐based treatments.
Methods
We used the PubMed and Medline databases in November 2021 to perform a literature review and searched for the following keywords: “postural orthostatic tachycardia syndrome,” “POTS,” “autonomic nervous system,” AND “migraine,” “headache.”
Results
The high prevalence of migraine in patients with POTS may be explained by common pathologic mechanisms. There is evidence that dysregulation of the sympathetic nervous system, alterations in central and peripheral hemodynamics, and central sensitization increase vulnerability to both POTS and migraine. Non‐pharmacologic and pharmacologic treatments that target these shared mechanisms may provide significant benefit for the patient with POTS and migraine.
Conclusions
Identification of common affected pathways may provide important insight that advances our understanding and treatment of both migraine and POTS.
Growing interest surrounds how sustainable practices can be incorporated into a company's supply base. A growing stream of research has examined how companies can incorporate “green” criteria into ...their supplier selection decisions. This research focuses on a specialized supplier selection decision: transportation carriers. Trucking companies in particular are under pressure to reduce their environmental footprint and improve working conditions for their drivers. As such, the purpose of this research is to explore how carriers' environmental and social sustainability performance influence shippers' selection decisions and trust perceptions. Two scenario-based experiments were conducted to understand whether shippers incorporate the environmental and social sustainability performance of carriers into the selection decision. The carrier selection decision was characterized by a long-term arrangement in study one and a short-term arrangement in study two, and both studies controlled for the economic dimension so that the distinct effects of the social and environmental dimensions could be isolated. The results find that environmental and social dimensions of sustainability play differential roles in short-term and long-term carrier selection decisions, with environmental dimensions playing a more significant role in long-term selection decisions and social dimensions playing a more significant role in short-term selection decisions. The findings offer a more nuanced theoretical understanding of sustainable carrier selection decisions and practical guidance for practitioners and policymakers.
Purpose
Drawing on social exchange theory, social capital theory, and perspectives of political influence in organizations, this study develops and tests a model in which managerial political skill ...is associated with internal, supplier and customer supply chain integration through two mediating mechanisms: facilitating a supply chain orientation and mitigating self-serving politics.
Design/methodology/approach
Data were collected from three independent samples, one for each achieved state of integration (i.e. internal, customer and supplier) (ninternal = 225; ncustomer = 225; nsupplier = 225; N = 675). Hypotheses were tested with structural equation modeling and indirect effects analysis. The potential impact of unmeasured endogenous factors was mitigated through appropriate survey design, statistical control, marker variable analysis and instrument variable usage.
Findings
Managerial political skill exhibited a positive, direct relationship with achieved internal and supplier integration. Supply chain orientation partially mediated the relationship for achieving integration with both customers and suppliers. Self-serving organizational politics was not associated with achieving internal, customer or supplier integration.
Research limitations/implications
By demonstrating the importance of political influence in achieving supply chain integration, the findings support the role of managerial social capital in the underlying social exchange processes that drive integration.
Originality/value
Despite the fundamental role of informal, social dynamics in supply chain integration, past research has largely focused on either the technical prowess of middle managers or the political skill of executives in supporting integration. The present study explicates the critical role of middle management political skill in actually achieving supply chain integration.
This work analyses the presence and management As personalized digital networks have increased in cultural and political relevance, there is a more urgent need to understand their role in democratic ...memory-formation. Moreover, scholars have suggested that, in a globalized digitalized age, collective memory could extend to transnational publics. This study aims to advance the understanding of memory on global social networks by investigating the way the death of George Floyd in the summer of 2020 was treated and understood by Twitter-users outside the United States. Using a combination of big data and contemporaneous qualitative interviews with users in Norway, Sweden, and Denmark, the paper brings the concept of cosmopolitan memory into the social media era. The study finds that users fused the event and its aftermath with observations of injustice in their own countries. However, this process operated differently among users of different ideological outlooks. Another key finding is that users on the radical right resented the uptake of the event as a cosmopolitan memory, and employed techniques termed as “combative counter-memory”.
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