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Sample records for rat ssc self-renewal

  1. Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal.

    Science.gov (United States)

    Kanatsu-Shinohara, Mito; Tanaka, Takashi; Ogonuki, Narumi; Ogura, Atsuo; Morimoto, Hiroko; Cheng, Pei Feng; Eisenman, Robert N; Trumpp, Andreas; Shinohara, Takashi

    2016-12-01

    Myc plays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs), Myc controls SSC fate decisions because Myc overexpression induces enhanced self-renewal division, while depletion of Max, a Myc-binding partner, leads to meiotic induction. However, the mechanism by which Myc acts on SSC fate is unclear. Here we demonstrate a critical link between Myc/Mycn gene activity and glycolysis in SSC self-renewal. In SSCs, Myc/Mycn are regulated by Foxo1, whose deficiency impairs SSC self-renewal. Myc/Mycn-deficient SSCs not only undergo limited self-renewal division but also display diminished glycolytic activity. While inhibition of glycolysis decreased SSC activity, chemical stimulation of glycolysis or transfection of active Akt1 or Pdpk1 (phosphoinositide-dependent protein kinase 1 ) augmented self-renewal division, and long-term SSC cultures were derived from a nonpermissive strain that showed limited self-renewal division. These results suggested that Myc-mediated glycolysis is an important factor that increases the frequency of SSC self-renewal division. © 2016 Kanatsu-Shinohara et al.; Published by Cold Spring Harbor Laboratory Press.

  2. ROS Are Required for Mouse Spermatogonial Stem Cell Self-Renewal

    OpenAIRE

    Morimoto, Hiroko; Iwata, Kazumi; Ogonuki, Narumi; Inoue, Kimiko; Ogura, Atsuo; Kanatsu-Shinohara, Mito; Morimoto, Takeshi; Yabe-Nishimura, Chihiro; Shinohara, Takashi

    2013-01-01

    Reactive oxygen species (ROS) generation is implicated in stem cell self-renewal in several tissues but is thought to be detrimental for spermatogenesis as well as spermatogonial stem cells (SSCs). Using cultured SSCs, we show that ROS are generated via the AKT and MEK signaling pathways under conditions where the growth factors glial cell line-derived neurotrophic factor and fibroblast growth factor 2 drive SSC self-renewal and, instead, stimulate self-renewal at physiological levels. SSCs d...

  3. Extrinsic and intrinsic factors controlling spermatogonial stem cell self-renewal and differentiation

    OpenAIRE

    Mei, Xing-Xing; Wang, Jian; Wu, Ji

    2015-01-01

    Spermatogonial stem cells (SSCs), the stem cells responsible for male fertility, are one of a small number of cells with the abilities of both self-renewal and generation of large numbers of haploid cells. Technology improvements, most importantly, transplantation assays and in vitro culture systems have greatly expanded our understanding of SSC self-renewal and differentiation. Many important molecules crucial for the balance between self-renewal and differentiation have been recently identi...

  4. Extrinsic and intrinsic factors controlling spermatogonial stem cell self-renewal and differentiation

    Directory of Open Access Journals (Sweden)

    Xing-Xing Mei

    2015-06-01

    Full Text Available Spermatogonial stem cells (SSCs, the stem cells responsible for male fertility, are one of a small number of cells with the abilities of both self-renewal and generation of large numbers of haploid cells. Technology improvements, most importantly, transplantation assays and in vitro culture systems have greatly expanded our understanding of SSC self-renewal and differentiation. Many important molecules crucial for the balance between self-renewal and differentiation have been recently identified although the exact mechanism(s remain largely undefined. In this review, we give a brief introduction to SSCs, and then focus on extrinsic and intrinsic factors controlling SSCs self-renewal and differentiation.

  5. Extrinsic and intrinsic factors controlling spermatogonial stem cell self-renewal and differentiation.

    Science.gov (United States)

    Mei, Xing-Xing; Wang, Jian; Wu, Ji

    2015-01-01

    Spermatogonial stem cells (SSCs), the stem cells responsible for male fertility, are one of a small number of cells with the abilities of both self-renewal and generation of large numbers of haploid cells. Technology improvements, most importantly, transplantation assays and in vitro culture systems have greatly expanded our understanding of SSC self-renewal and differentiation. Many important molecules crucial for the balance between self-renewal and differentiation have been recently identified although the exact mechanism(s) remain largely undefined. In this review, we give a brief introduction to SSCs, and then focus on extrinsic and intrinsic factors controlling SSCs self-renewal and differentiation.

  6. Porcine spermatogonial stem cells self-renew effectively in a three dimensional culture microenvironment.

    Science.gov (United States)

    Park, Ji Eun; Park, Min Hee; Kim, Min Seong; Park, Yeo Reum; Yun, Jung Im; Cheong, Hee Tae; Kim, Minseok; Choi, Jung Hoon; Lee, Eunsong; Lee, Seung Tae

    2017-12-01

    Generally, self-renewal of spermatogonial stem cells (SSCs) is maintained in vivo in a three-dimensional (3D) microenvironment consisting of the seminiferous tubule basement membrane, indicating the importance of the 3D microenvironment for in vitro culture of SSCs. Here, we report a 3D culture microenvironment that effectively maintains porcine SSC self-renewal during culture. Porcine SSCs were cultured in an agarose-based 3D hydrogel and in 2D culture plates either with or without feeder cells. Subsequently, the effects of 3D culture on the maintenance of undifferentiated SSCs were identified by analyzing cell colony formation and morphology, AP activity, and transcriptional and translational regulation of self-renewal-related genes and the effects on proliferation by analyzing cell viability and single cell-derived colony number. The 3D culture microenvironment constructed using a 0.2% (w/v) agarose-based 3D hydrogel showed the strongest maintenance of porcine SSC self-renewal and induced significant improvements in proliferation compared with 2D culture microenvironments. These results demonstrate that self-renewal of porcine SSCs can be maintained more effectively in a 3D than in a 2D culture microenvironment. Moreover, this will play a significant role in developing novel culture systems for SSCs derived from diverse species in the future, which will contribute to SSC-related research. © 2017 International Federation for Cell Biology.

  7. Satellite Cell Self-Renewal.

    Science.gov (United States)

    Giordani, Lorenzo; Parisi, Alice; Le Grand, Fabien

    2018-01-01

    Adult skeletal muscle is endowed with regenerative potential through partially recapitulating the embryonic developmental program. Upon acute injury or in pathological conditions, quiescent muscle-resident stem cells, called satellite cells, become activated and give rise to myogenic progenitors that massively proliferate, differentiate, and fuse to form new myofibers and restore tissue functionality. In addition, a proportion of activated cells returns back to quiescence and replenish the pool of satellite cells in order to maintain the ability of skeletal muscle tissue to repair. Self-renewal is the process by which stem cells divide to make more stem cells to maintain the stem cell population throughout life. This process is controlled by cell-intrinsic transcription factors regulated by cell-extrinsic signals from the niche and the microenvironment. This chapter provides an overview about the general aspects of satellite cell biology and focuses on the cellular and molecular aspects of satellite cell self-renewal. To date, we are still far from understanding how a very small proportion of the satellite cell progeny maintain their stem cell identity when most of their siblings progress through the myogenic program to construct myofibers. © 2018 Elsevier Inc. All rights reserved.

  8. Glial cell line-derived neurotrophic factor and endothelial cells promote self-renewal of rabbit germ cells with spermatogonial stem cell properties.

    Science.gov (United States)

    Kubota, Hiroshi; Wu, Xin; Goodyear, Shaun M; Avarbock, Mary R; Brinster, Ralph L

    2011-08-01

    Previous studies suggest that exogenous factors crucial for spermatogonial stem cell (SSC) self-renewal are conserved among several mammalian species. Since glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2) are critical for rodent SSC self-renewal, we hypothesized that they might promote self-renewal of nonrodent SSCs. Therefore, we cultured testicular germ cells from prepubertal rabbits in the presence of GDNF and FGF2 and found they proliferated indefinitely as cellular clumps that displayed characteristics previously identified for rodent SSCs. The rabbit germ cells could not be maintained on mouse embryonic fibroblast (STO) feeders that support rodent SSC self-renewal in vitro but were rather supported on mouse yolk sac-derived endothelial cell (C166) feeder layers. Proliferation of rabbit germ cells was dependent on GDNF. Of critical importance was that clump-forming rabbit germ cells colonized seminiferous tubules of immunodeficient mice, proliferated for at least 6 mo, while retaining an SSC phenotype in the testes of recipient mice, indicating that they were rabbit SSCs. This study demonstrates that GDNF is a mitogenic factor promoting self-renewal that is conserved between rodent and rabbit SSCs; with an evolutionary separation of ∼ 60 million years. These findings provide a foundation to study the mechanisms governing SSC self-renewal in nonrodent species.

  9. Depletion of Tcf3 and Lef1 maintains mouse embryonic stem cell self-renewal

    OpenAIRE

    Ye, Shoudong; Zhang, Tao; Tong, Chang; Zhou, Xingliang; He, Kan; Ban, Qian; Liu, Dahai; Ying, Qi-Long

    2017-01-01

    ABSTRACT Mouse and rat embryonic stem cell (ESC) self-renewal can be maintained by dual inhibition of glycogen synthase kinase 3 (GSK3) and mitogen-activated protein kinase kinase (MEK). Inhibition of GSK3 promotes ESC self-renewal by abrogating T-cell factor 3 (TCF3)-mediated repression of the pluripotency network. How inhibition of MEK mediates ESC self-renewal, however, remains largely unknown. Here, we show that inhibition of MEK can significantly suppress lymphoid enhancer factor 1 (LEF1...

  10. On the self-renewal of teachers.

    Science.gov (United States)

    Waters, David J; Waters, Lane S

    2011-01-01

    In previous issues of the Journal of Veterinary Medical Education, wide-ranging insights on how to achieve excellence in the classroom have been framed by award-winning teachers. These recipes for educational success, however, invariably lack a key ingredient-the teacher's process of self-renewal. What skills and attitudes prime the teacher for continued high performance? To stay out of the ruts of expertise, where does the teacher turn? Teachers and administrators alike recognize its great importance, yet few opportunities for the renewal of teachers are built into the educational system. In this article, we challenge teachers to see their own self-renewal as an underutilized approach to innovate education. We propose a schema for sustained self-renewal: each educator developing her own personalized, hand-picked gallery of intellectual heroes who in turn serve as the educator's life-long teachers. To illustrate the value of this activity, we introduce our own collection of 10 gifted thinkers, providing a brief encounter with each sage as a way of stimulating new thinking on the skills and attitudes that promote personal growth and transformative teaching. We conclude that the veterinary profession should work to create better opportunities for the self-renewal of teachers. By envisioning even our best teachers as unfinished and under construction, we open up a new dialogue situating the self-renewal of teachers at the very core of educational excellence.

  11. Lipopolysaccharide inhibits the self-renewal of spermatogonial stem cells in vitro via downregulation of GDNF expression in Sertoli cells.

    Science.gov (United States)

    Zhang, Xiaoli; Shi, Kun; Li, Yi; Zhang, Haiyu; Hao, Jing

    2014-06-01

    Lipopolysaccharide (LPS) can reduce sperm count and sperm quality. The molecular mechanisms underlying this process are not fully understood. In this report, we investigated the effects of LPS-treated Sertoli cells on self-renewal and differentiation of spermatogoinial stem cells (SSCs). Sertoli cell cultures were established and incubated with LPS (10μg/ml) for 1, 2 or 3 days, respectively. The culture media were collected and used as conditioned media (CM) to culture SSCs. The expression of glial cell-derived neurotrophic factor (GDNF), stem cell factor (SCF) and bone morphogenetic protein 4 (BMP4) in Sertoli cells treated with LPS was analyzed by RT-PCR and Western blotting. The results showed that the expression of SSC differentiation markers, c-kit and Sohlh2, was increased, while the expression of SSC self-renewal markers, plzf, oct4, and PCNA, was repressed when cultured in CM from LPS-treated Sertoli cells. GDNF levels in Sertoli cells and CM reduced dramatically after LPS treatments, while SCF and BMP4 levels did not show any significant changes. Moreover, correlated with the GDNF levels in CM, GDNF target genes, Bcl6b and Etv5, were reduced markedly in SSCs. Our results suggest that LPS inhibits the expression of GDNF in Sertoli cells, and might prevent the SSC self-renewal via down-regulation of GDNF target genes. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Somatic ACE regulates self-renewal of mouse spermatogonial stem cells via the MAPK signaling pathway.

    Science.gov (United States)

    Gao, Tingting; Zhao, Xin; Liu, Chenchen; Shao, Binbin; Zhang, Xi; Li, Kai; Cai, Jinyang; Wang, Su; Huang, Xiaoyan

    2018-05-24

    Spermatogonial stem cell (SSC) self-renewal is an indispensable part of spermatogenesis. Angiotensin I-converting enzyme (ACE) is a zinc dipeptidyl carboxypeptidase that plays a critical role in regulation of the renin-angiotensin system. Here, we used RT-PCR and Western blot analysis to confirm that somatic ACE (sACE) but not testicular ACE (tACE) is highly expressed in mouse testis before postpartum day 7 and in cultured SSCs. Our results revealed that sACE is located on the membrane of SSCs. Treating cultured SSCs with the ACE competitive inhibitor captopril was found to inhibit sACE activity, and significantly reduced the proliferation rate of SSCs. Microarray analysis identified 651 genes with significant differential expression. KEGG pathway analysis showed that these differentially expressed genes are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway and cell cycle. sACE was found to play an important role in SSC self-renewal via the regulation of MAPK-dependent cell proliferation.

  13. Self-renewal molecular mechanisms of colorectal cancer stem cells

    OpenAIRE

    Pan, Tianhui; Xu, Jinghong; Zhu, Yongliang

    2016-01-01

    Colorectal cancer stem cells (CCSCs) represent a small fraction of the colorectal cancer cell population that possess self-renewal and multi-lineage differentiation potential and drive tumorigenicity. Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood, the aberrant activation of signaling pathways, such as Wnt, Notch, transforming growth facto...

  14. Self-renewal molecular mechanisms of colorectal cancer stem cells.

    Science.gov (United States)

    Pan, Tianhui; Xu, Jinghong; Zhu, Yongliang

    2017-01-01

    Colorectal cancer stem cells (CCSCs) represent a small fraction of the colorectal cancer cell population that possess self-renewal and multi-lineage differentiation potential and drive tumorigenicity. Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood, the aberrant activation of signaling pathways, such as Wnt, Notch, transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) and Hedgehog-Gli (HH-GLI), specific roles mediated by cell surface markers and micro-environmental factors are involved in the regulation of self-renewal. The elucidation of the molecular mechanisms behind self-renewal may lead to the development of novel targeted interventions for the treatment of colorectal cancer.

  15. Hmga2 regulates self-renewal of retinal progenitors.

    Science.gov (United States)

    Parameswaran, Sowmya; Xia, Xiaohuan; Hegde, Ganapati; Ahmad, Iqbal

    2014-11-01

    In vertebrate retina, histogenesis occurs over an extended period. To sustain the temporal generation of diverse cell types, retinal progenitor cells (RPCs) must self-renew. However, self-renewal and regulation of RPCs remain poorly understood. Here, we demonstrate that cell-extrinsic factors coordinate with the epigenetic regulator high-mobility group AT-hook 2 (Hmga2) to regulate self-renewal of late retinal progenitor cells (RPCs). We observed that a small subset of RPCs was capable of clonal propagation and retained multipotentiality of parents in the presence of endothelial cells (ECs), known self-renewal regulators in various stem cell niches. The self-renewing effects, also observed in vivo, involve multiple intercellular signaling pathways, engaging Hmga2. As progenitors exhaust during retinal development, expression of Hmga2 progressively decreases. Analyses of Hmga2-expression perturbation, in vitro and in vivo, revealed that Hmga2 functionally helps to mediate cell-extrinsic influences on late-retinal progenitor self-renewal. Our results provide a framework for integrating the diverse intercellular influences elicited by epigenetic regulators for self-renewal in a dynamic stem cell niche: the developing vertebrate retina. © 2014. Published by The Company of Biologists Ltd.

  16. Expression dynamics of self-renewal factors for spermatogonial stem cells in the mouse testis.

    Science.gov (United States)

    Sakai, Mizuki; Masaki, Kaito; Aiba, Shota; Tone, Masaaki; Takashima, Seiji

    2018-04-16

    Glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2) are bona fide self-renewal factors for spermatogonial stem cells (SSCs). Although GDNF is indispensable for the maintenance of SSCs, the role of FGF2 in the testis remains to be elucidated. To clarify this, the expression dynamics and regulatory mechanisms of Fgf2 and Gdnf in the mouse testes were analyzed. It is well known that Sertoli cells express Gdnf, and its receptor is expressed in a subset of undifferentiated spermatogonia, including SSCs. However, we found that Fgf2 was mainly expressed in the germ cells and its receptors were expressed not only in the cultured spermatogonial cell line, but also in testicular somatic cells. Aging, hypophysectomy, retinoic acid treatment, and testicular injury induced distinct Fgf2 and Gdnf expression dynamics, suggesting a difference in the expression mechanism of Fgf2 and Gdnf in the testis. Such differences might cause a dynamic fluctuation of Gdnf/Fgf2 ratio depending on the intrinsic/extrinsic cues. Considering that FGF2-cultured spermatogonia exhibit more differentiated phenotype than those cultured with GDNF, FGF2 might play a role distinct from that of GDNF in the testis, despite the fact that both factors are self-renewal factor for SSC in vitro.

  17. Bmi-1 Regulates Extensive Erythroid Self-Renewal

    Directory of Open Access Journals (Sweden)

    Ah Ram Kim

    2015-06-01

    Full Text Available Red blood cells (RBCs, responsible for oxygen delivery and carbon dioxide exchange, are essential for our well-being. Alternative RBC sources are needed to meet the increased demand for RBC transfusions projected to occur as our population ages. We previously have discovered that erythroblasts derived from the early mouse embryo can self-renew extensively ex vivo for many months. To better understand the mechanisms regulating extensive erythroid self-renewal, global gene expression data sets from self-renewing and differentiating erythroblasts were analyzed and revealed the differential expression of Bmi-1. Bmi-1 overexpression conferred extensive self-renewal capacity upon adult bone-marrow-derived self-renewing erythroblasts, which normally have limited proliferative potential. Importantly, Bmi-1 transduction did not interfere with the ability of extensively self-renewing erythroblasts (ESREs to terminally mature either in vitro or in vivo. Bmi-1-induced ESREs can serve to generate in vitro models of erythroid-intrinsic disorders and ultimately may serve as a source of cultured RBCs for transfusion therapy.

  18. SirT1—A Sensor for Monitoring Self-Renewal and Aging Process in Retinal Stem Cells

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    Chi-Hsien Peng

    2010-06-01

    Full Text Available Retinal stem cells bear potency of proliferation, self-renewal, and differentiation into many retinal cells. Utilizing appropriate sensors one can effectively detect the self-renewal and aging process abilities. Silencing information regulator (SirT1, a member of the sirtuin family, is a NAD-dependent histone deacetylase and an essential mediator for longevity in normal cells by calorie restriction. We firstly investigate the SirT1 mRNA expression in retinal stem cells from rats and 19 human eyes of different ages. Results revealed that SirT1 expression was significantly decreased in in vivo aged eyes, associated with poor self-renewal abilities. Additionally, SirT1 mRNA levels were dose-dependently increased in resveratrol- treated retinal stem cells. The expression of SirT1 on oxidative stress-induced damage was significantly decreased, negatively correlated with the level of intracellular reactive oxygen species production. Treatment with resveratrol could effectively further reduce oxidative stress induced by H2O2 treatment in retinal stem cells. Importantly, the anti-oxidant effects of resveratrol in H2O2-treated retinal stem cells were significantly abolished by knockdown of SirT1 expression (sh-SirT1. SirT1 expression provides a feasible sensor in assessing self-renewal and aging process in retinal stem cells. Resveratrol can prevent reactive oxygen species-induced damages via increased retinal SirT1 expression.

  19. Self-Renewal, Personal Development and Change: An Inexorable Link.

    Science.gov (United States)

    Krupp, Judy-Arin

    1995-01-01

    Self-renewal, personal development, and change create an inexorable link. Change management processes include the following: (1) internal locus of control; (2) freedom from institutional crutches; (3) flexible teaching; (4) recognition of emotional reactions to change; and (5) identification of the causes of indecisiveness and insecurities. (JOW)

  20. Resveratrol Enhances Self-Renewal of Mouse Embryonic Stem Cells.

    Science.gov (United States)

    Li, Na; Du, Zhaoyu; Shen, Qiaoyan; Lei, Qijing; Zhang, Ying; Zhang, Mengfei; Hua, Jinlian

    2017-07-01

    Resveratrol (RSV) has been shown to affect the differentiation of several types of stem cells, while the detailed mechanism is elusive. Here, we aim to investigate the function of RSV in self-renewal of mouse embryonic stem cells (ESCs) and the related mechanisms. In contrast with its reported roles, we found unexpectedly that differentiated ESCs or iPSCs treated by RSV would not show further differentiation, but regained a naïve pluripotency state with higher expressions of core transcriptional factors and with the ability to differentiate into all three germ layers when transplanted in vivo. In accordance with these findings, RSV also enhanced cell cycle progression of ESCs via regulating cell cycle-related proteins. Finally, enhanced activation of JAK/STAT3 signaling pathway and suppressed activation of mTOR were found essential in enhancing the self-renewal of ESCs by RSV. Our finding discovered a novel function of RSV in enhancing the self-renewal of ESCs, and suggested that the timing of treatment and concentration of RSV determined the final effect of it. Our work may contribute to understanding of RSV in the self-renewal maintenance of pluripotent stem cells, and may also provide help to the generation and maintenance of iPSCs in vitro. J. Cell. Biochem. 118: 1928-1935, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  1. Hematopoietic stem cells : Self-renewing or aging?

    NARCIS (Netherlands)

    de Haan, G

    2002-01-01

    Stem cells are defined by their extensive self-renewal properties, and yet there is abundant evidence of erosion of stem cell functioning during aging. Whereas intracellular repair and protection mechanisms determine the lifespan of an individual cell, here an argument is made that somatic stem

  2. SUPERCOLLIDER: SDC for SSC

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    1992-03-15

    On a scale to match the 87-kilometre Superconducting Supercollider (SSC) planned for Ellis County, Texas, the Solenoidal Detector Collaboration (SDC) is designing a large general purpose detector to pursue a broad range of physics goals.

  3. SSC seeks aid

    CERN Multimedia

    1990-01-01

    The chairman of the science committee in the US House of representatives will ask Congress to pass a law requiring that at least a quarter of the funds for the SSC come from foreign money (2 paragraphs).

  4. SUPERCOLLIDER: SDC for SSC

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    On a scale to match the 87-kilometre Superconducting Supercollider (SSC) planned for Ellis County, Texas, the Solenoidal Detector Collaboration (SDC) is designing a large general purpose detector to pursue a broad range of physics goals

  5. Prospects for SSC physics

    International Nuclear Information System (INIS)

    Paige, F.E.

    1986-03-01

    The SSC is primarily designed to explore the physics of the 1 TeV mass scale. Since new heavy particles will decay either into other new particles or into the quanta of the standard model, the main goal of SSC experiments will be to identify and to measure these quanta well. Progress in simulating events and in understanding the signature and backgrounds for standard-model physics is described. 51 refs

  6. Identification of CHD1L as an Important Regulator for Spermatogonial Stem Cell Survival and Self-Renewal

    Directory of Open Access Journals (Sweden)

    Shan-Shan Liu

    2016-01-01

    Full Text Available Chromodomain helicase/ATPase DNA binding protein 1-like gene (Chd1l participates in chromatin-dependent processes, including transcriptional activation and DNA repair. In this study, we have found for the first time that Chd1l is mainly expressed in the testicular tissues of prepubertal and adult mice and colocalized with PLZF, OCT4, and GFRα1 in the neonatal mouse testis and THY1+ undifferentiated spermatogonia or spermatogonial stem cells (SSCs. Knockdown of endogenous Chd1l in cultured mouse undifferentiated SSCs inhibited the expression levels of Oct4, Plzf, Gfrα1, and Pcna genes, suppressed SSC colony formation, and reduced BrdU incorporation, while increasing SSC apoptosis. Moreover, the Chd1l gene expression is activated by GDNF in the cultured mouse SSCs, and the GDNF signaling pathway was modulated by endogenous levels of Chd1l; as demonstrated by the gene expression levels of GDNF, inducible transcripts Etv5, Bcl6b, Pou3f, and Lhx1, but not that of GDNF-independent gene, Taf4b, were significantly downregulated by Chd1l knockdown in mouse SSCs. Taken together, this study provides the first evidence to support the notion that Chd1l is an intrinsic and novel regulator for SSC survival and self-renewal, and it exerts such regulation at least partially through a GDNF signaling pathway.

  7. SSC accelerator availability allocation

    International Nuclear Information System (INIS)

    Dixon, K.T.; Franciscovich, J.

    1991-03-01

    Superconducting Super Collider (SSC) operational availability is an area of major concern, judged by the Central Design Group to present such risk that use of modern engineering tools would be essential to program success. Experience has shown that as accelerator beam availability falls below about 80%, efficiency of physics experiments degrades rapidly due to inability to maintain adequate coincident accelerator and detector operation. For this reason, the SSC availability goal has been set at 80%, even though the Fermi National Accelerator Laboratory accelerator, with a fraction of the SSC's complexity, has only recently approached that level. This paper describes the allocation of the top-level goal to part-level reliability and maintainability requirements, and it gives the results of parameter sensitivity studies designed to help identify the best approach to achieve the needed system availability within funding and schedule constraints. 1 ref., 12 figs., 4 tabs

  8. Metabolic rate determines haematopoietic stem cell self-renewal.

    Science.gov (United States)

    Sastry, P S R K

    2004-01-01

    The number of haematopoietic stem cells (HSCs) per animal is conserved across species. This means the HSCs need to maintain hematopoiesis over a longer period in larger animals. This would result in the requirement of stem cell self-renewal. At present the three existing models are the stochastic model, instructive model and the third more recently proposed is the chiaro-scuro model. It is a well known allometric law that metabolic rate scales to the three quarter power. Larger animals have a lower metabolic rate, compared to smaller animals. Here it is being hypothesized that metabolic rate determines haematopoietic stem cell self-renewal. At lower metabolic rate the stem cells commit for self-renewal, where as at higher metabolic rate they become committed to different lineages. The present hypothesis can explain the salient features of the different models. Recent findings regarding stem cell self-renewal suggest an important role for Wnt proteins and their receptors known as frizzleds, which are an important component of cell signaling pathway. The role of cGMP in the Wnts action provides further justification for the present hypothesis as cGMP is intricately linked to metabolic rate. One can also explain the telomere homeostasis by the present hypothesis. One prediction of the present hypothesis is with reference to the limit of cell divisions known as Hayflick limit, here it is being suggested that this is the result of metabolic rate in laboratory conditions and there can be higher number of cell divisions in vivo if the metabolic rate is lower. Copyright 2004 Elsevier Ltd.

  9. Muscle satellite cell heterogeneity and self-renewal

    Science.gov (United States)

    Motohashi, Norio; Asakura, Atsushi

    2014-01-01

    Adult skeletal muscle possesses extraordinary regeneration capacities. After muscle injury or exercise, large numbers of newly formed muscle fibers are generated within a week as a result of expansion and differentiation of a self-renewing pool of muscle stem cells termed muscle satellite cells. Normally, satellite cells are mitotically quiescent and reside beneath the basal lamina of muscle fibers. Upon regeneration, satellite cells are activated, and give rise to daughter myogenic precursor cells. After several rounds of proliferation, these myogenic precursor cells contribute to the formation of new muscle fibers. During cell division, a minor population of myogenic precursor cells returns to quiescent satellite cells as a self-renewal process. Currently, accumulating evidence has revealed the essential roles of satellite cells in muscle regeneration and the regulatory mechanisms, while it still remains to be elucidated how satellite cell self-renewal is molecularly regulated and how satellite cells are important in aging and diseased muscle. The number of satellite cells is decreased due to the changing niche during ageing, resulting in attenuation of muscle regeneration capacity. Additionally, in Duchenne muscular dystrophy (DMD) patients, the loss of satellite cell regenerative capacity and decreased satellite cell number due to continuous needs for satellite cells lead to progressive muscle weakness with chronic degeneration. Thus, it is necessary to replenish muscle satellite cells continuously. This review outlines recent findings regarding satellite cell heterogeneity, asymmetric division and molecular mechanisms in satellite cell self-renewal which is crucial for maintenance of satellite cells as a muscle stem cell pool throughout life. In addition, we discuss roles in the stem cell niche for satellite cell maintenance, as well as related cell therapies for approaching treatment of DMD. PMID:25364710

  10. Muscle Satellite Cell Heterogeneity and Self-Renewal

    Directory of Open Access Journals (Sweden)

    Norio eMotohashi

    2014-01-01

    Full Text Available Adult skeletal muscle possesses extraordinary regeneration capacities. After muscle injury or exercise, large numbers of newly formed muscle fibers are generated within a week as a result of expansion and differentiation of a self-renewing pool of muscle stem cells termed muscle satellite cells. Normally, satellite cells are mitotically quiescent and reside beneath the basal lamina of muscle fibers. Upon regeneration, satellite cells are activated, and give rise to daughter myogenic precursor cells. After several rounds of proliferation, these myogenic precursor cells contribute to the formation of new muscle fibers. During cell division, a minor population of myogenic precursor cells returns to quiescent satellite cells as a self-renewal process. Currently, accumulating evidence has revealed the essential roles of satellite cells in muscle regeneration and the regulatory mechanisms, while it still remains to be elucidated how satellite cell self-renewal is molecularly regulated and how satellite cells are important in aging and diseased muscle. The number of satellite cells is decreased due to the changing niche during ageing, resulting in attenuation of muscle regeneration capacity. Additionally, in Duchenne muscular dystrophy (DMD patients, the loss of satellite cell regenerative capacity and decreased satellite cell number due to continuous needs for satellite cells lead to progressive muscle weakness with chronic degeneration. Thus, it is necessary to replenish muscle satellite cells continuously. This review outlines recent findings regarding satellite cell heterogeneity, asymmetric division and molecular mechanisms in satellite cell self-renewal which is crucial for maintenance of satellite cells as a muscle stem cell pool throughout life. In addition, we discuss roles in the stem cell niche for satellite cell maintenance, as well as related cell therapies for approaching treatment of DMD.

  11. SSC accelerator physics

    International Nuclear Information System (INIS)

    Anon.

    1985-01-01

    Accelerator physicists at LBL began intensive work on the SSC in 1983, in support of the proposed 6.5-T magnet design, which, in turn, became reference design A during the Reference Designs Study. In that same study, LBL physicists formed the core of the accelerator physics group led by Fermilab's Don Edwards. In a period of only a few months, that group established preliminary parameters for a near-optimal design, produced conceptual designs based on three magnet types, addressed all significant beam lifetime and stability issues, and identified areas requiring further R and D. Since the conclusion of the Reference Designs Study, work has focused on the key SSC design issue, namely, single-particle stability in an imperfect magnetic field. At the end of fiscal 1984, much of the LBL accelerator physics group took its place in the SSC Central Design Group, whose headquarters at LBL will be the focus of nationwide SSC R and D efforts over the next several years

  12. SSC design update

    International Nuclear Information System (INIS)

    Syphers, M.J.

    1992-11-01

    Recent developments in the design and construction of the SSC are presented. Topics include status of the 20 TeV Collider rings, including interaction regions, utility regions, and main arcs, plus some remarks on the injector accelerators. Remaining issues facing the design of the colliding beams synchrotron and its injectors are discussed

  13. Calorimetry at the SSC

    International Nuclear Information System (INIS)

    Wigmans, R.

    1988-01-01

    The state of the art, and the present understanding of the basic limitations in hadron calorimetry, are briefly described. The various options for SSC calorimeters are discussed, and the R ampersand D needed for the ones that look most promising is outlined. The most promising candidates are (1) lead/scintillating fibers and (2) lead (or uranium)/TMS (or other warm liquids)

  14. Calorimetry at the SSC

    International Nuclear Information System (INIS)

    Wigmans, R.

    1987-09-01

    The state of the art, and our present understanding of the basic limitations in hadron calorimetry, are briefly described. The various options for SSC calorimeters are discussed, and the R and D needed for the ones that look most promising is outlined. 13 refs.; 8 figs

  15. Software methodologies for the SSC

    International Nuclear Information System (INIS)

    Loken, S.C.

    1990-01-01

    This report describes some of the considerations that will determine how the author developed software for the SSC. He begins with a review of the general computing problem for SSC experiments and recent experiences in software engineering for the present generation of experiments. This leads to a discussion of the software technologies that will be critical for the SSC experiments. He describes the emerging software standards and commercial products that may be useful in addressing the SSC needs. He concludes with some comments on how collaborations and the SSC Lab should approach the software development issue

  16. SSC Cryogenic System

    International Nuclear Information System (INIS)

    Brown, D.P.; Louttit, R.I.; Rode, C.; VanderArend, P.C.

    1985-01-01

    The design of the 4.5 K primary cooling system and higher temperature shield cooling systems for the SSC are described. Typical flow diagrams for the magnet piping systems are presented. Estimated heat loads are given. The systems have been designed to accomodate the great distances, 90 km and up, over which the load will be distributed. Provision has been made for cooldown, warmup, quench recovery and magnet replacement, as well as for steady-state operation

  17. SSC kicker impedances

    International Nuclear Information System (INIS)

    Colton, E.P.; Wang, T.F.

    1985-01-01

    The longitudinal and transverse complex impedances Z/sub l//n and Z/sub t/, respectively, have been calculated for both the SSC injection and abort kickers. The calculations assumed that no attempt was made to shield the beam from the kickers. We took the injection and abort kickers to be as specified. The injection kickers were ferrite with a single-turn design, and the abort kickers were of a ''window-frame design'' with tape wound cores

  18. Pleiotropy of Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Self-Renewal of Embryonic Stem Cells from Refractory Mouse Strains

    Science.gov (United States)

    Ye, Shoudong; Tan, Li; Yang, Rongqing; Fang, Bo; Qu, Su; Schulze, Eric N.; Song, Houyan; Ying, Qilong; Li, Ping

    2012-01-01

    Background Inhibition of glycogen synthase kinase-3 (GSK-3) improves the efficiency of embryonic stem (ES) cell derivation from various strains of mice and rats, as well as dramatically promotes ES cell self-renewal potential. β-catenin has been reported to be involved in the maintenance of self-renewal of ES cells through TCF dependent and independent pathway. But the intrinsic difference between ES cell lines from different species and strains has not been characterized. Here, we dissect the mechanism of GSK-3 inhibition by CHIR99021 in mouse ES cells from refractory mouse strains. Methodology/Principal Findings We found that CHIR99021, a GSK-3 specific inhibitor, promotes self-renewal of ES cells from recalcitrant C57BL/6 (B6) and BALB/c mouse strains through stabilization of β-catenin and c-Myc protein levels. Stabilized β-catenin promoted ES self-renewal through two mechanisms. First, β-catenin translocated into the nucleus to maintain stem cell pluripotency in a lymphoid-enhancing factor/T-cell factor–independent manner. Second, β-catenin binds plasma membrane-localized E-cadherin, which ensures a compact, spherical morphology, a hallmark of ES cells. Further, elevated c-Myc protein levels did not contribute significantly to CH-mediated ES cell self-renewal. Instead, the role of c-Myc is dependent on its transformation activity and can be replaced by N-Myc but not L-Myc. β-catenin and c-Myc have similar effects on ES cells derived from both B6 and BALB/c mice. Conclusions/Significance Our data demonstrated that GSK-3 inhibition by CH promotes self-renewal of mouse ES cells with non-permissive genetic backgrounds by regulation of multiple signaling pathways. These findings would be useful to improve the availability of normally non-permissive mouse strains as research tools. PMID:22540008

  19. Involvement of extracellular factors in maintaining self-renewal of neural stem cell by nestin.

    Science.gov (United States)

    Di, Chun Guang; Xiang, Andy Peng; Jia, Lei; Liu, Jun Feng; Lahn, Bruce T; Ma, Bao Feng

    2014-07-09

    Nestin knockout leads to embryonic lethality and self-renewal deficiency in neural stem cells (NSCs). However, how nestin maintains self-renewal remains uncertain. Here, we used the dosage effect of nestin in heterozygous mice (Nes+/-) to study self-renewal of NSCs. With existing extracellular signaling in vivo or in vitro, nestin levels do not affect proliferation ability or apoptosis when compared between Nes+/- and Nes+/+ NSCs. However, self-renewal ability of Nes+/- NSCs is impaired when plated at a low cell density and completely lost at a clonal density. This deficiency in self-renewal at a clonal density is rescued using a medium conditioned by Nes+/+ NSCs. In addition, the Akt signaling pathway is altered at low density and reversed by conditioned medium. Our data show that secreted factors contribute toward maintaining self-renewal of NSCs by nestin, potentially through Akt signaling.

  20. Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells

    OpenAIRE

    Soucie, E.L.; Weng, Z.; Geirsdottir, L.; Molawi, K.; Maurizio, J.; Fenouil, R.; Mossadegh-Keller, N.; Gimenez, G.; VanHille, L.; Beniazza, M.; Favret, J.; Berruyer, C.; Perrin, P.; Hacohen, N.; Andrau, J.C.

    2016-01-01

    Differentiated macrophages can self-renew in tissues and expand long-term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network controlling self-renewal. Single cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down...

  1. Calorimetry for the SSC

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, H.A.; Grannis, P.D.

    1984-01-01

    The activities related to calorimetry at Snowmass took place in three main areas. These were: (1) The performance criteria for SSC calorimetry, including the requirements on hermeticity, shower containment, segmentation and time resolution. The use of calorimetric means of particle identification was studied. (2) The study of triggering methods using calorimeter energy, angle and timing information. (3) A review of a wide variety of calorimeter materials for absorber and sampling, as well as several means of obtaining the readout of the energy deposits. 48 references, 10 figures, 1 table.

  2. Calorimetry for the SSC

    International Nuclear Information System (INIS)

    Gordon, H.A.; Grannis, P.D.

    1984-01-01

    The activities related to calorimetry at Snowmass took place in three main areas. These were: (1) The performance criteria for SSC calorimetry, including the requirements on hermeticity, shower containment, segmentation and time resolution. The use of calorimetric means of particle identification was studied. (2) The study of triggering methods using calorimeter energy, angle and timing information. (3) A review of a wide variety of calorimeter materials for absorber and sampling, as well as several means of obtaining the readout of the energy deposits. 48 references, 10 figures, 1 table

  3. WLWL scattering at the SSC

    International Nuclear Information System (INIS)

    Bagger, J.; Valencia, G.

    1990-01-01

    We use higher-order chiral Lagrangians to study W L W L scattering at the SSC. We analyze a model that is consistent with crossing, unitarity and chiral symmetry, with no resonant behavior at SSC energies. The only signal is a slightly enhanced rate for W L W L scattering. Our results indicate the level of sensitivity that must be reached before the SSC can be assured of discovering the mechanism for electroweak symmetry breaking. 19 refs., 4 figs., 2 tabs

  4. Chiral Lagrangians and the SSC

    International Nuclear Information System (INIS)

    Dawson, S.

    1991-09-01

    In the event that the SSC does not observe any resonances such as a Higgs boson or a techni-rho meson, we would like to know if the SSC can still discover something about the nature of the electroweak symmetry breaking. We will use chiral Lagrangian techniques to address this question and analyze their utility for studying events containing W and Z gauge bosons at the SSC. 20 refs., 4 figs

  5. Self-renewal and cancer of the gut: two sides of a coin.

    NARCIS (Netherlands)

    Radtke, F.; Clevers, J.C.

    2005-01-01

    The intestinal epithelium follows the paradigms of stem cell biology established for other self-renewing tissues. With a unique topology, it constitutes a two-dimensional structure folded into valleys and hills: the proliferative crypts and the differentiated villi. Its unprecedented self-renewal

  6. Fibroblast growth factors as regulators of stem cell self-renewal and aging

    NARCIS (Netherlands)

    Yeoh, Joyce S. G.; de Haan, Gerald

    Organ and tissue dysfunction which is readily observable during aging results from a loss of cellular homeostasis and reduced stem cell self-renewal. Over the past 10 years, studies have been aimed at delineating growth factors that will sustain and promote the self-renewal potential of stem cells

  7. STAT5-mediated self-renewal of normal hematopoietic and leukemic stem cells

    NARCIS (Netherlands)

    Schepers, Hein; Wierenga, Albertus T. J.; Vellenga, Edo; Schuringa, Jan Jacob

    2012-01-01

    The level of transcription factor activity critically regulates cell fate decisions such as hematopoietic stem cell self-renewal and differentiation. The balance between hematopoietic stem cell self-renewal and differentiation needs to be tightly controlled, as a shift toward differentiation might

  8. Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells.

    Science.gov (United States)

    Soucie, Erinn L; Weng, Ziming; Geirsdóttir, Laufey; Molawi, Kaaweh; Maurizio, Julien; Fenouil, Romain; Mossadegh-Keller, Noushine; Gimenez, Gregory; VanHille, Laurent; Beniazza, Meryam; Favret, Jeremy; Berruyer, Carole; Perrin, Pierre; Hacohen, Nir; Andrau, J-C; Ferrier, Pierre; Dubreuil, Patrice; Sidow, Arend; Sieweke, Michael H

    2016-02-12

    Differentiated macrophages can self-renew in tissues and expand long term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network that controls self-renewal. Single-cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down-regulation of Maf transcription factors. The network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers. This indicates that distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal potential in both stem and mature cells. Copyright © 2016, American Association for the Advancement of Science.

  9. Radiation effects at the SSC

    Energy Technology Data Exchange (ETDEWEB)

    Gilchriese, M.G.D. [ed.] [Superconducting Super Collider Lab., Dallas, TX (United States)

    1988-06-01

    This report contains a preliminary study of the effects of the radiation levels expected at the SSC on potential detector components and a subset of materials to be used in the SSC accelerators. The report does not contain a discussion of radiation damage to electronics components that may be used at the SSC. We have investigated many of the effects of radiation on silicon detectors, on wire chambers, on scintillating materials and the associated readout, on optical fibers for data transmission and on structural or other materials to be used in detector or accelerator components. In the SSC accelerator complex, in particular the storage rings, radiation damage will not present significant problems different than those now faced by existing high energy accelerators. We find that the effects of radiation damage on SSC detector components will be significant at the design luminosity of the ssc and will limit, or determine, many of the options for different detector components. In this regard the reader should keep in mind that, in the absence of a specific detector design, it is not possible to form definitive conclusions regarding the viability of the detector components. Since the radiation levels in experiments at the SSC will depend on the geometry and composition of the apparatus, simple yes /no generalizations about the feasibility of a detector component are not possible.

  10. Differential Connexin Function Enhances Self-Renewal in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Masahiro Hitomi

    2015-05-01

    Full Text Available The coordination of complex tumor processes requires cells to rapidly modify their phenotype and is achieved by direct cell-cell communication through gap junction channels composed of connexins. Previous reports have suggested that gap junctions are tumor suppressive based on connexin 43 (Cx43, but this does not take into account differences in connexin-mediated ion selectivity and intercellular communication rate that drive gap junction diversity. We find that glioblastoma cancer stem cells (CSCs possess functional gap junctions that can be targeted using clinically relevant compounds to reduce self-renewal and tumor growth. Our analysis reveals that CSCs express Cx46, while Cx43 is predominantly expressed in non-CSCs. During differentiation, Cx46 is reduced, while Cx43 is increased, and targeting Cx46 compromises CSC maintenance. The difference between Cx46 and Cx43 is reflected in elevated cell-cell communication and reduced resting membrane potential in CSCs. Our data demonstrate a pro-tumorigenic role for gap junctions that is dependent on connexin expression.

