The SWI/SNF BAF-A complex is essential for neural crest development

Growing evidence indicates that chromatin remodeler mutations underlie the pathogenesis of human neurocristopathies or disorders that affect neural crest cells (NCCs). However, causal relationships among chromatin remodeler subunit mutations and NCC defects remain poorly understood. Here we show that homozygous loss of ARID1A-containing, SWI/SNF chromatin remodeling complexes (BAF-A) in NCCs results in embryonic lethality in mice, with mutant embryos succumbing to heart defects. Strikingly, monoallelic loss of ARID1A in NCCs led to craniofacial defects in adult mice, including shortened snouts and low set ears, and these defects were more pronounced following homozygous loss of ARID1A, with the ventral cranial bones being greatly reduced in size. Early NCC specification and expression of the BRG1 NCC target gene, PLEXINA2, occurred normally in the absence of ARID1A. Nonetheless, mutant embryos displayed incomplete conotruncal septation of the cardiac outflow tract and defects in the posterior pharyngeal arteries, culminating in persistent truncus arteriosus and agenesis of the ductus arteriosus. Consistent with this, migrating cardiac NCCs underwent apoptosis within the circumpharyngeal ridge. Our data support the notion that multiple, distinct chromatin remodeling complexes govern genetically separable events in NCC development and highlight a potential pathogenic role for NCCs in the human BAF complex disorder, Coffin-Siris Syndrome

Star Formation in Bright Rimmed Clouds. I. Millimeter and Submillimeter Molecular Line Surveys

We present the results of the first detailed millimeter and submillimeter molecular line survey of bright rimmed clouds, observed at FCRAO in the CO (J=1-0), C18O (J=1-0), HCO+ (J=1-0), H13CO+ (J=1-0), and N2H+ (J=1-0) transitions, and at the HHT in the CO (J=2-1), HCO+ (J=3-2), HCO+ (J=4-3), H13CO+ (J=3-2), and H13CO+ (J=4-3) molecular line transitions. The source list is composed of a selection of bright rimmed clouds from the catalog of such objects compiled by Sugitani et al. (1991). We also present observations of three Bok globules done for comparison with the bright rimmed clouds. We find that the appearance of the millimeter CO and HCO+ emission is dominated by the morphology of the shock front in the bright rimmed clouds. The HCO+ (J=1-0) emission tends to trace the swept up gas ridge and overdense regions which may be triggered to collapse as a result of sequential star formation. Five of the seven bright rimmed clouds we observe seem to have an outflow, however only one shows the spectral line blue-asymmetric signature that is indicative of infall, in the optically thick HCO+ emission. We also present evidence that in bright rimmed clouds the nearby shock front may heat the core from outside-in thereby washing out the normally observed line infall signatures seen in isolated star forming regions. We find that the derived core masses of these bright rimmed clouds are similar to other low and intermediate mass star forming regions.Comment: 67 pages, including 35 figures and 6 tables. Accepted for publication in ApJ. Version with embedded full-resolution figures available at http://www.astro.umass.edu/~devries/brc1

Characterization of a Brg1 hypomorphic allele demonstrates that genetic and biochemical activity are tightly correlated

Mammalian SWI/SNF-related complexes are recruited to the promoters of numerous target genes, and the BRG1 catalytic subunit confers ATPase activity necessary to slide or evict nucleosomes and to regulate transcription. Based on gene-targeting experiments in mice, BRG1 is essential for early embryonic development. However, Brg1 null mutants have provided limited insight into gene-dosage considerations and structure-function relationships. To extend our knowledge of BRG1 function, we describe the genetic and biochemical characteristics of an ENU-induced hypomorphic mutation that encodes a protein with a single amino-acid substitution (E1083G) within the bilobal ATPase/chromatin-remodeling domain. Brg1ENU1/ENU1 mice have ~50% genetic activity and survive embryogenesis but exhibit a postnatal developmental phenotype associated with runting and incompletely penetrant lethality. The E1083G mutant protein is stable, and experiments with recombinant FLAG-tagged BRG1 proteins demonstrated that it retains full ATPase activity. Yet the biochemical activity of the mutant protein is diminished to ~50% of normal in chromatin-remodeling assays. Consistent with these findings, the E1083G substitution is predicted to disrupt a structurally conserved α-helix within the lobe that participates in DNA translocation but does not contain the ATPase catalytic site. We propose that this α-helix participates in the DNA translocation cycle by mechanistically linking DNA interaction surfaces at the DNA entry/anchor point to those within the Helicase C domain of lobe 2 of the bilobal ATPase motor. Taken together, these results demonstrate that BRG1 genetic and biochemical activities are tightly correlated. They also indicate that BRG1 ATPase activity is necessary but not sufficient for chromatin remodeling

Joint TGF-β Type II Receptor-Expressing Cells: Ontogeny and Characterization as Joint Progenitors

TGF-β type II receptor (Tgfbr2) signaling plays an essential role in joint-element development. The Tgfbr2PRX-1KO mouse, in which the Tgfbr2 is conditionally inactivated in developing limbs, lacks interphalangeal joints and tendons. In this study, we used the Tgfbr2-β-Gal-GFP-BAC mouse as a LacZ/green fluorescent protein (GFP)-based read-out to determine: the spatial and temporally regulated expression pattern of Tgfbr2-expressing cells within joint elements; their expression profile; and their slow-cycling labeling with bromodeoxyuridine (BrdU). Tgfbr2-β-Gal activity was first detected at embryonic day (E) 13.5 within the interphalangeal joint interzone. By E16.5, and throughout adulthood, Tgfbr2-expressing cells clustered in a contiguous niche that comprises the groove of Ranvier and the synovio-entheseal complex including part of the perichondrium, the synovium, the articular cartilage superficial layer, and the tendon's entheses. Tgfbr2-expressing cells were found in the synovio-entheseal complex niche with similar temporal pattern in the knee, where they were also detected in meniscal surface, ligaments, and the synovial lining of the infrapatellar fat pad. Tgfbr2-β-Gal-positive cells were positive for phospho-Smad2, signifying that the Tgfbr2 reporter was accurate. Developmental-stage studies showed that Tgfbr2 expression was in synchrony with expression of joint-morphogenic genes such as Noggin, GDF5, Notch1, and Jagged1. Prenatal and postnatal BrdU-incorporation studies showed that within this synovio-entheseal-articular-cartilage niche most of the Tgfbr2-expressing cells labeled as slow-proliferating cells, namely, stem/progenitor cells. Tgfbr2-positive cells, isolated from embryonic limb mesenchyme, expressed joint progenitor markers in a time- and TGF-β-dependent manner. Our studies provide evidence that joint Tgfbr2-expressing cells have anatomical, ontogenic, slow-cycling trait and in-vivo and ex-vivo expression profiles of progenitor joint cells

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling

Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumors with OCCC-like histopathology, culminating in hemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting tumor cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signaling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumor growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodeling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signaling. We propose that ARID1A protects against inflammation-driven tumorigenesis

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure