The balance between N-cadherin and E-cadherin orchestrates major neuroectodermal cell fate choices

Numerous cadherin proteins, including N‐cadherin (Ncad), E‐cadherin (Ecad), Cadherin‐11 (Cad11) and Cadherin‐7 (Cad7), are expressed in the developing neural plate as well as in neural crest cells as they delaminate from the newly closed neural tube. To clarify whether these proteins function independently or coordinately during development, we examined their relative expression in the cranial region of chick embryos. The results revealed surprising overlap of Ecad, Ncad and Cad7 in the neural tube, suggesting possible heterotypic interactions. Using a proximity ligation assay and co‐immunoprecipitation to test this hypothesis, we found that Ncad formed heterophilic complexes in the developing neural tube with Ecad. We also determined that modulation of either Ncad or Ecad levels led to reciprocal gain or reduction of the other cadherin protein. Altering levels of the two cadherin proteins affected the early fate specification of ectodermal derivatives, forcing an aberrant choice between neural crest and epidermal cells. Finally, we identified that the availability of β‐catenin plays a critical role in maintaining the balance between Ncad and Ecad in early development since co‐expression of activated β‐catenin rescues the Ncad‐overexpression phenotype. These results suggest that β‐catenin‐mediated balance of Ncad and Ecad proteins is critical for the normal development of the three ectodermal derivatives

A Stable Cranial Neural Crest Cell Line from Mouse

Cranial neural crest cells give rise to ectomesenchymal derivatives such as cranial bones, cartilage, smooth muscle, dentin, as well as melanocytes, corneal endothelial cells, and neurons and glial cells of the peripheral nervous system. Previous studies have suggested that although multipotent stem-like cells may exist during the course of cranial neural crest development, they are transient, undergoing lineage restriction early in embryonic development. We have developed culture conditions that allow cranial neural crest cells to be grown as multipotent stem-like cells. With these methods, we obtained 2 independent cell lines, O9-1 and i10-1, which were derived from mass cultures of Wnt1-Cre; R26R-GFP-expressing cells. These cell lines can be propagated and passaged indefinitely, and can differentiate into osteoblasts, chondrocytes, smooth muscle cells, and glial cells. Whole-genome expression profiling of O9-1 cells revealed that this line stably expresses stem cell markers (CD44, Sca-1, and Bmi1) and neural crest markers (AP-2α, Twist1, Sox9, Myc, Ets1, Dlx1, Dlx2, Crabp1, Epha2, and Itgb1). O9-1 cells are capable of contributing to cranial mesenchymal (osteoblast and smooth muscle) neural crest fates when injected into E13.5 mouse cranial tissue explants and chicken embryos. These results suggest that O9-1 cells represent multipotent mesenchymal cranial neural crest cells. The O9-1 cell line should serve as a useful tool for investigating the molecular properties of differentiating cranial neural crest cells

Tracking the Care of Patients with Severe Chronic Illness - The Dartmouth Atlas of Health Care 2008

In 2001 the Institute of Medicine (IOM) issued Crossing the Quality Chasm, a report that sent a wake-up call to patients, providers, and policy makers about the poor quality of American health care. The IOM argued that one of the central drivers of poor quality has been the unsystematic and fragmentary nature of our health care delivery system. Nowhere are the system’s failings more apparent than in the care of the chronically ill. More than 90 million Americans live with at least one chronic illness, and seven out of ten Americans die from chronic disease. Among the Medicare population, the toll is even greater: about nine out of ten deaths are associated with just nine chronic illnesses, including congestive heart failure, chronic lung disease, cancer, coronary artery disease, renal failure, peripheral vascular disease, diabetes, chronic liver disease, and dementia

Tokamak Physics Experiment (TPX) power supply design and development

The Tokamak Physics Experiment (TPX) is an advanced tokamak project aimed at the production of quasi-steady state plasmas with advanced shape, heating, and particle control. TPX is to be built at the Princeton Plasma Physics Laboratory (PPPL) using many of the facilities from the Tokamak Fusion Test Reactor (TFTR). TPX will be the first tokamak to utilize superconducting (SC) magnets in both the toroidal field (TF) and poloidal field (PF) systems. This new feature requires a departure from the traditional tokamak power supply schemes. This paper describes the plan for the adaptation of the PPPL/FTR power system facilities to supply TPX. Five major areas are addressed, namely the AC power system, the TF, PF and Fast Plasma Position Control (FPPC) power supplies, and quench protection for the TF and PF systems. Special emphasis is placed on the development of new power supply and protection schemes

Continental weathering and recovery from ocean nutrient stress during the Early Triassic Biotic Crisis

