Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta - regulation by selective estrogen receptor modulators and importance in breast cancer

Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents

ERK5 MAP Kinase Regulates Neurogenin1 during Cortical Neurogenesis

The commitment of multi-potent cortical progenitors to a neuronal fate depends on the transient induction of the basic-helix-loop-helix (bHLH) family of transcription factors including Neurogenin 1 (Neurog1). Previous studies have focused on mechanisms that control the expression of these proteins while little is known about whether their pro-neural activities can be regulated by kinase signaling pathways. Using primary cultures and ex vivo slice cultures, here we report that both the transcriptional and pro-neural activities of Neurog1 are regulated by extracellular signal-regulated kinase (ERK) 5 signaling in cortical progenitors. Activation of ERK5 potentiated, while blocking ERK5 inhibited Neurog1-induced neurogenesis. Furthermore, endogenous ERK5 activity was required for Neurog1-initiated transcription. Interestingly, ERK5 activation was sufficient to induce Neurog1 phosphorylation and ERK5 directly phosphorylated Neurog1 in vitro. We identified S179/S208 as putative ERK5 phosphorylation sites in Neurog1. Mutations of S179/S208 to alanines inhibited the transcriptional and pro-neural activities of Neurog1. Our data identify ERK5 phosphorylation of Neurog1 as a novel mechanism regulating neuronal fate commitment of cortical progenitors

Is the EU Disinformation Review Compliant with EU Law? Complaint to the European Ombudsman About the EU Anti-Fake News Initiative

The EU’s approach to fake news, as epitomised by the European External Action (EEAS) Service East Stratcom Disinformation Review, violates the rights to freedom of expression and due process of those accused of distributing disinformation. The EU Disinformation Review is a publication of the European External Action Service (the European Union’s diplomatic service) to target fake news and online disinformation. Following our request for access to documents, EEAS conceded that the EU Disinformation Review uses an “ad hoc” methodology for conducting its fact-checks, which makes it an outlier in the international fact-checking community led by the International Fact-Checking Network (IFCN). Despite being a well-intentioned initiative to respond to the challenges posed by pro-Kremlin disinformation, the EU should ensure the respect of fundamental rights when engaging in fact-checking.The EU Disinformation Review seeks to control the right to freedom of expression by labelling publishers as “disinforming outlets” and their content as “disinformation,” creating a chilling effect on the work of journalists that is central to democracy. The right to freedom of expression is expressed in Article 11.1 of the Charter of Fundamental Rights of the European Union (2000/C 364/01) and Article 10 of the European Convention on Human Rights. The labelling of publishers as “disinformation outlets” is contrary to principle of the freedom of press established by the European Court of Human Rights: “[a] general requirement for journalists systematically and formally to distance themselves from the content of a quotation that might insult or provoke others or damage their reputation is not reconcilable with the press’ role of providing information on current events, opinion and ideas.”In addition, the methodology used by EEAS in the EU Disinformation Review is “ad hoc,” which constitutes a violation of the fundamental right to good administration in Article 41 of the European Charter of Fundamental Rights. Specifically, the ad hoc design and operation of the EU Disinformation Review fails to ensure the review acts “impartially, fairly and within a reasonable time.”First, publications are not provided with the right to be heard or proper notice. The EU Disinformation Review’s homepage offers an opportunity to contact the Task Force report a suspected mistake in a fact-check but the page is only available in English, in violation of the principle of multilingualism, and no notice if given to outlets accused of being “disinforming outlets” before or after fact-checks of their content are published.Second, the EEAS does not fulfil its duty to motivate. EEAS is given a broad margin of discretion to identify disinformation, but fails to do so according to a consistent methodology. Therefore, EEAS cannot justify, on the basis of objective criteria, its choice of which content to review and how to determine its truth or falsehood.To comply with EU law and ensure the respect of fundamental rights, the EEAS should develop and make public (1) a methodology for selecting partnerships and reviewing fact-checks in line with international standards and (2) a notice and response mechanism for journalists, publishers and citizens whose content is being reviewed. If EEAS is unable to comply with the above, the EU Disinformation Review should be shut down

Shining a Spotlight on EU Political Group Spending: Legal Guide on Access to Document Requests

The purpose of this legal memorandum is to provide advice to organisations and individuals interested in submitting a request for public access to documents under Regulation (EC) No 1049/01 (“Regulation 1049/01”) to the European Parliament for documents related to the spending of political groups covered by Budget Item 400 appropriations under Chapter 7.Requests for those documents may face rejection on grounds related to exceptions provided for in Regulation 1049/01, specifically those found in Articles 4(1)b, 4(2), and 4(3) pertaining to privacy and integrity of the individual, commercial interests, and institution’s decision-making process respectively.This legal memorandum addresses the applicability of those exceptions to the documents requested for potential use in a confirmatory request to be submitted to the European Parliament subsequent to the initial rejection in line with Article 7 of Regulation 1049/01. The memo also provides arguments for overcoming these exceptions in light of: 1) recent developments in the case law of the Court of Justice of the European Union (“CJEU”) relating to the privacy exception; and 2) the strict legal requirements for triggering the commercial interests and institutional decision-making exceptions.The last section of the memo is structured to provide draft responses to the denial of requests for documents and should be tailored to the specific situation in question

The Problem of Unpaid Internships: Legal Guide to Complaints Under the European Social Charter

Young people entering the job market are in a precarious economic position. Across Europe, and in Belgium in particular, those who wish to enter into the professional world are faced with the de facto mandate that in order to gain experience and build the connections that will enable them to find paid professional work in the future, they must complete several internships. Yet many of these internships are unpaid or underpaid, forcing some young people to rely on their savings or their parents and shutting others out of the process entirely.The European Committee of Social Rights (the “Committee”) accepts collective complaints lodged by non-governmental organisations alleging violations of the European Social Charter (the “Charter”). The EU Public Interest Clinic prepared this draft Complaint for the non-profit organization European Youth Forum, alleging that unpaid internships in Belgium violate the Charter. Specifically, the provisions in Belgian law that enable unpaid internships, and the lack of enforcement of provisions that aim to curtail them, violate Articles 4, 7, and 10 of the Charter, which provide for fair remuneration, the protection of young people, and financial assistance for vocational training, respectively

Relating psychiatric symptoms and self-regulation during the COVID-19 crisis

Disruptions of self-regulation are a hallmark of numerous psychiatric disorders. Here, we examine the relationship between transdiagnostic dimensions of psychopathology and changes in self-regulation in the early phase of the COVID-19 pandemic. We used data-driven approach on a large number of cognitive tasks and self-reported surveys in training datasets. Then we derived measures of self-regulation and psychiatric functioning in an independent population sample (N = 102) tested both before and after the onset of the COVID-19 pandemic, when the restrictions in place represented a threat to mental health and forced people to flexibly adjust to modifications of daily routines. We found independent relationships between transdiagnostic dimensions of psychopathology and longitudinal alterations in specific domains of self-regulation defined using the drift diffusion model. Compared to the period preceding the onset of the pandemic, a symptom dimension related to anxiety and depression was characterized by a more cautious behavior, indexed by the need to accumulate more evidence before making a decision. Instead, social-withdrawal related to faster non-decision processes. Self-reported measures of self-regulation predicted variance in psychiatric symptoms both concurrently and prospectively, revealing the psychological dimensions relevant for separate transdiagnostic dimensions of psychiatry, but tasks did not. Taken together, our study shows that self-regulation can be affected depending on the interaction between external events and trait-like vulnerabilities and suggests that the study of cognition needs to take into account the dynamic nature of real-world events as well as within-subject variability over time