  11. SSC muon detector group report

    International Nuclear Information System (INIS)

    Carlsmith, D.; Groom, D.; Hedin, D.; Kirk, T.; Ohsugi, T.; Reeder, D.; Rosner, J.; Wojcicki, S.

    1986-01-01

    We report here on results from the Muon Detector Group which met to discuss aspects of muon detection for the reference 4π detector models put forward for evaluation at the Snowmass 1986 Summer Study. We report on: suitable overall detector geometry; muon energy loss mechanisms; muon orbit determination; muon momentum and angle measurement resolution; raw muon rates and trigger concepts; plus we identify SSC physics for which muon detection will play a significant role. We conclude that muon detection at SSC energies and luminosities is feasible and will play an important role in the evolution of physics at the SSC

  12. SSC muon detector group report

    Energy Technology Data Exchange (ETDEWEB)

    Carlsmith, D.; Groom, D.; Hedin, D.; Kirk, T.; Ohsugi, T.; Reeder, D.; Rosner, J.; Wojcicki, S.

    1986-01-01

    We report here on results from the Muon Detector Group which met to discuss aspects of muon detection for the reference 4..pi.. detector models put forward for evaluation at the Snowmass 1986 Summer Study. We report on: suitable overall detector geometry; muon energy loss mechanisms; muon orbit determination; muon momentum and angle measurement resolution; raw muon rates and trigger concepts; plus we identify SSC physics for which muon detection will play a significant role. We conclude that muon detection at SSC energies and luminosities is feasible and will play an important role in the evolution of physics at the SSC.

  13. The self-renewal signaling pathways utilized by gastric cancer stem cells.

    Science.gov (United States)

    Fu, Ying; Li, Hui; Hao, Xishan

    2017-04-01

    Gastric cancer is a leading cause of cancer-related mortality worldwide. Cancer stem cells are the source of tumor recurrence and metastasis. Self-renewal is a marker of cancer stem cells and also the basis of long-lasting survival and tumor progression. Although the mechanism of gastric cancer stem cell self-renewal is not clear, there are several signaling pathways and environmental factors known to be involved. This mini review describes recent developments in the self-renewal signaling pathway of gastric cancer stem cell research. Advancements made in this field of research will likely support the development of novel therapeutic strategies for gastric cancer.

  14. Educational opportunities from the SSC

    International Nuclear Information System (INIS)

    Doddy, G.J.; Rider, A.H.; Halff, A.H.

    1990-01-01

    High energy physics and education are very closely interwoven. Most physics laboratories are located at universities or are operated by consortiums of universities. Fermilab and the SSC are operated by the Universities Research Association, URA, a consortium of 69 major research universities and 3 associate members. Another example of this laboratory and universities relationship is the Continuous Electron Beam Accelerator Facility, CEBAF, which is operated by the Southeastern Universities Research Association, SURA, another consortium of 39 major universities. The education potential inherent in the planning, construction and operation of the SSC is immense. The SSC, as the world's largest scientific instrument and, as the most power accelerator, will have a natural attraction as the preeminent institution in the scientific community. In addition to the primary objective of probing the fundamental composition of matter, the SSC will appear to a broad segment of the population and will create the opportunity for both passive and active educational experiences on the part of staff, students and visitors. On the esoteric level, the SSC will be a magnet for the scientific community and will attract from around the world the finest minds in the field of high energy physics. On the human level, the laboratory will become an integral part of the community and will be an object of great interest to local residents and visitors. The SSC planners should recognize the opportunity to be a contributing institution to both the local and the world community

  15. SSC detector solenoid

    International Nuclear Information System (INIS)

    Fast, R.W.; Grimson, J.H.; Kephart, R.D.; Krebs, H.J.; Stone, M.E.; Theriot, E.D.; Wands, R.H.

    1989-01-01

    A detector utilizing a superconducting solenoid is being discussed for the Superconducting Super Collider (SSC). A useful field volume of 8 m diameter x 16 m length at 1.5-2 T (--1 GJ at 2T) is required. It has been decided that all of the particle physics calorimetry will be inside the bore of the solenoid and that there is no need for the coil and cryostat to be ''thin'' in radiation lengths. An iron yoke will reduce the excitation required and will provide muon identification and a redundant momentum measurement of the muons. The authors have developed a conceptual design to meet these requirements. The magnet will use a copper-stabilized Nb-Ti conductor sized for a cryostable pool boiling heat flux --0.025 W/cm/sup 2/. A thermosiphon from a storage vessel above the cryostat will be used to prevent bubble stagnation in the liquid helium bath. The operating current, current density, coil subdivision and dump resistor have been chosen to guarantee that the coil will be undamaged should a quench occur. The axial electromagnetic force will be reacted by metallic support links; the stainless steel coil case will support the radial force. The 5000 metric tons of calorimetry will be supported from the iron yoke through a trussed cylindrical shell structure separate from the cryostat. The coil and case, radiation shield and stainless vacuum vessel would be fabricated and cryogenically tested as two 8-m sections. These would be lowered into the underground experimental hall and installed into the iron flux return yoke to provide the required 16-m length

  16. Argonaute-2-null embryonic stem cells are retarded in self-renewal ...

    Indian Academy of Sciences (India)

    Present address: Institute of Stem Cells and Regenerative Medicine, Bangalore, India ... [Chandra Shekar P, Naim A, Partha Sarathi D and Kumar S 2011 Argonaute-2-null embryonic stem cells are retarded in self-renewal ..... Research, India.

  17. wnt3a but not wnt11 supports self-renewal of embryonic stem cells

    International Nuclear Information System (INIS)

    Singla, Dinender K.; Schneider, David J.; LeWinter, Martin M.; Sobel, Burton E.

    2006-01-01

    wnt proteins (wnts) promote both differentiation of midbrain dopaminergic cells and self-renewal of haematopoietic stem cells. Mouse embryonic stem (ES) cells can be maintained and self-renew on mouse feeder cell layers or in media containing leukemia inhibitory factor (LIF). However, the effects of wnts on ES cells self-renewal and differentiation are not clearly understood. In the present study, we found that conditioned medium prepared from L cells expressing wnt3a can replace feeder cell layers and medium containing LIF in maintaining ES cells in the proliferation without differentiation (self-renewal) state. By contrast, conditioned medium from NIH3T3 cells expressing wnt11 did not. Alkaline phosphatase staining and compact colony formation were used as criteria of cells being in the undifferentiated state. ES cells maintained in medium conditioned by Wnt3a expressing cells underwent freezing and thawing while maintaining properties seen with LIF maintained ES cells. Purified wnt3a did not maintain self-renewal of ES cells for prolonged intervals. Thus, other factors in the medium conditioned by wnt3a expressing cells may have contributed to maintenance of ES cells in a self-renewal state. Pluripotency of ES cells was determined with the use of embryoid bodies in vitro. PD98059, a MEK specific inhibitor, promoted the growth of undifferentiated ES cells maintained in conditioned medium from wnt3a expressing cells. By contrast, the P38 MAPK inhibitor SB230580 did not, suggesting a role for the MEK pathway in self-renewal and differentiation of ES cells maintained in the wnt3a cell conditioned medium. Thus, our results show that conditioned medium from wnt3a but not wnt11 expressing cells can maintain ES cells in self-renewal and in a pluripotent state

  18. Endogenous production of fibronectin is required for self-renewal of cultured mouse embryonic stem cells.

    Science.gov (United States)

    Hunt, Geoffrey C; Singh, Purva; Schwarzbauer, Jean E

    2012-09-10

    Pluripotent cells are attached to the extracellular matrix (ECM) as they make cell fate decisions within the stem cell niche. Here we show that the ubiquitous ECM protein fibronectin is required for self-renewal decisions by cultured mouse embryonic stem (mES) cells. Undifferentiated mES cells produce fibronectin and assemble a fibrillar matrix. Increasing the level of substrate fibronectin increased cell spreading and integrin receptor signaling through focal adhesion kinase, while concomitantly inducing the loss of Nanog and Oct4 self-renewal markers. Conversely, reducing fibronectin production by mES cells growing on a feeder-free gelatin substrate caused loss of cell adhesion, decreased integrin signaling, and decreased expression of self-renewal markers. These effects were reversed by providing the cells with exogenous fibronectin, thereby restoring adhesion to the gelatin substrate. Interestingly, mES cells do not adhere directly to the gelatin substrate, but rather adhere indirectly through gelatin-bound fibronectin, which facilitates self-renewal via its effects on cell adhesion. These results provide new insights into the mechanism of regulation of self-renewal by growth on a gelatin-coated surface. The effects of increasing or decreasing fibronectin levels show that self-renewal depends on an intermediate level of cell-fibronectin interactions. By providing cell adhesive signals that can act with other self-renewal factors to maintain mES cell pluripotency, fibronectin is therefore a necessary component of the self-renewal signaling pathway in culture. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Embryonic stem cell self-renewal pathways converge on the transcription factor Tfcp2l1

    Science.gov (United States)

    Ye, Shoudong; Li, Ping; Tong, Chang; Ying, Qi-Long

    2013-01-01

    Mouse embryonic stem cell (mESC) self-renewal can be maintained by activation of the leukaemia inhibitory factor (LIF)/signal transducer and activator of transcription 3 (Stat3) signalling pathway or dual inhibition (2i) of glycogen synthase kinase 3 (Gsk3) and mitogen-activated protein kinase kinase (MEK). Several downstream targets of the pathways involved have been identified that when individually overexpressed can partially support self-renewal. However, none of these targets is shared among the involved pathways. Here, we show that the CP2 family transcription factor Tfcp2l1 is a common target in LIF/Stat3- and 2i-mediated self-renewal, and forced expression of Tfcp2l1 can recapitulate the self-renewal-promoting effect of LIF or either of the 2i components. In addition, Tfcp2l1 can reprogram post-implantation epiblast stem cells to naïve pluripotent ESCs. Tfcp2l1 upregulates Nanog expression and promotes self-renewal in a Nanog-dependent manner. We conclude that Tfcp2l1 is at the intersection of LIF- and 2i-mediated self-renewal pathways and plays a critical role in maintaining ESC identity. Our study provides an expanded understanding of the current model of ground-state pluripotency. PMID:23942238

  20. Myostatin signals through Pax7 to regulate satellite cell self-renewal

    International Nuclear Information System (INIS)

    McFarlane, Craig; Hennebry, Alex; Thomas, Mark; Plummer, Erin; Ling, Nicholas; Sharma, Mridula; Kambadur, Ravi

    2008-01-01

    Myostatin, a Transforming Growth Factor-beta (TGF-β) super-family member, has previously been shown to negatively regulate satellite cell activation and self-renewal. However, to date the mechanism behind Myostatin function in satellite cell biology is not known. Here we show that Myostatin signals via a Pax7-dependent mechanism to regulate satellite cell self-renewal. While excess Myostatin inhibited Pax7 expression via ERK1/2 signaling, an increase in Pax7 expression was observed following both genetic inactivation and functional antagonism of Myostatin. As a result, we show that either blocking or inactivating Myostatin enhances the partitioning of the fusion-incompetent self-renewed satellite cell lineage (high Pax7 expression, low MyoD expression) from the pool of actively proliferating myogenic precursor cells. Consistent with this result, over-expression of Pax7 in C2C12 myogenic cells resulted in increased self-renewal through a mechanism which slowed both myogenic proliferation and differentiation. Taken together, these results suggest that increased expression of Pax7 promotes satellite cell self-renewal, and furthermore Myostatin may control the process of satellite cell self-renewal through regulation of Pax7. Thus we speculate that, in addition to the intrinsic factors (such as Pax7), extrinsic factors both positive and negative in nature, will play a major role in determining the stemness of skeletal muscle satellite cells

  1. Forward spectrometers at the SSC

    International Nuclear Information System (INIS)

    Bjorken, J.D.

    1986-01-01

    Most of SSC phase space and a great deal of physics potential is in the forward/backward region (absolute value of theta < 100 mrad). Comprehensive open-geometry spectrometers are feasible and very cost effective. Examples of such devices are sketched. Because such spectrometers are very long and may operate at high β and longer bunch spacing, they impact now on SSC interaction - region design. The data acquisition load is as heavy as for central detectors, although there may be less emphasis on speed and more emphasis on sophisticated parallel and/or distributed processing for event selection, as well as on high-capacity buffering

  2. Design of SSC collider structures

    International Nuclear Information System (INIS)

    Monsees, J.E.

    1994-01-01

    The authors would like to set the record straight. To date, underground construction contracts on the SSC main ring have been bid at a savings of $77 million dollars or 33 percent below the baseline cost estimate. The SSC is the largest single underground project ever built anywhere in the world. When completed it will have approximately 70 miles of tunnels, 60 shafts, two huge underground experiment halls -- each the size of a football stadium -- and numerous other structures, each of which would be considered a major facility on any other project

  3. Simulating supersymmetry at the SSC

    International Nuclear Information System (INIS)

    Barnett, R.M.; Haber, H.E.

    1984-08-01

    Careful study of supersymmetric signatures at the SSC is required in order to distinguish them from Standard Model physics backgrounds. To this end, we have created an efficient, accurate computer program which simulates supersymmetric particle production and decay (or other new particles). We have incorporated the full matrix elements, keeping track of the polarizations of all intermediate states. (At this time hadronization of final-state partons is ignored). Using Monte Carlo techniques this program can generate any desired final-state distribution or individual events for Lego plots. Examples of the results of our study of supersymmetry at SSC are provided

  4. CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion.

    Science.gov (United States)

    Rogers, Natasha M; Zhang, Zheng J; Wang, Jiao-Jing; Thomson, Angus W; Isenberg, Jeffrey S

    2016-08-01

    Defects in renal tubular epithelial cell repair contribute to renal ischemia reperfusion injury, cause acute kidney damage, and promote chronic renal disease. The matricellular protein thrombospondin-1 and its receptor CD47 are involved in experimental renal ischemia reperfusion injury, although the role of this interaction in renal recovery is unknown. We found upregulation of self-renewal genes (transcription factors Oct4, Sox2, Klf4 and cMyc) in the kidney of CD47(-/-) mice after ischemia reperfusion injury. Wild-type animals had minimal self-renewal gene expression, both before and after injury. Suggestive of cell autonomy, CD47(-/-) renal tubular epithelial cells were found to increase expression of the self-renewal genes. This correlated with enhanced proliferative capacity compared with cells from wild-type mice. Exogenous thrombospondin-1 inhibited self-renewal gene expression in renal tubular epithelial cells from wild-type but not CD47(-/-) mice, and this was associated with decreased proliferation. Treatment of renal tubular epithelial cells with a CD47 blocking antibody or CD47-targeting small interfering RNA increased expression of some self-renewal transcription factors and promoted cell proliferation. In a syngeneic kidney transplant model, treatment with a CD47 blocking antibody increased self-renewal transcription factor expression, decreased tissue damage, and improved renal function compared with that in control mice. Thus, thrombospondin-1 via CD47 inhibits renal tubular epithelial cell recovery after ischemia reperfusion injury through inhibition of proliferation/self-renewal. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  5. Fostering the Self-Renewal of Teachers: An Underutilized Approach to Innovating Interdisciplinary Education

    Directory of Open Access Journals (Sweden)

    David J. Waters

    2013-06-01

    Full Text Available Our goal is to call teachers’ attention to the need for selfrenewal, challenging them to consider it a necessary approach to innovating interdisciplinary education. Our prescription for sustained self-renewal: Each teacher assembles a gallery of intellectual heroes — gifted and articulate thinkers — to serve as their own life-long teachers. In this paper, we share our experience teaching a "skills course" to interdisciplinary graduate students in Purdue University’s Center on Aging and the Life Course. The course, titled "To See and To Seize Opportunities", exposes scholars-in-training to an array of skills and attitudes that foster self-renewal and peak performance. Leading educators must work hard to create better opportunities for self-renewal. By envisioning even our best teachers as unfinished and under construction, we open up a new dialogue situating the self-renewal of teachers at the very core of educational excellence across a broad range of disciplines. To innovate interdisciplinary education, we believe it is time for a curricular re-think, emphasizing the importance of a transdisciplinary skills course in which teachers and their students can explore transformative ideas on personal development and self-renewal — in the classroom together.

  6. Human mesenchymal stem cells self-renew and differentiate according to a deterministic hierarchy.

    Directory of Open Access Journals (Sweden)

    Rahul Sarugaser

    Full Text Available BACKGROUND: Mesenchymal progenitor cells (MPCs have been isolated from a variety of connective tissues, and are commonly called "mesenchymal stem cells" (MSCs. A stem cell is defined as having robust clonal self-renewal and multilineage differentiation potential. Accordingly, the term "MSC" has been criticised, as there is little data demonstrating self-renewal of definitive single-cell-derived (SCD clonal populations from a mesenchymal cell source. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that a tractable MPC population, human umbilical cord perivascular cells (HUCPVCs, was capable of multilineage differentiation in vitro and, more importantly, contributed to rapid connective tissue healing in vivo by producing bone, cartilage and fibrous stroma. Furthermore, HUCPVCs exhibit a high clonogenic frequency, allowing us to isolate definitive SCD parent and daughter clones from mixed gender suspensions as determined by Y-chromosome fluorescent in situ hybridization. CONCLUSIONS/SIGNIFICANCE: Analysis of the multilineage differentiation capacity of SCD parent clones and daughter clones enabled us to formulate a new hierarchical schema for MSC self-renewal and differentiation in which a self-renewing multipotent MSC gives rise to more restricted self-renewing progenitors that gradually lose differentiation potential until a state of complete restriction to the fibroblast is reached.

  7. Aubergine Controls Germline Stem Cell Self-Renewal and Progeny Differentiation via Distinct Mechanisms.

    Science.gov (United States)

    Ma, Xing; Zhu, Xiujuan; Han, Yingying; Story, Benjamin; Do, Trieu; Song, Xiaoqing; Wang, Su; Zhang, Ying; Blanchette, Marco; Gogol, Madelaine; Hall, Kate; Peak, Allison; Anoja, Perera; Xie, Ting

    2017-04-24

    Piwi family protein Aubergine (Aub) maintains genome integrity in late germ cells of the Drosophila ovary through Piwi-associated RNA-mediated repression of transposon activities. Although it is highly expressed in germline stem cells (GSCs) and early progeny, it remains unclear whether it plays any roles in early GSC lineage development. Here we report that Aub promotes GSC self-renewal and GSC progeny differentiation. RNA-iCLIP results show that Aub binds the mRNAs encoding self-renewal and differentiation factors in cultured GSCs. Aub controls GSC self-renewal by preventing DNA-damage-induced Chk2 activation and by translationally controlling the expression of self-renewal factors. It promotes GSC progeny differentiation by translationally controlling the expression of differentiation factors, including Bam. Therefore, this study reveals a function of Aub in GSCs and their progeny, which promotes translation of self-renewal and differentiation factors by directly binding to its target mRNAs and interacting with translational initiation factors. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Sp5 induces the expression of Nanog to maintain mouse embryonic stem cell self-renewal.

    Science.gov (United States)

    Tang, Ling; Wang, Manman; Liu, Dahai; Gong, Mengting; Ying, Qi-Long; Ye, Shoudong

    2017-01-01

    Activation of signal transducer and activator of transcription 3 (STAT3) by leukemia inhibitory factor (LIF) maintains mouse embryonic stem cell (mESC) self-renewal. Our previous study showed that trans-acting transcription factor 5 (Sp5), an LIF/STAT3 downstream target, supports mESC self-renewal. However, the mechanism by which Sp5 exerts these effects remains elusive. Here, we found that Nanog is a direct target of Sp5 and mediates the self-renewal-promoting effect of Sp5 in mESCs. Overexpression of Sp5 induced Nanog expression, while knockdown or knockout of Sp5 decreased the Nanog level. Moreover, chromatin immunoprecipitation (ChIP) assays showed that Sp5 directly bound to the Nanog promoter. Functional studies revealed that knockdown of Nanog eliminated the mESC self-renewal-promoting ability of Sp5. Finally, we demonstrated that the self-renewal-promoting function of Sp5 was largely dependent on its zinc finger domains. Taken together, our study provides unrecognized functions of Sp5 in mESCs and will expand our current understanding of the regulation of mESC pluripotency.

  9. SSC Test Operations Contract Overview

    Science.gov (United States)

    Kleim, Kerry D.

    2010-01-01

    This slide presentation reviews the Test Operations Contract at the Stennis Space Center (SSC). There are views of the test stands layouts, and closer views of the test stands. There are descriptions of the test stand capabilities, some of the other test complexes, the Cryogenic propellant storage facility, the High Pressure Industrial Water (HPIW) facility, and Fluid Component Processing Facility (FCPF).

  10. Ep option at the SSC

    International Nuclear Information System (INIS)

    Prescott, C.Y.

    1984-05-01

    The possibilities for colliding electrons with the 20 TeV proton beams of the SSC are considered. Kinematics of ep colliding beams is reviewed. Energies that may be possible and interesting are suggested, and detector problems associated with the highly imbalanced collisions are briefly considered

  11. Present status and physics prospects of SSC

    International Nuclear Information System (INIS)

    Sugimoto, Shojiro

    1990-01-01

    Physics prospects of Superconducting Super Collider (SSC) are discussed, referring to other coming colliders. In addition, the present status of the SSC project and detector proposals for the experiments are described. (author)

  12. Icaritin enhances mESC self-renewal through upregulating core pluripotency transcription factors mediated by ER?

    OpenAIRE

    Tsang, Wing Pui; Zhang, Fengjie; He, Qiling; Cai, Waijiao; Huang, Jianhua; Chan, Wai Yee; Shen, Ziyin; Wan, Chao

    2017-01-01

    Utilization of small molecules in modulation of stem cell self-renewal is a promising approach to expand stem cells for regenerative therapy. Here, we identify Icaritin, a phytoestrogen molecule enhances self-renewal of mouse embryonic stem cells (mESCs). Icaritin increases mESCs proliferation while maintains their self-renewal capacity in vitro and pluripotency in vivo. This coincides with upregulation of key pluripotency transcription factors OCT4, NANOG, KLF4 and SOX2. The enhancement of m...

  13. Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation

    DEFF Research Database (Denmark)

    Klauke, Karin; Radulović, Višnja; Broekhuis, Mathilde

    2013-01-01

    The balance between self-renewal and differentiation of adult stem cells is essential for tissue homeostasis. Here we show that in the haematopoietic system this process is governed by polycomb chromobox (Cbx) proteins. Cbx7 is specifically expressed in haematopoietic stem cells (HSCs), and its...... overexpression enhances self-renewal and induces leukaemia. This effect is dependent on integration into polycomb repressive complex-1 (PRC1) and requires H3K27me3 binding. In contrast, overexpression of Cbx2, Cbx4 or Cbx8 results in differentiation and exhaustion of HSCs. ChIP-sequencing analysis shows that Cbx......7 and Cbx8 share most of their targets; we identified approximately 200 differential targets. Whereas genes targeted by Cbx8 are highly expressed in HSCs and become repressed in progenitors, Cbx7 targets show the opposite expression pattern. Thus, Cbx7 preserves HSC self-renewal by repressing...

  14. Redox homeostasis: the linchpin in stem cell self-renewal and differentiation.

    Science.gov (United States)

    Wang, Kui; Zhang, Tao; Dong, Qiang; Nice, Edouard Collins; Huang, Canhua; Wei, Yuquan

    2013-03-14

    Stem cells are characterized by their unique ability of self-renewal to maintain the so-called stem cell pool. Over the past decades, reactive oxygen species (ROS) have been recognized as toxic aerobic metabolism byproducts that are harmful to stem cells, leading to DNA damage, senescence or cell death. Recently, a growing body of literature has shown that stem cells reside in redox niches with low ROS levels. The balance of Redox homeostasis facilitates stem cell self-renewal by an intricate network. Thus, to fully decipher the underlying molecular mechanisms involved in the maintenance of stem cell self-renewal, it is critical to address the important role of redox homeostasis in the regulation of self-renewal and differentiation of stem cells. In this regard, we will discuss the regulatory mechanisms involved in the subtly orchestrated balance of redox status in stem cells by scavenger antioxidant enzyme systems that are well monitored by the hypoxia niches and crucial redox regulators including forkhead homeobox type O family (FoxOs), apurinic/apyrimidinic (AP) endonuclease1/redox factor-1 (APE1/Ref-1), nuclear factor erythroid-2-related factor 2 (Nrf2) and ataxia telangiectasia mutated (ATM). We will also introduce several pivotal ROS-sensitive molecules, such as hypoxia-inducible factors, p38 mitogen-activated protein kinase (p38) and p53, involved in the redox-regulated stem cell self-renewal. Specifically, all the aforementioned molecules can act as 'redox sensors' by virtue of redox modifications of their cysteine residues, which are critically important in the control of protein function. Given the importance of redox homeostasis in the regulation of stem cell self-renewal, understanding the underlying molecular mechanisms involved will provide important new insights into stem cell biology.

  15. Nrf2 is required to maintain the self-renewal of glioma stem cells

    International Nuclear Information System (INIS)

    Zhu, Jianhong; Wang, Handong; Sun, Qing; Ji, Xiangjun; Zhu, Lin; Cong, Zixiang; Zhou, Yuan; Liu, Huandong; Zhou, Mengliang

    2013-01-01

    Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioma stem cells (GSCs). Self-renewal is a complex biological process necessary for maintaining the glioma stem cells. Nuclear factor rythroid 2-related factor 2(Nrf2) plays a significant role in protecting cells from endogenous and exogenous stresses. Nrf2 is a key nuclear transcription factor that regulates antioxidant response element (ARE)-containing genes. Previous studies have demonstrated the significant role of Nrf2 in the proliferation of glioblastoma, and in their resistance to radioactive therapies. We examined the effect of knocking down Nrf2 in GSCs. Nrf2 expression was down-regulated by shRNA transinfected with lentivirus. Expression levels of Nestin, Nrf2, BMI-1, Sox2 and Cyclin E were assessed by western blotting, quantitative polymerase chain reaction (qPCR) and immunohistochemistry analysis. The capacity for self-renewal in vitro was assessed by genesis of colonies. The capacity for self-renewal in vivo was analyzed by tumor genesis of xenografts in nude mice. Knockdown of Nrf2 inhibited the proliferation of GSCs, and significantly reduced the expression of BMI-1, Sox2 and CyclinE. Knocking down of Nrf2 changed the cell cycle distribution of GSCs by causing an uncharacteristic increase in the proportion of cells in the G2 phase and a decrease in the proportion of cells in the S phase of the cell cycle. Nrf2 is required to maintain the self-renewal of GSCs, and its down-regulation can attenuate the self-renewal of GSCs significantly

  16. Dermal Contributions to Human Interfollicular Epidermal Architecture and Self-Renewal

    Directory of Open Access Journals (Sweden)

    Kynan T. Lawlor

    2015-11-01

    Full Text Available The human interfollicular epidermis is renewed throughout life by populations of proliferating basal keratinocytes. Though interfollicular keratinocyte stem cells have been identified, it is not known how self-renewal in this compartment is spatially organized. At the epidermal-dermal junction, keratinocytes sit atop a heterogeneous mix of dermal cells that may regulate keratinocyte self-renewal by influencing local tissue architecture and signalling microenvironments. Focusing on the rete ridges and complementary dermal papillae in human skin, we review the identity and organisation of abundant dermal cells types and present evidence for interactions between the dermal microenvironment and the interfollicular keratinocytes.

  17. Computing for an SSC experiment

    International Nuclear Information System (INIS)

    Gaines, I.

    1993-01-01

    The hardware and software problems for SSC experiments are similar to those faced by present day experiments but larger in scale. In particular, the Solenoidal Detector Collaboration (SDC) anticipates the need for close to 10**6 MIPS of off-line computing and will produce several Petabytes (10**15 bytes) of data per year. Software contributions will be made from large numbers of highly geographically dispersed physicists. Hardware and software architectures to meet these needs have been designed. Providing the requisites amount of computing power and providing tools to allow cooperative software development using extensions of existing techniques look achievable. The major challenges will be to provide efficient methods of accessing and manipulating the enormous quantities of data that will be produced at the SSC, and to enforce the use of software engineering tools that will ensure the open-quotes correctnessclose quotes of experiment critical software

  18. Intrinsic Chevrolets at the SSC

    International Nuclear Information System (INIS)

    Brodsky, S.J.; Collins, J.C.; Ellis, S.D.; Gunion, J.F.; Mueller, A.H.

    1984-01-01

    The possibility of the production at high energy of heavy quarks, supersymmetric particles and other large mass colored systems via the intrinsic twist-six components in the proton wave function is discussed. While the existing data do not rule out the possible relevance of intrinsic charm production at present energies, the extrapolation of such intrinsic contributions to very high masses and energies suggests that they will not play an important role at the SSC

  19. Weak interactions at the SSC

    International Nuclear Information System (INIS)

    Chanowitz, M.S.

    1986-03-01

    Prospects for the study of standard model weak interactions at the SSC are reviewed, with emphasis on the unique capability of the SSC to study the mechanism of electroweak symmetry breaking whether the associated new quanta are at the TeV scale or higher. Symmetry breaking by the minimal Higgs mechanism and by related strong interaction dynamical variants is summarized. A set of measurements is outlined that would calibrate the proton structure functions and the backgrounds to new physics. The ability to measure the three weak gauge boson vertex is found to complement LEP II, with measurements extending to larger Q 2 at a comparable statistical level in detectable decays. B factory physics is briefly reviewed as one example of a possible broad program of high statistics studies of sub-TeV scale phenomena. The largest section of the talk is devoted to the possible manifestations of symmetry breaking in the WW and ZZ production cross sections. Some new results are presented bearing on the ability to detect high mass WW and ZZ pairs. The principal conclusion is that although nonstandard model scenarios are typically more forgiving, the capability to study symmetry breaking in the standard model (and in related strong interaction dynamical variants) requires achieving the SSC design goals of √ s,L = 40Tev, 10 33 cm -2 sec -1 . 28 refs., 5 figs

  20. REST controls self-renewal and tumorigenic competence of human glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Luciano Conti

    Full Text Available The Repressor Element 1 Silencing Transcription factor (REST/NRSF is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets.

  1. Establishing long-term cultures with self-renewing acute myeloid leukemia stem/progenitor cells

    NARCIS (Netherlands)

    van Gosliga, Djoke; Schepers, Hein; Rizo, Aleksandra; van der Kolk, Dorina; Vellenga, Edo; Schuringa, Jan Jacob

    2007-01-01

    Objective. With the emergence of the concept of the leukemia stem cell, assays to study them remain pivotal in understanding (leukemic) stem cell biology. Methods. We have cultured acute myeloid leukemia CD34(+) cells on bone marrow stroma. Long-term expansion was monitored and self-renewal was

  2. Tissue-resident adult stem cell populations of rapidly self-renewing organs

    NARCIS (Netherlands)

    Barker, N.; Bartfeld, S.; Clevers, H.

    2010-01-01

    The epithelial lining of the intestine, stomach, and skin is continuously exposed to environmental assault, imposing a requirement for regular self-renewal. Resident adult stem cell populations drive this renewal, and much effort has been invested in revealing their identity. Reliable adult stem

  3. Erk signaling suppresses embryonic stem cell self-renewal to specify endoderm

    DEFF Research Database (Denmark)

    Hamilton, William B; Brickman, Joshua M

    2014-01-01

    Fgf signaling via Erk activation has been associated with both neural induction and the generation of a primed state for the differentiation of embryonic stem cells (ESCs) to all somatic lineages. To dissect the role of Erk in both ESC self-renewal and lineage specification, we explored...

  4. New insights into redox regulation of stem cell self-renewal and differentiation.

    Science.gov (United States)

    Ren, Fenglian; Wang, Kui; Zhang, Tao; Jiang, Jingwen; Nice, Edouard Collins; Huang, Canhua

    2015-08-01

    Reactive oxygen species (ROS), the natural byproducts of aerobic metabolism, are precisely orchestrated to evoke diverse signaling pathways. To date, studies have focused mainly on the detrimental effects of ROS in stem cells. Recently, accumulating evidence has suggested that ROS also function as second messengers that modulate stem cell self-renewal and differentiation by regulating intricate signaling networks. Although many efforts have been made to clarify the general effects of ROS on signal transduction in stem cells, less is known about the initial and direct executors of ROS signaling, which are known as 'redox sensors'. Modifications of cysteine residues in redox sensors are of significant importance in the modulation of protein function in response to different redox conditions. Intriguingly, most key molecules in ROS signaling and cell cycle regulation (including transcriptional factors and kinases) that are crucial in the regulation of stem cell self-renewal and differentiation have the potential to be redox sensors. We highlight herein the importance of redox regulation of these key regulators in stem cell self-renewal and differentiation. Understanding the mechanisms of redox regulation in stem cell self-renewal and differentiation will open exciting new perspectives for stem cell biology. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Protein Kinase-A Inhibition Is Sufficient to Support Human Neural Stem Cells Self-Renewal.

    Science.gov (United States)

    Georges, Pauline; Boissart, Claire; Poulet, Aurélie; Peschanski, Marc; Benchoua, Alexandra

    2015-12-01

    Human pluripotent stem cell-derived neural stem cells offer unprecedented opportunities for producing specific types of neurons for several biomedical applications. However, to achieve it, protocols of production and amplification of human neural stem cells need to be standardized, cost effective, and safe. This means that small molecules should progressively replace the use of media containing cocktails of protein-based growth factors. Here we have conducted a phenotypical screening to identify pathways involved in the regulation of hNSC self-renewal. We analyzed 80 small molecules acting as kinase inhibitors and identified compounds of the 5-isoquinolinesulfonamide family, described as protein kinase A (PKA) and protein kinase G inhibitors, as candidates to support hNSC self-renewal. Investigating the mode of action of these compounds, we found that modulation of PKA activity was central in controlling the choice between self-renewal or terminal neuronal differentiation of hNSC. We finally demonstrated that the pharmacological inhibition of PKA using the small molecule HA1004 was sufficient to support the full derivation, propagation, and long-term maintenance of stable hNSC in absence of any other extrinsic signals. Our results indicated that tuning of PKA activity is a core mechanism regulating hNSC self-renewal and differentiation and delineate the minimal culture media requirement to maintain undifferentiated hNSC in vitro. © 2015 AlphaMed Press.

  6. Fine-tuning Hematopoiesis: Microenvironmental factors regulating self-renewal and differentiation of hematopoietic stem cells

    NARCIS (Netherlands)

    T.C. Luis (Tiago)

    2010-01-01

    markdownabstract__Abstract__ Hematopoietic stem cells (HSCs) have the ability to self renew and generate all lineages of blood cells. Although it is currently well established that hematopoietic stem cells (HSCs) regenerate the blood compartment, it was only in the 1960s that was introduced the

  7. CrxOS maintains the self-renewal capacity of murine embryonic stem cells

    International Nuclear Information System (INIS)

    Saito, Ryota; Yamasaki, Tokiwa; Nagai, Yoko; Wu, Jinzhan; Kajiho, Hiroaki; Yokoi, Tadashi; Noda, Eiichiro; Nishina, Sachiko; Niwa, Hitoshi; Azuma, Noriyuki; Katada, Toshiaki; Nishina, Hiroshi

    2009-01-01

    Embryonic stem (ES) cells maintain pluripotency by self-renewal. Several homeoproteins, including Oct3/4 and Nanog, are known to be key factors in maintaining the self-renewal capacity of ES cells. However, other genes required for the mechanisms underlying this process are still unclear. Here we report the identification by in silico analysis of a homeobox-containing gene, CrxOS, that is specifically expressed in murine ES cells and is essential for their self-renewal. ES cells mainly express the short isoform of endogenous CrxOS. Using a polyoma-based episomal expression system, we demonstrate that overexpression of the CrxOS short isoform is sufficient for maintaining the undifferentiated morphology of ES cells and stimulating their proliferation. Finally, using RNA interference, we show that CrxOS is essential for the self-renewal of ES cells, and provisionally identify foxD3 as a downstream target gene of CrxOS. To our knowledge, ours is the first delineation of the physiological role of CrxOS in ES cells.

  8. Ferritin nanoparticles for improved self-renewal and differentiation of human neural stem cells.

    Science.gov (United States)

    Lee, Jung Seung; Yang, Kisuk; Cho, Ann-Na; Cho, Seung-Woo

    2018-01-01

    Biomaterials that promote the self-renewal ability and differentiation capacity of neural stem cells (NSCs) are desirable for improving stem cell therapy to treat neurodegenerative diseases. Incorporation of micro- and nanoparticles into stem cell culture has gained great attention for the control of stem cell behaviors, including proliferation and differentiation. In this study, ferritin, an iron-containing natural protein nanoparticle, was applied as a biomaterial to improve the self-renewal and differentiation of NSCs and neural progenitor cells (NPCs). Ferritin nanoparticles were added to NSC or NPC culture during cell growth, allowing for incorporation of ferritin nanoparticles during neurosphere formation. Compared to neurospheres without ferritin treatment, neurospheres with ferritin nanoparticles showed significantly promoted self-renewal and cell-cell interactions. When spontaneous differentiation of neurospheres was induced during culture without mitogenic factors, neuronal differentiation was enhanced in the ferritin-treated neurospheres. In conclusion, we found that natural nanoparticles can be used to improve the self-renewal ability and differentiation potential of NSCs and NPCs, which can be applied in neural tissue engineering and cell therapy for neurodegenerative diseases.

  9. FOXO3 Promotes Quiescence in Adult Muscle Stem Cells during the Process of Self-Renewal

    Directory of Open Access Journals (Sweden)

    Suchitra D. Gopinath

    2014-04-01

    Full Text Available Skeletal muscle stem cells, or “satellite cells” (SCs, are required for the regeneration of damaged muscle tissue. Although SCs self-renew during regeneration, the mechanisms that govern SC re-entry into quiescence remain elusive. We show that FOXO3, a member of the forkhead family of transcription factors, is expressed in quiescent SCs (QSCs. Conditional deletion of Foxo3 in QSCs impairs self-renewal and increases the propensity of SCs to adopt a differentiated fate. Transcriptional analysis of SCs lacking FOXO3 revealed a downregulation of Notch signaling, a key regulator of SC quiescence. Conversely, overexpression of Notch intracellular domain (NICD rescued the self-renewal deficit of FOXO3-deficient SCs. We show that FOXO3 regulates NOTCH1 and NOTCH3 receptor expression and that decreasing expression of NOTCH1 and NOTCH3 receptors phenocopies the effect of FOXO3 deficiency in SCs. We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.

  10. LncMAPK6 drives MAPK6 expression and liver TIC self-renewal.

    Science.gov (United States)

    Huang, Guanqun; Jiang, Hui; He, Yueming; Lin, Ye; Xia, Wuzheng; Luo, Yuanwei; Liang, Min; Shi, Boyun; Zhou, Xinke; Jian, Zhixiang

    2018-05-15

    Liver tumor initiating cells (TICs) have self-renewal and differentiate capacities, and largely contribute to tumor initiation, metastasis and drug resistance. MAPK signaling is a critical pathway in many biological processes, while its role in liver TICs hasn't been explored. Online-available dataset was used for unbiased screening. Liver TICs were examined CD133 FACS or oncosphere formation. TIC self-renewal was detected by oncosphere formation and tumor initiation assay. LncRNA function was detected by loss of function or gain of function assays. The molecular mechanism of lncRNA was explored by RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH. Here, we examined the expression profiles of MAPK components (MAPKs, MAP2Ks, MAP3Ks, MAP4Ks), and found MAPK6 is most highly expressed in liver cancer samples. Moreover, a divergent lncRNA (long noncoding RNA) of MAPK6, termed lncMAPK6 here, is also overexpressed along with liver tumorigenesis. LncMAPK6 promotes liver tumor propagation and TIC self-renewal through MAPK6. LncMAPK6 interacts with and recruits RNA polymerase II to MAPK6 promoter, and finally activates the transcription of MAPK6. Through MAPK6 transcriptional regulation, lncMAPK6 drives MARK signaling activation. LncMAPK6-MAPK6 pathway can be used for liver TIC targeting. Altogether, lncMAPK6 promotes MARK signaling and the self-renewal of liver TICs through MAPK6 expression. MAPK6 was the most highly expressed MAPK component in liver cancer and liver TICs and lncMAPK6 participated in the transcriptional regulation of MAPK6in cis. This work revealed the importance role of MAPK signaling in liver TIC self-renewal and added a new layer for liver TIC and MAPK6 expression regulation.

  11. [Tricostantin A inhibits self-renewal of breast cancer stem cells in vitro].

    Science.gov (United States)

    Peng, Li; Li, Fu-Xi; Shao, Wen-Feng; Xiong, Jing-Bo

    2013-10-01

    To investigate the effect of tricostantin A (TSA) on self-renewal of breast cancer stem cells and explore the mechanisms. Breast cancer cell lines MDA-MB-468, MDA-MB-231, MCF-7 and SKBR3 were cultured in suspension and treated with different concentrations of TSA for 7 days, using 0.1% DMSO as the control. Secondary mammosphere formation efficiency and percentage of CD44(+)/CD24(-) sub-population in the primary mammospheres were used to evaluate the effects of TSA on self-renewal of breast cancer stem cells. The breast cancer stem cell surface marker CD44(+)/CD24(-) and the percentage of apoptosis in the primary mammospheres were assayed using flow cytometry. The mRNA expressions of Nanog, Sox2 and Oct4 in the primary mammospheres were assayed with quantitative PCR. TSA at both 100 and 500 nmol/L, but not at 10 nmol/L, partially inhibited the self-renewal of breast cancer stem cells from the 4 cell lines. TSA at 500 nmol/L induced cell apoptosis in the primary mammospheres. TSA down-regulated the mRNA expression of Nanog and Sox2 in the primary mammospheres. TSA can partially inhibit the self-renewal of breast cancer stem cells through a mechanism involving the down-regulation of Nanog and Sox2 expression, indicating the value of combined treatments with low-dose TSA and other anticancer drugs to achieve maximum inhibition of breast cancer stem cell self-renewal. The core transcriptional factor of embryonic stem cells Nanog and Sox2 can be potential targets of anticancer therapy.

  12. Overview of SSC accelerator requirements

    International Nuclear Information System (INIS)

    Dugan, G.

    1992-03-01

    This paper will present a general overview of the requirements of the Superconducting Super Collider (SSC) accelerators. Each accelerator in the injector chain will be discussed separately, followed by a discussion of the collider itself. In conclusion, the top level requirements of the overall accelerator system will be presented. For each accelerator, the primary operating parameters will be presented in tabular form. A brief narrative discussion of the principal technical features of each machine will be given. Finally, the principal technical design challenges for the machine will be noted, together with the currently planned solution to these challenges

  13. SCL, LMO1 and Notch1 Reprogram Thymocytes into Self-Renewing Cells

    Science.gov (United States)

    Rojas-Sutterlin, Shanti; Herblot, Sabine; Hébert, Josée; Sauvageau, Guy; Lemieux, Sébastien; Lécuyer, Eric; Veiga, Diogo F. T.; Hoang, Trang

    2014-01-01

    The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem cells are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model to define the critical initiating events in this disease. First, thymocytes that are reprogrammed by the SCL and LMO1 oncogenic transcription factors into self-renewing pre-leukemic stem cells (pre-LSCs) remain non-malignant, as evidenced by their capacities to generate functional T cells. Second, we provide strong genetic evidence that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1. Moreover, LYL1 can substitute for SCL to reprogram thymocytes in concert with LMO1. In contrast, inhibition of E2A was not sufficient to substitute for SCL, indicating that thymocyte reprogramming requires transcription activation by SCL-LMO1. Third, only a specific subset of normal thymic cells, known as DN3 thymocytes, is susceptible to reprogramming. This is because physiological NOTCH1 signals are highest in DN3 cells compared to other thymocyte subsets. Consistent with this, overexpression of a ligand-independent hyperactive NOTCH1 allele in all immature thymocytes is sufficient to sensitize them to SCL-LMO1, thereby increasing the pool of self-renewing cells. Surprisingly, hyperactive NOTCH1 cannot reprogram thymocytes on its own, despite the fact that NOTCH1 is activated by gain of function mutations in more than 55% of T-ALL cases. Rather, elevating NOTCH1 triggers a parallel pathway involving Hes1 and Myc that dramatically enhances the activity of SCL-LMO1 We conclude that the acquisition of self-renewal and the genesis of pre-LSCs from thymocytes with a finite lifespan represent a critical first event in T-ALL. Finally, LYL1 and LMO1 or LMO2 are co-expressed in most human T-ALL samples, except the cortical T subtype. We therefore anticipate that the self-renewal network

  14. p38 MAPK pathway is essential for self-renewal of mouse male germline stem cells (mGSCs).

    Science.gov (United States)

    Niu, Zhiwei; Mu, Hailong; Zhu, Haijing; Wu, Jiang; Hua, Jinlian

    2017-02-01

    Male germline stem cells (mGSCs), also called spermatogonial stem cells (SSCs), constantly generate spermatozoa in male animals. A number of preliminary studies on mechanisms of mGSC self-renewal have previously been conducted, revealing that several factors are involved in this regulated process. The p38 MAPK pathway is widely conserved in multiple cell types in vivo, and plays an important role in cell proliferation, differentiation, inflammation and apoptosis. However, its role in self-renewal of mGSCs has not hitherto been determined. Here, the mouse mGSCs were cultured and their identity was verified by semi-RT-PCR, alkaline phosphatase (AP) staining and immunofluorescence staining. Then, the p38 MAPK pathway was blocked by p38 MAPK-specific inhibitor SB202190. mGSC self-renewal ability was then analysed by observation of morphology, cell number, cell growth analysis, TUNEL incorporation assay and cell cycle analysis. Results showed that mouse mGSC self-renewal ability was significantly inhibited by SB202190. This study showed for the first time that the p38 MAPK pathway plays a key role in maintaining self-renewal capacity of mouse mGSCs, which offers a new self-renewal pathway for these cells and contributes to overall knowledge of the mechanisms of mGSC self-renewal. © 2016 John Wiley & Sons Ltd.

  15. Activin pathway enhances colorectal cancer stem cell self-renew and tumor progression.

    Science.gov (United States)

    Liu, Rui; Wang, Jun-Hua; Xu, Chengxiong; Sun, Bo; Kang, Sa-Ouk

    2016-10-28

    Activin belongs to transforming growth factor (TGF)-β super family of growth and differentiation factors and activin pathway participated in broad range of cell process. Studies elaborated activin pathway maintain pluripotency in human stem cells and suggest that the function of activin/nodal signaling in self-renew would be conserved across embryonic and adult stem cells. In this study, we tried to determine the effect of activin signaling pathway in regulation of cancer stem cells as a potential target for cancer therapy in clinical trials. A population of colorectal cancer cells was selected by the treatment of activin A. This population of cell possessed stem cell character with sphere formation ability. We demonstrated activin pathway enhanced the colorectal cancer stem cells self-renew and contribute to colorectal cancer progression in vivo. Targeting activin pathway potentially provide effective strategy for colorectal cancer therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. The effects of silver nanoparticles on mouse embryonic stem cell self-renewal and proliferation

    Directory of Open Access Journals (Sweden)

    Pavan Rajanahalli

    2015-01-01

    Full Text Available Silver nanoparticles (AgNPs are gaining rapid popularity in many commonly used medical and commercial products for their unique anti-bacterial properties. The molecular mechanisms of effects of AgNPs on stem cell self-renewal and proliferation have not yet been well understood. The aim of the work is to use mouse embryonic stem cells (mESCs as a cellular model to evaluate the toxicity of AgNPs. mESC is a very special cell type which has self-renewal and differentiation properties. The objective of this project is to determine the effects of AgNPs with different surface chemical compositions on the self-renewal and cell cycle of mESCs. Two different surface chemical compositions of AgNPs, polysaccharide-coated and hydrocarbon-coated, were used to test their toxic effects on self-renewal and proliferation of mESCs. The results indicated that both polysaccharide-coated and hydrocarbon-coated AgNPs changed the cell morphology of mESCs. Cell cycle analysis indicated that AgNPs induced mESCs cell cycle arrest at G1 and S phases through inhibition of the hyperphosphorylation of Retinoblastoma (Rb protein. Furthermore, AgNPs exposure reduced Oct4A isoform expression which is responsible for the pluripotency of mESCs, and induced the expression of several isoforms OCT4B-265, OCT4B-190, OCT4B-164 which were suggested involved in stem cell stresses responses. In addition, the evidence of reactive oxygen species (ROS production with two different surface chemical compositions of AgNPs supported our hypothesis that the toxic effect AgNPs exposure is due to overproduction of ROS which altered the gene expression and protein modifications. Polysaccharide coating reduced ROS production, and thus reduced the AgNPs toxicity.

  17. Methamphetamine decreases dentate gyrus stem cell self-renewal and shifts the differentiation towards neuronal fate

    Directory of Open Access Journals (Sweden)

    Sofia Baptista

    2014-09-01

    Full Text Available Methamphetamine (METH is a highly addictive psychostimulant drug of abuse that negatively interferes with neurogenesis. In fact, we have previously shown that METH triggers stem/progenitor cell death and decreases neuronal differentiation in the dentate gyrus (DG. Still, little is known regarding its effect on DG stem cell properties. Herein, we investigate the impact of METH on mice DG stem/progenitor cell self-renewal functions. METH (10 nM decreased DG stem cell self-renewal, while 1 nM delayed cell cycle in the G0/G1-to-S phase transition and increased the number of quiescent cells (G0 phase, which correlated with a decrease in cyclin E, pEGFR and pERK1/2 protein levels. Importantly, both drug concentrations (1 or 10 nM did not induce cell death. In accordance with the impairment of self-renewal capacity, METH (10 nM decreased Sox2+/Sox2+ while increased Sox2−/Sox2− pairs of daughter cells. This effect relied on N-methyl-d-aspartate (NMDA signaling, which was prevented by the NMDA receptor antagonist, MK-801 (10 μM. Moreover, METH (10 nM increased doublecortin (DCX protein levels consistent with neuronal differentiation. In conclusion, METH alters DG stem cell properties by delaying cell cycle and decreasing self-renewal capacities, mechanisms that may contribute to DG neurogenesis impairment followed by cognitive deficits verified in METH consumers.

  18. DNMT1 Maintains Progenitor Function in Self-Renewing Somatic Tissue

    OpenAIRE

    Sen, George L.; Reuter, Jason A.; Webster, Daniel E.; Zhu, Lilly; Khavari, Paul A.

    2010-01-01

    Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation1,2. DNA methylation3,4,5 provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1)6,7 maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintena...

  19. Leptin and Adiponectin Modulate the Self-renewal of Normal Human Breast Epithelial Stem Cells.

    Science.gov (United States)

    Esper, Raymond M; Dame, Michael; McClintock, Shannon; Holt, Peter R; Dannenberg, Andrew J; Wicha, Max S; Brenner, Dean E

    2015-12-01

    Multiple mechanisms are likely to account for the link between obesity and increased risk of postmenopausal breast cancer. Two adipokines, leptin and adiponectin, are of particular interest due to their opposing biologic functions and associations with breast cancer risk. In the current study, we investigated the effects of leptin and adiponectin on normal breast epithelial stem cells. Levels of leptin in human adipose explant-derived conditioned media positively correlated with the size of the normal breast stem cell pool. In contrast, an inverse relationship was found for adiponectin. Moreover, a strong linear relationship was observed between the leptin/adiponectin ratio in adipose conditioned media and breast stem cell self-renewal. Consistent with these findings, exogenous leptin stimulated whereas adiponectin suppressed breast stem cell self-renewal. In addition to local in-breast effects, circulating factors, including leptin and adiponectin, may contribute to the link between obesity and breast cancer. Increased levels of leptin and reduced amounts of adiponectin were found in serum from obese compared with age-matched lean postmenopausal women. Interestingly, serum from obese women increased stem cell self-renewal by 30% compared with only 7% for lean control serum. Taken together, these data suggest a plausible explanation for the obesity-driven increase in postmenopausal breast cancer risk. Leptin and adiponectin may function as both endocrine and paracrine/juxtacrine factors to modulate the size of the normal stem cell pool. Interventions that disrupt this axis and thereby normalize breast stem cell self-renewal could reduce the risk of breast cancer. ©2015 American Association for Cancer Research.

  20. Hedgehog-GLI signaling drives self-renewal and tumorigenicity of human melanoma-initiating cells.

    Science.gov (United States)

    Santini, Roberta; Vinci, Maria C; Pandolfi, Silvia; Penachioni, Junia Y; Montagnani, Valentina; Olivito, Biagio; Gattai, Riccardo; Pimpinelli, Nicola; Gerlini, Gianni; Borgognoni, Lorenzo; Stecca, Barbara

    2012-09-01

    The question of whether cancer stem/tumor-initiating cells (CSC/TIC) exist in human melanomas has arisen in the last few years. Here, we have used nonadherent spheres and the aldehyde dehydrogenase (ALDH) enzymatic activity to enrich for CSC/TIC in a collection of human melanomas obtained from a broad spectrum of sites and stages. We find that melanomaspheres display extensive in vitro self-renewal ability and sustain tumor growth in vivo, generating human melanoma xenografts that recapitulate the phenotypic composition of the parental tumor. Melanomaspheres express high levels of Hedgehog (HH) pathway components and of embryonic pluripotent stem cell factors SOX2, NANOG, OCT4, and KLF4. We show that human melanomas contain a subset of cells expressing high ALDH activity (ALDH(high)), which is endowed with higher self-renewal and tumorigenic abilities than the ALDH(low) population. A good correlation between the number of ALDH(high) cells and sphere formation efficiency was observed. Notably, both pharmacological inhibition of HH signaling by the SMOOTHENED (SMO) antagonist cyclopamine and GLI antagonist GANT61 and stable expression of shRNA targeting either SMO or GLI1 result in a significant decrease in melanoma stem cell self-renewal in vitro and a reduction in the number of ALDH(high) melanoma stem cells. Finally, we show that interference with the HH-GLI pathway through lentiviral-mediated silencing of SMO and GLI1 drastically diminishes tumor initiation of ALDH(high) melanoma stem cells. In conclusion, our data indicate an essential role of the HH-GLI1 signaling in controlling self-renewal and tumor initiation of melanoma CSC/TIC. Targeting HH-GLI1 is thus predicted to reduce the melanoma stem cell compartment. Copyright © 2012 AlphaMed Press.

  1. Endogenous production of fibronectin is required for self-renewal of cultured mouse embryonic stem cells

    OpenAIRE

    Hunt, Geoffrey C.; Singh, Purva; Schwarzbauer, Jean E.

    2012-01-01

    Pluripotent cells are attached to the extracellular matrix (ECM) as they make cell fate decisions within the stem cell niche. Here we show that the ubiquitous ECM protein fibronectin is required for self-renewal decisions by cultured mouse embryonic stem (mES) cells. Undifferentiated mES cells produce fibronectin and assemble a fibrillar matrix. Increasing the level of substrate fibronectin increased cell spreading and integrin receptor signaling through focal adhesion kinase, while concomita...

  2. Accelerator physics issues at the SSC

    International Nuclear Information System (INIS)

    Dugan, G.F.

    1993-05-01

    Realization of the design energy and luminosity goals of the Superconducting Super Collider (SSC) will require proper resolutions of a number of challenging problems in accelerator physics. The status of several salient issues in the design of the SSC will be reviewed and updated in this paper. The emphasis will be on the superconducting accelerators

  3. A GEM of an SSC detector

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    The SSC Laboratory has decided to support the GEM (Gammas, Electrons, and Muons) detector collaboration in the next stage of its work, development of a Technical Design Report. Initial ideas for GEM as the second major SSC detector were aired last year

  4. Dual role of BMP signaling in the regulation of Drosophila intestinal stem cell self-renewal.

    Science.gov (United States)

    Tian, Aiguo; Jiang, Jin

    2017-10-02

    Many adult organs including Drosophila adult midguts rely on resident stem cells to replenish damaged cells during tissue homeostasis and regeneration. Previous studies have shown that, upon injury, intestinal stem cells (ISCs) in the midguts can increase proliferation and lineage differentiation to meet the demand for tissue repair. Our recent study has demonstrated that, in response to certain injury, midguts can expand ISC population size as an additional regenerative mechanism. We found that injury elicited by bleomycin feeding or bacterial infection increased the production of two BMP ligands (Dpp and Gbb) in enterocytes (ECs), leading to elevated BMP signaling in progenitor cells that drove an expansion of ISCs by promoting their symmetric self-renewing division. Interestingly, we also found that BMP signaling in ECs inhibits the production of Dpp and Gbb, and that this negative feedback mechanism is required to reset ISC pool size to the homeostatic state. Our findings suggest that BMP signaling exerts two opposing influences on stem cell activity depending on where it acts: BMP signaling in progenitor cells promotes ISC self-renewal while BMP signaling in ECs restricts ISC self-renewal by preventing excessive production of BMP ligands. Our results further suggest that transient expansion of ISC population in conjunction with increasing ISC proliferation provides a more effective strategy for tissue regeneration.

  5. Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal

    Science.gov (United States)

    Lackford, Brad; Yao, Chengguo; Charles, Georgette M; Weng, Lingjie; Zheng, Xiaofeng; Choi, Eun-A; Xie, Xiaohui; Wan, Ji; Xing, Yi; Freudenberg, Johannes M; Yang, Pengyi; Jothi, Raja; Hu, Guang; Shi, Yongsheng

    2014-01-01

    mRNA alternative polyadenylation (APA) plays a critical role in post-transcriptional gene control and is highly regulated during development and disease. However, the regulatory mechanisms and functional consequences of APA remain poorly understood. Here, we show that an mRNA 3′ processing factor, Fip1, is essential for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. Fip1 promotes stem cell maintenance, in part, by activating the ESC-specific APA profiles to ensure the optimal expression of a specific set of genes, including critical self-renewal factors. Fip1 expression and the Fip1-dependent APA program change during ESC differentiation and are restored to an ESC-like state during somatic reprogramming. Mechanistically, we provide evidence that the specificity of Fip1-mediated APA regulation depends on multiple factors, including Fip1-RNA interactions and the distance between APA sites. Together, our data highlight the role for post-transcriptional control in stem cell self-renewal, provide mechanistic insight on APA regulation in development, and establish an important function for APA in cell fate specification. PMID:24596251

  6. An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma.

    Science.gov (United States)

    Gujar, Amit D; Le, Son; Mao, Diane D; Dadey, David Y A; Turski, Alice; Sasaki, Yo; Aum, Diane; Luo, Jingqin; Dahiya, Sonika; Yuan, Liya; Rich, Keith M; Milbrandt, Jeffrey; Hallahan, Dennis E; Yano, Hiroko; Tran, David D; Kim, Albert H

    2016-12-20

    Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD + ). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD + synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD + levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD + -dependent network. Accordingly, we demonstrate E2F2 is required for GSC self-renewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD + metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.

  7. DNMT1 maintains progenitor function in self-renewing somatic tissue.

    Science.gov (United States)

    Sen, George L; Reuter, Jason A; Webster, Daniel E; Zhu, Lilly; Khavari, Paul A

    2010-01-28

    Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation. DNA methylation provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1) maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance, the role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is unclear. Here we show that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual tissue loss. Genome-wide analysis showed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, UHRF1 (refs 9, 10), a component of the DNA methylation machinery that targets DNMT1 to hemi-methylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A and B, which promote active DNA demethylation, are required for full epidermal differentiation gene induction. These data demonstrate that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue.

  8. The histone demethylase Jarid1b is required for hematopoietic stem cell self-renewal

    DEFF Research Database (Denmark)

    Stewart, Morag H; Albert, Mareike; Sroczynska, Patrycja

    2015-01-01

    Jarid1b/KDM5b is a histone demethylase that regulates self-renewal and differentiation in stem cells and cancer, however its function in hematopoiesis is unclear. Here, we find that Jarid1b is highly expressed in primitive hematopoietic compartments and is overexpressed in acute myeloid leukemias...... compromises hematopoietic stem cell (HSC) self-renewal capacity and suggest that Jarid1b is a positive regulator of HSC potential.......Jarid1b/KDM5b is a histone demethylase that regulates self-renewal and differentiation in stem cells and cancer, however its function in hematopoiesis is unclear. Here, we find that Jarid1b is highly expressed in primitive hematopoietic compartments and is overexpressed in acute myeloid leukemias....... Constitutive genetic deletion of Jarid1b did not impact steady-state hematopoiesis. In contrast, acute deletion of Jarid1b from bone marrow increased peripheral blood T cells and, following secondary transplantation, resulted in loss of bone marrow reconstitution. Our results reveal that deletion of Jarid1b...

  9. Cultural connections of the SSC

    International Nuclear Information System (INIS)

    Kirk, T.B.W.

    1984-01-01

    This paper has as its purpose, to consider explicitly and in more than cursory detail, the cultural involvement of a major scientific facility, the SSC, with its public surroundings. At the moment of writing, it is uncertain whether the project will evolve under US-national or under international sponsorship. Since most of the paper's substantive content is invariant with respect to this question (but the means of implementation are not), the author proceeds as though the machine will be US sponsored. This assumption avoids the irritation of having to identify continually the particular methods for implementation of the ideas presented. If the international route is chosen, a second paper could be written to accommodate this outcome. By cultural involvement, the author is principally concerned with the following areas: i) accessibility of the facility to the general public; ii) educational potential at and away from the site; iii) architectural and aesthetic considerations; and iv) formal history of the project

  10. Commissioning plans for SSC linac

    International Nuclear Information System (INIS)

    Hurd, J.W.; Aprile, R.L.; Chang, C.R.; Crist, C.E.; Cutler, R.I.; Funk, L.W.; Guy, F.W.; Leifeste, G.T.; Raparia, D.; Saadatmand, K.; Sethi, R.C.; Swenson, D.A.; Tooker, J.; Yao, C.G.

    1992-01-01

    Presented are the general description of the SSC linac and the plans for commissioning. Sections of the linac are installed, tested, and beam commissioned in a serial approach. A specialized set of diagnostics is used to characterize the beam through each section. In addition to the standard diagnostic set, plans call for the use of a bunch shape monitor and x-ray spectrometer. Streak camera and digital imaging diagnostics will be developed. The commissioning plan is folded into the general linac project schedule to show the relation between delivery, staging, installation, conditioning, and actual commissioning with beam. These plans form the basis for coordination between the various organizations responsible for different elements of the linac including the technical components, infrastructure, and temporary staging and operation facilities. (Author) 2 figs., 17 refs

  11. Conversion of Human Fibroblasts to Stably Self-Renewing Neural Stem Cells with a Single Zinc-Finger Transcription Factor

    Directory of Open Access Journals (Sweden)

    Ebrahim Shahbazi

    2016-04-01

    Full Text Available Direct conversion of somatic cells into neural stem cells (NSCs by defined factors holds great promise for mechanistic studies, drug screening, and potential cell therapies for different neurodegenerative diseases. Here, we report that a single zinc-finger transcription factor, Zfp521, is sufficient for direct conversion of human fibroblasts into long-term self-renewable and multipotent NSCs. In vitro, Zfp521-induced NSCs maintained their characteristics in the absence of exogenous factor expression and exhibited morphological, molecular, developmental, and functional properties that were similar to control NSCs. In addition, the single-seeded induced NSCs were able to form NSC colonies with efficiency comparable with control NSCs and expressed NSC markers. The converted cells were capable of surviving, migrating, and attaining neural phenotypes after transplantation into neonatal mouse and adult rat brains, without forming tumors. Moreover, the Zfp521-induced NSCs predominantly expressed rostral genes. Our results suggest a facilitated approach for establishing human NSCs through Zfp521-driven conversion of fibroblasts.

  12. Physics possibilities at LHC/SSC

    International Nuclear Information System (INIS)

    Hinchliffe, I.

    1991-01-01

    This document reviews some recent work on physics simulations for SSC/LHC. Included are reviews of some of the recent developments in physics simulations for the SSC/LHC and comments upon the requirements that are placed upon detectors by the need to extract specific physics signatures. The material in the various EOI/LOI documents submitted to the SCC Laboratory and the work done at the Aachen LHC workshop are discussed. In the following discussion 1 SSC (LHC) year corresponds to an integrated luminosity of 10 (100) fb -1 . 41 refs., 14 figs

  13. Systems engineering and integrated for the SSC

    International Nuclear Information System (INIS)

    Laintz, D.J.; Crosby, B.; Davis, M.; Eben, D.; Gliozzi, J.; Kientz, E.; Knafelc, J.; Phelps, J.; Rider, M.; Shearer, K.

    1989-01-01

    Experience in high technology projects of scale and scope similar to the SSC, leads the authors to propose utilization of a Systems Engineering and Integration (SE and I) process tailored specifically to the SSC project. They begin by giving an overview of SE and I. This overview includes the purpose, history, definition, and a discussion of when to use it. They then proceeded to give a description of a formalized SE and I process. They discuss tailoring the process to a project and close by recommending an early commitment to an SE and I methodology for the SSC. 2 refs., 2 figs

  14. Detector problems at the SSC

    International Nuclear Information System (INIS)

    Wojcicki, S.G.

    1985-02-01

    During the last couple of years there has been considerable concern expressed among the US high energy community as to whether detector limitations would prevent one from being able to fully exploit a luminosity of 10 33 cm -2 sec -1 at a hadron-hadron high energy collider. As a result of these concerns, a considerable amount of work has been done recently in trying to understand the nature of potential difficulties and the required R and D that needs to be performed. A lot of this work has been summarized in the 1984 DPF Summer Study at Snowmass. This paper attempts to review some of these results. This work is limited to the discussion of detector problems associated with the study of high energy hadron-hadron collisions. We shall start with the discussion of the desirable features of the detectors and of the SSC environment in which they will have to work. After a brief discussion of the model 4π detectors, we shall discuss specific detector aspects: lepton identification, tracking, calorimetry and computing and triggering. We shall end with some remarks about possible future course of events. 15 refs., 10 figs

  15. Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells.

    Science.gov (United States)

    Sastry, K S R; Al-Muftah, M A; Li, Pu; Al-Kowari, M K; Wang, E; Ismail Chouchane, A; Kizhakayil, D; Kulik, G; Marincola, F M; Haoudi, A; Chouchane, L

    2014-12-01

    Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44(+)/CD24(-) cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44(+) CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

  16. Earmuff restricts progenitor cell potential by attenuating the competence to respond to self-renewal factors.

    Science.gov (United States)

    Janssens, Derek H; Komori, Hideyuki; Grbac, Daniel; Chen, Keng; Koe, Chwee Tat; Wang, Hongyan; Lee, Cheng-Yu

    2014-03-01

    Despite expressing stem cell self-renewal factors, intermediate progenitor cells possess restricted developmental potential, which allows them to give rise exclusively to differentiated progeny rather than stem cell progeny. Failure to restrict the developmental potential can allow intermediate progenitor cells to revert into aberrant stem cells that might contribute to tumorigenesis. Insight into stable restriction of the developmental potential in intermediate progenitor cells could improve our understanding of the development and growth of tumors, but the mechanisms involved remain largely unknown. Intermediate neural progenitors (INPs), generated by type II neural stem cells (neuroblasts) in fly larval brains, provide an in vivo model for investigating the mechanisms that stably restrict the developmental potential of intermediate progenitor cells. Here, we report that the transcriptional repressor protein Earmuff (Erm) functions temporally after Brain tumor (Brat) and Numb to restrict the developmental potential of uncommitted (immature) INPs. Consistently, endogenous Erm is detected in immature INPs but undetectable in INPs. Erm-dependent restriction of the developmental potential in immature INPs leads to attenuated competence to respond to all known neuroblast self-renewal factors in INPs. We also identified that the BAP chromatin-remodeling complex probably functions cooperatively with Erm to restrict the developmental potential of immature INPs. Together, these data led us to conclude that the Erm-BAP-dependent mechanism stably restricts the developmental potential of immature INPs by attenuating their genomic responses to stem cell self-renewal factors. We propose that restriction of developmental potential by the Erm-BAP-dependent mechanism functionally distinguishes intermediate progenitor cells from stem cells, ensuring the generation of differentiated cells and preventing the formation of progenitor cell-derived tumor-initiating stem cells.

  17. Albumin-associated lipids regulate human embryonic stem cell self-renewal.

    Directory of Open Access Journals (Sweden)

    Francesc R Garcia-Gonzalo

    Full Text Available BACKGROUND: Although human embryonic stem cells (hESCs hold great promise as a source of differentiated cells to treat several human diseases, many obstacles still need to be surmounted before this can become a reality. First among these, a robust chemically-defined system to expand hESCs in culture is still unavailable despite recent advances in the understanding of factors controlling hESC self-renewal. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we attempted to find new molecules that stimulate long term hESC self-renewal. In order to do this, we started from the observation that a commercially available serum replacement product has a strong positive effect on the expansion of undifferentiated hESCs when added to a previously reported chemically-defined medium. Subsequent experiments demonstrated that the active ingredient within the serum replacement is lipid-rich albumin. Furthermore, we show that this activity is trypsin-resistant, strongly suggesting that lipids and not albumin are responsible for the effect. Consistent with this, lipid-poor albumin shows no detectable activity. Finally, we identified the major lipids bound to the lipid-rich albumin and tested several lipid candidates for the effect. CONCLUSIONS/SIGNIFICANCE: Our discovery of the role played by albumin-associated lipids in stimulating hESC self-renewal constitutes a significant advance in the knowledge of how hESC pluripotency is maintained by extracellular factors and has important applications in the development of increasingly chemically defined hESC culture systems.

  18. Transient inhibition of cell proliferation does not compromise self-renewal of mouse embryonic stem cells.

    Science.gov (United States)

    Wang, Ruoxing; Guo, Yan-Lin

    2012-10-01

    Embryonic stem cells (ESCs) have unlimited capacity for self-renewal and can differentiate into various cell types when induced. They also have an unusual cell cycle control mechanism driven by constitutively active cyclin dependent kinases (Cdks). In mouse ESCs (mESCs). It is proposed that the rapid cell proliferation could be a necessary part of mechanisms that maintain mESC self-renewal and pluripotency, but this hypothesis is not in line with the finding in human ESCs (hESCs) that the length of the cell cycle is similar to differentiated cells. Therefore, whether rapid cell proliferation is essential for the maintenance of mESC state remains unclear. We provide insight into this uncertainty through chemical intervention of mESC cell cycle. We report here that inhibition of Cdks with olomoucine II can dramatically slow down cell proliferation of mESCs with concurrent down-regulation of cyclin A, B and E, and the activation of the Rb pathway. However, mESCs display can recover upon the removal of olomoucine II and are able to resume normal cell proliferation without losing self-renewal and pluripotency, as demonstrated by the expression of ESC markers, colony formation, embryoid body formation, and induced differentiation. We provide a mechanistic explanation for these observations by demonstrating that Oct4 and Nanog, two major transcription factors that play critical roles in the maintenance of ESC properties, are up-regulated via de novo protein synthesis when the cells are exposed to olomoucine II. Together, our data suggest that short-term inhibition of cell proliferation does not compromise the basic properties of mESCs. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Measuring structure functions at SSC energies

    International Nuclear Information System (INIS)

    Morfin, J.G.; Owens, J.F.

    1985-01-01

    Topics discussed include measuring Λ, tests of QCD using hard scattering processes, and measuring parton distributions. In each case, any opportunities and advantages afforded by the unique features of the SSC are emphasized. The working group on structure functions was charged with investigating two specific questions: (1) How well are the various parton distributions known in the kinematic region relevant to calculations for the SSC. (2) What new information can be learned about parton distributions at the SSC. Especially for this working group, the advantages of having a fixed-target facility at the SSC for the measurement of the parton distributions with multi-TeV leptons, were to be examined. 15 references

  20. Decoupling schemes for the SSC Collider

    International Nuclear Information System (INIS)

    Cai, Y.; Bourianoff, G.; Cole, B.; Meinke, R.; Peterson, J.; Pilat, F.; Stampke, S.; Syphers, M.; Talman, R.

    1993-05-01

    A decoupling system is designed for the SSC Collider. This system can accommodate three decoupling schemes by using 44 skew quadrupoles in the different configurations. Several decoupling schemes are studied and compared in this paper

  1. Physics motivations for SSC/LHC detectors

    International Nuclear Information System (INIS)

    Hinchliffe, I.

    1993-06-01

    In this talk, I review the some of the physics goals and simulation work done in the SSC and LHC experimental proposal. I select the processes that illustrate the strengths and weaknesses the proposed detectors

  2. SSC-K code user's manual

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Y M; Lee, Y B; Chang, W P; Hahn, D

    2000-07-01

    The Supper System Code of KAERI (SSC-K) is a best-estimate system code for analyzing a variety of off-normal or accidents in the heat transport system of a pool type LMR design. It is being developed at Korea Atomic Energy Research Inititution (KAERI) on the basis of SSC-L, originally developed at BNL to analyze loop-type LMR transients. SSC-K can handle both designs of loop and pool type LMRs. SSC-K contains detailed mechanistic models of transient thermal, hydraulic, neutronic, and mechanical phenomena to describe the response of the reactor core, coolant, fuel elements, and structures to accident conditions. This report provides an overview of recent model developmentsvfor the SSC-K computer code, focusing on phenomenological model descriptions for new thermal, hydraulic, neutronic, and mechnaical modules. A comprehensive description of the models for pool-type reactor is given in Chapters 2 and 3; the steady-state plant characterization, prior to the initiation of transient is described in Chapter 2 and their transient counterparts are discussed in Chapter 3. In Chapter 4, a discussion on the intermediate heat exchanger (IHX) is presented. The IHX model of SSC-K is similar to that used in the SSC-L, except for some changes required for the pool-type configuration of reactor vessel. In Chapter 5, an electromagnetic (EM) pump is modeled as a component. There are two pump choices available in SSC-K; a centrifugal pump which was originally imbedded into the SSC-L, and an EM pump which was introduced for the KALIMER design. In Chapter 6, a model of passive safety decay heat removal system(PSDRS) is discussed, which removes decay heat through the reactor and containment vessel walls to the ambient air heat sink. In Chapter 7, models for various reactivity feedback effects are discussed. Reactivity effects of importance in fast reactor include the Doppler effect, effects of sodium density changes, effects of dimensional changes in core geometry. Finally in Chapter 8

  3. Transient inhibition of cell proliferation does not compromise self-renewal of mouse embryonic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ruoxing [Department of Biological Sciences, The University of Southern Mississippi, 118 College Drive 5018, Hattiesburg, MS 39406 (United States); Guo, Yan-Lin, E-mail: yanlin.guo@usm.edu [Department of Biological Sciences, The University of Southern Mississippi, 118 College Drive 5018, Hattiesburg, MS 39406 (United States)

    2012-10-01

    Embryonic stem cells (ESCs) have unlimited capacity for self-renewal and can differentiate into various cell types when induced. They also have an unusual cell cycle control mechanism driven by constitutively active cyclin dependent kinases (Cdks). In mouse ESCs (mESCs). It is proposed that the rapid cell proliferation could be a necessary part of mechanisms that maintain mESC self-renewal and pluripotency, but this hypothesis is not in line with the finding in human ESCs (hESCs) that the length of the cell cycle is similar to differentiated cells. Therefore, whether rapid cell proliferation is essential for the maintenance of mESC state remains unclear. We provide insight into this uncertainty through chemical intervention of mESC cell cycle. We report here that inhibition of Cdks with olomoucine II can dramatically slow down cell proliferation of mESCs with concurrent down-regulation of cyclin A, B and E, and the activation of the Rb pathway. However, mESCs display can recover upon the removal of olomoucine II and are able to resume normal cell proliferation without losing self-renewal and pluripotency, as demonstrated by the expression of ESC markers, colony formation, embryoid body formation, and induced differentiation. We provide a mechanistic explanation for these observations by demonstrating that Oct4 and Nanog, two major transcription factors that play critical roles in the maintenance of ESC properties, are up-regulated via de novo protein synthesis when the cells are exposed to olomoucine II. Together, our data suggest that short-term inhibition of cell proliferation does not compromise the basic properties of mESCs. -- Highlights: Black-Right-Pointing-Pointer Inhibition of Cdks slows down mESCs proliferation. Black-Right-Pointing-Pointer mESCs display remarkable recovery capacity from short-term cell cycle interruption. Black-Right-Pointing-Pointer Short-term cell cycle interruption does not compromise mESC self-renewal. Black

  4. Protein kinase C regulates human pluripotent stem cell self-renewal.

    Directory of Open Access Journals (Sweden)

    Masaki Kinehara

    Full Text Available The self-renewal of human pluripotent stem (hPS cells including embryonic stem and induced pluripotent stem cells have been reported to be supported by various signal pathways. Among them, fibroblast growth factor-2 (FGF-2 appears indispensable to maintain self-renewal of hPS cells. However, downstream signaling of FGF-2 has not yet been clearly understood in hPS cells.In this study, we screened a kinase inhibitor library using a high-throughput alkaline phosphatase (ALP activity-based assay in a minimal growth factor-defined medium to understand FGF-2-related molecular mechanisms regulating self-renewal of hPS cells. We found that in the presence of FGF-2, an inhibitor of protein kinase C (PKC, GF109203X (GFX, increased ALP activity. GFX inhibited FGF-2-induced phosphorylation of glycogen synthase kinase-3β (GSK-3β, suggesting that FGF-2 induced PKC and then PKC inhibited the activity of GSK-3β. Addition of activin A increased phosphorylation of GSK-3β and extracellular signal-regulated kinase-1/2 (ERK-1/2 synergistically with FGF-2 whereas activin A alone did not. GFX negated differentiation of hPS cells induced by the PKC activator, phorbol 12-myristate 13-acetate whereas Gö6976, a selective inhibitor of PKCα, β, and γ isoforms could not counteract the effect of PMA. Intriguingly, functional gene analysis by RNA interference revealed that the phosphorylation of GSK-3β was reduced by siRNA of PKCδ, PKCε, and ζ, the phosphorylation of ERK-1/2 was reduced by siRNA of PKCε and ζ, and the phosphorylation of AKT was reduced by PKCε in hPS cells.Our study suggested complicated cross-talk in hPS cells that FGF-2 induced the phosphorylation of phosphatidylinositol-3 kinase (PI3K/AKT, mitogen-activated protein kinase/ERK-1/2 kinase (MEK, PKC/ERK-1/2 kinase, and PKC/GSK-3β. Addition of GFX with a MEK inhibitor, U0126, in the presence of FGF-2 and activin A provided a long-term stable undifferentiated state of hPS cells even though h

  5. Protein Kinase C Regulates Human Pluripotent Stem Cell Self-Renewal

    Science.gov (United States)

    Kinehara, Masaki; Kawamura, Suguru; Tateyama, Daiki; Suga, Mika; Matsumura, Hiroko; Mimura, Sumiyo; Hirayama, Noriko; Hirata, Mitsuhi; Uchio-Yamada, Kozue; Kohara, Arihiro; Yanagihara, Kana; Furue, Miho K.

    2013-01-01

    Background The self-renewal of human pluripotent stem (hPS) cells including embryonic stem and induced pluripotent stem cells have been reported to be supported by various signal pathways. Among them, fibroblast growth factor-2 (FGF-2) appears indispensable to maintain self-renewal of hPS cells. However, downstream signaling of FGF-2 has not yet been clearly understood in hPS cells. Methodology/Principal Findings In this study, we screened a kinase inhibitor library using a high-throughput alkaline phosphatase (ALP) activity-based assay in a minimal growth factor-defined medium to understand FGF-2-related molecular mechanisms regulating self-renewal of hPS cells. We found that in the presence of FGF-2, an inhibitor of protein kinase C (PKC), GF109203X (GFX), increased ALP activity. GFX inhibited FGF-2-induced phosphorylation of glycogen synthase kinase-3β (GSK-3β), suggesting that FGF-2 induced PKC and then PKC inhibited the activity of GSK-3β. Addition of activin A increased phosphorylation of GSK-3β and extracellular signal-regulated kinase-1/2 (ERK-1/2) synergistically with FGF-2 whereas activin A alone did not. GFX negated differentiation of hPS cells induced by the PKC activator, phorbol 12-myristate 13-acetate whereas Gö6976, a selective inhibitor of PKCα, β, and γ isoforms could not counteract the effect of PMA. Intriguingly, functional gene analysis by RNA interference revealed that the phosphorylation of GSK-3β was reduced by siRNA of PKCδ, PKCε, and ζ, the phosphorylation of ERK-1/2 was reduced by siRNA of PKCε and ζ, and the phosphorylation of AKT was reduced by PKCε in hPS cells. Conclusions/Significance Our study suggested complicated cross-talk in hPS cells that FGF-2 induced the phosphorylation of phosphatidylinositol-3 kinase (PI3K)/AKT, mitogen-activated protein kinase/ERK-1/2 kinase (MEK), PKC/ERK-1/2 kinase, and PKC/GSK-3β. Addition of GFX with a MEK inhibitor, U0126, in the presence of FGF-2 and activin A provided a long

  6. SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells.

    Science.gov (United States)

    Santini, R; Pietrobono, S; Pandolfi, S; Montagnani, V; D'Amico, M; Penachioni, J Y; Vinci, M C; Borgognoni, L; Stecca, B

    2014-09-18

    Melanoma is one of the most aggressive types of human cancer, characterized by enhanced heterogeneity and resistance to conventional therapy at advanced stages. We and others have previously shown that HEDGEHOG-GLI (HH-GLI) signaling is required for melanoma growth and for survival and expansion of melanoma-initiating cells (MICs). Recent reports indicate that HH-GLI signaling regulates a set of genes typically expressed in embryonic stem cells, including SOX2 (sex-determining region Y (SRY)-Box2). Here we address the function of SOX2 in human melanomas and MICs and its interaction with HH-GLI signaling. We find that SOX2 is highly expressed in melanoma stem cells. Knockdown of SOX2 sharply decreases self-renewal in melanoma spheres and in putative melanoma stem cells with high aldehyde dehydrogenase activity (ALDH(high)). Conversely, ectopic expression of SOX2 in melanoma cells enhances their self-renewal in vitro. SOX2 silencing also inhibits cell growth and induces apoptosis in melanoma cells. In addition, depletion of SOX2 progressively abrogates tumor growth and leads to a significant decrease in tumor-initiating capability of ALDH(high) MICs upon xenotransplantation, suggesting that SOX2 is required for tumor initiation and for continuous tumor growth. We show that SOX2 is regulated by HH signaling and that the transcription factors GLI1 and GLI2, the downstream effectors of HH-GLI signaling, bind to the proximal promoter region of SOX2 in primary melanoma cells. In functional studies, we find that SOX2 function is required for HH-induced melanoma cell growth and MIC self-renewal in vitro. Thus SOX2 is a critical factor for self-renewal and tumorigenicity of MICs and an important mediator of HH-GLI signaling in melanoma. These findings could provide the basis for novel therapeutic strategies based on the inhibition of SOX2 for the treatment of a subset of human melanomas.

  7. Transient inhibition of cell proliferation does not compromise self-renewal of mouse embryonic stem cells

    International Nuclear Information System (INIS)

    Wang, Ruoxing; Guo, Yan-Lin

    2012-01-01

    Embryonic stem cells (ESCs) have unlimited capacity for self-renewal and can differentiate into various cell types when induced. They also have an unusual cell cycle control mechanism driven by constitutively active cyclin dependent kinases (Cdks). In mouse ESCs (mESCs). It is proposed that the rapid cell proliferation could be a necessary part of mechanisms that maintain mESC self-renewal and pluripotency, but this hypothesis is not in line with the finding in human ESCs (hESCs) that the length of the cell cycle is similar to differentiated cells. Therefore, whether rapid cell proliferation is essential for the maintenance of mESC state remains unclear. We provide insight into this uncertainty through chemical intervention of mESC cell cycle. We report here that inhibition of Cdks with olomoucine II can dramatically slow down cell proliferation of mESCs with concurrent down-regulation of cyclin A, B and E, and the activation of the Rb pathway. However, mESCs display can recover upon the removal of olomoucine II and are able to resume normal cell proliferation without losing self-renewal and pluripotency, as demonstrated by the expression of ESC markers, colony formation, embryoid body formation, and induced differentiation. We provide a mechanistic explanation for these observations by demonstrating that Oct4 and Nanog, two major transcription factors that play critical roles in the maintenance of ESC properties, are up-regulated via de novo protein synthesis when the cells are exposed to olomoucine II. Together, our data suggest that short-term inhibition of cell proliferation does not compromise the basic properties of mESCs. -- Highlights: ► Inhibition of Cdks slows down mESCs proliferation. ► mESCs display remarkable recovery capacity from short-term cell cycle interruption. ► Short-term cell cycle interruption does not compromise mESC self-renewal. ► Oct4 and Nanog are up-regulated via de novo synthesis by cell cycle interruption.

  8. Tracking with wire chambers at the SSC

    International Nuclear Information System (INIS)

    Hanson, G.G.; Gundy, M.C.; Palounek, A.P.T.

    1989-07-01

    Limitations placed on wire chambers by radiation damage and rate requirements in the SSC environment are reviewed. Possible conceptual designs for wire chamber tacking systems that meet these requirements are discussed. Computer simulation studies of tracking in such systems are presented. Simulations of events from interesting physics at the SSC, including hits from minimum bias background events, are examined. Results of some preliminary pattern recognition studies are given. 13 refs., 11 fig., 1 tab

  9. Validation of SSC using the FFTF natural-circulation tests

    International Nuclear Information System (INIS)

    Horak, W.C.; Guppy, J.G.; Kennett, R.J.

    1982-01-01

    As part of the Super System Code (SSC) validation program, the 100% power FFTF natural circulation test has been simulated using SSC. A detailed 19 channel, 2 loop model was used in SSC. Comparisons showed SSC calculations to be in good agreement with the Fast Flux Test Facility (FFTF), test data. Simulation of the test was obtained in real time

  10. Intermittent Stem Cell Cycling Balances Self-Renewal and Senescence of the C. elegans Germ Line.

    Directory of Open Access Journals (Sweden)

    Amanda Cinquin

    2016-04-01

    Full Text Available Self-renewing organs often experience a decline in function in the course of aging. It is unclear whether chronological age or external factors control this decline, or whether it is driven by stem cell self-renewal-for example, because cycling cells exhaust their replicative capacity and become senescent. Here we assay the relationship between stem cell cycling and senescence in the Caenorhabditis elegans reproductive system, defining this senescence as the progressive decline in "reproductive capacity," i.e. in the number of progeny that can be produced until cessation of reproduction. We show that stem cell cycling diminishes remaining reproductive capacity, at least in part through the DNA damage response. Paradoxically, gonads kept under conditions that preclude reproduction keep cycling and producing cells that undergo apoptosis or are laid as unfertilized gametes, thus squandering reproductive capacity. We show that continued activity is in fact beneficial inasmuch as gonads that are active when reproduction is initiated have more sustained early progeny production. Intriguingly, continued cycling is intermittent-gonads switch between active and dormant states-and in all likelihood stochastic. Other organs face tradeoffs whereby stem cell cycling has the beneficial effect of providing freshly-differentiated cells and the detrimental effect of increasing the likelihood of cancer or senescence; stochastic stem cell cycling may allow for a subset of cells to preserve proliferative potential in old age, which may implement a strategy to deal with uncertainty as to the total amount of proliferation to be undergone over an organism's lifespan.