Following the latest Permian extinction ∼252 million years ago, normal marine and terrestrial ecosystems did not recover for another 5-9 million years. The driver(s) for the Early Triassic biotic crisis, marked by high atmospheric CO2 concentration, extreme ocean warming, and marine anoxia, remains unclear. Here we constrain the timing of authigenic K-bearing mineral formation extracted from supergene weathering profiles of NW-Pangea by Argon geochronology, to demonstrate that an accelerated hydrological cycle causing intense chemical alteration of the continents occurred between ∼254 and 248 Ma, and continued throughout the Triassic period. We show that enhanced ocean nutrient supply from this intense continental weathering did not trigger increased ocean productivity during the Early Triassic biotic crisis, due to strong thermal ocean stratification off NW Pangea. Nitrogen isotope constraints suggest, instead, that full recovery from ocean nutrient stress, despite some brief amelioration ∼1.5 million years after the latest Permian extinction, did not commence until climate cooling revitalized the global upwelling systems and ocean mixing ∼10 million years after the mass extinction

Evidence for dynamic rearrangements but lack of fate or position restrictions in premigratory avian trunk neural crest

Neural crest (NC) cells emerge from the dorsal trunk neural tube (NT) and migrate ventrally to colonize neuronal derivatives, as well as dorsolaterally to form melanocytes. Here, we test whether different dorsoventral levels in the NT have similar or differential ability to contribute to NC cells and their derivatives. To this end, we precisely labeled NT precursors at specific dorsoventral levels of the chick NT using fluorescent dyes and a photoconvertible fluorescent protein. NT and NC cell dynamics were then examined in vivo and in slice culture using two-photon and confocal time-lapse imaging. The results show that NC precursors undergo dynamic rearrangements within the neuroepithelium, yielding an overall ventral to dorsal movement toward the midline of the NT, where they exit in a stochastic manner to populate multiple derivatives. No differences were noted in the ability of precursors from different dorsoventral levels of the NT to contribute to NC derivatives, with the exception of sympathetic ganglia, which appeared to be ‘filled’ by the first population to emigrate. Rather than restricted developmental potential, however, this is probably due to a matter of timing

A Genome-Wide Assessment of the Ancestral Neural Crest Gene Regulatory Network

The neural crest (NC) is an embryonic cell population that contributes to key vertebrate-specific features including the craniofacial skeleton and peripheral nervous system. Here we examine the transcriptional and epigenomic profiles of NC cells in the sea lamprey, in order to gain insight into the ancestral state of the NC gene regulatory network (GRN). Transcriptome analyses identify clusters of co-regulated genes during NC specification and migration that show high conservation across vertebrates but also identify transcription factors (TFs) and cell-adhesion molecules not previously implicated in NC migration. ATAC-seq analysis uncovers an ensemble of cis-regulatory elements, including enhancers of Tfap2B, SoxE1 and Hox-α2 validated in the embryo. Cross-species deployment of lamprey elements identifies the deep conservation of lamprey SoxE1 enhancer activity, mediating homologous expression in jawed vertebrates. Our data provide insight into the core GRN elements conserved to the base of the vertebrates and expose others that are unique to lampreys

Great Expectations: The role of the wig stylist (sheitel macher) in orthodox Jewish salons

Wigs are curious liminal objects that hover somewhere between the categories of prosthesis and clothing and offer a variety of possibilities from transformation to hair substitution, covering and disguise. In this article I focus on the particular demands and expectations placed upon the sheitel (Yiddish term for wig) worn by increasing numbers of married Jewish women who identify as frum (Torah-observant). Based on research in Jewish wig salons in Britain and the United States and on Jewish online forums, internet discussions and blogs with a wider geographic reach, this article sets out to show the complex web of material, social, emotional, aesthetic and moral concerns that cluster around the sheitel and to highlight the role of the sheitel macher (wig stylist) in managing these anxieties and expectations. If all wigs are fraught with expectations in terms of their capacity to enable successful social performances, sheitels, it is argued, carry a particularly high burden of expectations owing to their contested and multivalent role as material embodiments of religious commitment, social status and fashion competence and owing to the ambivalent feelings many Jewish women have towards their wigs

The amphioxus genome and the evolution of the chordate karyotype

Lancelets ('amphioxus') are the modern survivors of an ancient chordate lineage, with a fossil record dating back to the Cambrian period. Here we describe the structure and gene content of the highly polymorphic approx520-megabase genome of the Florida lancelet Branchiostoma floridae, and analyse it in the context of chordate evolution. Whole-genome comparisons illuminate the murky relationships among the three chordate groups (tunicates, lancelets and vertebrates), and allow not only reconstruction of the gene complement of the last common chordate ancestor but also partial reconstruction of its genomic organization, as well as a description of two genome-wide duplications and subsequent reorganizations in the vertebrate lineage. These genome-scale events shaped the vertebrate genome and provided additional genetic variation for exploitation during vertebrate evolution

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells