The BAF chromatin remodelling complex is an epigenetic regulator of lineage specification in the early mouse embryo.

Dynamic control of gene expression is essential for the development of a totipotent zygote into an embryo with defined cell lineages. The accessibility of genes responsible for cell specification to transcriptional machinery is dependent on chromatin remodelling complexes such as the SWI\SNF (BAF) complex. However, the role of the BAF complex in early mouse development has remained unclear. Here, we demonstrate that BAF155, a major BAF complex subunit, regulates the assembly of the BAF complex in vivo and regulates lineage specification of the mouse blastocyst. We find that associations of BAF155 with other BAF complex subunits become enriched in extra-embryonic lineages just prior to implantation. This enrichment is attributed to decreased mobility of BAF155 in extra-embryonic compared with embryonic lineages. Downregulation of BAF155 leads to increased expression of the pluripotency marker Nanog and its ectopic expression in extra-embryonic lineages, whereas upregulation of BAF155 leads to the upregulation of differentiation markers. Finally, we show that the arginine methyltransferase CARM1 methylates BAF155, which differentially influences assembly of the BAF complex between the lineages and the expression of pluripotency markers. Together, our results indicate a novel role of BAF-dependent chromatin remodelling in mouse development via regulation of lineage specification.We are grateful to: W. Xu for an antibody against methylated BAF155; R. Kemler for an antibody against Troma1, A. Surani for TS cells, P. Almeida Coelho, S. Vuoristo and A. Hupalowska for technical assistance; M. Bredford for the CARM1 -/- line; D. Glover, M-E Torres-Padilla, P. P. Amaral, K. Miyamoto, A. Bruce, I. Bedzhov and J. Gurdon for helpful suggestions. This work was supported by The Wellcome Trust Senior Fellowship to MZG; M.P. is supported by the Darwin Trust of Edinburgh.This is the final version of the article. It first appeared from The Company of Biologists via https://doi.org/10.1242/dev.13196

Legal Advertising and Warranty Liability: “Let the Lawyer Beware”

This article will examine the realistic possibility of expanded lawyer liability by juxtaposing upon the clearly commercial flavor of legal advertising, the growing trend expanding warranty application under Article 2 of the Uniform Commercial Code by use of analogy

The unexpected resurgence of Weyl geometry in late 20-th century physics

Weyl's original scale geometry of 1918 ("purely infinitesimal geometry") was withdrawn by its author from physical theorizing in the early 1920s. It had a comeback in the last third of the 20th century in different contexts: scalar tensor theories of gravity, foundations of gravity, foundations of quantum mechanics, elementary particle physics, and cosmology. It seems that Weyl geometry continues to offer an open research potential for the foundations of physics even after the turn to the new millennium.Comment: Completely rewritten conference paper 'Beyond Einstein', Mainz Sep 2008. Preprint ELHC (Epistemology of the LHC) 2017-02, 92 pages, 1 figur

Attorney-Client Confidentiality and the Assessment of Claimants Who Allege Posttraumatic Stress Disorder

Posttraumatic Stress Disorder (PTSD) was first recognized by the American Psychiatric Association in 1980. A PTSD diagnosis requires an individual or individual\u27s loved ones to have experienced a traumatic event that was a threat to life or physical integrity and caused the individual to react to the incident with a specific number of avoidance, reexperiencing, and hyper-arousal symptoms. Obtaining a PTSD diagnosis can be of great value to a personal-injury plaintiff who claims damages due to a traumatic event. Further, if the traumatic event is unquestioned and the individual reports the classic symptoms, a PTSD diagnosis is relatively easy to apply and difficult to disprove. These plaintiffs will most often be examined and evaluated by mental-health professionals retained by the defendants. The question of whether the claimant was told or provided materials about common PTSD symptoms is crucial to the defense evaluator\u27s accurate PTSD assessment. One source of such information would be plaintiffs counsel, but questions concerning information provided by counsel implicate the attorney-client privilege. This Article suggests that the policy bases underlying the attorney-client privilege and protecting a defendant\u27s right to test the validity of a plaintiff\u27s claims are best served by the creation of a narrowly drawn waiver or exception to the attorney-client privilege. Consistent with the patient-litigant exception to the physician-patient privilege, the proposed exception would be limited to those matters directly related to the nature, diagnosis, and symptoms of PTSD placed in issue by the plaintiff. The exception would also be limited to statements and materials about PTSD symptoms the attorney provided the client. This Article also notes the difficult ethical boundary between an attorney providing essential advice to a client about the nature of emotional and psychological damages versus improper coaching. The proposed exception would help discourage improper coaching and lead to the discovery of any improper coaching that had already occurred. Even where the information provided by the attorney was appropriate from an ethical standpoint, discovery of that information is essential to an accurate diagnosis and fairness to defendants

Attorney-Client Confidentiality and the Assessment of Claimants Who Allege Posttraumatic Stress Disorder

Posttraumatic Stress Disorder (PTSD) was first recognized by the American Psychiatric Association in 1980. A PTSD diagnosis requires an individual or individual\u27s loved ones to have experienced a traumatic event that was a threat to life or physical integrity and caused the individual to react to the incident with a specific number of avoidance, reexperiencing, and hyper-arousal symptoms. Obtaining a PTSD diagnosis can be of great value to a personal-injury plaintiff who claims damages due to a traumatic event. Further, if the traumatic event is unquestioned and the individual reports the classic symptoms, a PTSD diagnosis is relatively easy to apply and difficult to disprove. These plaintiffs will most often be examined and evaluated by mental-health professionals retained by the defendants. The question of whether the claimant was told or provided materials about common PTSD symptoms is crucial to the defense evaluator\u27s accurate PTSD assessment. One source of such information would be plaintiffs counsel, but questions concerning information provided by counsel implicate the attorney-client privilege. This Article suggests that the policy bases underlying the attorney-client privilege and protecting a defendant\u27s right to test the validity of a plaintiff\u27s claims are best served by the creation of a narrowly drawn waiver or exception to the attorney-client privilege. Consistent with the patient-litigant exception to the physician-patient privilege, the proposed exception would be limited to those matters directly related to the nature, diagnosis, and symptoms of PTSD placed in issue by the plaintiff. The exception would also be limited to statements and materials about PTSD symptoms the attorney provided the client. This Article also notes the difficult ethical boundary between an attorney providing essential advice to a client about the nature of emotional and psychological damages versus improper coaching. The proposed exception would help discourage improper coaching and lead to the discovery of any improper coaching that had already occurred. Even where the information provided by the attorney was appropriate from an ethical standpoint, discovery of that information is essential to an accurate diagnosis and fairness to defendants

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease

BACKGROUND. Autoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals. METHODS. We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (= 30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period. RESULTS. Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1 beta plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1 beta plasma levels. CONCLUSION. We demonstrated that IL-1 beta inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1 beta plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1 beta inhibition is warranted

Video; Health Law & Ethics 2020

This program will focus on the current climate of health law and the necessary steps used through federal practice to adjust to the ever-changing atmosphere of new legislation. Attendees will learn about the various paths within the practice, about emerging new laws, outreach and training, and how to become involved in the federal practice of health law. The presenters will explain what you need to get started, what different types of experiences and exposure might be helpful in entering the field and instruct you on maintaining ethics by knowing and following the Federal Rules of Civil Procedure and Model Rules of Professional Responsibility. By utilizing key tips and strategies, you will learn how to position yourself for a strong career in federal practice by learning about the different avenues of health law and how to effectively represent clients in this field of law. Discussions will include a general overview of health law, the impact of COVID-19 in conjunction with health law, and the enactment of new laws and statutes created. This program is for students, new and seasoned attorneys alike