  11. Adhesion-mediated self-renewal abilities of Ph+ blastoma cells

    International Nuclear Information System (INIS)

    Funayama, Keiji; Saito-Kurimoto, Yumi; Ebihara, Yasuhiro; Shimane, Miyuki; Nomura, Hitoshi; Tsuji, Ko-ichiro; Asano, Shigetaka

    2010-01-01

    The Philadelphia chromosome-positive blastoma, maintained by serial subcutaneous transplantation in nude mice, is a highly proliferating biological mass consisting of homogenous CD34 + CD38 - myeloblastoid cells. These cells newly evolved from pluripotent leukemia stem cells of chronic myeloid leukemia in the chronic phase. Therefore, this mass may provide a unique tool for better understanding cellular and molecular mechanisms of self-renewal of leukemia stem cells. In this paper, we demonstrated that intravenously injected blastoma cells can cause Ph+ blastic leukemia with multiple invasive foci in NOD/SCID mice but not in nude mice. In addition, using an in vitro culture system, we clearly showed that blastoma cell adhesion to OP9 stromal cells accelerates blastoma cell proliferation that is associated with up-regulation of BMI1 gene expression; increased levels of β-catenin and the Notch1 intra-cellular domain; and changed the expression pattern of variant CD44 forms, which are constitutively expressed in these blastoma cells. These findings strongly suggest that adhesion of leukemic stem cells to stromal cells via CD44 might be indispensable for their cellular defense against attack by immune cells and for maintenance of their self-renewal ability.

  12. miR-99 regulates normal and malignant hematopoietic stem cell self-renewal.

    Science.gov (United States)

    Khalaj, Mona; Woolthuis, Carolien M; Hu, Wenhuo; Durham, Benjamin H; Chu, S Haihua; Qamar, Sarah; Armstrong, Scott A; Park, Christopher Y

    2017-07-21

    The microRNA-99 ( miR-99 ) family comprises a group of broadly conserved microRNAs that are highly expressed in hematopoietic stem cells (HSCs) and acute myeloid leukemia stem cells (LSCs) compared with their differentiated progeny. Herein, we show that miR-99 regulates self-renewal in both HSCs and LSCs. miR-99 maintains HSC long-term reconstitution activity by inhibiting differentiation and cell cycle entry. Moreover, miR-99 inhibition induced LSC differentiation and depletion in an MLL-AF9-driven mouse model of AML, leading to reduction in leukemia-initiating activity and improved survival in secondary transplants. Confirming miR-99 's role in established AML, miR-99 inhibition induced primary AML patient blasts to undergo differentiation. A forward genetic shRNA library screen revealed Hoxa1 as a critical mediator of miR-99 function in HSC maintenance, and this observation was independently confirmed in both HSCs and LSCs. Together, these studies demonstrate the importance of noncoding RNAs in the regulation of HSC and LSC function and identify miR-99 as a critical regulator of stem cell self-renewal. © 2017 Khalaj et al.

  13. The p53 inhibitor, pifithrin-{alpha}, suppresses self-renewal of embryonic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Abdelalim, Essam Mohamed, E-mail: essam_abdelalim@yahoo.com [Molecular Neuroscience Research Center, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192 (Japan); Department of Cytology and Histology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522 (Egypt); Tooyama, Ikuo [Molecular Neuroscience Research Center, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192 (Japan)

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer We determine the role of p53 in ES cells under unstressful conditions. Black-Right-Pointing-Pointer PFT-{alpha} suppresses ES cell proliferation. Black-Right-Pointing-Pointer PFT-{alpha} induces ES cell cycle arrest. Black-Right-Pointing-Pointer PFT-{alpha} downregulates Nanog and cyclin D1. -- Abstract: Recent studies have reported the role of p53 in suppressing the pluripotency of embryonic stem (ES) cells after DNA damage and blocking the reprogramming of somatic cells into induced pluripotent stem (iPS) cells. However, to date no evidence has been presented to support the function of p53 in unstressed ES cells. In this study, we investigated the effect of pifithrin (PFT)-{alpha}, an inhibitor of p53-dependent transcriptional activation, on self-renewal of ES cells. Our results revealed that treatment of ES cells with PFT-{alpha} resulted in the inhibition of ES cell propagation in a dose-dependent manner, as indicated by a marked reduction in the cell number and colony size. Also, PFT-{alpha} caused a cell cycle arrest and significant reduction in DNA synthesis. In addition, inhibition of p53 activity reduced the expression levels of cyclin D1 and Nanog. These findings indicate that p53 pathway in ES cells rather than acting as an inactive gene, is required for ES cell proliferation and self-renewal under unstressful conditions.

  14. Dclk1+ small intestinal epithelial tuft cells display the hallmarks of quiescence and self-renewal

    Science.gov (United States)

    Chandrakesan, Parthasarathy; May, Randal; Qu, Dongfeng; Weygant, Nathaniel; Taylor, Vivian E.; Li, James D.; Ali, Naushad; Sureban, Sripathi M.; Qante, Michael; Wang, Timothy C.; Bronze, Michael S.; Houchen, Courtney W.

    2015-01-01

    To date, no discrete genetic signature has been defined for isolated Dclk1+ tuft cells within the small intestine. Furthermore, recent reports on the functional significance of Dclk1+ cells in the small intestine have been inconsistent. These cells have been proposed to be fully differentiated cells, reserve stem cells, and tumor stem cells. In order to elucidate the potential function of Dclk1+ cells, we FACS-sorted Dclk1+ cells from mouse small intestinal epithelium using transgenic mice expressing YFP under the control of the Dclk1 promoter (Dclk1-CreER;Rosa26-YFP). Analysis of sorted YFP+ cells demonstrated marked enrichment (~6000 fold) for Dclk1 mRNA compared with YFP− cells. Dclk1+ population display ~6 fold enrichment for the putative quiescent stem cell marker Bmi1. We observed significantly greater expression of pluripotency genes, pro-survival genes, and quiescence markers in the Dclk1+ population. A significant increase in self-renewal capability (14-fold) was observed in in vitro isolated Dclk1+ cells. The unique genetic report presented in this manuscript suggests that Dclk1+ cells may maintain quiescence, pluripotency, and metabolic activity for survival/longevity. Functionally, these reserve characteristics manifest in vitro, with Dclk1+ cells exhibiting greater ability to self-renew. These findings indicate that quiescent stem-like functionality is a feature of Dclk1-expressing tuft cells. PMID:26362399

  15. Alternative Splicing of MBD2 Supports Self-Renewal in Human Pluripotent Stem Cells

    Science.gov (United States)

    Lu, Yu; Loh, Yuin-Han; Li, Hu; Cesana, Marcella; Ficarro, Scott B.; Parikh, Jignesh R.; Salomonis, Nathan; Toh, Cheng-Xu Delon; Andreadis, Stelios T.; Luckey, C. John; Collins, James J.; Daley, George Q.; Marto, Jarrod A.

    2014-01-01

    Summary Alternative RNA splicing (AS) regulates proteome diversity, including isoform-specific expression of several pluripotency genes. Here, we integrated global gene expression and proteomic analyses and identified a molecular signature suggesting a central role for AS in maintaining human pluripotent stem cell (hPSC) self-renewal. We demonstrate the splicing factor SFRS2 is an OCT4 target gene required for pluripotency. SFRS2 regulates AS of the methyl-CpG-binding protein MBD2, whose isoforms play opposing roles in maintenance of, and reprogramming to, pluripotency. While both MDB2a and MBD2c are enriched at the OCT4 and NANOG promoters, MBD2a preferentially interacts with repressive NuRD chromatin remodeling factors and promotes hPSC differentiation, whereas overexpression of MBD2c enhances reprogramming of fibroblasts to pluripotency. The miR-301 and miR-302 families provide additional regulation by targeting SFRS2 and MDB2a. These data suggest that OCT4, SFRS2, and MBD2 participate in a positive feedback loop, regulating proteome diversity complexity in support of hPSC self-renewal and reprogramming. PMID:24813856

  16. The p53 inhibitor, pifithrin-α, suppresses self-renewal of embryonic stem cells

    International Nuclear Information System (INIS)

    Abdelalim, Essam Mohamed; Tooyama, Ikuo

    2012-01-01

    Highlights: ► We determine the role of p53 in ES cells under unstressful conditions. ► PFT-α suppresses ES cell proliferation. ► PFT-α induces ES cell cycle arrest. ► PFT-α downregulates Nanog and cyclin D1. -- Abstract: Recent studies have reported the role of p53 in suppressing the pluripotency of embryonic stem (ES) cells after DNA damage and blocking the reprogramming of somatic cells into induced pluripotent stem (iPS) cells. However, to date no evidence has been presented to support the function of p53 in unstressed ES cells. In this study, we investigated the effect of pifithrin (PFT)-α, an inhibitor of p53-dependent transcriptional activation, on self-renewal of ES cells. Our results revealed that treatment of ES cells with PFT-α resulted in the inhibition of ES cell propagation in a dose-dependent manner, as indicated by a marked reduction in the cell number and colony size. Also, PFT-α caused a cell cycle arrest and significant reduction in DNA synthesis. In addition, inhibition of p53 activity reduced the expression levels of cyclin D1 and Nanog. These findings indicate that p53 pathway in ES cells rather than acting as an inactive gene, is required for ES cell proliferation and self-renewal under unstressful conditions.

  17. Adult hematopoietic stem cells lacking Hif-1α self-renew normally

    Science.gov (United States)

    Vukovic, Milica; Sepulveda, Catarina; Subramani, Chithra; Guitart, Amélie V.; Mohr, Jasmine; Allen, Lewis; Panagopoulou, Theano I.; Paris, Jasmin; Lawson, Hannah; Villacreces, Arnaud; Armesilla-Diaz, Alejandro; Gezer, Deniz; Holyoake, Tessa L.; Ratcliffe, Peter J.

    2016-01-01

    The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α–deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α–deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance. PMID:27060169

  18. KAT-Independent Gene Regulation by Tip60 Promotes ESC Self-Renewal but Not Pluripotency

    Directory of Open Access Journals (Sweden)

    Diwash Acharya

    2017-04-01

    Full Text Available Although histone-modifying enzymes are generally assumed to function in a manner dependent on their enzymatic activities, this assumption remains untested for many factors. Here, we show that the Tip60 (Kat5 lysine acetyltransferase (KAT, which is essential for embryonic stem cell (ESC self-renewal and pre-implantation development, performs these functions independently of its KAT activity. Unlike ESCs depleted of Tip60, KAT-deficient ESCs exhibited minimal alterations in gene expression, chromatin accessibility at Tip60 binding sites, and self-renewal, thus demonstrating a critical KAT-independent role of Tip60 in ESC maintenance. In contrast, KAT-deficient ESCs exhibited impaired differentiation into mesoderm and endoderm, demonstrating a KAT-dependent function in differentiation. Consistent with this phenotype, KAT-deficient mouse embryos exhibited post-implantation developmental defects. These findings establish separable KAT-dependent and KAT-independent functions of Tip60 in ESCs and during differentiation, revealing a complex repertoire of regulatory functions for this essential chromatin remodeling complex.

  19. Differential Radiosensitizing Effect of Valproic Acid in Differentiation Versus Self-Renewal Promoting Culture Conditions

    International Nuclear Information System (INIS)

    Debeb, Bisrat G.; Xu Wei; Mok, Henry; Li Li; Robertson, Fredika; Ueno, Naoto T.; Reuben, Jim; Lucci, Anthony; Cristofanilli, Massimo; Woodward, Wendy A.

    2010-01-01

    Purpose: It has been shown that valproic acid (VA) enhances the proliferation and self-renewal of normal hematopoietic stem cells and that breast cancer stem/progenitor cells can be resistant to radiation. From these data, we hypothesized that VA would fail to radiosensitize breast cancer stem/progenitor cells grown to three-dimensional (3D) mammospheres. Methods and Materials: We used the MCF7 breast cancer cell line grown under stem cell-promoting culture conditions (3D mammosphere) and standard nonstem cell monolayer culture conditions (two-dimensional) to examine the effect of pretreatment with VA on radiation sensitivity in clonogenic survival assays and on the expression of embryonic stem cell transcription factors. Results: 3D-cultured MCF-7 cells expressed higher levels of Oct4, Nanog, and Sox2. The 3D passage enriched self-renewal and increased radioresistance in the 3D mammosphere formation assays. VA radiosensitized adherent cells but radioprotected 3D cells in single-fraction clonogenic assays. Moreover, fractionated radiation sensitized VA-treated adherent MCF7 cells but did not have a significant effect on VA-treated single cells grown to mammospheres. Conclusion: We have concluded that VA might preferentially radiosensitize differentiated cells compared with those expressing stem cell surrogates and that stem cell-promoting culture is a useful tool for in vitro evaluation of novel cancer therapeutic agents and radiosensitizers.

  20. Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.

    Science.gov (United States)

    Yan, Xiao; Himburg, Heather A; Pohl, Katherine; Quarmyne, Mamle; Tran, Evelyn; Zhang, Yurun; Fang, Tiancheng; Kan, Jenny; Chao, Nelson J; Zhao, Liman; Doan, Phuong L; Chute, John P

    2016-11-01

    Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10 m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10 +/+ mice. After total body irradiation (TBI), Grb10 m/+ mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10 +/+ mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling.

    Science.gov (United States)

    Stoyanova, Tanya; Goldstein, Andrew S; Cai, Houjian; Drake, Justin M; Huang, Jiaoti; Witte, Owen N

    2012-10-15

    The cell surface protein Trop2 is expressed on immature stem/progenitor-like cells and is overexpressed in many epithelial cancers. However the biological function of Trop2 in tissue maintenance and tumorigenesis remains unclear. In this study, we demonstrate that Trop2 is a regulator of self-renewal, proliferation, and transformation. Trop2 controls these processes through a mechanism of regulated intramembrane proteolysis that leads to cleavage of Trop2, creating two products: the extracellular domain and the intracellular domain. The intracellular domain of Trop2 is released from the membrane and accumulates in the nucleus. Heightened expression of the Trop2 intracellular domain promotes stem/progenitor self-renewal through signaling via β-catenin and is sufficient to initiate precursor lesions to prostate cancer in vivo. Importantly, we demonstrate that loss of β-catenin or Trop2 loss-of-function cleavage mutants abrogates Trop2-driven self-renewal and hyperplasia in the prostate. These findings suggest that heightened expression of Trop2 is selected for in epithelial cancers to enhance the stem-like properties of self-renewal and proliferation. Defining the mechanism of Trop2 function in self-renewal and transformation is essential to identify new therapeutic strategies to block Trop2 activation in cancer.

  2. ERK2 suppresses self-renewal capacity of embryonic stem cells, but is not required for multi-lineage commitment.

    Directory of Open Access Journals (Sweden)

    William B Hamilton

    Full Text Available Activation of the FGF-ERK pathway is necessary for naïve mouse embryonic stem (ES cells to exit self-renewal and commit to early differentiated lineages. Here we show that genetic ablation of Erk2, the predominant ERK isozyme expressed in ES cells, results in hyper-phosphorylation of ERK1, but an overall decrease in total ERK activity as judged by substrate phosphorylation and immediate-early gene (IEG induction. Normal induction of this subset of canonical ERK targets, as well as p90RSK phosphorylation, was rescued by transgenic expression of either ERK1 or ERK2 indicating a degree of functional redundancy. In contrast to previously published work, Erk2-null ES cells exhibited no detectable defect in lineage specification to any of the three germ layers when induced to differentiate in either embryoid bodies or in defined neural induction conditions. However, under self-renewing conditions Erk2-null ES cells express increased levels of the pluripotency-associated transcripts, Nanog and Tbx3, a decrease in Nanog-GFP heterogeneity, and exhibit enhanced self-renewal in colony forming assays. Transgenic add-back of ERK2 is capable of restoring normal pluripotent gene expression and self-renewal capacity. We show that ERK2 contributes to the destabilization of ES cell self-renewal by reducing expression of pluripotency genes, such as Nanog, but is not specifically required for the early stages of germ layer specification.

  3. ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation.

    Science.gov (United States)

    Xing, Yang; Ge, Yuqing; Liu, Chanjuan; Zhang, Xiaobiao; Jiang, Jianhai; Wei, Yuanyan

    2016-06-14

    Glioma-initiating cells possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Therefore, their elimination is an essential factor for the development of efficient therapy. Here, we report that endoplasmic reticulum (ER) stress inducer tunicamycin inhibits glioma-initiating cell self-renewal as determined by neurosphere formation assay. Moreover, tunicamycin decreases the efficiency of glioma-initiating cell to initiate tumor formation. Although tunicamycin induces glioma-initiating cell apoptosis, apoptosis inhibitor z-VAD-fmk only partly abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Indeed, tunicamycin reduces the expression of self-renewal regulator Sox2 at translation level. Overexpression of Sox2 obviously abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Taken together, tunicamycin suppresses the self-renewal and tumorigenic potential of glioma-initiating cell partly through reducing Sox2 translation. This finding provides a cue to potential effective treatment of glioblastoma through controlling stem cells.

  4. Two distinct mechanisms silence chinmo in Drosophila neuroblasts and neuroepithelial cells to limit their self-renewal.

    Science.gov (United States)

    Dillard, Caroline; Narbonne-Reveau, Karine; Foppolo, Sophie; Lanet, Elodie; Maurange, Cédric

    2018-01-25

    Whether common principles regulate the self-renewing potential of neural stem cells (NSCs) throughout the developing central nervous system is still unclear. In the Drosophila ventral nerve cord and central brain, asymmetrically dividing NSCs, called neuroblasts (NBs), progress through a series of sequentially expressed transcription factors that limits self-renewal by silencing a genetic module involving the transcription factor Chinmo. Here, we find that Chinmo also promotes neuroepithelium growth in the optic lobe during early larval stages by boosting symmetric self-renewing divisions while preventing differentiation. Neuroepithelium differentiation in late larvae requires the transcriptional silencing of chinmo by ecdysone, the main steroid hormone, therefore allowing coordination of neural stem cell self-renewal with organismal growth. In contrast, chinmo silencing in NBs is post-transcriptional and does not require ecdysone. Thus, during Drosophila development, humoral cues or tissue-intrinsic temporal specification programs respectively limit self-renewal in different types of neural progenitors through the transcriptional and post-transcriptional regulation of the same transcription factor. © 2018. Published by The Company of Biologists Ltd.

  5. Icaritin enhances mESC self-renewal through upregulating core pluripotency transcription factors mediated by ERα.

    Science.gov (United States)

    Tsang, Wing Pui; Zhang, Fengjie; He, Qiling; Cai, Waijiao; Huang, Jianhua; Chan, Wai Yee; Shen, Ziyin; Wan, Chao

    2017-01-16

    Utilization of small molecules in modulation of stem cell self-renewal is a promising approach to expand stem cells for regenerative therapy. Here, we identify Icaritin, a phytoestrogen molecule enhances self-renewal of mouse embryonic stem cells (mESCs). Icaritin increases mESCs proliferation while maintains their self-renewal capacity in vitro and pluripotency in vivo. This coincides with upregulation of key pluripotency transcription factors OCT4, NANOG, KLF4 and SOX2. The enhancement of mESCs self-renewal is characterized by increased population in S-phase of cell cycle, elevation of Cylin E and Cyclin-dependent kinase 2 (CDK2) and downregulation of p21, p27 and p57. PCR array screening reveals that caudal-related homeobox 2 (Cdx2) and Rbl2/p130 are remarkably suppressed in mESCs treated with Icaritin. siRNA knockdown of Cdx2 or Rbl2/p130 upregulates the expression of Cyclin E, OCT4 and SOX2, and subsequently increases cell proliferation and colony forming efficiency of mESCs. We then demonstrate that Icaritin co-localizes with estrogen receptor alpha (ERα) and activates its nuclear translocation in mESCs. The promotive effect of Icaritin on cell cycle and pluripotency regulators are eliminated by siRNA knockdown of ERα in mESCs. The results suggest that Icaritin enhances mESCs self-renewal by regulating cell cycle machinery and core pluripotency transcription factors mediated by ERα.

  6. Benzo[a]pyrene impedes self-renewal and differentiation of mesenchymal stem cells and influences fracture healing.

    Science.gov (United States)

    Zhou, Yiqing; Jiang, Rong; An, Liqin; Wang, Hong; Cheng, Sicheng; Qiong, Shi; Weng, Yaguang

    2017-06-01

    Mesenchymal stem cells (MSCs) are implicated in the bone-forming process during fracture repair. Benzo[a]pyrene (BaP)-a cigarette smoke component and powerful motivator of the aryl hydrocarbon receptor (Ahr)-unfavorably influences bone condition and osteoblast differentiation. The first thing we noticed decreases self-renewal and differentiation of human bone marrow mesenchymal stem (hBM-MSCs) from smokers and activates Ahr signaling in MSCs by up-regulating the Ahr target gene cytochrome P450 (CYP) 1B1 expression. In vitro studies, we employed C3H10T1/2 and bone marrow mesenchymal stem cells (BM-MSCs) with BaP and discovered that BaP impaired innate properties of MSCs. Further investigation into MSCs showed that exposure to BaP activated Ahr signaling and inhibited TGF-β1/SMAD4 and TGF-β1/ERK/AKT signaling pathways. Corresponding with the outcomes, tibial fracture calluses produced by BaP-administered rats appeared to delay healing. This effect of BaP was abrogated by resveratrol, a natural Ahr antagonist, in vitro and in vivo. These data demonstrated that Ahr may play a key role in BaP-impaired innate properties by inhibiting SMAD-dependent signaling pathways TGF-β1/SMAD4 and SMAD-independent TGF-β1/ERK/AKT signaling pathways. Furthermore, resveratrol inhibited MSCs from adverse effects caused by BaP. Copyright © 2017. Published by Elsevier B.V.

  7. Layered double hydroxide nanoparticles promote self-renewal of mouse embryonic stem cells through the PI3K signaling pathway

    Science.gov (United States)

    Wu, Youjun; Zhu, Rongrong; Zhou, Yang; Zhang, Jun; Wang, Wenrui; Sun, Xiaoyu; Wu, Xianzheng; Cheng, Liming; Zhang, Jing; Wang, Shilong

    2015-06-01

    Embryonic stem cells (ESCs) hold great potential for regenerative medicine due to their two unique characteristics: self-renewal and pluripotency. Several groups of nanoparticles have shown promising applications in directing the stem cell fate. Herein, we investigated the cellular effects of layered double hydroxide nanoparticles (LDH NPs) on mouse ESCs (mESCs) and the associated molecular mechanisms. Mg-Al-LDH NPs with an average diameter of ~100 nm were prepared by hydrothermal methods. To determine the influences of LDH NPs on mESCs, cellular cytotoxicity, self-renewal, differentiation potential, and the possible signaling pathways were explored. Evaluation of cell viability, lactate dehydrogenase release, ROS generation and apoptosis demonstrated the low cytotoxicity of LDH NPs. The alkaline phosphatase activity and the expression of pluripotency genes in mESCs were examined, which indicated that exposure to LDH NPs could support self-renewal and inhibit spontaneous differentiation of mESCs under feeder-free culture conditions. The self-renewal promotion was further proved to be independent of the leukemia inhibitory factor (LIF). Furthermore, cells treated with LDH NPs maintained the potential to differentiate into all three germ layers both in vitro and in vivo through formation of embryoid bodies and teratomas. In addition, we observed that LDH NPs initiated the activation of the PI3K/Akt pathway, while treatment with the PI3K inhibitor LY294002 could block the effects of LDH NPs on mESCs. The results confirmed that the promotion of self-renewal by LDH NPs was associated with activation of the PI3K/Akt signaling pathway. Altogether, our studies identified a new role of LDH NPs in maintaining self-renewal of mouse ES cells which could potentially be applied in stem cell research.Embryonic stem cells (ESCs) hold great potential for regenerative medicine due to their two unique characteristics: self-renewal and pluripotency. Several groups of nanoparticles

  8. SSC [Superconducting Super Collider] site evaluations

    International Nuclear Information System (INIS)

    1988-11-01

    With this report, the SSC Site Task Force forwards to the Director, Office of Energy Research, US Department of Energy (DOE), its evaluation of the technical criteria and life-cycle costs for the proposed SSC sites judged to be the best qualified. The criteria against which each site was evaluated are those set forth in the Invitation for Site Proposals for the Superconducting Super Collider (DOE/ER-0315) (Invitation) which was prepared by the Task Force and issued in April 1987. The methodology followed by the Task Force in this report and in all other phases of the proposal evaluation has been consistent with the SSC site selection process approved by DOE's Energy System Acquisition Advisory Board (ESAAB). The goal of the site selection process is to identify a site that will permit the highest level of research productivity and overall effectiveness of the SSC at a reasonable cost of construction and operation and with minimial impact on the environment. The Task Force acknowledges that all seven sites are, indeed, highly qualified locations for the construction and operation of the SSC on the basis of technical and cost considerations. In performing its evaluation, which is presented in this paper, the Task Force took an in-depth look at each site on the basis of site visits and extensive technical analyses. A consensus rating for each technical evaluation criterion and subcriterion was developed for each site

  9. Novel insights into embryonic stem cell self-renewal revealed through comparative human and mouse systems biology networks.

    Science.gov (United States)

    Dowell, Karen G; Simons, Allen K; Bai, Hao; Kell, Braden; Wang, Zack Z; Yun, Kyuson; Hibbs, Matthew A

    2014-05-01

    Embryonic stem cells (ESCs), characterized by their ability to both self-renew and differentiate into multiple cell lineages, are a powerful model for biomedical research and developmental biology. Human and mouse ESCs share many features, yet have distinctive aspects, including fundamental differences in the signaling pathways and cell cycle controls that support self-renewal. Here, we explore the molecular basis of human ESC self-renewal using Bayesian network machine learning to integrate cell-type-specific, high-throughput data for gene function discovery. We integrated high-throughput ESC data from 83 human studies (~1.8 million data points collected under 1,100 conditions) and 62 mouse studies (~2.4 million data points collected under 1,085 conditions) into separate human and mouse predictive networks focused on ESC self-renewal to analyze shared and distinct functional relationships among protein-coding gene orthologs. Computational evaluations show that these networks are highly accurate, literature validation confirms their biological relevance, and reverse transcriptase polymerase chain reaction (RT-PCR) validation supports our predictions. Our results reflect the importance of key regulatory genes known to be strongly associated with self-renewal and pluripotency in both species (e.g., POU5F1, SOX2, and NANOG), identify metabolic differences between species (e.g., threonine metabolism), clarify differences between human and mouse ESC developmental signaling pathways (e.g., leukemia inhibitory factor (LIF)-activated JAK/STAT in mouse; NODAL/ACTIVIN-A-activated fibroblast growth factor in human), and reveal many novel genes and pathways predicted to be functionally associated with self-renewal in each species. These interactive networks are available online at www.StemSight.org for stem cell researchers to develop new hypotheses, discover potential mechanisms involving sparsely annotated genes, and prioritize genes of interest for experimental validation

  10. Immortal DNA strand cosegregation requires p53/IMPDH-dependent asymmetric self-renewal associated with adult stem cells.

    Science.gov (United States)

    Rambhatla, Lakshmi; Ram-Mohan, Sumati; Cheng, Jennifer J; Sherley, James L

    2005-04-15

    Because they are long-lived and cycle continuously, adult stem cells (ASCs) are predicted as the most common precursor for cancers in adult mammalian tissues. Two unique attributes have been proposed to restrict the carcinogenic potential of ASCs. These are asymmetric self-renewal that limits their number and immortal DNA strand cosegregation that limits their accumulation of mutations due to DNA replication errors. Until recently, the molecular basis and regulation of these important ASC-specific functions were unknown. We developed engineered cultured cells that exhibit asymmetric self-renewal and immortal DNA strand cosegregation. These model cells were used to show that both ASC-specific functions are regulated by the p53 cancer gene. Previously, we proposed that IMP dehydrogenase (IMPDH) was an essential factor for p53-dependent asymmetric self-renewal. We now confirm this proposal and provide quantitative evidence that asymmetric self-renewal is acutely sensitive to even modest changes in IMPDH expression. These analyses reveal that immortal DNA strand cosegregation is also regulated by IMPDH and confirm the original implicit precept that immortal DNA strand cosegregation is specific to cells undergoing asymmetric self-renewal (i.e., ASCs). With IMPDH being the rate-determining enzyme for guanine ribonucleotide (rGNP) biosynthesis, its requirement implicates rGNPs as important regulators of ASC asymmetric self-renewal and immortal DNA strand cosegregation. An in silico analysis of global gene expression data from human cancer cell lines underscored the importance of p53-IMPDH-rGNP regulation for normal tissue cell kinetics, providing further support for the concept that ASCs are key targets for adult tissue carcinogenesis.

  11. A fixed target facility at the SSC

    International Nuclear Information System (INIS)

    Loken, S.; Morfin, J.G.

    1984-01-01

    The question of whether a facility for fixed target physics should be provided at the SSC must be answered before the final technical design of the SSC can be completed, particularly if the eventual form of extraction would influence the magnet design. To this end, an enthusiastic group of experimentalists, theoreticians and accelerator specialists have studied this point. The accelerator physics issues were addressed by a group whose report is contained in these proceedings. The physics addressable by fixed target was considered by many of the Physics area working groups and in particular by the Structure Function Group. This report is the summary of the working group which considered various SSC fixed target experiments and determined which types of beams and detectors would be required

  12. Fixed target facility at the SSC

    Energy Technology Data Exchange (ETDEWEB)

    Loken, S.C.; Morfin, J.G.

    1985-01-01

    The question of whether a facility for fixed target physics should be provided at the SSC must be answered before the final technical design of the SSC can be completed, particularly if the eventual form of extraction would influence the magnet design. To this end, an enthusiastic group of experimentalists, theoreticians and accelerator specialists have studied this point. The accelerator physics issues were addressed by a group led by E. Colton whose report is contained in these proceedings. The physics addressable by fixed target was considered by many of the Physics area working groups and in particular by the Structure Function Group. This report is the summary of the working group which considered various SSC fixed target experiments and determined which types of beams and detectors would be required. 13 references, 5 figures.

  13. Fixed target facility at the SSC

    International Nuclear Information System (INIS)

    Loken, S.C.; Morfin, J.G.

    1985-01-01

    The question of whether a facility for fixed target physics should be provided at the SSC must be answered before the final technical design of the SSC can be completed, particularly if the eventual form of extraction would influence the magnet design. To this end, an enthusiastic group of experimentalists, theoreticians and accelerator specialists have studied this point. The accelerator physics issues were addressed by a group led by E. Colton whose report is contained in these proceedings. The physics addressable by fixed target was considered by many of the Physics area working groups and in particular by the Structure Function Group. This report is the summary of the working group which considered various SSC fixed target experiments and determined which types of beams and detectors would be required. 13 references, 5 figures

  14. First beam extracted from the SSC

    International Nuclear Information System (INIS)

    Anon.

    1986-01-01

    On the 25th July 1986 the first 2,8 μA 66 MeV proton beam was successfully extracted from the separated sector cyclotron (SSC) at the National Accelerator Centre at Faure, South Africa. The beam has now also been transported for the first time down the high-energy beamline up to the last Faraday cup in front of the neutron therapy vault. A brief description of the extraction system of the SSC, consisting of an electrostatic extraction channel and two septum magnets is given

  15. Highlights of the SSC Site Development Plan

    International Nuclear Information System (INIS)

    Sanford, J.R.

    1991-10-01

    This paper summarizes highlights of the Site Development Plan for the Superconducting Super Collider Laboratory. The Plan, sometimes called a Master Plan, was prepared by the architectural and engineering firm for the Laboratory: Parsons Brinckerhoff/Morrison Knudsen (PB/MK) working in association with CRSS. Their task was to interpret the SSC project needs in the context of the Ellis County, Texas site. The team effort was under the direction of Lewis May from CRSS, guided by Robert Sims from the SSC Laboratory. Conceptual drawings are presented in this report

  16. Analysis and design of SSC underground structures

    International Nuclear Information System (INIS)

    Clark, G.T.

    1993-01-01

    This paper describes the analysis and design of underground structures for the Superconducting Super Collider (SSC) Project. A brief overview of the SSC Project and the types of underground structures are presented. Engineering properties and non-linear behavior of the geologic materials are reviewed. The three-dimensional sequential finite element rock-structure interaction analysis techniques developed by the author are presented and discussed. Several examples of how the method works, specific advantages, and constraints are presented. Finally, the structural designs that resulted from the sequential interaction analysis are presented

  17. Analytical solutions to SSC coil end design

    International Nuclear Information System (INIS)

    Bossert, R.C.; Brandt, J.S.; Carson, J.A.; Fulton, H.J.; Lee, G.C.; Cook, J.M.

    1989-03-01

    As part of the SCC magnet effort, Fermilab will build and test a series of one meter model SSC magnets. The coils in these magnets will be constructed with several different end configurations. These end designs must satisfy both mechanical and magnetic criteria. Only the mechanical problem will be addressed. Solutions will attempt to minimize stresses and provide internal support for the cable. Different end designs will be compared in an attempt to determine which is most appropriate for the SSC dipole. The mathematics required to create each end configuration will be described. The computer aided design, programming and machine technology needed to make the parts will be reviewed. 2 refs., 10 figs

  18. A data acquisition architecture for the SSC

    International Nuclear Information System (INIS)

    Partridge, R.

    1990-01-01

    An SSC data acquisition architecture applicable to high-p T detectors is described. The architecture is based upon a small set of design principles that were chosen to simplify communication between data acquisition elements while providing the required level of flexibility and performance. The architecture features an integrated system for data collection, event building, and communication with a large processing farm. The interface to the front end electronics system is also discussed. A set of design parameters is given for a data acquisition system that should meet the needs of high-p T detectors at the SSC

  19. Seeding of single hemopoietic stem cells and self renewal of committed stem cells

    International Nuclear Information System (INIS)

    Brecher, G.

    1986-01-01

    Single cells and two to five proliferating cells were transfused into mice whose own stem cells had been killed by irradiation. When a small inoculum of 50,000 AB marrow cells was given only 4 of 20 recipients survived, but all 4 had only PGK A enzyme in their peripheral blood cells. The results indicate that the survivors received a single pluripotential stem cell capable of proliferating. Survivors showed no deterioration in their blood picture after many months. It was concluded that there is no clonal succession in the marrow cells. Further studies with transfusions of 100,000 and 10,000,000 marrow cells after lethal irradiation suggest that there is production of committed stem cells with significant self-renewal

  20. Higher 5-hydroxymethylcytosine identifies immortal DNA strand chromosomes in asymmetrically self-renewing distributed stem cells.

    Science.gov (United States)

    Huh, Yang Hoon; Cohen, Justin; Sherley, James L

    2013-10-15

    Immortal strands are the targeted chromosomal DNA strands of nonrandom sister chromatid segregation, a mitotic chromosome segregation pattern unique to asymmetrically self-renewing distributed stem cells (DSCs). By nonrandom segregation, immortal DNA strands become the oldest DNA strands in asymmetrically self-renewing DSCs. Nonrandom segregation of immortal DNA strands may limit DSC mutagenesis, preserve DSC fate, and contribute to DSC aging. The mechanisms responsible for specification and maintenance of immortal DNA strands are unknown. To discover clues to these mechanisms, we investigated the 5-methylcytosine and 5-hydroxymethylcytosine (5hmC) content on chromosomes in mouse hair follicle DSCs during nonrandom segregation. Although 5-methylcytosine content did not differ significantly, the relative content of 5hmC was significantly higher in chromosomes containing immortal DNA strands than in opposed mitotic chromosomes containing younger mortal DNA strands. The difference in relative 5hmC content was caused by the loss of 5hmC from mortal chromosomes. These findings implicate higher 5hmC as a specific molecular determinant of immortal DNA strand chromosomes. Because 5hmC is an intermediate during DNA demethylation, we propose a ten-eleven translocase enzyme mechanism for both the specification and maintenance of nonrandomly segregated immortal DNA strands. The proposed mechanism reveals a means by which DSCs "know" the generational age of immortal DNA strands. The mechanism is supported by molecular expression data and accounts for the selection of newly replicated DNA strands when nonrandom segregation is initiated. These mechanistic insights also provide a possible basis for another characteristic property of immortal DNA strands, their guanine ribonucleotide dependency.

  1. Gab2 promotes hematopoietic stem cell maintenance and self-renewal synergistically with STAT5.

    Directory of Open Access Journals (Sweden)

    Geqiang Li

    2010-02-01

    Full Text Available Grb2-associated binding (Gab adapter proteins play major roles in coordinating signaling downstream of hematopoietic cytokine receptors. In hematopoietic cells, Gab2 can modulate phosphatidylinositol-3 kinase and mitogen associated protein kinase activities and regulate the long-term multilineage competitive repopulating activity of hematopoietic stem cells (HSCs. Gab2 may also act in a linear pathway upstream or downstream of signal transducer and activator of transcription-5 (STAT5, a major positive regulator of HSC function. Therefore, we aimed to determine whether Gab2 and STAT5 function in hematopoiesis in a redundant or non-redundant manner.To do this we generated Gab2 mutant mice with heterozygous and homozygous deletions of STAT5. In heterozygous STAT5 mutant mice, deficiencies in HSC/multipotent progenitors were reflected by decreased long-term repopulating activity. This reduction in repopulation function was mirrored in the reduced growth response to early-acting cytokines from sorted double mutant c-Kit(+Lin(-Sca-1(+ (KLS cells. Importantly, in non-ablated newborn mice, the host steady-state engraftment ability was impaired by loss of Gab2 in heterozygous STAT5 mutant background. Fetal liver cells isolated from homozygous STAT5 mutant mice lacking Gab2 showed significant reduction in HSC number (KLS CD150(+CD48(-, reduced HSC survival, and dramatic loss of self-renewal potential as measured by serial transplantation.These data demonstrate new functions for Gab2 in hematopoiesis in a manner that is non-redundant with STAT5. Furthermore, important synergy between STAT5 and Gab2 was observed in HSC self-renewal, which might be exploited to optimize stem cell-based therapeutics.

  2. Self-renewing Monolayer of Primary Colonic or Rectal Epithelial CellsSummary

    Directory of Open Access Journals (Sweden)

    Yuli Wang

    2017-07-01

    Full Text Available Background & Aims: Three-dimensional organoid culture has fundamentally changed the in vitro study of intestinal biology enabling novel assays; however, its use is limited because of an inaccessible luminal compartment and challenges to data gathering in a three-dimensional hydrogel matrix. Long-lived, self-renewing 2-dimensional (2-D tissue cultured from primary colon cells has not been accomplished. Methods: The surface matrix and chemical factors that sustain 2-D mouse colonic and human rectal epithelial cell monolayers with cell repertoires comparable to that in vivo were identified. Results: The monolayers formed organoids or colonoids when placed in standard Matrigel culture. As with the colonoids, the monolayers exhibited compartmentalization of proliferative and differentiated cells, with proliferative cells located near the peripheral edges of growing monolayers and differentiated cells predominated in the central regions. Screening of 77 dietary compounds and metabolites revealed altered proliferation or differentiation of the murine colonic epithelium. When exposed to a subset of the compound library, murine organoids exhibited similar responses to that of the monolayer but with differences that were likely attributable to the inaccessible organoid lumen. The response of the human primary epithelium to a compound subset was distinct from that of both the murine primary epithelium and human tumor cells. Conclusions: This study demonstrates that a self-renewing 2-D murine and human monolayer derived from primary cells can serve as a physiologically relevant assay system for study of stem cell renewal and differentiation and for compound screening. The platform holds transformative potential for personalized and precision medicine and can be applied to emerging areas of disease modeling and microbiome studies. Keywords: Colonic Epithelial Cells, Monolayer, Organoids, Compound Screening

  3. A CREB-MPP7-AMOT Regulatory Axis Controls Muscle Stem Cell Expansion and Self-Renewal Competence

    Directory of Open Access Journals (Sweden)

    Lydia Li

    2017-10-01

    Full Text Available Summary: Skeletal muscle regeneration requires resident muscle stem cells, termed satellite cells (SCs. SCs are largely quiescent during homeostasis yet become activated upon injury to supply myonuclei and self-renewed SCs. Molecular mechanisms underlying the competence of SCs to proliferate and self-renew in response to injury remain unclear. Here, we show that CREB activity establishes proliferative potential during SC quiescence. SCs with inhibited CREB activity remain quiescent and positioned in their niche, but upon injury, they cannot enter or maintain a proliferative state for expansion and self-renewal. We demonstrate mechanistically that Mpp7 is a CREB target and its functional mediator. MPP7 loss affects the level and sub-cellular localization of AMOT and YAP1 in quiescent SCs. Furthermore, MPP7 and AMOT are required for YAP1 nuclear accumulation, and the three are individually required for a proliferative state in myoblasts. We propose that the CREB-MPP7-AMOT-YAP1 axis establishes the competence of quiescent SCs to expand and self-renew, thereby preserving stem cell function. : Satellite cells are quiescent muscle stem cells that have the ability to regenerate muscles after injury. Li and Fan reveal an MPP7-AMOT-YAP1 regulatory axis that acts downstream of CREB to instill satellite cell competence. They also show how this regulatory axis prepares satellite cells for robust muscle regeneration after injury.

  4. Aubergine and piRNAs promote germline stem cell self-renewal by repressing the proto-oncogene Cbl.

    Science.gov (United States)

    Rojas-Ríos, Patricia; Chartier, Aymeric; Pierson, Stéphanie; Simonelig, Martine

    2017-11-02

    PIWI proteins play essential roles in germ cells and stem cell lineages. In Drosophila , Piwi is required in somatic niche cells and germline stem cells (GSCs) to support GSC self-renewal and differentiation. Whether and how other PIWI proteins are involved in GSC biology remains unknown. Here, we show that Aubergine (Aub), another PIWI protein, is intrinsically required in GSCs for their self-renewal and differentiation. Aub needs to be loaded with piRNAs to control GSC self-renewal and acts through direct mRNA regulation. We identify the Cbl proto-oncogene, a regulator of mammalian hematopoietic stem cells, as a novel GSC differentiation factor. Aub stimulates GSC self-renewal by repressing Cbl mRNA translation and does so in part through recruitment of the CCR4-NOT complex. This study reveals the role of piRNAs and PIWI proteins in controlling stem cell homeostasis via translational repression and highlights piRNAs as major post-transcriptional regulators in key developmental decisions. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  5. A novel way to induce erythroid progenitor self renewal: cooperation of c-Kit with the erythropoietin receptor

    NARCIS (Netherlands)

    Wessely, O.; Bauer, A.; Quang, C. T.; Deiner, E. M.; von Lindern, M.; Mellitzer, G.; Steinlein, P.; Ghysdael, J.; Beug, H.

    1999-01-01

    Red blood cells are of vital importance for oxygen transport in vertebrates. Thus, their formation during development and homeostasis requires tight control of both progenitor proliferation and terminal red cell differentiation. Self renewal (i.e. long-term proliferation without differentiation) of

  6. Compensation of coupling in the SSC complex

    International Nuclear Information System (INIS)

    Pilat, F.; Bourianoff, G.

    1991-10-01

    This paper will describe a study of the coupling effects and their compensation by means of local depending techniques for some of the accelerators in the SSC Complex. Results concerning corrections and decoupling for the Low Energy and Medium Energy Boosters will be compared to results obtained for the Collider Ring. Some preliminary experimental data about measurement of coupling quantities will also be presented

  7. Liquid argon calorimetry for the SSC

    International Nuclear Information System (INIS)

    Gordon, H.A.

    1990-01-01

    Liquid argon calorimetry is a mature technique. However, adapting it to the challenging environment of the SSC requires a large amount of R ampersand D. The advantages of the liquid argon approach are summarized and the issues being addressed by the R ampersand D program are described. 18 refs

  8. Heavy particle production at the SSC

    International Nuclear Information System (INIS)

    Brodsky, S.J.; Haber, H.E.; Gunion, J.F.

    1984-03-01

    Predictions for the production of heavy quarks, supersymmetric particles, and other colored systems at high energy due to intrinsic twist-six components in the proton wavefunction are given. We also suggest the possibility of using asymmetric collision energies (e.g., via intersecting rings at the SSC) in order to facilitate the study of forward and diffractive particle production processes. 9 references

  9. Electron beam emittance monitor for the SSC

    International Nuclear Information System (INIS)

    Tsyganov, E.; Meinke, R.; Nexsen, W.; Kauffmann, S.; Zinchenko, A.; Taratin, A.

