BASS. XXXV. The MBH-σ* Relation of 105 Month Swift-BAT Type 1 AGNs

We present two independent measurements of stellar velocity dispersions (sigma(star)) from the Ca II H+K lambda 3969, 3934 and Mg I b lambda 5183, 5172, 5167 region (3880-5550 angstrom) and the calcium triplet region (8350-8750 angstrom) for 173 hard X-ray-selected Type 1 active galactic nuclei (AGNs; z <= 0.08) from the 105 month Swift-BAT catalog. We construct one of the largest samples of local Type 1 AGNs that have both single-epoch virial black hole mass (M-BH) estimates and sigma(star) measurements obtained from high spectral resolution data, allowing us to test the usage of such methods for supermassive black hole studies. We find that the two independent sigma(star) measurements are highly consistent with each other, with an average offset of only 0.002 +/- 0.001 dex. Comparing M-BH estimates based on broad emission lines and stellar velocity dispersion measurements, we find that the former is systematically lower by approximate to 0.12 dex. Consequently, Eddington ratios estimated through broad-line MBH determinations are similarly biased (but in the opposite way). We argue that the discrepancy is driven by extinction in the broad-line region. We also find an anticorrelation between the offset from the M-BH-sigma(star) relation and the Eddington ratio. Our sample of Type 1 AGNs shows a shallower M-BH-sigma(star) relation (with a power-law exponent of approximate to 3.5) compared with that of inactive galaxies (with a power-law exponent of approximate to 4.5), confirming earlier results obtained from smaller samples

Antibodies against CD20 or B-Cell Receptor Induce Similar Transcription Patterns in Human Lymphoma Cell Lines

BACKGROUND: CD20 is a cell surface protein exclusively expressed on B cells. It is a clinically validated target for Non-Hodgkin's lymphomas (NHL) and autoimmune diseases. The B cell receptor (BCR) plays an important role for development and proliferation of pre-B and B cells. Physical interaction of CD20 with BCR and components of the BCR signaling cascade has been reported but the consequences are not fully understood. METHODOLOGY: In this study we employed antibodies against CD20 and against the BCR to trigger the respective signaling. These antibodies induced very similar expression patterns of up- and down-regulated genes in NHL cell lines indicating that CD20 may play a role in BCR signaling and vice versa. Two of the genes that were rapidly and transiently induced by both stimuli are CCL3 and CCL4. 4 hours after stimulation the concentration of these chemokines in culture medium reaches a maximum. Spleen tyrosine kinase Syk is a cytoplasmic tyrosine kinase and a key component of BCR signaling. Both siRNA mediated silencing of Syk and inhibition by selective small molecule inhibitors impaired CCL3/CCL4 protein induction after treatment with either anti-CD20 or anti-BCR antibodies. CONCLUSION: Our results suggest that treatment with anti-CD20 antibodies triggers at least partially a BCR activation-like response in NHL cell lines

Type I insulin-like growth factor receptor over-expression induces proliferation and anti-apoptotic signaling in a three-dimensional culture model of breast epithelial cells

INTRODUCTION: Activation of the type I insulin-like growth factor receptor (IGFIR) promotes proliferation and inhibits apoptosis in a variety of cell types. Transgenic mice expressing a constitutively active IGFIR or IGF-I develop mammary tumors and increased levels of IGFIR have been detected in primary breast cancers. However, the contribution of IGFIR activation in promoting breast cancer progression remains unknown. Mammary epithelial cell lines grown in three-dimensional cultures form acinar structures that mimic the round, polarized, hollow and growth-arrested features of mammary alveoli. We used this system to determine how proliferation and survival signaling by IGFIR activation affects breast epithelial cell biology and contributes to breast cancer progression. METHODS: Pooled, stable MCF-10A breast epithelial cells expressing wild-type IGFIR or kinase-dead IGFIR (K1003A) were generated using retroviral-mediated gene transfer. The effects of over-expression of wild-type or kinase-dead IGFIR on breast epithelial cell biology were analyzed by confocal microscopy of three-dimensional cultures. The contribution of signaling pathways downstream of IGFIR activation to proliferation and apoptosis were determined by pharmacological inhibition of phosphatidylinositol 3' kinase (PI3K) with LY294002, MAP kinase kinase (MEK) with UO126 and mammalian target of rapamycin (mTOR) with rapamycin. RESULTS: We found that MCF-10A cells over-expressing the IGFIR formed large, misshapen acinar structures with filled lumina and disrupted apico-basal polarization. This phenotype was ligand-dependent, occurring with IGF-I or supraphysiological doses of insulin, and did not occur in cells over-expressing the kinase-dead receptor. We observed increased proliferation, decreased apoptosis and increased phosphorylation of Ser(473 )of Akt and Ser(2448 )of mTOR throughout IGFIR structures. Inhibition of PI3K with LY294002 or MEK with UO126 prevented the development of acinar structures from IGFIR-expressing but not control cells. The mTOR inhibitor rapamycin failed to prevent IGFIR-induced hyperproliferation and survival signaling. CONCLUSION: Increased proliferation and survival signaling as well as loss of apico-basal polarity by IGFIR activation in mammary epithelial cells may promote early lesions of breast cancer. Three-dimensional cultures of MCF-10A cells over-expressing the IGFIR are a useful model with which to study the role of IGFIR signaling in breast cancer progression and for characterizing the effects of chemotherapeutics targeted to IGFIR signaling

Resolving early mesoderm diversification through single-cell expression profiling.

In mammals, specification of the three major germ layers occurs during gastrulation, when cells ingressing through the primitive streak differentiate into the precursor cells of major organ systems. However, the molecular mechanisms underlying this process remain unclear, as numbers of gastrulating cells are very limited. In the mouse embryo at embryonic day 6.5, cells located at the junction between the extra-embryonic region and the epiblast on the posterior side of the embryo undergo an epithelial-to-mesenchymal transition and ingress through the primitive streak. Subsequently, cells migrate, either surrounding the prospective ectoderm contributing to the embryo proper, or into the extra-embryonic region to form the yolk sac, umbilical cord and placenta. Fate mapping has shown that mature tissues such as blood and heart originate from specific regions of the pre-gastrula epiblast, but the plasticity of cells within the embryo and the function of key cell-type-specific transcription factors remain unclear. Here we analyse 1,205 cells from the epiblast and nascent Flk1(+) mesoderm of gastrulating mouse embryos using single-cell RNA sequencing, representing the first transcriptome-wide in vivo view of early mesoderm formation during mammalian gastrulation. Additionally, using knockout mice, we study the function of Tal1, a key haematopoietic transcription factor, and demonstrate, contrary to previous studies performed using retrospective assays, that Tal1 knockout does not immediately bias precursor cells towards a cardiac fate.We thank M. de Bruijn, A. Martinez-Arias, J. Nichols and C. Mulas for discussion, the Cambridge Institute for Medical Research Flow Cytometry facility for their expertise in single-cell index sorting, and S. Lorenz from the Sanger Single Cell Genomics Core for supervising purification of Tal1−/− sequencing libraries. ChIP-seq reads were processed by R. Hannah. Research in the authors’ laboratories is supported by the Medical Research Council, Cancer Research UK, the Biotechnology and Biological Sciences Research Council, Bloodwise, the Leukemia and Lymphoma Society, and the Sanger-EBI Single Cell Centre, and by core support grants from the Wellcome Trust to the Cambridge Institute for Medical Research and Wellcome Trust - MRC Cambridge Stem Cell Institute and by core funding from Cancer Research UK and the European Molecular Biology Laboratory. Y.T. was supported by a fellowship from the Japan Society for the Promotion of Science. W.J. is a Wellcome Trust Clinical Research Fellow. A.S. is supported by the Sanger-EBI Single Cell Centre. This work was funded as part of Wellcome Trust Strategic Award 105031/D/14/Z ‘Tracing early mammalian lineage decisions by single-cell genomics’ awarded to W. Reik, S. Teichmann, J. Nichols, B. Simons, T. Voet, S. Srinivas, L. Vallier, B. Göttgens and J. Marioni.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nature1863

Endurance performance is influenced by perceptions of pain and temperature: Theory, applications and safety considerations.

Models of endurance performance now recognise input from the brain, including an athlete’s ability to cope with various non-pleasurable perceptions during exercise, such as pain and temperature. Exercise training can reduce perceptions of both pain and temperature over time, partly explaining why athletes generally have a higher pain tolerance, despite a similar pain threshold, compared with active controls. Several strategies with varying efficacy may ameliorate the perceptions of pain (e.g. acetaminophen, transcranial direct current stimulation and transcutaneous electrical stimulation) and temperature (e.g. menthol beverages, topical menthol products and other cooling strategies, especially those targeting the head) during exercise to improve athletic performance. This review describes both the theory and practical applications of these interventions in the endurance sport setting, as well as the potentially harmful health consequences of their use

Integrating teamwork, clinician occupational well-being and patient safety – development of a conceptual framework based on a systematic review

BACKGROUND: There is growing evidence that teamwork in hospitals is related to both patient outcomes and clinician occupational well-being. Furthermore, clinician well-being is associated with patient safety. Despite considerable research activity, few studies include all three concepts, and their interrelations have not yet been investigated systematically. To advance our understanding of these potentially complex interrelations we propose an integrative framework taking into account current evidence and research gaps identified in a systematic review. METHODS: We conducted a literature search in six major databases (Medline, PsycArticles, PsycInfo, Psyndex, ScienceDirect, and Web of Knowledge). Inclusion criteria were: peer reviewed papers published between January 2000 and June 2015 investigating a statistical relationship between at least two of the three concepts; teamwork, patient safety, and clinician occupational well-being in hospital settings, including practicing nurses and physicians. We assessed methodological quality using a standardized rating system and qualitatively appraised and extracted relevant data, such as instruments, analyses and outcomes. RESULTS: The 98 studies included in this review were highly diverse regarding quality, methodology and outcomes. We found support for the existence of independent associations between teamwork, clinician occupational well-being and patient safety. However, we identified several conceptual and methodological limitations. The main barrier to advancing our understanding of the causal relationships between teamwork, clinician well-being and patient safety is the lack of an integrative, theory-based, and methodologically thorough approach investigating the three concepts simultaneously and longitudinally. Based on psychological theory and our findings, we developed an integrative framework that addresses these limitations and proposes mechanisms by which these concepts might be linked. CONCLUSION: Knowledge about the mechanisms underlying the relationships between these concepts helps to identify avenues for future research, aimed at benefiting clinicians and patients by using the synergies between teamwork, clinician occupational well-being and patient safety. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12913-016-1535-y) contains supplementary material, which is available to authorized users