    1993-05-01

    A nondestructive beam profile monitor for the Superconducting Super Collider (SSC) is presented using as a probe a low-energy electron beam interacting with the proton bunch charge. Results using a full Monte Carlo simulation code look promising for the transverse and longitudinal beam profile measurements

  10. Dicty_cDB: SSC474 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available SS (Link to library) SSC474 (Link to dictyBase) - - - Contig-U07719-1 SSC474P (Link... to Original site) SSC474F 368 SSC474Z 238 SSC474P 606 - - Show SSC474 Library SS (Link to library) Clone ID SSC474 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U07719-1 Original site URL http://dict...logy vs DNA Score E Sequences producing significant alignments: (bits) Value N ( AU071762 ) Dictyostelium di...scoideum slug cDNA, clone SSC474. 448 e-121 1 ( AU060185 ) Dictyostelium discoideum slug cDNA, clone SLA535.

  11. SSC beam dynamics scaled to the Eloisatron

    International Nuclear Information System (INIS)

    Ritson, D.

    1992-03-01

    As crosssections drop as E -2 a desirable target for a 100 TeV the Eloisatron would be to achieve luminosities ∼1.10 35 cm 2 /sec. To understand the impact of such an objective we have compared parameters for the SSC and Eloisatron to differentiate areas which involve considerable extrapolations from current technologies from those which represent more conventional scale-ups. Synchrotron radiation losses per m for the same guide magnetic field associated with such luminosities would be up by E 2 x I where E is the energy and I is the circulating current. This would result in energy densities of ∼250 times the nominal SSC values. The SSC is already limited by installed refrigeration power and if the circulating current was to be increased would have to use liners at liquid nitrogen temperatures to intercept the radiation as is proposed for the LHC. This issue was the subject of lively discussion at the workshop and is dealt with elsewhere by other authors. This author believed that the radiation could be intercepted by room temperature catchers spaced every 15--25 m around the ring. To obtain the requisite luminosities it assumes similar bunch spacing but circulating currents an order of magnitude larger than at the SSC. The SSC already uses a bunch spacing as small as 5 m and further reduction does not appear easy. The justification for the choice of bore for the magnets, emittances and attainable luminosities are discussed below. A further section looks into whether seismic ground disturbances might cause unacceptable emittance growth. The conclusion of this section is that careful use of current design practices should be adequate and that it is unlikely that exotic vibration free mounts will be required

  12. Cell-type-specific predictive network yields novel insights into mouse embryonic stem cell self-renewal and cell fate.

    Directory of Open Access Journals (Sweden)

    Karen G Dowell

    Full Text Available Self-renewal, the ability of a stem cell to divide repeatedly while maintaining an undifferentiated state, is a defining characteristic of all stem cells. Here, we clarify the molecular foundations of mouse embryonic stem cell (mESC self-renewal by applying a proven Bayesian network machine learning approach to integrate high-throughput data for protein function discovery. By focusing on a single stem-cell system, at a specific developmental stage, within the context of well-defined biological processes known to be active in that cell type, we produce a consensus predictive network that reflects biological reality more closely than those made by prior efforts using more generalized, context-independent methods. In addition, we show how machine learning efforts may be misled if the tissue specific role of mammalian proteins is not defined in the training set and circumscribed in the evidential data. For this study, we assembled an extensive compendium of mESC data: ∼2.2 million data points, collected from 60 different studies, under 992 conditions. We then integrated these data into a consensus mESC functional relationship network focused on biological processes associated with embryonic stem cell self-renewal and cell fate determination. Computational evaluations, literature validation, and analyses of predicted functional linkages show that our results are highly accurate and biologically relevant. Our mESC network predicts many novel players involved in self-renewal and serves as the foundation for future pluripotent stem cell studies. This network can be used by stem cell researchers (at http://StemSight.org to explore hypotheses about gene function in the context of self-renewal and to prioritize genes of interest for experimental validation.

  13. Orphan nuclear receptor TLX activates Wnt/β-catenin signalling to stimulate neural stem cell proliferation and self-renewal

    Science.gov (United States)

    Qu, Qiuhao; Sun, Guoqiang; Li, Wenwu; Yang, Su; Ye, Peng; Zhao, Chunnian; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.; Shi, Yanhong

    2010-01-01

    The nuclear receptor TLX (also known as NR2E1) is essential for adult neural stem cell self-renewal; however, the molecular mechanisms involved remain elusive. Here we show that TLX activates the canonical Wnt/β-catenin pathway in adult mouse neural stem cells. Furthermore, we demonstrate that Wnt/β-catenin signalling is important in the proliferation and self-renewal of adult neural stem cells in the presence of epidermal growth factor and fibroblast growth factor. Wnt7a and active β-catenin promote neural stem cell self-renewal, whereas the deletion of Wnt7a or the lentiviral transduction of axin, a β-catenin inhibitor, led to decreased cell proliferation in adult neurogenic areas. Lentiviral transduction of active β-catenin led to increased numbers of type B neural stem cells in the subventricular zone of adult brains, whereas deletion of Wnt7a or TLX resulted in decreased numbers of neural stem cells retaining bromodeoxyuridine label in the adult brain. Both Wnt7a and active β-catenin significantly rescued a TLX (also known as Nr2e1) short interfering RNA-induced deficiency in neural stem cell proliferation. Lentiviral transduction of an active β-catenin increased cell proliferation in neurogenic areas of TLX-null adult brains markedly. These results strongly support the hypothesis that TLX acts through the Wnt/β-catenin pathway to regulate neural stem cell proliferation and self-renewal. Moreover, this study suggests that neural stem cells can promote their own self-renewal by secreting signalling molecules that act in an autocrine/paracrine mode. PMID:20010817

  14. Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal.

    Science.gov (United States)

    Qu, Qiuhao; Sun, Guoqiang; Li, Wenwu; Yang, Su; Ye, Peng; Zhao, Chunnian; Yu, Ruth T; Gage, Fred H; Evans, Ronald M; Shi, Yanhong

    2010-01-01

    The nuclear receptor TLX (also known as NR2E1) is essential for adult neural stem cell self-renewal; however, the molecular mechanisms involved remain elusive. Here we show that TLX activates the canonical Wnt/beta-catenin pathway in adult mouse neural stem cells. Furthermore, we demonstrate that Wnt/beta-catenin signalling is important in the proliferation and self-renewal of adult neural stem cells in the presence of epidermal growth factor and fibroblast growth factor. Wnt7a and active beta-catenin promote neural stem cell self-renewal, whereas the deletion of Wnt7a or the lentiviral transduction of axin, a beta-catenin inhibitor, led to decreased cell proliferation in adult neurogenic areas. Lentiviral transduction of active beta-catenin led to increased numbers of type B neural stem cells in the subventricular zone of adult brains, whereas deletion of Wnt7a or TLX resulted in decreased numbers of neural stem cells retaining bromodeoxyuridine label in the adult brain. Both Wnt7a and active beta-catenin significantly rescued a TLX (also known as Nr2e1) short interfering RNA-induced deficiency in neural stem cell proliferation. Lentiviral transduction of an active beta-catenin increased cell proliferation in neurogenic areas of TLX-null adult brains markedly. These results strongly support the hypothesis that TLX acts through the Wnt/beta-catenin pathway to regulate neural stem cell proliferation and self-renewal. Moreover, this study suggests that neural stem cells can promote their own self-renewal by secreting signalling molecules that act in an autocrine/paracrine mode.

  15. SVM classifier to predict genes important for self-renewal and pluripotency of mouse embryonic stem cells

    Directory of Open Access Journals (Sweden)

    Xu Huilei

    2010-12-01

    Full Text Available Abstract Background Mouse embryonic stem cells (mESCs are derived from the inner cell mass of a developing blastocyst and can be cultured indefinitely in-vitro. Their distinct features are their ability to self-renew and to differentiate to all adult cell types. Genes that maintain mESCs self-renewal and pluripotency identity are of interest to stem cell biologists. Although significant steps have been made toward the identification and characterization of such genes, the list is still incomplete and controversial. For example, the overlap among candidate self-renewal and pluripotency genes across different RNAi screens is surprisingly small. Meanwhile, machine learning approaches have been used to analyze multi-dimensional experimental data and integrate results from many studies, yet they have not been applied to specifically tackle the task of predicting and classifying self-renewal and pluripotency gene membership. Results For this study we developed a classifier, a supervised machine learning framework for predicting self-renewal and pluripotency mESCs stemness membership genes (MSMG using support vector machines (SVM. The data used to train the classifier was derived from mESCs-related studies using mRNA microarrays, measuring gene expression in various stages of early differentiation, as well as ChIP-seq studies applied to mESCs profiling genome-wide binding of key transcription factors, such as Nanog, Oct4, and Sox2, to the regulatory regions of other genes. Comparison to other classification methods using the leave-one-out cross-validation method was employed to evaluate the accuracy and generality of the classification. Finally, two sets of candidate genes from genome-wide RNA interference screens are used to test the generality and potential application of the classifier. Conclusions Our results reveal that an SVM approach can be useful for prioritizing genes for functional validation experiments and complement the analyses of high

  16. miR-544 Regulates Dairy Goat Male Germline Stem Cell Self-Renewal via Targeting PLZF.

    Science.gov (United States)

    Song, Wencong; Mu, Hailong; Wu, Jiang; Liao, Mingzhi; Zhu, Haijing; Zheng, Liming; He, Xin; Niu, Bowen; Zhai, Yuanxin; Bai, Chunling; Lei, Anmin; Li, Guangpeng; Hua, Jinlian

    2015-10-01

    The balance between the self-renewal and differentiation of male germline stem cells (mGSCs) is critical for the initiation and maintenance of mammalian spermatogenesis. The promyelocytic leukemia zinc finger (PLZF), a zinc finger protein, is a critical factor for maintaining the self-renewal of mGSCs, so, evaluation of the PLZF pathway in mGSCs may provide a deeper insight into mammalian spermatogenesis. miRNA was also an important regulating factor for the self-renewal and differentiation of mGSCs; however, there is currently no data indicating that which miRNA regulate the self-renewal and differentiation of mGSCs via PLZF. Here, we predicted the prospective miRNA targeting to PLZF using the online Bioinformatics database-Targetscan, and performed an analysis of the dual-luciferase recombinant vector, psiCHCEKTM-2-PLZF-3'UTR. miR-544 mimics (miR-544m), miR-544 inhibitors (miR-544i), Control (NC, scrambled oligonucleotides transfection), pPLZF-IRES2-EGFP or PLZF siRNA were transfected into mGSCs; the cells proliferation was evaluated by BRDU incorporation assay and flow cytometry, and the mGSC marker, GFRa1, PLZF, KIT, DAZL, and VASA expression were analyzed by RT-qPCR, immunofluorescence and Western blot. The results showed that miR-544 regulates dairy goat male germline stem cell self-renewal via targeting PLZF. Our study identifies a new regulatory pathway for PLZF and expands upon the PLZF regulatory network in mGSCs. © 2015 Wiley Periodicals, Inc.

  17. Dicty_cDB: SSC836 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available SS (Link to library) SSC836 (Link to dictyBase) - - - - SSC836E (Link to Original s...ite) - - - - - - SSC836E 502 Show SSC836 Library SS (Link to library) Clone ID SSC836 (Link to dictyBase) Atlas ID - NBRP ID - dict...yBase ID - Link to Contig - Original site URL http://dictycdb.biol.tsukuba.ac.jp/CSM/...t alignments: (bits) Value N M77492 |M77492.1 Dictyostelium discoideum glycoprotein phosphorylase 2 (glpD) g...ene, complete cds. 779 0.0 1 AC116984 |AC116984.2 Dictyostelium discoideum chromo

  18. System engineering in the SSC Linac

    International Nuclear Information System (INIS)

    Tooker, J.F.; Chang, C.R.; Cutler, R.I.; Funk, L.W.; Guy, F.W.; Hale, R.; Leifeste, G.T.; Nonte, J.; Prichard, B.; Raparia, D.; Saadatmand, K.; Sethi, R.C.; Yao, C.G.

    1992-01-01

    The design and construction of the SSC Linac involves various departments within the SSCL and many outside vendors. The adaptive incorporation of system engineering principles into the SSC Linac is described. This involves the development of specification trees with the breakdown and flow of functional and physical requirements from the top level system specifications to the lower level component specifications. Interfaces are defined, which specify and control the interconnections between the various components. Review cycles are presented during which the requirements, evolution of the design, and test plans are reviewed, monitored, and finalized. The Linac specification tree, interface definition, and reviews of the Linac are presented, including typical examples. (Author) 2 refs., 3 tabs

  19. Magnetic field decay in model SSC dipoles

    International Nuclear Information System (INIS)

    Gilbert, W.S.; Althaus, R.F.; Barale, P.J.; Benjegerdes, R.W.; Green, M.A.; Green, M.I.; Scanlan, R.M.

    1988-08-01

    We have observed that some of our model SSC dipoles have long time constant decays of the magnetic field harmonics with amplitudes large enough to result in significant beam loss, if they are not corrected. The magnets were run at constant current at the SSC injection field level of 0.3 tesla for one to three hours and changes in the magnetic field were observed. One explanation for the observed field decay is time dependent superconductor magnetization. Another explanation involves flux creep or flux flow. Data are presented on how the decay changes with previous flux history. Similar magnets with different Nb-Ti filament spacings and matrix materials have different long time field decay. A theoretical model using proximity coupling and flux creep for the observed field decay is discussed. 10 refs., 5 figs., 2 tabs

  20. Silicon calorimetry for the SSC[ Superconducting Supercollider

    International Nuclear Information System (INIS)

    Bertrand, C.; Borchi, E.; Brau, J.E.

    1989-01-01

    SSC experiments will rely heavily on their calorimeters. Silicon calorimetry, which has been introduced in recent years as a useful technology, has many attractive characteristics which may make it a viable option for consideration. The many attractive properties of silicon detectors are reviewed. The relevant present day applications of large areas of silicon detectors are summarize to illustrate the emerging use. The troublesome issue of radiation damage in a high luminosity environment like the SSC is considered with a summary of much of the recent new measurements which help clarify this situation. A discussion of the electronics and a possible mechanical configuration is presented, followed by a summary of the outstanding R and D issues. 31 refs., 11 figs., 3 tabs

  1. Reactivity feedback models for SSC-K

    Energy Technology Data Exchange (ETDEWEB)

    Han, Do Hee; Kwon, Young Min; Kim, Kyung Du; Chang, Won Pyo [Korea Atomic Energy Research Institute, Taejon (Korea)

    1998-06-01

    Safety of KALIMER is assured by the inherent safety of the core and passive safety of the safety-related systems. For the safety analysis of a new reactor design such as KALIMER, analysis models, which are consistent with the design, have to be developed for a plant-wide transient and safety analysis code. Efforts for the development of reactivity feedback models for SSC-K, which is now being developed for the safety analysis of KALIMER, is described in this report. Models for Doppler, sodium density/void, fuel axial expansion, core radial expansion, and CRDL expansion have been developed. Test runs have been performed for the unprotected accident for the verification of the models. Use of KALIMER reactivity coefficients and future development of models for GEM and PSDRS would make it possible to analyze the response of KALIMER under TOP as well as LOF and LOHS accident conditions using SSC-K. (author). 5 refs., 64 figs., 2 tabs.

  2. Compositeness and QCD at the SSC

    International Nuclear Information System (INIS)

    Barnes, V.; Blumenfeld, B.; Cahn, R.

    1987-01-01

    Compositeness may be signaled by an increase in the production of high transverse momentum hadronic jet pairs or lepton pairs. The hadronic jet signal competes with the QCD production of jets, a subject of interest in its own right. Tests of perturbative QCD at the SSC will be of special interest because the calculations are expected to be quite reliable. Studies show that compositeness up to a scale of 20 to 35 TeV would be detected in hadronic jets at the SSC. Leptonic evidence would be discovered for scales up to 10 to 20 TeV. The charge asymmetry for leptons would provide information on the nature of the compositeness interaction. Calorimetry will play a crucial role in the detection of compositeness in the hadronic jet signal. Deviations from an e/h response of 1 could mask the effect. The backgrounds for lepton pair production seem manageable. 30 refs., 19 figs., 10 tabs

  3. The SSC access shafts calculational study

    International Nuclear Information System (INIS)

    Baishev, I.S.; Mokhov, N.V.; Toohig, T.E.

    1991-06-01

    The SSC generic shaft requirements and access spacing are considered elsewhere. The shafts connecting the ground surface with the underground accelerator tunnel deliver to the surface some portion of the radiation created in the tunnel. The radiation safety problem of access shafts consists of two major questions: Does the dose equivalent at the ground surface exceed permissible limits? If it exceeds those limits, what additional shielding measures are required? A few works deal with this problem for high energy machines. This work is an attempt to answer these questions for the basic types of shafts specific to the SSC magnet delivery, utility and personnel shafts using full-scale Monte-Carlo calculations of the entire process from hadronic cascades in the lattice elements to particles scattered in the tunnel, niches, alcoves, shafts and surface bunkers and buildings. 9 refs., 16 figs., 1 tab

  4. An industrial cabling machine for the SSC

    International Nuclear Information System (INIS)

    Royet, J.; Armer, R.; Hannaford, R.; Scanlan, R.

    1989-02-01

    The SSC project will need the manufacturing of some 25,000 kilometers of keystoned flat cable. The technical specifications of the various cables to be produced are the result of five years of research and development work at LBL. An experimental cable machine was built and run in the laboratory; many improvements were implemented and tested. Semi-industrial production of the various cables was performed, and the resulting cables were used and tested in the one-meter model magnets and 17.5 meter dipole prototypes. From these experiments an industrial cabler specification was generated and used for an international RFQ. The winner of the contract is Dour Metal, a Belgium company that built the first industrial prototype which is now in a production line at New England Electric Wire Company. In this paper we describe the main characteristics of the machine and give the first industrial production results of superconducting keystoned cable for the SSC project. 4 refs

  5. Autophagy in Stem Cell Biology: A Perspective on Stem Cell Self-Renewal and Differentiation

    Directory of Open Access Journals (Sweden)

    Xihang Chen

    2018-01-01

    Full Text Available Autophagy is a highly conserved cellular process that degrades modified, surplus, or harmful cytoplasmic components by sequestering them in autophagosomes which then fuses with the lysosome for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis, as well as for remodeling during normal development. Impairment of this process has been implicated in various diseases, in the pathogenic response to bacterial and viral infections, and in aging. Pluripotent stem cells, with their ability to self-replicate and to give rise to any specialized cell type, are very valuable resources for cell-based medical therapies and open a number of promising avenues for studying human development and disease. It has been suggested that autophagy is vital for the maintenance of cellular homeostasis in stem cells, and subsequently more in-depth knowledge about the regulation of autophagy in stem cell biology has been acquired recently. In this review, we describe the most significant advances in the understanding of autophagy regulation in hematopoietic and mesenchymal stem cells, as well as in induced pluripotent stem cells. In particular, we highlight the roles of various autophagy activities in the regulation of self-renewal and differentiation of these stem cells.

  6. Long-Term Culture of Self-renewing Pancreatic Progenitors Derived from Human Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Jamie Trott

    2017-06-01

    Full Text Available Pluripotent stem cells have been proposed as an unlimited source of pancreatic β cells for studying and treating diabetes. However, the long, multi-step differentiation protocols used to generate functional β cells inevitably exhibit considerable variability, particularly when applied to pluripotent cells from diverse genetic backgrounds. We have developed culture conditions that support long-term self-renewal of human multipotent pancreatic progenitors, which are developmentally more proximal to the specialized cells of the adult pancreas. These cultured pancreatic progenitor (cPP cells express key pancreatic transcription factors, including PDX1 and SOX9, and exhibit transcriptomes closely related to their in vivo counterparts. Upon exposure to differentiation cues, cPP cells give rise to pancreatic endocrine, acinar, and ductal lineages, indicating multilineage potency. Furthermore, cPP cells generate insulin+ β-like cells in vitro and in vivo, suggesting that they offer a convenient alternative to pluripotent cells as a source of adult cell types for modeling pancreatic development and diabetes.

  7. The effect of irradiation on function in self-renewing normal tissues with differing proliferative organisation

    International Nuclear Information System (INIS)

    Wheldon, T.E.; Michalowski, A.S.

    1982-01-01

    The primary effect of irradiation on self-renewing normal tissues is sterilisation of their proliferative cells, but how this translates into failure of tissue function depends on the mode of organisation of the tissue concerned. It has recently been suggested (Michalowski, 1981) that proliferative normal tissues may be classed as ''hierarchical'' (like haemopoietic tissues) or as ''flexible'' (like liver parenchyma) and that radiation injury to tissue function develops by different pathways in these tissues. Mathematical model studies confirm the different radiation responses of differently organized tissues. Tissues of the ''flexible'' or ''F-type'' category display a variety of novel radiobiological properties, different from those of the more familiar ''hierarchical'' or ''H-type'' tissues. The ''F-type'' responses are strongly influenced by radiation-sterilised (''doomed'') cells, and is is suggested that the role of ''doomed'' cells has been undervalued relative to that of clonogenic survivors. Since ''F-type'' tissues have characteristically low rates of cell renewal, it is possible that these tissues are preferentially responsible for late effects of irradiation in clinical radiotherapy. (author)

  8. The death-inducer obliterator 1 (Dido1) gene regulates embryonic stem cell self-renewal.

    Science.gov (United States)

    Liu, Yinyin; Kim, Hyeung; Liang, Jiancong; Lu, Weisi; Ouyang, Bin; Liu, Dan; Songyang, Zhou

    2014-02-21

    The regulatory network of factors that center on master transcription factors such as Oct4, Nanog, and Sox2 help maintain embryonic stem (ES) cells and ensure their pluripotency. The target genes of these master transcription factors define the ES cell transcriptional landscape. In this study, we report our findings that Dido1, a target of canonical transcription factors such as Oct4, Sox2, and Nanog, plays an important role in regulating ES cell maintenance. We found that depletion of Dido1 in mouse ES cells led to differentiation, and ectopic expression of Dido1 inhibited differentiation induced by leukemia inhibitory factor withdrawal. We further demonstrated that whereas Nanog and Oct4 could occupy the Dido1 locus and promote its transcription, Dido1 could also target to the loci of pluripotency factors such as Nanog and Oct4 and positively regulate their expression. Through this feedback and feedforward loop, Dido1 is able to regulate self-renewal of mouse ES cells.

  9. Hedgehog regulates Norrie disease protein to drive neural progenitor self-renewal.

    Science.gov (United States)

    McNeill, Brian; Mazerolle, Chantal; Bassett, Erin A; Mears, Alan J; Ringuette, Randy; Lagali, Pamela; Picketts, David J; Paes, Kim; Rice, Dennis; Wallace, Valerie A

    2013-03-01

    Norrie disease (ND) is a congenital disorder characterized by retinal hypovascularization and cognitive delay. ND has been linked to mutations in 'Norrie Disease Protein' (Ndp), which encodes the secreted protein Norrin. Norrin functions as a secreted angiogenic factor, although its role in neural development has not been assessed. Here, we show that Ndp expression is initiated in retinal progenitors in response to Hedgehog (Hh) signaling, which induces Gli2 binding to the Ndp promoter. Using a combination of genetic epistasis and acute RNAi-knockdown approaches, we show that Ndp is required downstream of Hh activation to induce retinal progenitor proliferation in the retina. Strikingly, Ndp regulates the rate of cell-cycle re-entry and not cell-cycle kinetics, thereby uncoupling the self-renewal and cell-cycle progression functions of Hh. Taken together, we have uncovered a cell autonomous function for Ndp in retinal progenitor proliferation that is independent of its function in the retinal vasculature, which could explain the neural defects associated with ND.

  10. Multilineage Potential and Self-Renewal Define an Epithelial Progenitor Cell Population in the Adult Thymus

    Directory of Open Access Journals (Sweden)

    Kahlia Wong

    2014-08-01

    Full Text Available Thymic epithelial cells (TECs are critical for T cell development and self-tolerance but are gradually lost with age. The existence of thymic epithelial progenitors (TEPCs in the postnatal thymus has been inferred, but their identity has remained enigmatic. Here, we assessed the entire adult TEC compartment in order to reveal progenitor capacity is retained exclusively within a subset of immature thymic epithelium displaying several hallmark features of stem/progenitor function. These adult TEPCs generate mature cortical and medullary lineages in a stepwise fashion, including Aire+ TEC, within fetal thymus reaggregate grafts. Although relatively quiescent in vivo, adult TEPCs demonstrate significant in vitro colony formation and self-renewal. Importantly, 3D-cultured TEPCs retain their capacity to differentiate into cortical and medullary TEC lineages when returned to an in vivo thymic microenvironment. No other postnatal TEC subset exhibits this combination of properties. The characterization of adult TEPC will enable progress in understanding TEC biology in aging and regeneration.

  11. Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch.

    Science.gov (United States)

    López-Arribillaga, Erika; Rodilla, Verónica; Pellegrinet, Luca; Guiu, Jordi; Iglesias, Mar; Roman, Angel Carlos; Gutarra, Susana; González, Susana; Muñoz-Cánoves, Pura; Fernández-Salguero, Pedro; Radtke, Freddy; Bigas, Anna; Espinosa, Lluís

    2015-01-01

    Genetic data indicate that abrogation of Notch-Rbpj or Wnt-β-catenin pathways results in the loss of the intestinal stem cells (ISCs). However, whether the effect of Notch is direct or due to the aberrant differentiation of the transit-amplifying cells into post-mitotic goblet cells is unknown. To address this issue, we have generated composite tamoxifen-inducible intestine-specific genetic mouse models and analyzed the expression of intestinal differentiation markers. Importantly, we found that activation of β-catenin partially rescues the differentiation phenotype of Rbpj deletion mutants, but not the loss of the ISC compartment. Moreover, we identified Bmi1, which is expressed in the ISC and progenitor compartments, as a gene that is co-regulated by Notch and β-catenin. Loss of Bmi1 resulted in reduced proliferation in the ISC compartment accompanied by p16(INK4a) and p19(ARF) (splice variants of Cdkn2a) accumulation, and increased differentiation to the post-mitotic goblet cell lineage that partially mimics Notch loss-of-function defects. Finally, we provide evidence that Bmi1 contributes to ISC self-renewal. © 2015. Published by The Company of Biologists Ltd.

  12. mir-300 promotes self-renewal and inhibits the differentiation of glioma stem-like cells

    KAUST Repository

    Zhang, Daming

    2014-01-28

    MicroRNAs (miRNAs) are small noncoding RNAs that have been critically implicated in several human cancers. miRNAs are thought to participate in various biological processes, including proliferation, cell cycle, apoptosis, and even the regulation of the stemness properties of cancer stem cells. In this study, we explore the potential role of miR-300 in glioma stem-like cells (GSLCs). We isolated GSLCs from glioma biopsy specimens and identified the stemness properties of the cells through neurosphere formation assays, multilineage differentiation ability analysis, and immunofluorescence analysis of glioma stem cell markers. We found that miR-300 is commonly upregulated in glioma tissues, and the expression of miR-300 was higher in GSLCs. The results of functional experiments demonstrated that miR-300 can enhance the self-renewal of GSLCs and reduce differentiation toward both astrocyte and neural fates. In addition, LZTS2 is a direct target of miR-300. In conclusion, our results demonstrate the critical role of miR-300 in GSLCs and its functions in LZTS2 inhibition and describe a new approach for the molecular regulation of tumor stem cells. © 2014 Springer Science+Business Media.

  13. New linac technology - for SSC, and beyond

    International Nuclear Information System (INIS)

    Jameson, R.A.

    1983-01-01

    With recent agreement on the high priority of seeking funding for a Superconducting Super Collider (SSC), it is appropriate to consider the injector linac requirements for such a machine. In so doing, the status of established technique and advantages of near-term R and D with relatively clear payoff are established, giving a base line for some speculation about linac possibilities even further in the future

  14. Neural networks, D0, and the SSC

    International Nuclear Information System (INIS)

    Barter, C.; Cutts, D.; Hoftun, J.S.; Partridge, R.A.; Sornborger, A.T.; Johnson, C.T.; Zeller, R.T.

    1989-01-01

    We outline several exploratory studies involving neural network simulations applied to pattern recognition in high energy physics. We describe the D0 data acquisition system and a natual means by which algorithms derived from neural networks techniques may be incorporated into recently developed hardware associated with the D0 MicroVAX farm nodes. Such applications to the event filtering needed by SSC detectors look interesting. 10 refs., 11 figs

  15. SSC collider dipole magnet end mechanical design

    International Nuclear Information System (INIS)

    Delchamps, S.W.; Bossert, R.C.; Carson, J.; Ewald, K.; Fulton, H.; Kerby, J.; Koska, W.; Strait, J.; Wake, M.; Leung, K.K.

    1991-01-01

    This paper describes the mechanical design of the ends of Superconducting Super Collider dipole magnets to be constructed and tested at Fermilab. Coil end clamps, end yoke configuration, and end plate design are discussed. Loading of the end plate by axial Lorentz forces is discussed. Relevant data from 40 mm and 50 mm aperture model dipole magnets built and tested at Fermilab are presented. In particular, the apparent influence of end clamp design on the quench behavior of model SSC dipoles is described

  16. Engineered design of SSC cooling ponds

    International Nuclear Information System (INIS)

    Bear, J.B.

    1993-05-01

    The cooling requirements of the SSC are significant and adequate cooling water systems to meet these requirements are critical to the project's successful operation. The use of adequately designed cooling ponds will provide reliable cooling for operation while also meeting environmental goals of the project to maintain streamflow and flood peaks to preconstruction levels as well as other streamflow and water quality requirements of the Texas Water Commission and the Environmental Protection Agency

  17. Computing facility at SSC for detectors

    International Nuclear Information System (INIS)

    Leibold, P.; Scipiono, B.

    1990-01-01

    A description of the RISC-based distributed computing facility for detector simulaiton being developed at the SSC Laboratory is discussed. The first phase of this facility is scheduled for completion in early 1991. Included is the status of the project, overview of the concepts used to model and define system architecture, networking capabilities for user access, plans for support of physics codes and related topics concerning the implementation of this facility

  18. Integrated transcriptome and binding sites analysis implicates E2F in the regulation of self-renewal in human pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Hock Chuan Yeo

    Full Text Available Rapid cellular growth and multiplication, limited replicative senescence, calibrated sensitivity to apoptosis, and a capacity to differentiate into almost any cell type are major properties that underline the self-renewal capabilities of human pluripotent stem cells (hPSCs. We developed an integrated bioinformatics pipeline to understand the gene regulation and functions involved in maintaining such self-renewal properties of hPSCs compared to matched fibroblasts. An initial genome-wide screening of transcription factor activity using in silico binding-site and gene expression microarray data newly identified E2F as one of major candidate factors, revealing their significant regulation of the transcriptome. This is underscored by an elevated level of its transcription factor activity and expression in all tested pluripotent stem cell lines. Subsequent analysis of functional gene groups demonstrated the importance of the TFs to self-renewal in the pluripotency-coupled context; E2F directly targets the global signaling (e.g. self-renewal associated WNT and FGF pathways and metabolic network (e.g. energy generation pathways, molecular transports and fatty acid metabolism to promote its canonical functions that are driving the self-renewal of hPSCs. In addition, we proposed a core self-renewal module of regulatory interplay between E2F and, WNT and FGF pathways in these cells. Thus, we conclude that E2F plays a significant role in influencing the self-renewal capabilities of hPSCs.

  19. The status of detectors at the SSC

    International Nuclear Information System (INIS)

    Stefanski, R.

    1990-09-01

    The announcement of the location of the SSC at the site near Waxahachie, Texas was made in January, 1989. Since then a great many important steps have been taken toward the start of the new Laboratory. Some 900 people have been brought to the site as the starting nucleus of the staff that will ultimate number about 2200. A design baseline has been completed that includes a conceptual design for the accelerator, and the detectors. Also, the process has begun to determine the configuration of detectors that will be built for the SSC. This process has several steps, and now the first of these has been taken: The detector collaborations have submitted the Expression of Interest to the Laboratory. These were reviewed by Laboratory management and the Physics Advisory Committee in July, 1990 and recommendations were made to the collaborations. Decisions were deferred for all of the detectors. But perhaps the most significant recommendation was the request to reduce the size and cost of the general purpose detectors. The detector collaborations are now reviewing their initial designs to prepare for the Letters of Intent, the next step in the detector planning process. This is clearly a difficult and crucial step in that the redesign of the detectors must be done with minimal reduction in detector quality. It is an interesting time in the development of the new laboratory, and a crucial time for the ultimate physics that will be done at the SSC

  20. Relational databases for SSC design and control

    International Nuclear Information System (INIS)

    Barr, E.; Peggs, S.; Saltmarsh, C.

    1989-01-01

    Most people agree that a database is A Good Thing, but there is much confusion in the jargon used, and in what jobs a database management system and its peripheral software can and cannot do. During the life cycle of an enormous project like the SSC, from conceptual and theoretical design, through research and development, to construction, commissioning and operation, an enormous amount of data will be generated. Some of these data, originating in the early parts of the project, will be needed during commissioning or operation, many years in the future. Two of these pressing data management needs-from the magnet research and industrialization programs and the lattice design-have prompted work on understanding and adapting commercial database practices for scientific projects. Modern relational database management systems (rDBMS's) cope naturally with a large proportion of the requirements of data structures, like the SSC database structure built for the superconduction cable supplies, uses, and properties. This application is similar to the commercial applications for which these database systems were developed. The SSC application has further requirements not immediately satisfied by the commercial systems. These derive from the diversity of the data structures to be managed, the changing emphases and uses during the project lifetime, and the large amount of scientific data processing to be expected. 4 refs., 5 figs

  1. Roles of Retinoids and Retinoic Acid Receptors in the Regulation of Hematopoietic Stem Cell Self-Renewal and Differentiation

    Directory of Open Access Journals (Sweden)

    Louise E. Purton

    2007-01-01

    Full Text Available Multipotent hematopoietic stem cells (HSCs sustain blood cell production throughout an individual's lifespan through complex processes ultimately leading to fates of self-renewal, differentiation or cell death decisions. A fine balance between these decisions in vivo allows for the size of the HSC pool to be maintained. While many key factors involved in regulating HSC/progenitor cell differentiation and cell death are known, the critical regulators of HSC self-renewal are largely unknown. In recent years, however, a number of studies describing methods of increasing or decreasing the numbers of HSCs in a given population have emerged. Of major interest here are the emerging roles of retinoids in the regulation of HSCs.

  2. The Role of Controlled Surface Topography and Chemistry on Mouse Embryonic Stem Cell Attachment, Growth and Self-Renewal.

    Science.gov (United States)

    Macgregor, Melanie; Williams, Rachel; Downes, Joni; Bachhuka, Akash; Vasilev, Krasimir

    2017-09-14

    The success of stem cell therapies relies heavily on our ability to control their fate in vitro during expansion to ensure an appropriate supply. The biophysical properties of the cell culture environment have been recognised as a potent stimuli influencing cellular behaviour. In this work we used advanced plasma-based techniques to generate model culture substrates with controlled nanotopographical features of 16 nm, 38 nm and 68 nm in magnitude, and three differently tailored surface chemical functionalities. The effect of these two surface properties on the adhesion, spreading, and self-renewal of mouse embryonic stem cells (mESCs) were assessed. The results demonstrated that physical and chemical cues influenced the behaviour of these stem cells in in vitro culture in different ways. The size of the nanotopographical features impacted on the cell adhesion, spreading and proliferation, while the chemistry influenced the cell self-renewal and differentiation.

  3. TMPRSS2- driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation.

    Directory of Open Access Journals (Sweden)

    Orla M Casey

    Full Text Available Genomic rearrangements commonly occur in many types of cancers and often initiate or alter the progression of disease. Here we describe an in vivo mouse model that recapitulates the most frequent rearrangement in prostate cancer, the fusion of the promoter region of TMPRSS2 with the coding region of the transcription factor, ERG. A recombinant bacterial artificial chromosome including an extended TMPRSS2 promoter driving genomic ERG was constructed and used for transgenesis in mice. TMPRSS2-ERG expression was evaluated in tissue sections and FACS-fractionated prostate cell populations. In addition to the anticipated expression in luminal cells, TMPRSS2-ERG was similarly expressed in the Sca-1(hi/EpCAM(+ basal/progenitor fraction, where expanded numbers of clonogenic self-renewing progenitors were found, as assayed by in vitro sphere formation. These clonogenic cells increased intrinsic self renewal in subsequent generations. In addition, ERG dependent self-renewal and invasion in vitro was demonstrated in prostate cell lines derived from the model. Clinical studies have suggested that the TMPRSS2-ERG translocation occurs early in prostate cancer development. In the model described here, the presence of the TMPRSS2-ERG fusion alone was not transforming but synergized with heterozygous Pten deletion to promote PIN. Taken together, these data suggest that one function of TMPRSS2-ERG is the expansion of self-renewing cells, which may serve as targets for subsequent mutations. Primary prostate epithelial cells demonstrated increased post transcriptional turnover of ERG compared to the TMPRSS2-ERG positive VCaP cell line, originally isolated from a prostate cancer metastasis. Finally, we determined that TMPRSS2-ERG expression occurred in both castration-sensitive and resistant prostate epithelial subpopulations, suggesting the existence of androgen-independent mechanisms of TMPRSS2 expression in prostate epithelium.

  4. Identification of key factors regulating self-renewal and differentiation in EML hematopoietic precursor cells by RNA-sequencing analysis.

    Science.gov (United States)

    Zong, Shan; Deng, Shuyun; Chen, Kenian; Wu, Jia Qian

    2014-11-11

    Hematopoietic stem cells (HSCs) are used clinically for transplantation treatment to rebuild a patient's hematopoietic system in many diseases such as leukemia and lymphoma. Elucidating the mechanisms controlling HSCs self-renewal and differentiation is important for application of HSCs for research and clinical uses. However, it is not possible to obtain large quantity of HSCs due to their inability to proliferate in vitro. To overcome this hurdle, we used a mouse bone marrow derived cell line, the EML (Erythroid, Myeloid, and Lymphocytic) cell line, as a model system for this study. RNA-sequencing (RNA-Seq) has been increasingly used to replace microarray for gene expression studies. We report here a detailed method of using RNA-Seq technology to investigate the potential key factors in regulation of EML cell self-renewal and differentiation. The protocol provided in this paper is divided into three parts. The first part explains how to culture EML cells and separate Lin-CD34+ and Lin-CD34- cells. The second part of the protocol offers detailed procedures for total RNA preparation and the subsequent library construction for high-throughput sequencing. The last part describes the method for RNA-Seq data analysis and explains how to use the data to identify differentially expressed transcription factors between Lin-CD34+ and Lin-CD34- cells. The most significantly differentially expressed transcription factors were identified to be the potential key regulators controlling EML cell self-renewal and differentiation. In the discussion section of this paper, we highlight the key steps for successful performance of this experiment. In summary, this paper offers a method of using RNA-Seq technology to identify potential regulators of self-renewal and differentiation in EML cells. The key factors identified are subjected to downstream functional analysis in vitro and in vivo.

  5. Low Oxygen Modulates Multiple Signaling Pathways, Increasing Self-Renewal, While Decreasing Differentiation, Senescence, and Apoptosis in Stromal MIAMI Cells

    Science.gov (United States)

    Rios, Carmen; D'Ippolito, Gianluca; Curtis, Kevin M.; Delcroix, Gaëtan J.-R.; Gomez, Lourdes A.; El Hokayem, Jimmy; Rieger, Megan; Parrondo, Ricardo; de las Pozas, Alicia; Perez-Stable, Carlos; Howard, Guy A.

    2016-01-01

    Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and β-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells. PMID:27059084

  6. Inhibition of Focal Adhesion Kinase Signaling by Integrin α6β1 Supports Human Pluripotent Stem Cell Self-Renewal.

    Science.gov (United States)

    Villa-Diaz, Luis G; Kim, Jin Koo; Laperle, Alex; Palecek, Sean P; Krebsbach, Paul H

    2016-07-01

    Self-renewal of human embryonic stem cells and human induced pluripotent stem cells (hiPSCs)-known as pluripotent stem cells (PSC)-is influenced by culture conditions, including the substrate on which they are grown. However, details of the molecular mechanisms interconnecting the substrate and self-renewal of these cells remain unclear. We describe a signaling pathway in hPSCs linking self-renewal and expression of pluripotency transcription factors to integrin α6β1 and inactivation of focal adhesion kinase (FAK). Disruption of this pathway results in hPSC differentiation. In hPSCs, α6β1 is the dominant integrin and FAK is not phosphorylated at Y397, and thus, it is inactive. During differentiation, integrin α6 levels diminish and Y397 FAK is phosphorylated and activated. During reprogramming of fibroblasts into iPSCs, integrin α6 is upregulated and FAK is inactivated. Knockdown of integrin α6 and activation of β1 integrin lead to FAK phosphorylation and reduction of Nanog, Oct4, and Sox2, suggesting that integrin α6 functions in inactivation of integrin β1 and FAK signaling and prevention of hPSC differentiation. The N-terminal domain of FAK, where Y397 is localized, is in the nuclei of hPSCs interacting with Oct4 and Sox2, and this immunolocalization is regulated by Oct4. hPSCs remodel the extracellular microenvironment and deposit laminin α5, the primary ligand of integrin α6β1. Knockdown of laminin α5 resulted in reduction of integrin α6 expression, phosphorylation of FAK and decreased Oct4. In conclusion, hPSCs promote the expression of integrin α6β1, and nuclear localization and inactivation of FAK to supports stem cell self-renewal. Stem Cells 2016;34:1753-1764. © 2016 AlphaMed Press.

  7. The Drosophila BCL6 homolog Ken and Barbie promotes somatic stem cell self-renewal in the testis niche.

    Science.gov (United States)

    Issigonis, Melanie; Matunis, Erika

    2012-08-15

    Stem cells sustain tissue regeneration by their remarkable ability to replenish the stem cell pool and to generate differentiating progeny. Signals from local microenvironments, or niches, control stem cell behavior. In the Drosophila testis, a group of somatic support cells called the hub creates a stem cell niche by locally activating the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway in two adjacent types of stem cells: germline stem cells (GSCs) and somatic cyst stem cells (CySCs). Here, we find that ken and barbie (ken) is autonomously required for the self-renewal of CySCs but not GSCs. Furthermore, Ken misexpression in the CySC lineage induces the cell-autonomous self-renewal of somatic cells as well as the nonautonomous self-renewal of germ cells outside the niche. Thus, Ken, like Stat92E and its targets ZFH1 (Leatherman and Dinardo, 2008) and Chinmo (Flaherty et al., 2010), is necessary and sufficient for CySC renewal. However, ken is not a JAK-STAT target in the testis, but instead acts in parallel to Stat92E to ensure CySC self-renewal. Ken represses a subset of Stat92E targets in the embryo (Arbouzova et al., 2006) suggesting that Ken maintains CySCs by repressing differentiation factors. In support of this hypothesis, we find that the global JAK-STAT inhibitor Protein tyrosine phosphatase 61F (Ptp61F) is a JAK-STAT target in the testis that is repressed by Ken. Together, our work demonstrates that Ken has an important role in the inhibition of CySC differentiation. Studies of ken may inform our understanding of its vertebrate orthologue B-Cell Lymphoma 6 (BCL6) and how misregulation of this oncogene leads to human lymphomas. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Phosphorylation of ULK1 by AMPK is essential for mouse embryonic stem cell self-renewal and pluripotency.

    Science.gov (United States)

    Gong, Jiaqi; Gu, Haifeng; Zhao, Lin; Wang, Liang; Liu, Pinglei; Wang, Fuping; Xu, Haoyu; Zhao, Tongbiao

    2018-01-18

    Autophagy is a catabolic process to degrade both damaged organelles and aggregated proteins in somatic cells. We have recently identified that autophagy is an executor for mitochondrial homeostasis in embryonic stem cell (ESC), and thus contribute to stemness regulation. However, the regulatory and functional mechanisms of autophagy in ESC are still largely unknown. Here we have shown that activation of ULK1 by AMPK is essential for ESC self-renewal and pluripotency. Dysfunction of Ulk1 decreases the autophagic flux in ESC, leading to compromised self-renewal and pluripotency. These defects can be rescued by reacquisition of wild-type ULK1 and ULK1(S757A) mutant, but not ULK1(S317A, S555A and S777A) and kinase dead ULK1(K46I) mutant. These data indicate that phosphorylation of ULK1 by AMPK, but not mTOR, is essential for stemness regulation in ESC. The findings highlight a critical role for AMPK-dependent phosphorylation of ULK1 pathway to maintain ESC self-renewal and pluripotency.

  9. Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2.

    Science.gov (United States)

    Ting, Stephen B; Deneault, Eric; Hope, Kristin; Cellot, Sonia; Chagraoui, Jalila; Mayotte, Nadine; Dorn, Jonas F; Laverdure, Jean-Philippe; Harvey, Michael; Hawkins, Edwin D; Russell, Sarah M; Maddox, Paul S; Iscove, Norman N; Sauvageau, Guy

    2012-03-15

    The stem cell-intrinsic model of self-renewal via asymmetric cell division (ACD) posits that fate determinants be partitioned unequally between daughter cells to either activate or suppress the stemness state. ACD is a purported mechanism by which hematopoietic stem cells (HSCs) self-renew, but definitive evidence for this cellular process remains open to conjecture. To address this issue, we chose 73 candidate genes that function within the cell polarity network to identify potential determinants that may concomitantly alter HSC fate while also exhibiting asymmetric segregation at cell division. Initial gene-expression profiles of polarity candidates showed high and differential expression in both HSCs and leukemia stem cells. Altered HSC fate was assessed by our established in vitro to in vivo screen on a subcohort of candidate polarity genes, which revealed 6 novel positive regulators of HSC function: Ap2a2, Gpsm2, Tmod1, Kif3a, Racgap1, and Ccnb1. Interestingly, live-cell videomicroscopy of the endocytic protein AP2A2 shows instances of asymmetric segregation during HSC/progenitor cell cytokinesis. These results contribute further evidence that ACD is functional in HSC self-renewal, suggest a role for Ap2a2 in HSC activity, and provide a unique opportunity to prospectively analyze progeny from HSC asymmetric divisions.

  10. Yap1 is dispensable for self-renewal but required for proper differentiation of mouse embryonic stem (ES) cells.

    Science.gov (United States)

    Chung, HaeWon; Lee, Bum-Kyu; Uprety, Nadima; Shen, Wenwen; Lee, Jiwoon; Kim, Jonghwan

    2016-04-01

    Yap1 is a transcriptional co-activator of the Hippo pathway. The importance of Yap1 in early cell fate decision during embryogenesis has been well established, though its role in embryonic stem (ES) cells remains elusive. Here, we report that Yap1 plays crucial roles in normal differentiation rather than self-renewal of ES cells. Yap1-depleted ES cells maintain undifferentiated state with a typical colony morphology as well as robust alkaline phosphatase activity. These cells also retain comparable levels of the core pluripotent factors, such as Pou5f1 and Sox2, to the levels in wild-type ES cells without significant alteration of lineage-specific marker genes. Conversely, overexpression of Yap1 in ES cells promotes nuclear translocation of Yap1, resulting in disruption of self-renewal and triggering differentiation by up-regulating lineage-specific genes. Moreover, Yap1-deficient ES cells show impaired induction of lineage markers during differentiation. Collectively, our data demonstrate that Yap1 is a required factor for proper differentiation of mouse ES cells, while remaining dispensable for self-renewal. © 2016 The Authors.

  11. GDNF/GFRα1 Complex Abrogates Self-Renewing Activity of Cortical Neural Precursors Inducing Their Differentiation

    Directory of Open Access Journals (Sweden)

    Antonela Bonafina

    2018-03-01

    Full Text Available Summary: The balance between factors leading to proliferation and differentiation of cortical neural precursors (CNPs determines the correct cortical development. In this work, we show that GDNF and its receptor GFRα1 are expressed in the neocortex during the period of cortical neurogenesis. We show that the GDNF/GFRα1 complex inhibits the self-renewal capacity of mouse CNP cells induced by fibroblast growth factor 2 (FGF2, promoting neuronal differentiation. While GDNF leads to decreased proliferation of cultured cortical precursor cells, ablation of GFRα1 in glutamatergic cortical precursors enhances its proliferation. We show that GDNF treatment of CNPs promoted morphological differentiation even in the presence of the self-renewal-promoting factor, FGF2. Analysis of GFRα1-deficient mice shows an increase in the number of cycling cells during cortical development and a reduction in dendrite development of cortical GFRα1-expressing neurons. Together, these results indicate that GDNF/GFRα1 signaling plays an essential role in regulating the proliferative condition and the differentiation of cortical progenitors. : In this article, Ledda and colleagues show that GDNF acting through its receptor GFRα1 plays a critical role in the maturation of cortical progenitors by counteracting FGF2 self-renewal activity on neural stem cells and promoting neuronal differentiation. Keywords: GDNF, GFRα1, cortical precursors, proliferation, postmitotic neurons, neuronal differentiation

  12. BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Krüppel-like Factors.

    Science.gov (United States)

    Morikawa, Masato; Koinuma, Daizo; Mizutani, Anna; Kawasaki, Natsumi; Holmborn, Katarina; Sundqvist, Anders; Tsutsumi, Shuichi; Watabe, Tetsuro; Aburatani, Hiroyuki; Heldin, Carl-Henrik; Miyazono, Kohei

    2016-01-12

    Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Krüppel-like factors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells

    Science.gov (United States)

    Butler, Jason M.; Nolan, Daniel J.; L.Vertes, Eva; Varnum-Finney, Barbara; Kobayashi, Hideki; Hooper, Andrea T.; Seandel, Marco; Shido, Koji; White, Ian A.; Kobayashi, Mariko; Witte, Larry; May, Chad; Shawber, Carrie; Kimura, Yuki; Kitajewski, Jan; Rosenwaks, Zev; Bernstein, Irwin D.; Rafii, Shahin

    2010-01-01

    Bone marrow endothelial cells (ECs) are essential for reconstitution of hematopoiesis, but their role in self-renewal of long term-hematopoietic stem cells (LT-HSCs) is unknown. We have developed angiogenic models to demonstrate that EC-derived angiocrine growth factors support in vitro self-renewal and in vivo repopulation of authentic LT-HSCs. In serum/cytokine-free co-cultures, ECs through direct cellular contact, stimulated incremental expansion of repopulating CD34−Flt3−cKit+Lineage−Sca1+ LT-HSCs, which retained their self-renewal ability, as determined by single cell and serial transplantation assays. Angiocrine expression of Notch-ligands by ECs promoted proliferation and prevented exhaustion of LT-HSCs derived from wild-type, but not Notch1/Notch2 deficient mice. In transgenic notch-reporter (TNR.Gfp) mice, regenerating TNR.Gfp+ LT-HSCs were detected in cellular contact with sinusoidal ECs and interfering with angiocrine, but not perfusion function, of SECs impaired repopulation of TNR.Gfp+ LT-HSCs. ECs establish an instructive vascular niche for clinical scale expansion of LT-HSCs and a cellular platform to identify stem cell-active trophogens. PMID:20207228

  14. GROα regulates human embryonic stem cell self-renewal or adoption of a neuronal fate

    Science.gov (United States)

    Krtolica, Ana; Larocque, Nick; Genbacev, Olga; Ilic, Dusko; Coppe, Jean-Philippe; Patil, Christopher K.; Zdravkovic, Tamara; McMaster, Michael; Campisi, Judith; Fisher, Susan J.

    2012-01-01

    Previously we reported that feeders formed from human placental fibroblasts (hPFs) support derivation and long-term self-renewal of human embryonic stem cells (hESCs) under serum-free conditions. Here, we show, using antibody array and ELISA platforms, that hPFs secrete ~6-fold higher amounts of the CXC-type chemokine, GROα, than IMR 90, a human lung fibroblast line, which does not support hESC growth. Furthermore, immunocytochemistry and immunoblot approaches revealed that hESCs express CXCR, a GROα receptor. We used this information to develop defined culture medium for feeder-free propagation of hESCs in an undifferentiated state. Cells passaged as small aggregates and maintained in the GROα-containing medium had a normal karyotype, expressed pluripotency markers, and exhibited apical–basal polarity, i.e., had the defining features of pluripotent hESCs. They also differentiated into the three primary (embryonic) germ layers and formed teratomas in immunocompromised mice. hESCs cultured as single cells in the GROα-containing medium also had a normal karyotype, but they downregulated markers of pluripotency, lost apical–basal polarity, and expressed markers that are indicative of the early stages of neuronal differentiation—βIII tubulin, vimentin, radial glial protein, and nestin. These data support our hypothesis that establishing and maintaining cell polarity is essential for the long-term propagation of hESCs in an undifferentiated state and that disruption of cell–cell contacts can trigger adoption of a neuronal fate. PMID:21396766

  15. Enhancement of human neural stem cell self-renewal in 3D hypoxic culture.

    Science.gov (United States)

    Ghourichaee, Sasan Sharee; Powell, Elizabeth M; Leach, Jennie B

    2017-05-01

    The pathology of neurological disorders is associated with the loss of neuronal and glial cells that results in functional impairments. Human neural stem cells (hNSCs), due to their self-renewing and multipotent characteristics, possess enormous tissue-specific regenerative potential. However, the efficacy of clinical applications is restricted due to the lack of standardized in vitro cell production methods with the capability of generating hNSC populations with well-defined cellular compositions. At any point, a population of hNSCs may include undifferentiated stem cells, intermediate and terminally differentiated progenies, and dead cells. Due to the plasticity of hNSCs, environmental cues play crucial roles in determining the cellular composition of hNSC cultures over time. Here, we investigated the independent and synergistic effect of three important environmental factors (i.e., culture dimensionality, oxygen concentration, and growth factors) on the survival, renewal potential, and differentiation of hNSCs. Our experimental design included two dimensional (2D) versus three dimensional (3D) cultures and normoxic (21% O 2 ) versus hypoxic (3% O 2 ) conditions in the presence and absence of epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2). Additionally, we discuss the feasibility of mathematical models that predict hNSC growth and differentiation under these culture conditions by adopting a negative feedback regulatory term. Our results indicate that the synergistic effect of culture dimensionality and hypoxic oxygen concentration in the presence of growth factors enhances the proliferation of viable, undifferentiated hNSCs. Moreover, the same synergistic effect in the absence of growth factors promotes the differentiation of hNSCs. Biotechnol. Bioeng. 2017;114: 1096-1106. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell.

    Directory of Open Access Journals (Sweden)

    Luciano Conti

    2005-09-01

    Full Text Available Pluripotent mouse embryonic stem (ES cells multiply in simple monoculture by symmetrical divisions. In vivo, however, stem cells are generally thought to depend on specialised cellular microenvironments and to undergo predominantly asymmetric divisions. Ex vivo expansion of pure populations of tissue stem cells has proven elusive. Neural progenitor cells are propagated in combination with differentiating progeny in floating clusters called neurospheres. The proportion of stem cells in neurospheres is low, however, and they cannot be directly observed or interrogated. Here we demonstrate that the complex neurosphere environment is dispensable for stem cell maintenance, and that the combination of fibroblast growth factor 2 (FGF-2 and epidermal growth factor (EGF is sufficient for derivation and continuous expansion by symmetrical division of pure cultures of neural stem (NS cells. NS cells were derived first from mouse ES cells. Neural lineage induction was followed by growth factor addition in basal culture media. In the presence of only EGF and FGF-2, resulting NS cells proliferate continuously, are diploid, and clonogenic. After prolonged expansion, they remain able to differentiate efficiently into neurons and astrocytes in vitro and upon transplantation into the adult brain. Colonies generated from single NS cells all produce neurons upon growth factor withdrawal. NS cells uniformly express morphological, cell biological, and molecular features of radial glia, developmental precursors of neurons and glia. Consistent with this profile, adherent NS cell lines can readily be established from foetal mouse brain. Similar NS cells can be generated from human ES cells and human foetal brain. The extrinsic factors EGF plus FGF-2 are sufficient to sustain pure symmetrical self-renewing divisions of NS cells. The resultant cultures constitute the first known example of tissue-specific stem cells that can be propagated without accompanying

  17. Environmental oxygen tension regulates the energy metabolism and self-renewal of human embryonic stem cells.

    Science.gov (United States)

    Forristal, Catherine E; Christensen, David R; Chinnery, Fay E; Petruzzelli, Raffaella; Parry, Kate L; Sanchez-Elsner, Tilman; Houghton, Franchesca D

    2013-01-01

    Energy metabolism is intrinsic to cell viability but surprisingly has been little studied in human embryonic stem cells (hESCs). The current study aims to investigate the effect of environmental O2 tension on carbohydrate utilisation of hESCs. Highly pluripotent hESCs cultured at 5% O2 consumed significantly more glucose, less pyruvate and produced more lactate compared to those maintained at 20% O2. Moreover, hESCs cultured at atmospheric O2 levels expressed significantly less OCT4, SOX2 and NANOG than those maintained at 5% O2. To determine whether this difference in metabolism was a reflection of the pluripotent state, hESCs were cultured at 5% O2 in the absence of FGF2 for 16 hours leading to a significant reduction in the expression of SOX2. In addition, these cells consumed less glucose and produced significantly less lactate compared to those cultured in the presence of FGF2. hESCs maintained at 5% O2 were found to consume significantly less O2 than those cultured in the absence of FGF2, or at 20% O2. GLUT1 expression correlated with glucose consumption and using siRNA and chromatin immunoprecipitation was found to be directly regulated by hypoxia inducible factor (HIF)-2α at 5% O2. In conclusion, highly pluripotent cells associated with hypoxic culture consume low levels of O2, high levels of glucose and produce large amounts of lactate, while at atmospheric conditions glucose consumption and lactate production are reduced and there is an increase in oxidative metabolism. These data suggest that environmental O2 regulates energy metabolism and is intrinsic to the self-renewal of hESCs.

  18. SSC education: Science to capture the imagination

    International Nuclear Information System (INIS)

    Gadsden, T.; Kivlighn, S.

    1992-01-01

    To the great majority of Americans, science is merely a collection of facts and theories that should (for unknown reasons) be memorized and perhaps even understood in order for one to function as a responsible citizen. Few see science as a way of thinking and questioning and as an approach to learning the secrets of our world. In addition, most children and many adults have a stereotypical view of scientists as studious men in lab coats who spend all their time working alone in dark and smelly chemical or biological laboratories. The Superconducting Super Collider (SSC) totally contradicts such a perception. This great instrument is being created by thousands of scientists, engineers, business people, technicians, administrators, and others, from dozens of nations, working together to realize a shared vision to seek answers to shared questions. The SSCL also provides an opportunity to change the mistaken impressions about science and scientists that have resulted in fewer students pursuing careers in fields related to science. In addition, it will serve as a catalyst to help people understand the roles that scientific thought and inquiry can play in bettering their lives and the lives of their offspring. Recognizing this problem in our society, the creators of the SSC Laboratory made a commitment to use the SSC to improve science education. Consequently, in addition to building the world's premier high-energy physics laboratory, the SSCL has a second goal: creation of a major national and international educational resource. To achieve the latter goal, the Education Office of the SSCL is charged with using the resources of the Laboratory, both during construction and during operation, to improve education in science and mathematics at all levels (prekindergarten through post-doctorate) and for all components of our society (including the general public), in the United States and around the world

  19. SSC lattice database and graphical interface

    International Nuclear Information System (INIS)

    Trahern, C.G.; Zhou, J.

    1991-11-01

    When completed the Superconducting Super Collider will be the world's largest accelerator complex. In order to build this system on schedule, the use of database technologies will be essential. In this paper we discuss one of the database efforts underway at the SSC, the lattice database. The SSC lattice database provides a centralized source for the design of each major component of the accelerator complex. This includes the two collider rings, the High Energy Booster, Medium Energy Booster, Low Energy Booster, and the LINAC as well as transfer and test beam lines. These designs have been created using a menagerie of programs such as SYNCH, DIMAD, MAD, TRANSPORT, MAGIC, TRACE3D AND TEAPOT. However, once a design has been completed, it is entered into a uniform database schema in the database system. In this paper we discuss the reasons for creating the lattice database and its implementation via the commercial database system SYBASE. Each lattice in the lattice database is composed of a set of tables whose data structure can describe any of the SSC accelerator lattices. In order to allow the user community access to the databases, a programmatic interface known as dbsf (for database to several formats) has been written. Dbsf creates ascii input files appropriate to the above mentioned accelerator design programs. In addition it has a binary dataset output using the Self Describing Standard data discipline provided with the Integrated Scientific Tool Kit software tools. Finally we discuss the graphical interfaces to the lattice database. The primary interface, known as OZ, is a simulation environment as well as a database browser

  20. Puerarin Suppresses the Self-Renewal of Murine Embryonic Stem Cells by Inhibition of REST-MiR-21 Regulatory Pathway.

    Science.gov (United States)

    Yin, Mengmeng; Yuan, Yin; Cui, Yurong; Hong, Xian; Luo, Hongyan; Hu, Xinwu; Tang, Ming; Hescheler, Jurgen; Xi, Jiaoya

    2015-01-01

    Puerarin shows a wide range of biological activities, including affecting the cardiac differentiation from murine embryonic stem (mES) cells. However, little is known about its effect and mechanism of action on the self-renewal of mES cells. This study aimed to determine the effect of puerarin on the self-renewal and pluripotency of mES cells and its underlying mechanisms. RT-PCR and real-time PCR were used to detect the transcripts of core transcription factors, specific markers for multiple lineages, REST and microRNA-21 (miR-21). Colony-forming assay was performed to estimate the self-renewal capacity of mES cells. Western blotting and wortmannin were employed to explore the role of PI3K/Akt signaling pathway in the inhibitory action of puerarin on REST transcript. Transfected mES cells with antagomir21 were used to confirm the role of miR-21 in the action of puerarin on cell self-renewal. Puerarin significantly decreased the percentage of the self-renewal colonies, and suppressed the transcripts of Oct4, Nanog, Sox2, c-Myc and REST. Besides, PECAM, NCAM and miR-21 were up-regulated both under the self-renewal conditions and at day 4 of differentiation. The PI3K inhibitor wortmannin successfully reversed the mRNA expression changes of REST, Nanog and Sox2. Transfection of antagomir21 efficiently reversed the effects of puerarin on mES cells self-renewal. Inhibition of REST-miR-21 regulatory pathway may be the key mechanism of puerarin-induced suppression of mES cells self-renewal.

  1. SSC collider dipole magnet end mechanical design

    International Nuclear Information System (INIS)

    Delchamps, S.W.; Bossert, R.C.; Carson, J.; Ewald, K.; Fulton, H.; Kerby, J.; Koska, W.; Strait, J.; Wake, S.M.; Leung, K.K.

    1991-05-01

    This paper describes the mechanical design of the ends of Superconducting Super Collider dipole magnets to be constructed and tested at Fermilab. Coil end clamps, end yoke configuration, and end plate design are discussed. Loading of the end plate by axial Lorentz forces is discussed. Relevant data from 40 mm and 50 mm aperture model dipole magnets built and tested at Fermilab are presented. In particular, the apparent influence of end clamp design on the quench behavior of model SSC dipoles is described. 8 refs., 3 figs

  2. Report of the Ad Hoc Committee on SSC physics

    International Nuclear Information System (INIS)

    1990-04-01

    The Ad Hoc Committee on SSC Physics has reexamined the relationship between beam energy, machine luminosity, and physics capability. In the next section, the physics motivation for the SSC is reviewed in general terms. This is followed by a discussion of the ability to detect a number of specific processes as a function of the SSC energy and luminosity. The viability of various detector technologies is then assessed as a function of luminosity. The report ends with a brief summary and some conclusions

  3. Parameter selection for the SSC trade-offs and optimization

    International Nuclear Information System (INIS)

    Edwards, D.A.; Syphers, M.J.

    1991-01-01

    In November of 1988, a site was selected in the state of Texas for the SSC. In January of 1989, the SSC Laboratory was established in Texas to adapt the design of the collider to the site and to manage the construction of the project. This paper describes the evolution of the SSC design since site selection, notes the increased concentration on the injector system, and addresses the rationale for choice of parameters

  4. Measurements of ground motion and SSC dipole vibrations

    International Nuclear Information System (INIS)

    Parkhomchuk, V.V.; Shiltsev, V.D.; Weaver, H.J.

    1993-06-01

    The results of seismic ground measurements at the Superconducting Super Collider (SSC) site and investigations of vibrational properties of superconducting dipoles for the SSC are presented. Spectral analysis of the data obtained in the large frequency band from 0.05 Hz to 2000 Hz is done. Resonant behavior and the dipole-to-ground transform ratio are investigated. The influence of measured vibrations on SSC operations is considered

  5. The C. elegans engrailed homolog ceh-16 regulates the self-renewal expansion division of stem cell-like seam cells.

    Science.gov (United States)

    Huang, Xinxin; Tian, E; Xu, Yanhua; Zhang, Hong

    2009-09-15

    Stem cells undergo symmetric and asymmetric division to maintain the dynamic equilibrium of the stem cell pool and also to generate a variety of differentiated cells. The homeostatic mechanism controlling the choice between self-renewal and differentiation of stem cells is poorly understood. We show here that ceh-16, encoding the C. elegans ortholog of the transcription factor Engrailed, controls symmetric and asymmetric division of stem cell-like seam cells. Loss of function of ceh-16 causes certain seam cells, which normally undergo symmetric self-renewal expansion division with both daughters adopting the seam cell fate, to divide asymmetrically with only one daughter retaining the seam cell fate. The human engrailed homolog En2 functionally substitutes the role of ceh-16 in promoting self-renewal expansion division of seam cells. Loss of function of apr-1, encoding the C. elegans homolog of the Wnt signaling component APC, results in transformation of self-renewal maintenance seam cell division to self-renewal expansion division, leading to seam cell hyperplasia. The apr-1 mutation suppresses the seam cell division defect in ceh-16 mutants. Our study reveals that ceh-16 interacts with the Wnt signaling pathway to control the choice between self-renewal expansion and maintenance division and also demonstrates an evolutionarily conserved function of engrailed in promoting cell proliferation.

  6. SOX2 plays a critical role in EGFR-mediated self-renewal of human prostate cancer stem-like cells.

    Science.gov (United States)

    Rybak, Adrian P; Tang, Damu

    2013-12-01

    SOX2 is an essential transcription factor for stem cells and plays a role in tumorigenesis, however its role in prostate cancer stem cells (PCSCs) remains unclear. We report here a significant upregulation of SOX2 at both mRNA and protein levels in DU145 PCSCs propagated as suspension spheres in vitro. The expression of SOX2 in DU145 PCSCs is positively regulated by epidermal growth factor receptor (EGFR) signaling. Activation of EGFR signaling, following the addition of epidermal growth factor (EGF) or ectopic expression of a constitutively-active EGFR mutant (EGFRvIII), increased SOX2 expression and the self-renewal of DU145 PCSCs. Conversely, a small molecule EGFR inhibitor (AG1478) blocked EGFR activation, reduced SOX2 expression and inhibited PCSC self-renewal activity, implicating SOX2 in mediating EGFR-dependent self-renewal of PCSCs. In line with this notion, ectopic SOX2 expression enhanced EGF-induced self-renewal of DU145 PCSCs, while SOX2 knockdown reduced PCSC self-renewal with EGF treatment no longer capable of enhancing their propagation. Furthermore, SOX2 knockdown reduced the capacity of DU145 PCSCs to grow under anchorage-independent conditions. Finally, DU145 PCSCs generated xenograft tumors more aggressively with elevated levels of SOX2 expression compared to xenograft tumors derived from non-PCSCs. Collectively, we provide evidence that SOX2 plays a critical role in EGFR-mediated self-renewal of DU145 PCSCs. © 2013.

  7. Control of germline stem cell self-renewal and differentiation in the Drosophila ovary: concerted actions of niche signals and intrinsic factors.

    Science.gov (United States)

    Xie, Ting

    2013-01-01

    In the Drosophila ovary, germline stem cells (GSCs) physically interact with their niche composed of terminal filament cells, cap cells, and possibly GSC-contacting escort cells (ECs). A GSC divides to generate a self-renewing stem cell that remains in the niche and a differentiating daughter that moves away from the niche. The GSC niche provides a bone morphogenetic protein (BMP) signal that maintains GSC self-renewal by preventing stem cell differentiation via repression of the differentiation-promoting gene bag of marbles (bam). In addition, it expresses E-cadherin, which mediates cell adhesion for anchoring GSCs in the niche, enabling continuous self-renewal. GSCs themselves also express different classes of intrinsic factors, including signal transducers, transcription factors, chromatin remodeling factors, translation regulators, and miRNAs, which control self-renewal by strengthening interactions with the niche and repressing various differentiation pathways. Differentiated GSC daughters, known as cystoblasts (CBs), also express distinct classes of intrinsic factors to inhibit self-renewal and promote germ cell differentiation. Surprisingly, GSC progeny are also dependent on their surrounding ECs for proper differentiation at least partly by preventing BMP from diffusing to the differentiated germ cell zone and by repressing ectopic BMP expression. Therefore, both GSC self-renewal and CB differentiation are controlled by collaborative actions of extrinsic signals and intrinsic factors. Copyright © 2012 Wiley Periodicals, Inc.

  8. Promyelocytic leukaemia zinc finger maintains self-renewal of male germline stem cells (mGSCs) and its expression pattern in dairy goat testis.

    Science.gov (United States)

    Song, W; Zhu, H; Li, M; Li, N; Wu, J; Mu, H; Yao, X; Han, W; Liu, W; Hua, J

    2013-08-01

    Previous studies have shown that promyelocytic leukaemia zinc finger (PLZF) is a spermatogonia-specific transcription factor in the testis, required to regulate self-renewal and maintenance of the spermatogonia stem cell. Up to now, expression and function of PLZF in the goat testis has not been known. The objectives of this study were to investigate PLZF expression pattern in the dairy goat and its effect on male goat germline stem cell (mGSC) self-renewal and differentiation. Testis development and expression patterns of PLZF in the dairy goat were analysed by haematoxylin and eosin staining, immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, effects of PLZF overexpression on mGSC self-renewal and differentiation were evaluated by quantitative RT-PCR (QRT-PCR), immunofluorescence and BrdU incorporation assay. Promyelocytic leukaemia zinc finger was essential for dairy goat testis development and expression of several proliferation and pluripotency-associated proteins including OCT4, C-MYC were upregulated by PLZF overexpression. The study demonstrated that PLZF played a key role in maintaining self-renewal of mGSCs and its overexpression enhanced expression of proliferation-associated genes. Promyelocytic leukaemia zinc finger could function in the dairy goat as well as in other species in maintaining self-renewal of germline stem cells and this study provides a model to study the mechanism on self-renewal and differentiation of mGSCs in livestock. © 2013 John Wiley & Sons Ltd.

  9. Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes.

    Science.gov (United States)

    Zhao, Jingyao; Chen, Xufeng; Song, Guangrong; Zhang, Jiali; Liu, Haifeng; Liu, Xiaolong

    2017-01-10

    Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the HSC pool, leading to hematopoietic failure and lethality. Uhrf1-deficient HSCs display normal survival and proliferation, yet undergo erythroid-biased differentiation at the expense of self-renewal capacity. Notably, Uhrf1 is required for the establishment of DNA methylation patterns of erythroid-specific genes during HSC division. The expression of these genes is enhanced in the absence of Uhrf1, which disrupts the HSC-division modes by promoting the symmetric differentiation and suppressing the symmetric self-renewal. Moreover, overexpression of one of the up-regulated genes, Gata1, in HSCs is sufficient to phenocopy Uhrf1-deficient HSCs, which show impaired HSC symmetric self-renewal and increased differentiation commitment. Taken together, our findings suggest that Uhrf1 controls the self-renewal versus differentiation of HSC through epigenetically regulating the cell-division modes, thus providing unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision.

  10. Uses of the chiral Lagrangian at the SSC

    International Nuclear Information System (INIS)

    Dawson, S.

    1992-09-01

    In the event that the SSC does not observe any resonances such as a Higgs boson or a techni-rho meson, we would like to know if the SSC can still discover something about the nature of the electroweak symmetry breaking. In particular, we consider the question of whether there is a ''no-lose'' corollary at the SSC. We will use chiral Lagrangian techniques to address this question and analyze their utility for studying events containing W and Z gauge bosons at the SSC

  11. Full length prototype SSC dipole test results

    International Nuclear Information System (INIS)

    Strait, J.; Brown, B.C.; Carson, J.

    1987-01-01

    Results are presented from tests of the first full length prototype SSC dipole magnet. The cryogenic behavior of the magnet during a slow cooldown to 4.5K and a slow warmup to room temperature has been measured. Magnetic field quality was measured at currents up to 2000 A. Averaged over the body field all harmonics with the exception of b 2 and b 8 are at or within the tolerances specified by the SSC Central Design Group. (The values of b 2 and b 8 result from known design and construction defects which will be be corrected in later magnets.) Using an NMR probe the average body field strength is measured to be 10.283 G/A with point to point variations on the order of one part in 1000. Data are presented on quench behavior of the magnet up to 3500 A (approximately 55% of full field) including longitudinal and transverse velocities for the first 250 msec of the quench

  12. Scintillating fiber detection development for the SSC

    International Nuclear Information System (INIS)

    Ruchti, R.

    1993-01-01

    SSC Detector Program at Notre Dame has been concentrating on the development of scintillating fiber detectors for tracking applications. Initial work has focused on the development of new scintillation materials for micro-tracking and central tracking detectors based on organic plastics and liquids, This effort has included studies of solvents, solutes and waveguides. Techniques capable of providing the detection of single photons from fibers, are also being developed, leading to a collaboration with Rockwell, UCLA, and UTexas-Dallas groups on the development and application of the Solid State Photomultiplier (SSPM). This initial collaboration has been strengthened and expanded to the formation of a larger collaboration whose goal is to develop a fiber tracking subsystem for SSC, incorporating scintillating fibers and solid state photodetectors. The major subsystem proposal submitted to SSCL by this new collaboration, known at the Fiber Tracking Group (FTG), has been approved and funding is being put in place. The collaboration consists of 12 institutions and Notre Dame is a spokesman group

  13. Preserving SSC Design Function Using RCM Principles

    International Nuclear Information System (INIS)

    Mohammadi, K.

    2009-01-01

    Reliability-Centered Maintenance (RCM) can be defined as an approach that employs preventive, predictive, proactive, and reactive maintenance practices and strategies in an integrated manner to increase the probability that a Structure, System, or Component (SSC) will function as designed over its life cycle with optimum maintenance. The goal of RCM is to preserve the SSC intended design function at the lowest cost by developing a maintenance strategy that is supported by sound technical and economic justification. RCM has been used extensively by the aircraft, space, defense, power generation, and manufacturing industries where functional failures of SSCs can have the potential to compromise worker or public safety, cause adverse environmental impact, cause loss of production, and/or result in excessive damage to critical SSCs. This paper provides a framework for performing an RCM analysis in support of DOE Order 430.1A (Life Cycle Asset Management) and DOE Order 420.1B (Facility Safety). The influence of RCM on the various aspects of the maintenance program including the work control process is also discussed

  14. An alternate end design for SSC dipoles

    International Nuclear Information System (INIS)

    Peters, C.; Caspi, S.; Taylor, C.

    1989-02-01

    Experience in the SSC dipole program has shown that fabrication of cylindrical coil ends is difficult. Cable stiffness requires large forces to maintain the proper position of the conductors in the end during winding. After winding, the coil ends remain distorted nd significant motion of the need conductors is required to force the coil end into the molding cavity. Local mechanical stresses are high during this process and extra pieces of insulation are required to prevent turn-to-turn shorts from developing during the winding and molding steps. Prior to assembly the coil end is compressed in a mold cavity and injected with a filler material to correct surface irregularities and fill voids in the end. LBL has developed an alternate design which permits the conductors to be wound over the end using minimal force and technician coerosion. The conductors are placed on a conical surface where the largest diameter over the outer layer conductors is 10 cm. No coil end spaces or insulation pieces between turns are required. The conductor geometry was analytically optimized to meet SSC multipole requirements for the ends. The first 1-m dipole utilizing this end geometry has been constructed and successfully tested. Design and construction data are presented. Also model test results, including training and multipole measurements of the end are given. 1 ref., 12 figs., 3 tabs

  15. Overexpression of HOXA4 and HOXA9 genes promotes self-renewal and contributes to colon cancer stem cell overpopulation.

    Science.gov (United States)

    Bhatlekar, Seema; Viswanathan, Vignesh; Fields, Jeremy Z; Boman, Bruce M

    2018-02-01

    Because HOX genes encode master regulatory transcription factors that regulate stem cells (SCs) during development and aberrant expression of HOX genes occurs in various cancers, our goal was to determine if dysregulation of HOX genes is involved in the SC origin of colorectal cancer (CRC). We previously reported that HOXA4 and HOXD10 are expressed in the colonic SC niche and are overexpressed in CRC. HOX gene expression was studied in SCs from human colon tissue and CRC cells (CSCs) using qPCR and immunostaining. siRNA-mediated knockdown of HOX expression was used to evaluate the role of HOX genes in modulating cancer SC (CSC) phenotype at the level of proliferation, SC marker expression, and sphere formation. All-trans-retinoic-acid (ATRA), a differentiation-inducing agent was evaluated for its effects on HOX expression and CSC growth. We found that HOXA4 and HOXA9 are up-regulated in CRC SCs. siRNA knockdown of HOXA4 and HOXA9 reduced: (i) proliferation and sphere-formation and (ii) gene expression of known SC markers (ALDH1, CD166, LGR5). These results indicate that proliferation and self-renewal ability of CRC SCs are reduced in HOXA4 and HOXA9 knockdown cells. ATRA decreased HOXA4, HOXA9, and HOXD10 expression in parallel with reduction in ALDH1 expression, self-renewal, and proliferation. Overall, our findings indicate that overexpression of HOXA4 and HOXA9 contributes to self-renewal and overpopulation of SCs in CRC. Strategies designed to modulate HOX expression may provide ways to target malignant SCs and to develop more effective therapies for CRC. © 2017 Wiley Periodicals, Inc.

  16. The adult spinal cord harbors a population of GFAP-positive progenitors with limited self-renewal potential.

    Science.gov (United States)

    Fiorelli, Roberto; Cebrian-Silla, Arantxa; Garcia-Verdugo, Jose-Manuel; Raineteau, Olivier

    2013-12-01

    Adult neural stem cells (aNSCs) of the forebrain are GFAP-expressing cells that are intercalated within ependymal cells of the subventricular zone (SVZ). Cells showing NSCs characteristics in vitro can also be isolated from the periaqueductal region in the adult spinal cord (SC), but contradicting results exist concerning their glial versus ependymal identity. We used an inducible transgenic mouse line (hGFAP-CreERT2) to conditionally label GFAP-expressing cells in the adult SVZ and SC periaqueduct, and directly and systematically compared their self-renewal and multipotential properties in vitro. We demonstrate that a population of GFAP(+) cells that share the morphology and the antigenic properties of SVZ-NSCs mostly reside in the dorsal aspect of the central canal (CC) throughout the spinal cord. These cells are non-proliferative in the intact spinal cord, but incorporate the S-phase marker EdU following spinal cord injury. Multipotent, clonal YFP-expressing neurospheres (i.e., deriving from recombined GFAP-expressing cells) were successfully obtained from both the intact and injured spinal cord. These spheres however showed limited self-renewal properties when compared with SVZ-neurospheres, even after spinal cord injury. Altogether, these results demonstrate that significant differences exist in NSCs lineages between neurogenic and non-neurogenic regions of the adult CNS. Thus, although we confirm that a population of multipotent GFAP(+) cells co-exists alongside with multipotent ependymal cells within the adult SC, we identify these cells as multipotent progenitors showing limited self-renewal properties. Copyright © 2013 Wiley Periodicals, Inc.

  17. Effects of the Endocrine-Disrupting Chemical DDT on Self-Renewal and Differentiation of Human Mesenchymal Stem Cells

    Science.gov (United States)

    Strong, Amy L.; Shi, Zhenzhen; Strong, Michael J.; Miller, David F.B.; Rusch, Douglas B.; Buechlein, Aaron M.; Flemington, Erik K.; McLachlan, John A.; Nephew, Kenneth P.

    2014-01-01

    Background: Although the global use of the endocrine-disrupting chemical DDT has decreased, its persistence in the environment has resulted in continued human exposure. Accumulating evidence suggests that DDT exposure has long-term adverse effects on development, yet the impact on growth and differentiation of adult stem cells remains unclear. Objectives: Human mesenchymal stem cells (MSCs) exposed to DDT were used to evaluate the impact on stem cell biology. Methods: We assessed DDT-treated MSCs for self-renewal, proliferation, and differentiation potential. Whole genome RNA sequencing was performed to assess gene expression in DDT-treated MSCs. Results: MSCs exposed to DDT formed fewer colonies, suggesting a reduction in self-renewal potential. DDT enhanced both adipogenic and osteogenic differentiation, which was confirmed by increased mRNA expression of glucose transporter type 4 (GLUT4), lipoprotein lipase (LpL), peroxisome proliferator-activated receptor gamma (PPARγ), leptin, osteonectin, core binding factor 1 (CBFA1), and FBJ murine osteosarcoma viral oncogene homolog (c-Fos). Expression of factors in DDT-treated cells was similar to that in estrogen-treated MSCs, suggesting that DDT may function via the estrogen receptor (ER)-mediated pathway. The coadministration of ICI 182,780 blocked the effects of DDT. RNA sequencing revealed 121 genes and noncoding RNAs to be differentially expressed in DDT-treated MSCs compared with controls cells. Conclusion: Human MSCs provide a powerful biological system to investigate and identify the molecular mechanisms underlying the effects of environmental agents on stem cells and human health. MSCs exposed to DDT demonstrated profound alterations in self-renewal, proliferation, differentiation, and gene expression, which may partially explain the homeostatic imbalance and increased cancer incidence among those exposed to long-term EDCs. Citation: Strong AL, Shi Z, Strong MJ, Miller DF, Rusch DB, Buechlein AM, Flemington EK

  18. Test of the hypothesis; a lymphoma stem cells exist which is capable of self-renewal

    DEFF Research Database (Denmark)

    Kjeldsen, Malene Krag

      Test of the hypothesis; a lymphoma stem cell exist which is capable of self-renewal   Malene Krag Pedersen, Karen Dybkaer, Hans E. Johnsen   The Research Laboratory, Department of Haematology, Aalborg Hospital, Århus University   Failure of current therapeutics in the treatment of diffuse large B...... and sustaining cells(1-3). My project is based on studies of stem and early progenitor cells in lymphoid cell lines from patients with advanced DLBCL. The cell lines are world wide recognised and generously provided by Dr. Hans Messner and colleagues.   Hypothesis and aims: A lymphoma stem and progenitor cell...

  19. Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations.

    Directory of Open Access Journals (Sweden)

    Michiya Sugimori

    Full Text Available Accumulating evidence indicates that cancer stem cells (CSCs drive tumorigenesis. This suggests that CSCs should make ideal therapeutic targets. However, because CSC populations in tumors appear heterogeneous, it remains unclear how CSCs might be effectively targeted. To investigate the mechanisms by which CSC populations maintain heterogeneity during self-renewal, we established a glioma sphere (GS forming model, to generate a population in which glioma stem cells (GSCs become enriched. We hypothesized, based on the clonal evolution concept, that with each passage in culture, heterogeneous clonal sublines of GSs are generated that progressively show increased proliferative ability.To test this hypothesis, we determined whether, with each passage, glioma neurosphere culture generated from four different glioma cell lines become progressively proliferative (i.e., enriched in large spheres. Rather than monitoring self-renewal, we measured heterogeneity based on neurosphere clone sizes (#cells/clone. Log-log plots of distributions of clone sizes yielded a good fit (r>0.90 to a straight line (log(% total clones = k*log(#cells/clone indicating that the system follows a power-law (y = xk with a specific degree exponent (k = -1.42. Repeated passaging of the total GS population showed that the same power-law was maintained over six passages (CV = -1.01 to -1.17. Surprisingly, passage of either isolated small or large subclones generated fully heterogeneous populations that retained the original power-law-dependent heterogeneity. The anti-GSC agent Temozolomide, which is well known as a standard therapy for glioblastoma multiforme (GBM, suppressed the self-renewal of clones, but it never disrupted the power-law behavior of a GS population.Although the data above did not support the stated hypothesis, they did strongly suggest a novel mechanism that underlies CSC heterogeneity. They indicate that power-law growth governs the self-renewal of heterogeneous

  20. A Complex Role for FGF-2 in Self-Renewal, Survival, and Adhesion of Human Embryonic Stem Cells

    Czech Academy of Sciences Publication Activity Database

    Eiselleová, L.; Matulka, K.; Kříž, V.; Kunová, M.; Schmidtová, Z.; Neradil, J.; Tichý, B.; Dvořáková, D.; Pospíšilová, Š.; Hampl, Aleš; Dvořák, Petr

    2009-01-01

    Roč. 27, č. 8 (2009), s. 1847-1857 ISSN 1066-5099 Grant - others:GA MŠk(CZ) 1M0538; GA MŠk(CZ) LC06077; EC FP6(XE) LSHG-CT-2006-018739 Program:1M; LC Institutional research plan: CEZ:AV0Z50390512; CEZ:AV0Z50390703 Keywords : fibroblast growth factor-2 * human ESCs * self-renewal Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.747, year: 2009

  1. Loss of quiescence and self-renewal capacity of hematopoietic stem cell in an in vitro leukemic niche.

    Science.gov (United States)

    Vanegas, Natalia-Del Pilar; Vernot, Jean-Paul

    2017-01-01

    Leukemic and mesenchymal stem cells interact in the leukemic microenvironment and affect each other differently. This interplay has also important implications for the hematopoietic stem cell (HSC) biology and function. This study evaluated human HSC self-renewal potential and quiescence in an in vitro leukemic niche without leukemic cells. A leukemic niche was established by co-culturing mesenchymal stem cells with a fresh conditioned medium obtained from a leukemic (REH) cell line. After 3 days, the REH-conditioned medium was removed and freshly isolated CD34+ at a density of up to 100,000 cells/ml were added to the leukemic niche. CD34+ cell evaluations (cell cycle, self-renewal gene expression and migration capacity) were performed after 3 further days of co-culture. Additionally, we preliminary investigated the soluble factors present in the leukemic niche and their effect on the mesenchymal stem cells. Statistical significance was assessed by Student's t test or the nonparametric test Kolmogorov-Smirnov. By co-culturing normal mesenchymal stem cells with the REH-conditioned medium we showed that hematopoietic stem cells, normally in a quiescent state, enter cell cycle and proliferate. This loss of quiescence was accompanied by an increased expression of Ki-67 and c-Myc, two well-known cell proliferation-associated markers. Two central regulators of quiescence GATA2 and p53 were also down regulated. Importantly, two genes involved in HSC self-renewal, Klf4 and the histone-lysine N -methyltransferase enzyme Ezh2, were severely affected. On the contrary, c-Kit expression, the stem cell factor receptor, was upregulated in hematopoietic stem cells when compared to the normal niche. Interestingly, mesenchymal stem cells incubated with the REH-conditioned medium stopped growing, showed a flattened morphology with the appearance of small vacuoles, and importantly, became positive for the senescence-associated beta-galactosidase activity. Evaluation of the leukemic

  2. The Hippo pathway: key interaction and catalytic domains in organ growth control, stem cell self-renewal and tissue regeneration.

    Science.gov (United States)

    Cherrett, Claire; Furutani-Seiki, Makoto; Bagby, Stefan

    2012-01-01

    The Hippo pathway is a conserved pathway that interconnects with several other pathways to regulate organ growth, tissue homoeostasis and regeneration, and stem cell self-renewal. This pathway is unique in its capacity to orchestrate multiple processes, from sensing to execution, necessary for organ expansion. Activation of the Hippo pathway core kinase cassette leads to cytoplasmic sequestration of the nuclear effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), consequently disabling their transcriptional co-activation function. Components upstream of the core kinase cassette have not been well understood, especially in vertebrates, but are gradually being elucidated and include cell polarity and cell adhesion proteins.

  3. Heat shock instructs hESCs to exit from the self-renewal program through negative regulation of OCT4 by SAPK/JNK and HSF1 pathway.

    Science.gov (United States)

    Byun, Kyunghee; Kim, Taek-Kyun; Oh, Jeehyun; Bayarsaikhan, Enkhjargal; Kim, Daesik; Lee, Min Young; Pack, Chan-Gi; Hwang, Daehee; Lee, Bonghee

    2013-11-01

    Environmental factors affect self-renewal of stem cells by modulating the components of self-renewal networks. Heat shock, an environmental factor, induces heat shock factors (HSFs), which up-regulate stress response-related genes. However, the link of heat shock to self-renewal of stem cells has not been elucidated yet. Here, we present the direct link of heat shock to a core stem cell regulator, OCT4, in the self-renewal network through SAPK/JNK and HSF1 pathway. We first showed that heat shock initiated differentiation of human embryonic stem cells (hESCs). Gene expression analysis revealed that heat shock increased the expression of many genes involved in cellular processes related to differentiation of stem cells. We then examined the effects of HSFs induced by heat shock on core self-renewal factors. Among HSFs, heat shock induced mainly HSF1 in hESCs. The HSF1 repressed the expression of OCT4, leading to the differentiation of hESCs and the above differentiation-related gene expression change. We further examined the effects of the upstream MAP (mitogen-activated protein) kinases of HSF1 on the repression of OCT4 expression by HSF1. Among the MAP kinases, SAPK/JNK controlled predominantly the repression of the OCT4 expression by HSF1. The direct link of heat shock to the core self-renewal regulator through SAPK/JNK and HSF1 provides a fundamental basis for understanding the effect of heat and other stresses involving activation of HSF1 on the self-renewal program and further controlling differentiation of hESCs in a broad spectrum of stem cell applications using these stresses. © 2013.

  4. Dicty_cDB: SSC534 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available SS (Link to library) SSC534 (Link to dictyBase) - - - Contig-U13922-1 SSC534Z (Link... to Original site) - - SSC534Z 711 - - - - Show SSC534 Library SS (Link to library) Clone ID SSC534 (Link to dic... 1.3 FM992688_1247( FM992688 |pid:none) Candida dubliniensis CD36 chrom... 35 3.0 EU565733_1( EU565733 |pid:none) Unculture... 20.0 %: nuclear 16.0 %: vesicles of secretory system 12.0 %: mitochondrial 8.0 %: Golgi 8.0 %: endoplasmic reticul...kholderia multivorans ATCC 1... 33 6.6 AM260479_1383( AM260479 |pid:none) Ralstonia e

  5. Dicty_cDB: SSC538 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available SS (Link to library) SSC538 (Link to dictyBase) - - - Contig-U13922-1 SSC538Z (Link... to Original site) - - SSC538Z 712 - - - - Show SSC538 Library SS (Link to library) Clone ID SSC538 (Link to dic...SHR34... 36 1.3 FM992688_1247( FM992688 |pid:none) Candida dubliniensis CD36 chrom... 35 3.0 EU565733_1( EU565733 |pid:none) Uncultur...9385_2728( AP009385 |pid:none) Burkholderia multivorans ATCC 1... 33 6.6 AM260479_1383( AM260479 |pid:none) ... reticulum 4.0 %: extracellular, including cell wall 4.0 %: cytoskeletal 4.0 %: vacu

  6. SSC [Superconducting Super Collider] magnet technology

    International Nuclear Information System (INIS)

    Taylor, C.

    1987-09-01

    To minimize cost of the SSC facility, small-bore high field dipole magnets have been developed;some of the new technology that has been developed at several U.S. national laboratories and in industry is summarized. Superconducting wire with high J/sub c/ and filaments as small as 5μm diameter is not produced iwht mechanical properties suitable for reliable cable production. A variety of collar designs of both aluminum and stainless steel have been used in model magnets. A low-heat leak post-type cryostat support system is used and a system for accurate alignment of coil-collar-yoke in the cryostat has been developed. Model magnets of 1-m, 1.8 m, 4.5 m, and 17 m lengths have been build during the past two years. 23 refs., 5 figs., 2 tabs

  7. SSC physics signatures and trigger requirements

    International Nuclear Information System (INIS)

    1985-01-01

    Strategies are considered for triggering on new physics processes on the environment of the SSC, where interaction rates will be very high and most new physics processes quite rare. The quantities available for use in the trigger at various levels are related to the signatures of possible new physics. Two examples were investigated in some detail using the ISAJET Monte Carlo program: Higgs decays to W pairs and a missing energy trigger applied to gluino pair production. In both of the examples studied in detail, it was found that workable strategies for reducing the trigger rate were obtainable which also produced acceptable efficiency for the processes of interest. In future work, it will be necessary to carry out such a program for the full spectrum of suggested new physics

  8. SSC [Superconducting Super Collider] magnet mechanical interconnections

    International Nuclear Information System (INIS)

    Bossert, R.C.; Niemann, R.C.; Carson, J.A.; Ramstein, W.L.; Reynolds, M.P.; Engler, N.H.

    1989-03-01

    Installation of superconducting accelerator dipole and quadrupole magnets and spool pieces in the SSC tunnel requires the interconnection of the cryostats. The connections are both of an electrical and mechanical nature. The details of the mechanical connections are presented. The connections include piping, thermal shields and insulation. There are seven piping systems to be connected. These systems must carry cryogenic fluids at various pressures or maintain vacuum and must be consistently leak tight. The interconnection region must be able to expand and contract as magnets change in length while cooling and warming. The heat leak characteristics of the interconnection region must be comparable to that of the body of the magnet. Rapid assembly and disassembly is required. The magnet cryostat development program is discussed. Results of quality control testing are reported. Results of making full scale interconnections under magnet test situations are reviewed. 11 figs., 4 tabs

  9. Integrated design of the SSC linac injector

    International Nuclear Information System (INIS)

    Evans, D.; Valiecnti, R.; Wood, F.

    1992-01-01

    The Ion Source, Low Energy Beam Transport (LEBT), and Radio Frequency Quadrupole (RFQ) of the Superconducting Super Collider (SSC) Linac act as a unit (referred to as the Linac Injector), the Ion Source and LEBT being cantilevered off of the RFQ. Immediately adjacent to both ends of the RFQ cavity proper are endwall chambers containing beam instrumentation and independently-operated vacuum isolation valves. The Linac Injector delivers 30 mA of H - beam at 2.5 MeV. This paper describes the design constraints imposed on the endwalls, aspects of the integration of the Ion Source and LEBT including attachment to the RFQ, maintainability and interchangeability of LEBTs, vacuum systems for each component, and the design of necessary support structure. (Author) 2 tab

  10. Closed orbit correction in the SSC

    International Nuclear Information System (INIS)

    Bourianoff, G.; Cole, B.; Ferede, H.; Pilat, F.

    1991-01-01

    Most of the techniques associated with closed orbit correction are widely known. The present paper gives a brief description of one such method and discusses the results obtained when it is applied to the SSC collider lattice. The emphasis is on features of the lattice which effect closed orbit correction and it is likely that any of the 8 methods cataloged in a cited reference would yield similar results. The global scheme described here is very robust and easy to apply. The results of three separate studies are briefly described. Typical results for the residual RMS closed orbit in the arc is calculated to be 0.65 mm with peak values of 3 mm

  11. GIS/FIS development for the SSC

    International Nuclear Information System (INIS)

    Oslin, A.; Butalla, M.

    1992-01-01

    Facility management for a project of the size and complexity of the SSCL is a challenging task. The Facility Information System/Geographic Information System (FIS/GIS) should provide an effective tool for the demanding work ahead. Both the FIS and GIS encompass information that many potential users across multiple disciplines will require for effective facility management. FIS will be integrated with the GIS for applications that involve duplicate needs of graphic and attribute data. In particular, infrastructure networks, environmental monitoring, emergency dispatching, and hazardous materials management have been identified as areas where the two systems will interface. In general, the GIS will manage graphic and attribute information outside the actual structure of the SSCL. The FIS will take over operation of components and networks within the SSCL facility. By providing a method for informed decision-making, implementation of the SSC FIS/GIS will facilitate the tasks involved in managing our Laboratory during all phases of its life

  12. The SSC full cell prototype string test

    International Nuclear Information System (INIS)

    Kraushaar, P.; Burgett, W.; Cromer, L.

    1994-11-01

    At the conclusion of the SSC half cell magnet string testing program. In February, 1993, the preliminary data analysis revealed that several substantive technical questions remained unresolved. These questions were: (1) could the high voltages to ground (>2 kV) measured during fault (quench) conditions be substantially reduced, (2) could the number of magnetic elements that became resistive (quenched) be controlled and (3) did the cryostats of the magnetic elements provide adequate insulation and isolation to meet designed refrigeration loads. To address these and other existing question a prototypical full cell of collider magnets (ten dipoles and two quadrupoles) was assembled and tested. At the conclusion of this testing there were definitive answers to most of the questions with numerical substantiation, the notable exception being the beat leak question. These answers and other results and issues are presented in this paper

  13. Physics requirements for LHC/SSC calorimetry

    International Nuclear Information System (INIS)

    Green, D.

    1991-10-01

    The goal of the next generation of collider detectors is to study the origin of electroweak symmetry breaking. The mass scale for this study is roughly 1 TeV. No matter what the details of the mechanism, one can be confident that new phenomena will occur, since weak interactions become strong, i.e., violate partial wave unitarity, at that mass scale. The partial wave amplitude for ee→ WW scattering is; ao∼4φ/α w (M w /M) 2 , ao∼1 if M ∼1 TeV. Therefore, the detectors for LHC/SSC must be able to confront this mass scale. In particular, the electroweak dynamics is such that the study of gauge boson pairs has a high priority. Given that the simplest decay modes for gauge boson are into leptons, the new detectors will naturally tend to optimize performance for leptons

  14. Requirements for SSC central computing staffing (conceptual)

    International Nuclear Information System (INIS)

    Pfister, J.

    1985-01-01

    Given a computation center with --10,000 MIPS supporting --1,000 users, what are the staffing requirements? The attempt in this paper is to list the functions and staff size required in a central computing or centrally supported computing complex. The organization assumes that although considerable computing power would exist (mostly for online) in the four interaction regions (IR) that there are functions/capabilities better performed outside the IR and in this model at a ''central computing facility.'' What follows is one staffing approach, not necessarily optimal, with certain assumptions about numbers of computer systems, media, networks and system controls, that is, one would get the best technology available. Thus, it is speculation about what the technology may bring and what it takes to operate it. From an end user support standpoint it is less clear, given the geography of an SSC, where and what the consulting support should look like and its location

  15. Single bunch instabilities in an SSC

    International Nuclear Information System (INIS)

    Ruth, R.D.

    1984-01-01

    In this note coherent instability thresholds are estimated for the SSC and discuss some of the subsequent design restrictions. The various instabilities are set out in a block diagram with the essential features of each. The assumption is made that long wavelength coupled bunch effects can be cured effectively by a feedback system (both longitudinal and transverse) and that the impedance of the feedback system is such as to cancel that of the environment (at low frequency). Alternatively, the long wake field is assumed to be exactly canceled, on the average, by a feedback wake field. This leaves only single bunch effects. Thresholds for fast-blowup are discussed both in the longitudinal and transverse and the transverse mode coupling instability more familiar in electron/positron storage rings is covered. The impedances considered are a broadband impedance and the resistive wall impedance

  16. 84 K nitrogen system for the SSC

    International Nuclear Information System (INIS)

    McAshan, M.; Thirumaleshwar, M.; Abramovich, S.; Ganni, V.; Scheidemantle, A.

    1992-01-01

    The nitrogen system for the Superconducting Super Collider (SSC) is designed to provide the 84 K (nominal) shield refrigeration for the collider rings. Liquid nitrogen is supplied to the collider tunnel from one, two, or more locations on the surface through the service shafts and is distributed along, the 87 km of both rings by the 84 K shield lines. Additional design requirements for the nitrogen distribution system include precooling, fluid supply to the helium plants, supplying makeup liquid nitrogen to the reservoirs located at the entrance of the main shafts, and providing an efficient cooldown means for the cold mass from 300 K to 90 K. The operational modes and possible emergency and maintenance conditions of the collider are taken into account for the nitrogen system design. The status of our work, including design considerations that address thermal aspects (heat load, recooling scheme, etc.) and hydraulic aspects (pressures, elevations, distances, etc.) of the nitrogen system will be discussed

  17. The SSC full cell prototype string test

    International Nuclear Information System (INIS)

    McInturff, A.D.; Kraushaar, P.; Burgett, W.; Cromer, L.

    1994-01-01

    At the conclusion of the SSC half cell magnet string testing program in February, 1993, the preliminary data analysis revealed that several substantive technical questions remained unresolved. These questions were: (1) could the high voltages to ground (>2 kV) measured during fault (quench) conditions be substantially reduced, (2) could the number of magnetic elements that became resistive (quenched) be controlled and 3) did the cryostats of the magnetic elements provide adequate insulation and isolation to meet designed refrigeration loads. To address these and other existing questions, a prototypical fall cell of collider magnets (ten dipoles and two quadrupoles) was assembled and tested. At the conclusion of this testing there were definitive answers to most of the questions with numerical substantiation, the notable exception being the beat leak question. These answers and other results and issues are presented in this paper

  18. Ac loss measurement of SSC dipole magnets

    International Nuclear Information System (INIS)

    Delchamps, S.; Hanft, R.; Jaffery, T.; Kinney, W.; Koska, W.; Lamm, M.J.; Mazur, P.O.; Orris, D.; Ozelis, J.P.; Strait, J.; Wake, M.

    1992-09-01

    AC losses in full length and 1.5 m model SSC collider dipoles were successfully measured by the direct observation of energy flow into and out of magnets during a ramp cycle. The measurement was performed by using two double-integrating type digital volt meters (DVM's) for current and voltage measurement. Measurements were performed for six is m long ASST magnets and five 1.5 m long model magnets, inducting one 40 mm diameter magnet. There were large variations in the eddy current losses. Since these magnets use conductors with slight deviations in their internal structures and processing of the copper surface depending on the manufacturer, it is likely that there are differences in the contact resistance between strands. Correlation between the ramp rate dependence of the,quench current and the eddy current loss was evident

  19. Radiation levels in the SSC interaction regions

    Energy Technology Data Exchange (ETDEWEB)

    Groom, D.E. [ed.

    1988-06-10

    The radiation environment in a typical SSC detector has been evaluated using the best available particle production models coupled with Monte Carlo simulations of hadronic and electromagnetic cascades. The problems studied include direct charged particle dose, dose inside a calorimeter from the cascades produced by incident photons and hadrons, the flux of neutrons and photons backscattered from the calorimeter into a central cavity, and neutron flux in the calorimeter. The luminosity lifetime at the SSC is dominated by collision losses in the interaction regions, where the luminosity is equivalent to losing an entire full-energy proton beam into the apparatus every six days. The result of an average p-p collision can be described quite simply. The mean charged multiplicity is about 110, and the particles are distributed nearly uniformly in pseudorapidity ({eta}) over all the angles of interest. The transverse momentum distribution is independent of angle, and for our purposes may be written as p{perpendicular}exp(-p{perpendicular}/{beta}). The mean value of p{perpendicular} may be as high as 0.6 GeV/c. Most of the radiation is produced by the very abundant low-p{perpendicular} particles. The dose or neutron fluence produced by individual particles in this energy region are simulated over a wide variety of conditions, and several measurements serve to confirm the simulation results. In general, the response (a dose, fluence, the number of backscattered neutrons, etc.) for an incident particle of momentum p can be parameterized in the form Np{sup {alpha}}, where 0.5 < {alpha}< 1.0. The authors believe most of their results to be accurate to within a factor of two or three, sufficiently precise to serve as the basis for detailed designs.

  20. Variance component analysis of quantitative trait loci for pork carcass composition and meat quality on SSC4 and SSC11

    NARCIS (Netherlands)

    Wijk, van H.J.; Dibbits, B.W.; Liefers, S.C.; Buschbell, H.; Harlizius, B.; Heuven, H.C.M.; Knol, E.F.; Bovenhuis, H.; Groenen, M.A.M.

    2007-01-01

    In a previous study, QTL for carcass composition and meat quality were identified in a commercial finisher cross. The main objective of the current study was to confirm and fine map the QTL on SSC4 and SSC11 by genotyping an increased number of individuals and markers and to analyze the data using a

  1. TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival.

    Science.gov (United States)

    Chavali, P L; Saini, R K R; Zhai, Q; Vizlin-Hodzic, D; Venkatabalasubramanian, S; Hayashi, A; Johansson, E; Zeng, Z-j; Mohlin, S; Påhlman, S; Hansford, L; Kaplan, D R; Funa, K

    2014-10-30

    Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity. In tumor spheres, TLX is coexpressed with the neural progenitor markers Nestin, CD133 and Oct-4. In addition, TLX is coexpressed with the migratory neural progenitor markers CD15 and matrix metalloproteinase-2 (MMP-2) in xenografts of primary NB cells from patients. Subsequently, we show the effect of TLX on the proliferative, invasive and migratory properties of IMR-32 cells. We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation. In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues. Further, the Kaplan-Meier estimator indicated a negative correlation between TLX expression and survival in 88 NB patients. Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.

  2. Distinct regulatory functions of calpain 1 and 2 during neural stem cell self-renewal and differentiation.

    Directory of Open Access Journals (Sweden)

    Daniela M Santos

    Full Text Available Calpains are calcium regulated cysteine proteases that have been described in a wide range of cellular processes, including apoptosis, migration and cell cycle regulation. In addition, calpains have been implicated in differentiation, but their impact on neural differentiation requires further investigation. Here, we addressed the role of calpain 1 and calpain 2 in neural stem cell (NSC self-renewal and differentiation. We found that calpain inhibition using either the chemical inhibitor calpeptin or the endogenous calpain inhibitor calpastatin favored differentiation of NSCs. This effect was associated with significant changes in cell cycle-related proteins and may be regulated by calcium. Interestingly, calpain 1 and calpain 2 were found to play distinct roles in NSC fate decision. Calpain 1 expression levels were higher in self-renewing NSC and decreased with differentiation, while calpain 2 increased throughout differentiation. In addition, calpain 1 silencing resulted in increased levels of both neuronal and glial markers, β-III Tubulin and glial fibrillary acidic protein (GFAP. Calpain 2 silencing elicited decreased levels of GFAP. These results support a role for calpain 1 in repressing differentiation, thus maintaining a proliferative NSC pool, and suggest that calpain 2 is involved in glial differentiation.

  3. Aldo Leopold's land health from a resilience point of view: self-renewal capacity of social-ecological systems.

    Science.gov (United States)

    Berkes, Fikret; Doubleday, Nancy C; Cumming, Graeme S

    2012-09-01

    Health approaches to ecology have a strong basis in Aldo Leopold's thinking, and contemporary ecohealth in turn has a strong philosophical basis in Leopold. To commemorate the 125th anniversary of Leopold's birth (1887-1948), we revisit his ideas, specifically the notions of stewardship (land ethic), productive use of ecosystems (land), and ecosystem renewal. We focus on Leopold's perspective on the self-renewal capacity of the land, as understood in terms of integrity and land health, from the contemporary perspective of resilience theory and ecological theory more generally. Using a broad range of literature, we explore insights and implications of Leopold's work for today's human-environment relationships (integrated social-ecological systems), concerns for biodiversity, the development of agency with respect to stewardship, and key challenges of his time and of ours. Leopold's seminal concept of land health can be seen as a triangulation of productive use, self-renewal, and stewardship, and it can be reinterpreted through the resilience lens as the health of social-ecological systems. In contemporary language, this involves the maintenance of biodiversity and ecosystem services, and the ability to exercise agency both for conservation and for environmental justice.

  4. Distinct Stromal Cell Factor Combinations Can Separately Control Hematopoietic Stem Cell Survival, Proliferation, and Self-Renewal

    Directory of Open Access Journals (Sweden)

    Stefan Wohrer

    2014-06-01

    Full Text Available Hematopoietic stem cells (HSCs are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation, and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential are variably supported by different Steel factor (SF-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings point to the molecular basis of HSC control and expansion.

  5. Evaluating the immortal strand hypothesis in cancer stem cells: symmetric/self-renewal as the relevant surrogate marker of tumorigenicity.

    Science.gov (United States)

    Winquist, Raymond J; Hall, Amy B; Eustace, Brenda K; Furey, Brinley F

    2014-09-15

    Stem cells subserve repair functions for the lifetime of the organism but, as a consequence of this responsibility, are candidate cells for accumulating numerous genetic and/or epigenetic aberrations leading to malignant transformation. However, given the importance of this guardian role, stem cells likely harbor some process for maintaining their precious genetic code such as non-random segregation of chromatid strands as predicted by the Immortal Strand Hypothesis (ISH). Discerning such non-random chromosomal segregation and asymmetric cell division in normal or cancer stem cells has been complicated by methodological shortcomings but also by differing division kinetics amongst tissues and the likelihood that both asymmetric and symmetric cell divisions, dictated by local extrinsic factors, are operant in these cells. Recent data suggest that cancer stem cells demonstrate a higher incidence of symmetric versus asymmetric cell division with both daughter cells retaining self-renewal characteristics, a profile which may underlie poorly differentiated morphology and marked clonal diversity in tumors. Pathways and targets are beginning to emerge which may provide opportunities for preventing such a predilection in cancer stem cells and that will hopefully translate into new classes of chemotherapeutics in oncology. Thus, although the existence of the ISH remains controversial, the shift of cell division dynamics to symmetric random chromosome segregation/self-renewal, which would negate any likelihood of template strand retention, appears to be a surrogate marker for the presence of highly malignant tumorigenic cell populations. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Histone deacetylase inhibition enhances self renewal and cardioprotection by human cord blood-derived CD34 cells.

    Directory of Open Access Journals (Sweden)

    Ilaria Burba

    Full Text Available BACKGROUND: Use of peripheral blood- or bone marrow-derived progenitors for ischemic heart repair is a feasible option to induce neo-vascularization in ischemic tissues. These cells, named Endothelial Progenitors Cells (EPCs, have been extensively characterized phenotypically and functionally. The clinical efficacy of cardiac repair by EPCs cells remains, however, limited, due to cell autonomous defects as a consequence of risk factors. The devise of "enhancement" strategies has been therefore sought to improve repair ability of these cells and increase the clinical benefit. PRINCIPAL FINDINGS: Pharmacologic inhibition of histone deacetylases (HDACs is known to enhance hematopoietic stem cells engraftment by improvement of self renewal and inhibition of differentiation in the presence of mitogenic stimuli in vitro. In the present study cord blood-derived CD34(+ were pre-conditioned with the HDAC inhibitor Valproic Acid. This treatment affected stem cell growth and gene expression, and improved ischemic myocardium protection in an immunodeficient mouse model of myocardial infarction. CONCLUSIONS: Our results show that HDAC blockade leads to phenotype changes in CD34(+ cells with enhanced self renewal and cardioprotection.

  7. Nac1 promotes self-renewal of embryonic stem cells through direct transcriptional regulation of c-Myc.

    Science.gov (United States)

    Ruan, Yan; He, Jianrong; Wu, Wei; He, Ping; Tian, Yanping; Xiao, Lan; Liu, Gaoke; Wang, Jiali; Cheng, Yuda; Zhang, Shuo; Yang, Yi; Xiong, Jiaxiang; Zhao, Ke; Wan, Ying; Huang, He; Zhang, Junlei; Jian, Rui

    2017-07-18

    The pluripotency transcriptional network in embryonic stem cells (ESCs) is composed of distinct functional units including the core and Myc units. It is hoped that dissection of the cellular functions and interconnections of network factors will aid our understanding of ESC and cancer biology. Proteomic and genomic approaches have identified Nac1 as a member of the core pluripotency network. However, previous studies have predominantly focused on the role of Nac1 in psychomotor stimulant response and cancer pathogenesis. In this study, we report that Nac1 is a self-renewal promoting factor, but is not required for maintaining pluripotency of ESCs. Loss of function of Nac1 in ESCs results in a reduced proliferation rate and an enhanced differentiation propensity. Nac1 overexpression promotes ESC proliferation and delays ESC differentiation in the absence of leukemia inhibitory factor (LIF). Furthermore, we demonstrated that Nac1 directly binds to the c-Myc promoter and regulates c-Myc transcription. The study also revealed that the function of Nac1 in promoting ESC self-renewal appears to be partially mediated by c-Myc. These findings establish a functional link between the core and c-Myc-centered networks and provide new insights into mechanisms of stemness regulation in ESCs and cancer.

  8. Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a.

    Science.gov (United States)

    Jackson, Jacob T; Shields, Benjamin J; Shi, Wei; Di Rago, Ladina; Metcalf, Donald; Nicola, Nicos A; McCormack, Matthew P

    2017-08-01

    The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin - Sca + Kit + cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16 Ink 4 a and p19 Arf . Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress. Stem Cells 2017;35:1948-1957. © 2017 AlphaMed Press.

  9. The CCR4 Deadenylase Acts with Nanos and Pumilio in the Fine-Tuning of Mei-P26 Expression to Promote Germline Stem Cell Self-Renewal

    Science.gov (United States)

    Joly, Willy; Chartier, Aymeric; Rojas-Rios, Patricia; Busseau, Isabelle; Simonelig, Martine

    2013-01-01

    Summary Translational regulation plays an essential role in Drosophila ovarian germline stem cell (GSC) biology. GSC self-renewal requires two translational repressors, Nanos (Nos) and Pumilio (Pum), which repress the expression of differentiation factors in the stem cells. The molecular mechanisms underlying this translational repression remain unknown. Here, we show that the CCR4 deadenylase is required for GSC self-renewal and that Nos and Pum act through its recruitment onto specific mRNAs. We identify mei-P26 mRNA as a direct and major target of Nos/Pum/CCR4 translational repression in the GSCs. mei-P26 encodes a protein of the Trim-NHL tumor suppressor family that has conserved functions in stem cell lineages. We show that fine-tuning Mei-P26 expression by CCR4 plays a key role in GSC self-renewal. These results identify the molecular mechanism of Nos/Pum function in GSC self-renewal and reveal the role of CCR4-NOT-mediated deadenylation in regulating the balance between GSC self-renewal and differentiation. PMID:24286029

  10. The thrombopoietin/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO

    Science.gov (United States)

    Chou, Fu-Sheng; Griesinger, Andrea; Wunderlich, Mark; Lin, Shan; Link, Kevin A.; Shrestha, Mahesh; Goyama, Susumu; Mizukawa, Benjamin; Shen, Shuhong; Marcucci, Guido

    2012-01-01

    AML1-ETO (AE) is a fusion product of translocation (8;21) that accounts for 40% of M2 type acute myeloid leukemia (AML). In addition to its role in promoting preleukemic hematopoietic cell self-renewal, AE represses DNA repair genes, which leads to DNA damage and increased mutation frequency. Although this latter function may promote leukemogenesis, concurrent p53 activation also leads to an increased baseline apoptotic rate. It is unclear how AE expression is able to counterbalance this intrinsic apoptotic conditioning by p53 to promote survival and self-renewal. In this report, we show that Bcl-xL is up-regulated in AE cells and plays an essential role in their survival and self-renewal. Further investigation revealed that Bcl-xL expression is regulated by thrombopoietin (THPO)/MPL-signaling induced by AE expression. THPO/MPL-signaling also controls cell cycle reentry and mediates AE-induced self-renewal. Analysis of primary AML patient samples revealed a correlation between MPL and Bcl-xL expression specifically in t(8;21) blasts. Taken together, we propose that survival signaling through Bcl-xL is a critical and intrinsic component of a broader self-renewal signaling pathway downstream of AML1-ETO–induced MPL. PMID:22337712

  11. Maintenance of Self-Renewal and Pluripotency in J1 Mouse Embryonic Stem Cells through Regulating Transcription Factor and MicroRNA Expression Induced by PD0325901

    Directory of Open Access Journals (Sweden)

    Zhiying Ai

    2016-01-01

    Full Text Available Embryonic stem cells (ESCs have the ability to grow indefinitely and retain their pluripotency in culture, and this self-renewal capacity is governed by several crucial molecular pathways controlled by specific regulatory genes and epigenetic modifications. It is reported that multiple epigenetic regulators, such as miRNA and pluripotency factors, can be tightly integrated into molecular pathways and cooperate to maintain self-renewal of ESCs. However, mouse ESCs in serum-containing medium seem to be heterogeneous due to the self-activating differentiation signal of MEK/ERK. Thus, to seek for the crucial miRNA and key regulatory genes that establish ESC properties in MEK/ERK pathway, we performed microarray analysis and small RNA deep-sequencing of J1 mESCs treated with or without PD0325901 (PD, a well-known inhibitor of MEK/ERK signal pathway, followed by verification of western blot analysis and quantitative real-time PCR verification; we found that PD regulated the transcript expressions related to self-renewal and differentiation and antagonized the action of retinoic acid- (RA- induced differentiation. Moreover, PD can significantly modulate the expressions of multiple miRNAs that have crucial functions in ESC development. Overall, our results demonstrate that PD could enhance ESC self-renewal capacity both by key regulatory genes and ES cell-specific miRNA, which in turn influences ESC self-renewal and cellular differentiation.

  12. Sevoflurane represses the self-renewal ability by regulating miR-7a,7b/Klf4 signalling pathway in mouse embryonic stem cells.

    Science.gov (United States)

    Wang, Qimin; Li, Guifeng; Li, Baolin; Chen, Qiu; Lv, Dongdong; Liu, Jiaying; Ma, Jieyu; Sun, Nai; Yang, Longqiu; Fei, Xuejie; Song, Qiong

    2016-10-01

    Sevoflurane is a frequently-used clinical inhalational anaesthetic and can cause toxicity to embryos during foetal development. Embryonic stem cells (ESCs) are derived from the inner cell mass of blastospheres and can be used as a useful model of early development. Here, we found that sevoflurane significantly influenced self-renewal ability of mESCs on stemness maintenance and cell proliferation. The cell cycle was arrested via G1 phase delay. We further found that sevoflurane upregulated expression of miR-7a,7b to repress self-renewal. Next we performed rescue experiments and found that after adding miR-7a,7b inhibitor into mESCs treated with sevoflurane, its influence on self-renewal could be blocked. Further we identified stemness factor Klf4 as the direct target of miR-7a,7b. Overexpression of Klf4 restored self-renewal ability repressed by miR-7a,7b or sevoflurane. In this work, we determined that sevoflurane repressed self-renewal ability by regulating the miR-7a,7b/Klf4 signalling pathway in mESCs. Our study demonstrated molecular mechanism underlying the side effects of sevoflurane during early development, laying the foundation for studies on safe usage of inhalational anaesthetic during non-obstetric surgery. © 2016 John Wiley & Sons Ltd.

  13. The CCR4 deadenylase acts with Nanos and Pumilio in the fine-tuning of Mei-P26 expression to promote germline stem cell self-renewal.

    Science.gov (United States)

    Joly, Willy; Chartier, Aymeric; Rojas-Rios, Patricia; Busseau, Isabelle; Simonelig, Martine

    2013-01-01

    Translational regulation plays an essential role in Drosophila ovarian germline stem cell (GSC) biology. GSC self-renewal requires two translational repressors, Nanos (Nos) and Pumilio (Pum), which repress the expression of differentiation factors in the stem cells. The molecular mechanisms underlying this translational repression remain unknown. Here, we show that the CCR4 deadenylase is required for GSC self-renewal and that Nos and Pum act through its recruitment onto specific mRNAs. We identify mei-P26 mRNA as a direct and major target of Nos/Pum/CCR4 translational repression in the GSCs. mei-P26 encodes a protein of the Trim-NHL tumor suppressor family that has conserved functions in stem cell lineages. We show that fine-tuning Mei-P26 expression by CCR4 plays a key role in GSC self-renewal. These results identify the molecular mechanism of Nos/Pum function in GSC self-renewal and reveal the role of CCR4-NOT-mediated deadenylation in regulating the balance between GSC self-renewal and differentiation.

  14. Personal extrapolation of CDF test beam use to the SSC

    International Nuclear Information System (INIS)

    Nodulman, L.

    1986-01-01

    The author's personal experience in test beam usage at CDF is used to predict SSC needs at the point of turn-on. It is concluded that the test beam demand will reflect the scale of effort involved in SSC detectors rather than the total number of them. Provision for later expansion is recommended. It is also recommended that the test beam facilities, as well as detector electronics, should reflect the available dynamic range; particularly, a single high energy beam derived from the SSC could be shared by several groups

  15. Geotechnical characterization and construction methods for SSC tunnel excavation

    International Nuclear Information System (INIS)

    Nelson, P.P.; Lundin, T.K.

    1990-06-01

    The site for the Superconducting Super Collider (SSC) facility was selected in 1988 after a nationwide proposal competition. The selected site is located in Ellis County, Texas, surrounding the town of Waxahachie which is about 30 miles (48 km) south of the City of Dallas central business district. This paper will describe the geotechnical conditions anticipated for excavation at the SSC site. A general geologic and geomechanical description of the rock present will be followed by a summary of the site-specific conceptual design for the tunneled components of the SSC machine. The Supercollider project will include about 70 miles (113) km of tunnel excavation

  16. Personal extrapolation of CDF test beam use to the SSC

    Energy Technology Data Exchange (ETDEWEB)

    Nodulman, L.

    1986-06-23

    The author's personal experience in test beam usage at CDF is used to predict SSC needs at the point of turn-on. It is concluded that the test beam demand will reflect the scale of effort involved in SSC detectors rather than the total number of them. Provision for later expansion is recommended. It is also recommended that the test beam facilities, as well as detector electronics, should reflect the available dynamic range; particularly, a single high energy beam derived from the SSC could be shared by several groups. (LEW)

  17. Recent developments in wire chamber tracking at SSC

    International Nuclear Information System (INIS)

    Ogren, H.

    1990-01-01

    All of the major SSC proposed detectors use wire chambers in their tracking systems. The feasibility of wire chambers in an SSC detector has now been established by a number of groups planning detectors at SSC. The major advances during the past year in understanding straw tube drift chambers are presented and several innovations in gaseous wire chambers are discussed. The R and D section will concentrate on progress in drift cell design, electronics and signal processing, and engineering aspects of the tracking designs

  18. The HPV16 E7 oncoprotein increases the expression of Oct3/4 and stemness-related genes and augments cell self-renewal

    Energy Technology Data Exchange (ETDEWEB)

    Organista-Nava, Jorge; Gómez-Gómez, Yazmín [Programa de Doctorado en Ciencias Biomédicas, Instituto de Fisiología Celular (IFC), Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, México (Mexico); Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Ciudad de México 07360, México (Mexico); Ocadiz-Delgado, Rodolfo; García-Villa, Enrique [Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Ciudad de México 07360, México (Mexico); Bonilla-Delgado, José [Unidad de Investigación, Hospital Juárez de México, Ciudad de México 07760, México (Mexico); Lagunas-Martínez, Alfredo [División de Biología Molecular de Patógenos, CISEI, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, México (Mexico); and others

    2016-12-15

    Oct3/4 is a transcription factor involved in maintenance of the pluripotency and self-renewal of stem cells. The E7 oncoprotein and 17β-estradiol (E{sub 2}) are key factors in cervical carcinogenesis. In the present study, we aimed to investigate the effect of the HPV16 E7 oncoprotein and E{sub 2} on the expression pattern of Oct3/4, Sox2, Nanog and Fgf4. We also determined whether the E7 oncoprotein is associated with cell self-renewal. The results showed that Oct3/4, Sox2, Nanog and Fgf4 were upregulated by the E7 oncoprotein in vivo and in vitro and implicate E{sub 2} in the upregulation of these factors in vivo. We also demonstrated that E7 is involved in cell self-renewal, suggesting that the HPV16 E7 oncoprotein upregulates Oct3/4, Sox2, Nanog and Fgf4 expression to maintain the self-renewal capacity of cancer stem cells. -- Graphical abstract: The HPV16 E7 oncoprotein and 17β-estradiol are involved in the upregulation of Oct3/4, Sox2, Nanog and Fgf4 expression to maintain the self-renewal ability of cancer stem cells in cervical cancer. - Highlights: •The HPV16 E7 oncoprotein enhances cellular proliferation and dedifferentiation. •The E7 oncoprotein induces stemness-related genes expression in vivo and in vitro. •The 17β-estradiol induces stemness-related genes expression in vivo. •The HPV16 E7 oncoprotein is involved in the cell self-renewal of cancer cells.

  19. The HPV16 E7 oncoprotein increases the expression of Oct3/4 and stemness-related genes and augments cell self-renewal

    International Nuclear Information System (INIS)

    Organista-Nava, Jorge; Gómez-Gómez, Yazmín; Ocadiz-Delgado, Rodolfo; García-Villa, Enrique; Bonilla-Delgado, José; Lagunas-Martínez, Alfredo

    2016-01-01

    Oct3/4 is a transcription factor involved in maintenance of the pluripotency and self-renewal of stem cells. The E7 oncoprotein and 17β-estradiol (E 2 ) are key factors in cervical carcinogenesis. In the present study, we aimed to investigate the effect of the HPV16 E7 oncoprotein and E 2 on the expression pattern of Oct3/4, Sox2, Nanog and Fgf4. We also determined whether the E7 oncoprotein is associated with cell self-renewal. The results showed that Oct3/4, Sox2, Nanog and Fgf4 were upregulated by the E7 oncoprotein in vivo and in vitro and implicate E 2 in the upregulation of these factors in vivo. We also demonstrated that E7 is involved in cell self-renewal, suggesting that the HPV16 E7 oncoprotein upregulates Oct3/4, Sox2, Nanog and Fgf4 expression to maintain the self-renewal capacity of cancer stem cells. -- Graphical abstract: The HPV16 E7 oncoprotein and 17β-estradiol are involved in the upregulation of Oct3/4, Sox2, Nanog and Fgf4 expression to maintain the self-renewal ability of cancer stem cells in cervical cancer. - Highlights: •The HPV16 E7 oncoprotein enhances cellular proliferation and dedifferentiation. •The E7 oncoprotein induces stemness-related genes expression in vivo and in vitro. •The 17β-estradiol induces stemness-related genes expression in vivo. •The HPV16 E7 oncoprotein is involved in the cell self-renewal of cancer cells.

  20. Cabling for an SSC silicon tracking system

    International Nuclear Information System (INIS)

    Ziock, H.; Boissevain, J.; Cooke, B.; Miller, W.

    1990-01-01

    As part of the Superconducting Super Collider Laboratory (SSCL) funded silicon tracking subsystem R ampersand D program, we examine the problems associated with cabling such a system. Different options for the cabling plant are discussed. A silicon microstrip tracking detector for an SSC experiment is an extremely complex system. The system consists of approximately 10 7 detector channels, each of which requires a communication link with the outside world and connections to the detector bias voltage supply, to a DC power supply for the onboard electronics, and to an adjustable discrimination level. The large number of channels and the short time between beam interactions (16 nanoseconds) dictates the need for high speed and large bandwidth communication channels, and a power distribution system that can handle the high current draw of the electronics including the large AC component due to their switching. At the same time the constraints imposed by the physics measurements require that the cable plant have absolutely minimal mass and radiation length. 4 refs., 2 figs

  1. Prospects for polarization at RHIC and SSC

    International Nuclear Information System (INIS)

    Lee, S.Y.

    1991-01-01

    In low to medium energy accelerators, betatron tune jumps and vertical orbit harmonic correction methods have been used to overcome the intrinsic and imperfection resonances. At high energy accelerators, snakes are needed to preserve polarization. We analyze the effects of snake resonances, snake imperfections overlapping resonances on the spin depolarization. We discuss also results of recent snake experiments at the IUCF Cooler Ring. The snake can overcome various kinds of spin depolarization resonances. These experiments pointed out further that partial snake can be used to cure the imperfection resonances in low to medium energy accelerators. We also examine various snake designs. A new generalized snake concept allows for two possible configurations. The compact configuration offers the advantages of shorter total snake length and smaller horizontal orbit displacement. The split snake configuration allows for dual functions of a snake and a 90 degree spin rotator at the mid-section of the snake, which provides helicity state collisions. The requirements for obtaining high luminosity polarized protons at high energy colliders, such as RHIC and SSC, are reviewed

  2. Engineering innovations on the SSC DTL accelerator

    International Nuclear Information System (INIS)

    Rymer, J.P.; Potter, J.M.; Givens, J.; Campbell, B.; Hansborough, L.

    1992-01-01

    The engineering design of the drift-tube linac (DTL) tanks for the Superconducting Super Collider (SSC) linac incorporates numerous innovative features, resulting in a reliable, cost-effective accelerator structure suitable for commercial production. The tank structure includes two integral strong-backs that provide stable mounting surfaces for the drift tubes and ion pumps and add mechanical stiffness. Drift tubes are mounted using AccSys' patented semi-hard socket technique, which includes separate metal seals for rf and vacuum. The socket allows repeatable adjustment of drift-tube location, thus allowing the tank to be fabricated to realistic tolerances. Transverse alignment of the drift tubes will be accomplished using a pulsed taut-wire technique to align the magnetic centers of the permanent magnet quadrupoles. This technique has been improved to allow drift-tube alignment throughout a 6 m long tank. For maximum reliability, the individual drift tubes include water-cooling channels that have no water-to-vacuum joints. Each tank will be driven through a waveguide iris coupler that can be adjusted to optimize the coupling. (Author) 3 refs., 3 figs

  3. GIS/FIS development for the SSC

    International Nuclear Information System (INIS)

    Oslin, A.; Butalla, M.

    1992-03-01

    Throughout all phases of the Superconducting Super Collider Laboratory (SSCL) project life decisions will be made on how to manage complex interactions of components, systems, and people with each other and with their environment at both micro and macro scales. The SSC has a distinct advantage compared to other large projects constructed and operated in the past, for even in the early phases scientists and engineers can use computer technology to provide faster computation and better modeling capability to resolve conflict and to make design, construction, and installation decisions. Computer systems today let us go beyond just making pictures of the components and objects under consideration. Not only can we know what objects look like, but we can visualize what and where they are, how they fit together to make networks, and how the networks relate to other types of objects and networks. Two such computer-based systems that relate object position and attributes to one another are Geographic Information Systems (GIS) and Facility Information Systems (FIS)

  4. Field measuring probe for SSC magnets

    International Nuclear Information System (INIS)

    Ganetis, G.; Herrera, J.; Hogue, R.; Skaritka, J.; Wanderer, P.; Willen, E.

    1987-01-01

    The field probe developed for measuring the field in SSC dipole magnets is an adaptation of the rotating tangential coil system in use at Brookhaven for several years. Also known as the MOLE, it is a self-contained room-temperature mechanism that is pulled through the aperture of the magnet with regular stops to measure the local field. Several minutes are required to measure the field at each point. The probe measures the multipole components of the field as well as the field angle relative to gravity. The sensitivity of the coil and electronics is such that the field up to the full 6.6 T excitation of the magnet as well as the field when warm with only 0.01 T excitation can be measured. Tethers are attached to both ends of the probe to carry electrical connections and to supply dry nitrogen to the air motors that rotate the tangential windings as well as the gravity sensor. A small computer is attached to the probe for control and for data collection, analysis and storage

  5. Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal.

    Science.gov (United States)

    Yan, Kelley S; Janda, Claudia Y; Chang, Junlei; Zheng, Grace X Y; Larkin, Kathryn A; Luca, Vincent C; Chia, Luis A; Mah, Amanda T; Han, Arnold; Terry, Jessica M; Ootani, Akifumi; Roelf, Kelly; Lee, Mark; Yuan, Jenny; Li, Xiao; Bolen, Christopher R; Wilhelmy, Julie; Davies, Paige S; Ueno, Hiroo; von Furstenberg, Richard J; Belgrader, Phillip; Ziraldo, Solongo B; Ordonez, Heather; Henning, Susan J; Wong, Melissa H; Snyder, Michael P; Weissman, Irving L; Hsueh, Aaron J; Mikkelsen, Tarjei S; Garcia, K Christopher; Kuo, Calvin J

    2017-05-11

    The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5 + intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5 + ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5 + ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5 + ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction

  6. Self-renewal and chemotherapy resistance of p75NTR positive cells in esophageal squamous cell carcinomas

    International Nuclear Information System (INIS)

    Huang, Sheng-Dong; Yuan, Yang; Liu, Xiao-Hong; Gong, De-Jun; Bai, Chen-Guang; Wang, Feng; Luo, Jun-Hui; Xu, Zhi-Yun

    2009-01-01

    p75 NTR has been used to isolate esophageal and corneal epithelial stem cells. In the present study, we investigated the expression of p75 NTR in esophageal squamous cell carcinoma (ESCC) and explored the biological properties of p75 NTR+ cells. p75 NTR expression in ESCC was assessed by immunohistochemistry. p75 NTR+ and p75 NTR- cells of 4 ESCC cell lines were separated by fluorescence-activated cell sorting. Differentially expressed genes between p75 NTR+ and p75 NTR- cells were determined by real-time quantitative reverse transcription-PCR. Sphere formation assay, DDP sensitivity assay, 64 copper accumulation assay and tumorigenicity analysis were performed to determine the capacity of self-renewal, chemotherapy resistance and tumorigenicity of p75 NTR+ cells. In ESCC specimens, p75 NTR was found mainly confined to immature cells and absent in cells undergoing terminal differentiation. The percentage of p75 NTR+ cells was 1.6%–3.7% in Eca109 and 3 newly established ESCC cell lines. The expression of Bmi-1, which is associated with self-renewal of stem cells, was significantly higher in p75 NTR+ cells. p63, a marker identified in keratinocyte stem cells, was confined mainly to p75 NTR+ cells. The expression of CTR1, which is associated with cisplatin (DDP)-resistance, was significantly decreased in p75 NTR+ cells. Expression levels of differentiation markers, such as involucrin, cytokeratin 13, β1-integrin and β4-integrin, were lower in p75 NTR+ cells. In addition, p75 NTR+ cells generated both p75 NTR+ and p75 NTR- cells, and formed nonadherent spherical clusters in serum-free medium supplemented with growth factors. Furthermore, p75 NTR+ cells were found to be more resistant to DDP and exhibited lower 64 copper accumulation than p75 NTR- cells. Our results demonstrated that p75 NTR+ cells possess some characteristics of CSCs, namely, self-renewal and chemotherapy resistance. Chemotherapy resistance of p75 NTR+ cells may probably be attributable to

  7. EGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side-population cells in non-small cell lung cancer.

    Science.gov (United States)

    Singh, Sandeep; Trevino, Jose; Bora-Singhal, Namrata; Coppola, Domenico; Haura, Eric; Altiok, Soner; Chellappan, Srikumar P

    2012-09-25

    Cancer stem cells are thought to be responsible for the initiation and progression of cancers. In non-small cell lung cancers (NSCLCs), Hoechst 33342 dye effluxing side population (SP) cells are shown to have stem cell like properties. The oncogenic capacity of cancer stem-like cells is in part due to their ability to self-renew; however the mechanistic correlation between oncogenic pathways and self-renewal of cancer stem-like cells has remained elusive. Here we characterized the SP cells at the molecular level and evaluated its ability to generate tumors at the orthotopic site in the lung microenvironment. Further, we investigated if the self-renewal of SP cells is dependent on EGFR mediated signaling. SP cells were detected and isolated from multiple NSCLC cell lines (H1650, H1975, A549), as well as primary human tumor explants grown in nude mice. SP cells demonstrated stem-like properties including ability to self-renew and grow as spheres; they were able to generate primary and metastatic tumors upon orthotopic implantation into the lung of SCID mice. In vitro study revealed elevated expression of stem cell associated markers like Oct4, Sox2 and Nanog as well as demonstrated intrinsic epithelial to mesenchymal transition features in SP cells. Further, we show that abrogation of EGFR, Src and Akt signaling through pharmacological or genetic inhibitors suppresses the self-renewal growth and expansion of SP-cells and resulted in specific downregulation of Sox2 protein expression. siRNA mediated depletion of Sox2 significantly blocked the SP phenotype as well as its self-renewal capacity; whereas other transcription factors like Oct4 and Nanog played a relatively lesser role in regulating self-renewal. Interestingly, Sox2 was elevated in metastatic foci of human NSCLC samples. Our findings suggest that Sox2 is a novel target of EGFR-Src-Akt signaling in NSCLCs that modulates self-renewal and expansion of stem-like cells from NSCLC. Therefore, the outcome of the

  8. EGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side-population cells in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Singh Sandeep

    2012-09-01

    Full Text Available Abstract Background Cancer stem cells are thought to be responsible for the initiation and progression of cancers. In non-small cell lung cancers (NSCLCs, Hoechst 33342 dye effluxing side population (SP cells are shown to have stem cell like properties. The oncogenic capacity of cancer stem-like cells is in part due to their ability to self-renew; however the mechanistic correlation between oncogenic pathways and self-renewal of cancer stem-like cells has remained elusive. Here we characterized the SP cells at the molecular level and evaluated its ability to generate tumors at the orthotopic site in the lung microenvironment. Further, we investigated if the self-renewal of SP cells is dependent on EGFR mediated signaling. Results SP cells were detected and isolated from multiple NSCLC cell lines (H1650, H1975, A549, as well as primary human tumor explants grown in nude mice. SP cells demonstrated stem-like properties including ability to self-renew and grow as spheres; they were able to generate primary and metastatic tumors upon orthotopic implantation into the lung of SCID mice. In vitro study revealed elevated expression of stem cell associated markers like Oct4, Sox2 and Nanog as well as demonstrated intrinsic epithelial to mesenchymal transition features in SP cells. Further, we show that abrogation of EGFR, Src and Akt signaling through pharmacological or genetic inhibitors suppresses the self-renewal growth and expansion of SP-cells and resulted in specific downregulation of Sox2 protein expression. siRNA mediated depletion of Sox2 significantly blocked the SP phenotype as well as its self-renewal capacity; whereas other transcription factors like Oct4 and Nanog played a relatively lesser role in regulating self-renewal. Interestingly, Sox2 was elevated in metastatic foci of human NSCLC samples. Conclusions Our findings suggest that Sox2 is a novel target of EGFR-Src-Akt signaling in NSCLCs that modulates self-renewal and expansion of

  9. Heavy neutrinos and new bosons at the SSC

    International Nuclear Information System (INIS)

    Kayser, B.; Deshpande, N.; Gunion, J.F.

    1984-01-01

    Methods for seeking and studying heavy neutrinos and new W bosons at the SSC are considered. Such particles are predicted by left-right symmetric models. Their properties and experimental signatures are analyzed. 25 refs., 5 figs

  10. Status of superconducting magnet development (SSC, RHIC, LHC)

    International Nuclear Information System (INIS)

    Wanderer, P.

    1993-01-01

    This paper summarize recent superconducting accelerator magnet construction and test activities at the Superconducting Super Collider Laboratory (SSC), the Large Hadron Collider at CERN (LHC), and the Relativistic Heavy Ion Collider at Brookhaven (RHIC). Future plan are also presented

  11. Orbit correction system for the SSC interaction regions

    International Nuclear Information System (INIS)

    Nosochkov, Y.; Pilat, F.; Ritson, D.M.

    1994-01-01

    In this paper we review our design of the orbit correction system for the SSC interaction regions, and discuss the principles of the local orbit correction at the IP. copyright 1994 American Institute of Physics

  12. Status of superconducting magnet development (SSC, RHIC, LHC)

    International Nuclear Information System (INIS)

    Wanderer, P.

    1993-01-01

    This paper summarizes recent superconducting accelerator magnet construction and test activities at the Superconducting Super Collider Laboratory (SSC), the Large Hardon Collider at CERN (LHC), and the Relativistic Heavy Ion Collider at Brookhaven (RHIC). Future plans are also presented

  13. SSC-K code user's manual

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Y.M.; Lee, Y.B.; Chang, W.P.; Hahn, D

    2000-07-01

    The Supper System Code of KAERI (SSC-K) is a best-estimate system code for analyzing a variety of off-normal or accidents in the heat transport system of a pool type LMR design. It is being developed at Korea Atomic Energy Research Inititution (KAERI) on the basis of SSC-L, originally developed at BNL to analyze loop-type LMR transients. SSC-K can handle both designs of loop and pool type LMRs. SSC-K contains detailed mechanistic models of transient thermal, hydraulic, neutronic, and mechanical phenomena to describe the response of the reactor core, coolant, fuel elements, and structures to accident conditions. This report provides an overview of recent model developmentsvfor the SSC-K computer code, focusing on phenomenological model descriptions for new thermal, hydraulic, neutronic, and mechnaical modules. A comprehensive description of the models for pool-type reactor is given in Chapters 2 and 3; the steady-state plant characterization, prior to the initiation of transient is described in Chapter 2 and their transient counterparts are discussed in Chapter 3. In Chapter 4, a discussion on the intermediate heat exchanger (IHX) is presented. The IHX model of SSC-K is similar to that used in the SSC-L, except for some changes required for the pool-type configuration of reactor vessel. In Chapter 5, an electromagnetic (EM) pump is modeled as a component. There are two pump choices available in SSC-K; a centrifugal pump which was originally imbedded into the SSC-L, and an EM pump which was introduced for the KALIMER design. In Chapter 6, a model of passive safety decay heat removal system(PSDRS) is discussed, which removes decay heat through the reactor and containment vessel walls to the ambient air heat sink. In Chapter 7, models for various reactivity feedback effects are discussed. Reactivity effects of importance in fast reactor include the Doppler effect, effects of sodium density changes, effects of dimensional changes in core geometry. Finally in Chapter 8

  14. SSC-K code users manual (rev.1)

    International Nuclear Information System (INIS)

    Kwon, Y. M.; Lee, Y. B.; Chang, W. P.; Hahn, D.

    2002-01-01

    The Supper System Code of KAERI (SSC-K) is a best-estimate system code for analyzing a variety of off-normal or accidents in the heat transport system of a pool type LMR design. It is being developed at Korea Atomic Energy Research Institution (KAERI) on the basis of SSC-L, originally developed at BNL to analyze loop-type LMR transients. SSC-K can handle both designs of loop and pool type LMRs. SSC-K contains detailed mechanistic models of transient thermal, hydraulic, neutronic, and mechanical phenomena to describe the response of the reactor core, coolant, fuel elements, and structures to accident conditions. This report provides a revised User's Manual (rev.1) of the SSC-K computer code, focusing on phenomenological model descriptions for new thermal, hydraulic, neutronic, and mechanical modules. A comprehensive description of the models for pool-type reactor is given in Chapters 2 and 3; the steady-state plant characterization, prior to the initiation of transient is described in Chapter 2 and their transient counterparts are discussed in Chapter 3. Discussions on the intermediate heat exchanger (IHX) and the electromagnetic (EM) pump are described in Chapter 4 and 5, respectively. A model of passive safety decay heat removal system (PSDRS) is discussed in Chapter 6, and models for various reactivity feedback effects are discussed in Chapter 7. In Chapter 8, constitutive laws and correlations required to execute the SSC-K are described. New models developed for SSC-K rev.1 are two dimensional hot pool model in Chapter 9, and long term cooling model in Chapter 10. Finally, a brief description of MINET code adopted to simulate BOP is presented in Chapter 11. Based on test runs for typical LMFBR accident analyses, it was found that the present version of SSC-K would be used for the safety analysis of KALIMER. However, the further validation of SSC-K is required for real applications. It is noted that the user's manual of SSC-K will be revised later with the

  15. Underground measurements of seismic vibrations at the SSC site

    International Nuclear Information System (INIS)

    Shiltsev, V.D.; Parkhomchuk, V.V.; Weaver, H.J.

    1995-01-01

    The results of underground measurements of seismic vibrations at the tunnel depth of the Superconducting Super Collider (SSC) site are presented. Spectral analysis of the data obtained in the frequency band from 0.05 Hz to 1500 Hz is performed. It is found that amplitudes of ambient ground motion are less than requirements for the Collider, but cultural vibrations are unacceptably large and will cause fast growth of transverse emittance of the SSC beams

  16. Tracking simulation and wire chamber requirements for the SSC

    International Nuclear Information System (INIS)

    Hanson, G.G.; Niczyporuk, B.B.; Palounek, A.P.T.

    1988-11-01

    Limitations placed on wire chambers by radiation damage and rate requirements in the SSC environment are reviewed. Possible conceptual designs for wire chamber tracking systems which meet these requirements are discussed. Computer simulation studies of tracking in such systems are presented. Simulations of events from interesting physics at the SSC, including hits from minimum bias background events, are examined. Results of some preliminary pattern recognition studies are given. 16 refs., 16 figs., 2 tabs

  17. Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis.

    Science.gov (United States)

    Cui, Qi; Yang, Su; Ye, Peng; Tian, E; Sun, Guoqiang; Zhou, Jiehua; Sun, Guihua; Liu, Xiaoxuan; Chen, Chao; Murai, Kiyohito; Zhao, Chunnian; Azizian, Krist T; Yang, Lu; Warden, Charles; Wu, Xiwei; D'Apuzzo, Massimo; Brown, Christine; Badie, Behnam; Peng, Ling; Riggs, Arthur D; Rossi, John J; Shi, Yanhong

    2016-02-03

    Glioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is critical for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumour development and prolongs survival. Moreover, we identify TET3 as a potent tumour suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma.

  18. New cancer diagnostics and therapeutics from a ninth 'hallmark of cancer': symmetric self-renewal by mutated distributed stem cells.

    Science.gov (United States)

    Sherley, James L

    2013-11-01

    A total of eight cellular alterations associated with human carcinogenesis have been framed as the 'hallmarks of cancer'. This representation overlooks a ninth hallmark of cancer: the requirement for tumor-originating distributed stem cells to shift sufficiently from asymmetric to symmetric self-renewal kinetics for attainment of the high cell production rate necessary to form clinically significant tumors within a human lifespan. Overlooking this ninth hallmark costs opportunities for discovery of more selective molecular targets for development of improved cancer therapeutics and missing cancer stem cell biomarkers of greater specificity. Here, the biological basis for the ninth hallmark of cancer is considered toward highlighting its importance in human carcinogenesis and, as such, its potential for revealing unique molecules for targeting cancer diagnostics and therapeutics.

  19. Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche

    Directory of Open Access Journals (Sweden)

    Heather A. Himburg

    2012-10-01

    Full Text Available The mechanisms through which the bone marrow (BM microenvironment regulates hematopoietic stem cell (HSC fate remain incompletely understood. We examined the role of the heparin-binding growth factor pleiotrophin (PTN in regulating HSC function in the niche. PTN−/− mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.

  20. R-spondin1/Wnt-enhanced Ascl2 autoregulation controls the self-renewal of colorectal cancer progenitor cells.

    Science.gov (United States)

    Ye, Jun; Liu, Shanxi; Shang, Yangyang; Chen, Haoyuan; Wang, Rongquan

    2018-06-25

    The Wnt signaling pathway controls stem cell identity in the intestinal epithelium and cancer stem cells (CSCs). The transcription factor Ascl2 (Wnt target gene) is fate decider of intestinal cryptic stem cells and colon cancer stem cells. It is unclear how Wnt signaling is translated into Ascl2 expression and keeping the self-renewal of CRC progenitor cells. We showed that the exogenous Ascl2 in colorectal cancer (CRC) cells activated the endogenous Ascl2 expression via a direct autoactivatory loop, including Ascl2 binding to its own promoter and further transcriptional activation. Higher Ascl2 expression in human CRC cancerous tissues led to greater enrichment in Ascl2 immunoprecipitated DNA within the Ascl2 promoter in the CRC cancerous sample than the peri-cancerous mucosa. Ascl2 binding to its own promoter and inducing further transcriptional activation of the Ascl2 gene was predominant in the CD133 + CD44 + CRC population. R-spondin1/Wnt activated Ascl2 expression dose-dependently in the CD133 + CD44 + CRC population, but not in the CD133 - CD44 - CRC population, which was caused by differences in Ascl2 autoregulation under R-spondin1/Wnt activation. R-spondin1/Wnt treatment in the CD133 + CD44 + or CRC CD133 - CD44 - populations exerted a different pattern of stemness maintenance, which was defined by alterations of the mRNA levels of stemness-associated genes, the protein expression levels (Bmi1, C-myc, Oct-4 and Nanog) and tumorsphere formation. The results indicated that Ascl2 autoregulation formed a transcriptional switch that was enhanced by Wnt signaling in the CD133 + CD44 + CRC population, thus conferring their self-renewal.

  1. Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal.

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    Mariana Rodova

    Full Text Available Dysregulation of the sonic hedgehog (Shh signaling pathway has been associated with cancer stem cells (CSC and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN, an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4 as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway

  2. Store-Operated Calcium Entries Control Neural Stem Cell Self-Renewal in the Adult Brain Subventricular Zone.

    Science.gov (United States)

    Domenichini, Florence; Terrié, Elodie; Arnault, Patricia; Harnois, Thomas; Magaud, Christophe; Bois, Patrick; Constantin, Bruno; Coronas, Valérie

    2018-05-01

    The subventricular zone (SVZ) is the major stem cell niche in the brain of adult mammals. Within this region, neural stem cells (NSC) proliferate, self-renew and give birth to neurons and glial cells. Previous studies underlined enrichment in calcium signaling-related transcripts in adult NSC. Because of their ability to mobilize sustained calcium influxes in response to a wide range of extracellular factors, store-operated channels (SOC) appear to be, among calcium channels, relevant candidates to induce calcium signaling in NSC whose cellular activities are continuously adapted to physiological signals from the microenvironment. By Reverse Transcription Polymerase Chain Reaction (RT-PCR), Western blotting and immunocytochemistry experiments, we demonstrate that SVZ cells express molecular actors known to build up SOC, namely transient receptor potential canonical 1 (TRPC1) and Orai1, as well as their activator stromal interaction molecule 1 (STIM1). Calcium imaging reveals that SVZ cells display store-operated calcium entries. Pharmacological blockade of SOC with SKF-96365 or YM-58483 (also called BTP2) decreases proliferation, impairs self-renewal by shifting the type of SVZ stem cell division from symmetric proliferative to asymmetric, thereby reducing the stem cell population. Brain section immunostainings show that TRPC1, Orai1, and STIM1 are expressed in vivo, in SOX2-positive SVZ NSC. Injection of SKF-96365 in brain lateral ventricle diminishes SVZ cell proliferation and reduces the ability of SVZ cells to form neurospheres in vitro. The present study combining in vitro and in vivo approaches uncovers a major role for SOC in the control of SVZ NSC population and opens new fields of investigation for stem cell biology in health and disease. Stem Cells 2018;36:761-774. © AlphaMed Press 2018.

  3. Qualitative modeling identifies IL-11 as a novel regulator in maintaining self-renewal in human pluripotent stem cells

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    Hedi ePeterson

    2013-10-01

    Full Text Available Pluripotency in human embryonic stem cells (hESCs and induced pluripotent stem cells (iPSCs is regulated by three transcription factors - OCT3/4, SOX2 and NANOG. To fully exploit the therapeutic potential of these cells it is essential to have a good mechanistic understanding of the maintenance of self-renewal and pluripotency. In this study, we demonstrate a powerful systems biology approach in which we first expand literature-based network encompassing the core regulators of pluripotency by assessing the behaviour of genes targeted by perturbation experiments. We focused our attention on highly regulated genes encoding cell surface and secreted proteins as these can be more easily manipulated by the use of inhibitors or recombinant proteins. Qualitative modeling based on combining boolean networks and in silico perturbation experiments were employed to identify novel pluripotency-regulating genes. We validated Interleukin-11 (IL-11 and demonstrate that this cytokine is a novel pluripotency-associated factor capable of supporting self-renewal in the absence of exogenously added bFGF in culture. To date, the various protocols for hESCs maintenance require supplementation with bFGF to activate the Activin/Nodal branch of the TGFβ signaling pathway. Additional evidence supporting our findings is that IL-11 belongs to the same protein family as LIF, which is known to be necessary for maintaining pluripotency in mouse but not in human ESCs. These cytokines operate through the same gp130 receptor which interacts with Janus kinases. Our finding might explain why mESCs are in a more naïve cell state compared to hESCs and how to convert primed hESCs back to the naïve state. Taken together, our integrative modeling approach has identified novel genes as putative candidates to be incorporated into the expansion of the current gene regulatory network responsible for inducing and maintaining pluripotency.

  4. Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

    Science.gov (United States)

    Sansone, Pasquale; Ceccarelli, Claudio; Berishaj, Marjan; Chang, Qing; Rajasekhar, Vinagolu K; Perna, Fabiana; Bowman, Robert L; Vidone, Michele; Daly, Laura; Nnoli, Jennifer; Santini, Donatella; Taffurelli, Mario; Shih, Natalie N C; Feldman, Michael; Mao, Jun J; Colameco, Christopher; Chen, Jinbo; DeMichele, Angela; Fabbri, Nicola; Healey, John H; Cricca, Monica; Gasparre, Giuseppe; Lyden, David; Bonafé, Massimiliano; Bromberg, Jacqueline

    2016-02-09

    The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.

  5. Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity

    International Nuclear Information System (INIS)

    Gatti, Monica; Pattarozzi, Alessandra; Bajetto, Adriana; Würth, Roberto; Daga, Antonio; Fiaschi, Pietro; Zona, Gianluigi; Florio, Tullio; Barbieri, Federica

    2013-01-01

    Cancer stem cells (CSCs) or tumor initiating cells (TICs) drive glioblastoma (GBM) development, invasiveness and drug resistance. Distinct molecular pathways might regulate CSC biology as compared to cells in the bulk tumor mass, representing potential therapeutic targets. Chemokine CXCL12 and its receptor CXCR4 control proliferation, invasion and angiogenesis in GBM cell lines and primary cultures, but little is known about their activity in GBM CSCs. We demonstrate that CSCs, isolated from five human GBMs, express CXCR4 and release CXCL12 in vitro, although different levels of expression and secretion were observed in individual cultures, as expected for the heterogeneity of GBMs. CXCL12 treatment induced Akt-mediated significant pro-survival and self-renewal activities, while proliferation was induced at low extent. The role of CXCR4 signaling in CSC survival and self-renewal was further demonstrated using the CXCR4 antagonist AMD3100 that reduced self-renewal and survival with greater efficacy in the cultures that released higher CXCL12 amounts. The specificity of CXCL12 in sustaining CSC survival was demonstrated by the lack of AMD3100-dependent inhibition of viability in differentiated cells derived from the same GBMs. These findings, although performed on a limited number of tumor samples, suggest that the CXCL12/CXCR4 interaction mediates survival and self-renewal in GBM CSCs with high selectivity, thus emerging as a candidate system responsible for maintenance of cancer progenitors, and providing survival benefits to the tumor

  6. Sparse feature selection identifies H2A.Z as a novel, pattern-specific biomarker for asymmetrically self-renewing distributed stem cells

    Directory of Open Access Journals (Sweden)

    Yang Hoon Huh

    2015-03-01

    Full Text Available There is a long-standing unmet clinical need for biomarkers with high specificity for distributed stem cells (DSCs in tissues, or for use in diagnostic and therapeutic cell preparations (e.g., bone marrow. Although DSCs are essential for tissue maintenance and repair, accurate determination of their numbers for medical applications has been problematic. Previous searches for biomarkers expressed specifically in DSCs were hampered by difficulty obtaining pure DSCs and by the challenges in mining complex molecular expression data. To identify such useful and specific DSC biomarkers, we combined a novel sparse feature selection method with combinatorial molecular expression data focused on asymmetric self-renewal, a conspicuous property of DSCs. The analysis identified reduced expression of the histone H2A variant H2A.Z as a superior molecular discriminator for DSC asymmetric self-renewal. Subsequent molecular expression studies showed H2A.Z to be a novel “pattern-specific biomarker” for asymmetrically self-renewing cells, with sufficient specificity to count asymmetrically self-renewing DSCs in vitro and potentially in situ.

  7. Comprehensive analysis of miRNAs expression profiles revealed potential key miRNA/mRNAs regulating colorectal cancer stem cell self-renewal.

    Science.gov (United States)

    Xu, Peng; Wang, Junhua; Sun, Bo; Xiao, Zhongdang

    2018-05-20

    Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood. Recently, miRNAs are reported to be relevant to the self-renewal ability of cancer stem cells. In this study, we first isolated colorectal cancer stem cell from colorectal cancer cell line HCT-116 by 1% low serum culture. Then we conducted a comprehensive analysis based on the miRNAs profiles data of both colorectal cancer stem cells and normal cultured colorectal cancer cells. Pathway analysis revealed multiple pathways including Jak-STAT, TGF-beta, PI3K-Akt and MAPK signaling pathway that are correlated to colorectal cancer. Further, we constructed a miRNA-mRNA network, based on which, several miRNA/mRNA pairs were ranked according to their impact index to the self-renewal of colorectal cancer stem cells. Further biological experiment showed that up-regulation of miR-92a-3p led to cell cycle arrest and reduced colony formation. This work provides clues to find the new potential biomarkers for colorectal cancer stem cell diagnosis and select effective miRNAs for targeted therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. bHLH-O proteins balance the self-renewal and differentiation of Drosophila neural stem cells by regulating Earmuff expression.

    Science.gov (United States)

    Li, Xiaosu; Chen, Rui; Zhu, Sijun

    2017-11-15

    Balancing self-renewal and differentiation of stem cells requires differential expression of self-renewing factors in two daughter cells generated from the asymmetric division of the stem cells. In Drosophila type II neural stem cell (or neuroblast, NB) lineages, the expression of the basic helix-loop-helix-Orange (bHLH-O) family proteins, including Deadpan (Dpn) and E(spl) proteins, is required for maintaining the self-renewal and identity of type II NBs, whereas the absence of these self-renewing factors is essential for the differentiation of intermediate neural progenitors (INPs) generated from type II NBs. Here, we demonstrate that Dpn maintains type II NBs by suppressing the expression of Earmuff (Erm). We provide evidence that Dpn and E(spl) proteins suppress Erm by directly binding to C-sites and N-boxes in the cis-regulatory region of erm. Conversely, the absence of bHLH-O proteins in INPs allows activation of erm and Erm-mediated maturation of INPs. Our results further suggest that Pointed P1 (PntP1) mediates the dedifferentiation of INPs resulting from the loss of Erm or overexpression of Dpn or E(spl) proteins. Taken together, these findings reveal mechanisms underlying the regulation of the maintenance of type II NBs and differentiation of INPs through the differential expression of bHLH-O family proteins. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice

    NARCIS (Netherlands)

    Bruggeman, SWM; Valk-Lingbeek, ME; van der Stoop, PPM; Jacobs, JJL; Kieboom, K; Tanger, E; Hulsman, D; Leung, C; Arsenijevic, Y; Marino, S; van Lohuizen, M

    2005-01-01

    The Polycomb group (PcG) gene Bmi1 promotes cell proliferation and stem cell self-renewal by repressing the Ink4a/Arf locus. We used a genetic approach to investigate whether Ink4a or Arf is more critical for relaying Bmi1 function in lymphoid cells, neural progenitors, and neural stem cells. We

  10. The cell cycle inhibitor p27Kip¹ controls self-renewal and pluripotency of human embryonic stem cells by regulating the cell cycle, Brachyury and Twist.

    Science.gov (United States)

    Menchón, Cristina; Edel, Michael J; Izpisua Belmonte, Juan Carlos

    2011-05-01

    The continued turn over of human embryonic stem cells (hESC) while maintaining an undifferentiated state is dependent on the regulation of the cell cycle. Here we asked the question if a single cell cycle gene could regulate the self-renewal or pluripotency properties of hESC. We identified that the protein expression of the p27(Kip)¹ cell cycle inhibitor is low in hESC cells and increased with differentiation. By adopting a gain and loss of function strategy we forced or reduced its expression in undifferentiating conditions to define its functional role in self-renewal and pluripotency. Using undifferentiation conditions, overexpression of p27(Kip)¹ in hESC lead to a G₁phase arrest with an enlarged and flattened hESC morphology and consequent loss of self-renewal ability. Loss of p27(Kip)¹ caused an elongated/scatter cell-like phenotype involving up-regulation of Brachyury and Twist gene expression. We demonstrate the novel finding that p27(Kip)¹ protein occupies the Twist1 gene promoter and manipulation of p27(Kip)¹ by gain and loss of function is associated with Twist gene expression changes. These results define p27(Kip)¹ expression levels as critical for self-renewal and pluripotency in hESC and suggest a role for p27(Kip)¹ in controlling an epithelial to mesenchymal transition (EMT) in hESC.

  11. The HPV16 E7 oncoprotein increases the expression of Oct3/4 and stemness-related genes and augments cell self-renewal.

    Science.gov (United States)

    Organista-Nava, Jorge; Gómez-Gómez, Yazmín; Ocadiz-Delgado, Rodolfo; García-Villa, Enrique; Bonilla-Delgado, José; Lagunas-Martínez, Alfredo; Tapia, Jesús Santa-Olalla; Lambert, Paul F; García-Carrancá, Alejandro; Gariglio, Patricio

    2016-12-01

    Oct3/4 is a transcription factor involved in maintenance of the pluripotency and self-renewal of stem cells. The E7 oncoprotein and 17β-estradiol (E 2 ) are key factors in cervical carcinogenesis. In the present study, we aimed to investigate the effect of the HPV16 E7 oncoprotein and E 2 on the expression pattern of Oct3/4, Sox2, Nanog and Fgf4. We also determined whether the E7 oncoprotein is associated with cell self-renewal. The results showed that Oct3/4, Sox2, Nanog and Fgf4 were upregulated by the E7 oncoprotein in vivo and in vitro and implicate E 2 in the upregulation of these factors in vivo. We also demonstrated that E7 is involved in cell self-renewal, suggesting that the HPV16 E7 oncoprotein upregulates Oct3/4, Sox2, Nanog and Fgf4 expression to maintain the self-renewal capacity of cancer stem cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Inhibition of Wnt/β-catenin signaling by IWR1 induces expression of Foxd3 to promote mouse epiblast stem cell self-renewal.

    Science.gov (United States)

    Liu, Kuisheng; Sun, Yuanyuan; Liu, Dahai; Ye, Shoudong

    2017-08-26

    Inhibition of Wnt/β-catenin signaling facilitates the derivation of mouse epiblast stem cells (EpiSCs), as well as dramatically promotes EpiSC self-renewal. The specific mechanism, however, is still unclear. Here, we showed that IWR1, a Wnt/β-catenin signaling inhibitor, allowed long-term self-renewal of EpiSCs in serum medium in combination with ROCK inhibitor Y27632. Through transcriptome data analysis, we arrived at a set of candidate transcription factors induced by IWR1. Among these, Forkhead box D3 (Foxd3) was most abundant. Forced expression of Foxd3 could recapitulate the self-renewal-promoting effect of IWR1 in EpiSCs. Conversely, knockdown of Foxd3 profoundly compromised responsiveness to IWR1, causing extinction of pluripotency markers and emergence of differentiation phenotype. Foxd3 thus is necessary and sufficient to mediate self-renewal downstream of Wnt/β-catenin signaling inhibitor. These findings highlight an important role for Foxd3 in regulating EpiSCs and will expand current understanding of the primed pluripotency. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Irradiation-injured brain tissues can self-renew in the absence of the pivotal tumor suppressor p53 in the medaka (Oryzias latipes) embryo

    International Nuclear Information System (INIS)

    Yasuda, Takako; Nagata, Kento; Igarashi, Kento; Watanabe-Asaka, Tomomi; Oda, Shoji; Mitani, Hiroshi; Kimori, Yoshitaka

    2016-01-01

    The tumor suppressor protein, p53, plays pivotal roles in regulating apoptosis and proliferation in the embryonic and adult central nervous system (CNS) following neuronal injuries such as those induced by ionizing radiation. There is increasing evidence that p53 negatively regulates the self-renewal of neural stem cells in the adult murine brain; however, it is still unknown whether p53 is essential for self-renewal in the injured developing CNS. Previously, we demonstrated that the numbers of apoptotic cells in medaka (Oryzias latipes) embryos decreased in the absence of p53 at 12-24 h after irradiation with 10-Gy gamma rays. Here, we used histology to examine the later morphological development of the irradiated medaka brain. In p53-deficient larvae, the embryonic brain possessed similar vacuoles in the brain and retina, although the vacuoles were much smaller and fewer than those found in wild-type embryos. At the time of hatching (6 days after irradiation), no brain abnormality was observed. In contrast, severe disorganized neuronal arrangements were still present in the brain of irradiated wild-type embryos. Our present results demonstrated that self-renewal of the brain tissue completed faster in the absence of p53 than wild type at the time of hatching because p53 reduces the acute severe neural apoptosis induced by irradiation, suggesting that p53 is not essential for tissue self-renewal in developing brain. (author)

  14. The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis.

    Directory of Open Access Journals (Sweden)

    Stephen N Sansom

    2009-06-01

    Full Text Available Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells

  15. Comprehensive Identification of Krüppel-Like Factor Family Members Contributing to the Self-Renewal of Mouse Embryonic Stem Cells and Cellular Reprogramming.

    Directory of Open Access Journals (Sweden)

    Hyojung Jeon

    Full Text Available Pluripotency is maintained in mouse embryonic stem (ES cells and is induced from somatic cells by the activation of appropriate transcriptional regulatory networks. Krüppel-like factor gene family members, such as Klf2, Klf4 and Klf5, have important roles in maintaining the undifferentiated state of mouse ES cells as well as in cellular reprogramming, yet it is not known whether other Klf family members exert self-renewal and reprogramming functions when overexpressed. In this study, we examined whether overexpression of any representative Klf family member, such as Klf1-Klf10, would be sufficient for the self-renewal of mouse ES cells. We found that only Klf2, Klf4, and Klf5 produced leukemia inhibitory factor (LIF-independent self-renewal, although most KLF proteins, if not all, have the ability to occupy the regulatory regions of Nanog, a critical Klf target gene. We also examined whether overexpression of any of Klf1-Klf10 would be sufficient to convert epiblast stem cells into a naïve pluripotent state and found that Klf5 had such reprogramming ability, in addition to Klf2 and Klf4. We also delineated the functional domains of the Klf2 protein for LIF-independent self-renewal and reprogramming. Interestingly, we found that both the N-terminal transcriptional activation and C-terminal zinc finger domains were indispensable for this activity. Taken together, our comprehensive analysis provides new insight into the contribution of Klf family members to mouse ES self-renewal and cellular reprogramming.

  16. Comprehensive Identification of Krüppel-Like Factor Family Members Contributing to the Self-Renewal of Mouse Embryonic Stem Cells and Cellular Reprogramming.

    Science.gov (United States)

    Jeon, Hyojung; Waku, Tsuyoshi; Azami, Takuya; Khoa, Le Tran Phuc; Yanagisawa, Jun; Takahashi, Satoru; Ema, Masatsugu

    2016-01-01

    Pluripotency is maintained in mouse embryonic stem (ES) cells and is induced from somatic cells by the activation of appropriate transcriptional regulatory networks. Krüppel-like factor gene family members, such as Klf2, Klf4 and Klf5, have important roles in maintaining the undifferentiated state of mouse ES cells as well as in cellular reprogramming, yet it is not known whether other Klf family members exert self-renewal and reprogramming functions when overexpressed. In this study, we examined whether overexpression of any representative Klf family member, such as Klf1-Klf10, would be sufficient for the self-renewal of mouse ES cells. We found that only Klf2, Klf4, and Klf5 produced leukemia inhibitory factor (LIF)-independent self-renewal, although most KLF proteins, if not all, have the ability to occupy the regulatory regions of Nanog, a critical Klf target gene. We also examined whether overexpression of any of Klf1-Klf10 would be sufficient to convert epiblast stem cells into a naïve pluripotent state and found that Klf5 had such reprogramming ability, in addition to Klf2 and Klf4. We also delineated the functional domains of the Klf2 protein for LIF-independent self-renewal and reprogramming. Interestingly, we found that both the N-terminal transcriptional activation and C-terminal zinc finger domains were indispensable for this activity. Taken together, our comprehensive analysis provides new insight into the contribution of Klf family members to mouse ES self-renewal and cellular reprogramming.

  17. Molecular integration of HoxB4 and STAT3 for self-renewal of hematopoietic stem cells: a model of molecular convergence for stemness.

    Science.gov (United States)

    Hong, Sung-Hyun; Yang, Seung-Jip; Kim, Tae-Min; Shim, Jae-Seung; Lee, Ho-Sun; Lee, Ga-Young; Park, Bo-Bae; Nam, Suk Woo; Ryoo, Zae Young; Oh, Il-Hoan

    2014-05-01

    The upregulation of HoxB4 promotes self-renewal of hematopoietic stem cells (HSCs) without overriding the normal stem cell pool size. A similar enhancement of HSC self-renewal occurs when signal transducer and activator of transcription 3 (STAT3) is activated in HSCs. In this study, to gain insight into the functional organization of individual transcription factors (TFs) that have similar effects on HSCs, we investigated the molecular interplay between HoxB4 and STAT3 in the regulation of HSC self-renewal. We found that while STAT3-C or HoxB4 similarly enhanced the in vitro self-renewal and in vivo repopulating activities of HSCs, simultaneous transduction of both TFs did not have additive effects, indicating their functional redundancy in HSCs. In addition, activation of STAT3 did not cause changes in the expression levels of HoxB4. In contrast, the inhibition of STAT3 activity in HoxB4-overexpressing hematopoietic cells significantly abrogated the enhancing effects of HoxB4, and the upregulation of HoxB4 caused a ligand-independent Tyr-phosphorylation of STAT3. Microarray analysis revealed a significant overlap of the transcriptomes regulated by STAT3 and HoxB4 in undifferentiated hematopoietic cells. Moreover, a gene set enrichment analysis showed significant overlap in the candidate TFs that can recapitulate the transcriptional changes induced by HoxB4 or STAT3. Interestingly, among these common TFs were the pluripotency-related genes Oct-4 and Nanog. These results indicate that tissue-specific TFs regulating HSC self-renewal are functionally organized to play an equivalent role in transcription and provide insights into the functional convergence of multiple entries of TFs toward a conserved transcription program for the stem cell state. © 2014 AlphaMed Press.

  18. α6β1- and αV-integrins are required for long-term self-renewal of murine embryonic stem cells in the absence of LIF.

    Science.gov (United States)

    Cattavarayane, Sandhanakrishnan; Palovuori, Riitta; Tanjore Ramanathan, Jayendrakishore; Manninen, Aki

    2015-02-27

    The growth properties and self-renewal capacity of embryonic stem (ES) cells are regulated by their immediate microenvironment such as the extracellular matrix (ECM). Integrins, a central family of cellular ECM receptors, have been implicated in these processes but their specific role in ES cell self-renewal remains unclear. Here we have studied the effects of different ECM substrates and integrins in mouse ES cells in the absence of Leukemia Inhibitory Factor (LIF) using short-term assays as well as long-term cultures. Removal of LIF from ES cell culture medium induced morphological differentiation of ES cells into polarized epistem cell-like cells. These cells maintained epithelial morphology and expression of key stemness markers for at least 10 passages in the absence of LIF when cultured on laminin, fibronectin or collagen IV substrates. The specific functional roles of α6-, αV- and β1-integrin subunits were dissected using stable lentivirus-mediated RNAi methodology. β1-integrins were required for ES cell survival in long-term cultures and for the maintenance of stem cell marker expression. Inhibition of α6-integrin expression compromised self-renewal on collagen while αV-integrins were required for robust ES cell adhesion on laminin. Analysis of the stemness marker expression revealed subtle differences between α6- and αV-depleted ES cells but the expression of both was required for optimal self-renewal in long-term ES cell cultures. In the absence of LIF, long-term ES cell cultures adapt an epistem cell-like epithelial phenotype and retain the expression of multiple stem cell markers. Long-term maintenance of such self-renewing cultures depends on the expression of β1-, α6- and αV-integrins.

  19. A parallel non-neural trigger tracker for the SSC

    International Nuclear Information System (INIS)

    Farber, R.M.; Kennison, W.; Lapedes, A.S.

    1991-01-01

    The Superconducting Super Collider (SSC) is a major project promising to open the vistas of very high particle physics. When the SSC is in operation, data will be produced at a staggering rate. Current estimates place the raw data coming our of the proposed silicon detector system at 2.5 x 10 16 bits/second. Clearly, storing all events for later off-line processing is totally impracticable. A hierarchy of triggers, firing only on events meeting increasingly specific criteria, are planned to cull interesting events from the flood of information. Each event consists of a sequence of isolated ''hits'', caused by particles hitting various parts of the detector. Collating these hits into the tracks of the approximately 500 particles/event, and then quickly deciding which events meet the criteria for later processing, is essential if the SSC is to produce usable information. This paper addresses the need for real-time triggering and track reconstruction. A benchmarked and buildable algorithm, operable at the required data rates, is described. The use of neural nets, suggested by other researchers, is specifically avoided as unnecessary and impractical. Instead, a parallel algorithm, and associated hardware architecture using only conventional technology, is presented. The algorithm has been tested on fully scaled up, extensively detailed, simulated SSC events, with extremely encouraging results. Preliminary hardware analysis indicate that the trigger/tracker may be built within proposed SSC budget guidelines. 7 refs., 4 figs

  20. HPV16-E2 protein modifies self-renewal and differentiation rate in progenitor cells of human immortalized keratinocytes.

    Science.gov (United States)

    Domínguez-Catzín, Victoria; Reveles-Espinoza, Alicia-María; Sánchez-Ramos, Janet; Cruz-Cadena, Raúl; Lemus-Hernández, Diana; Garrido, Efraín

    2017-04-03

    Cervical cancer is the fourth cause of death worldwide by cancer in women and is a disease associated to persistent infection with human papillomavirus (HPV), particularly from two high-risk types HPV16 and 18. The virus initiates its replicative cycle infecting cells located in the basal layer of the epithelium, where a small population of epithelial stem cells is located performing important functions of renewal and maintenance of the tissue. Viral E2 gene is one of the first expressed after infection and plays relevant roles in the replicative cycle of the virus, modifying fundamental processes in the infected cells. Thus, the aim of the present study was to demonstrate the presence of hierarchic subpopulations in HaCaT cell line and evaluate the effect of HPV16-E2 expression, on their biological processes. HaCaT-HPV16-E2 cells were generated by transduction of HaCaT cell line with a lentiviral vector. The α6-integrin-CD71 expression profile was established by immunostaining and flow cytometric analysis. After sorting, cell subpopulations were analyzed in biological assays for self-renewal, clonogenicity and expression of stemness factors (RT-qPCR). We identified in HaCaT cell line three different subpopulations that correspond to early differentiated cells (α6-integrin dim ), transitory amplifying cells (α6-integrin bri /CD71 bri ) and progenitor cells (α6-integrin bri /CD71 dim ). The last subpopulation showed stem cell characteristics, such as self-renewal ability, clonogenicity and expression of the well-known stem cell factors SOX2, OCT4 and NANOG, suggesting they are stem-like cells. Interestingly, the expression of HPV16-E2 in HaCaT cells changed its α6-integrin-CD71 immunophenotype modifying the relative abundance of the cell subpopulations, reducing significantly the percentage of α6-integrin bri /CD71 dim cells. Moreover, the expression of the stem cell markers was also modified, increasing the expression of SOX2 and NANOG, but decreasing notably

  1. The Super Fixed Target beauty facility at the SSC

    International Nuclear Information System (INIS)

    Lau, Kwong

    1991-01-01

    The rationale for pursuing beauty physics at the SSC in a fixed target configuration is described. The increased beauty production cross section at the SSC, combined with high interaction rate capability of the proposed detector, results in 10 10-11 produced BB events per year. The long decay length of the B hadrons (≅ 10 cm) allows direct observation of B decays in the high resolution silicon microstrip vertex detector. To optimize the operation of the proposed beauty spectrometer and the SSC, parasitic extraction of attendant or artificially generated large amplitude protons using crystal channeling is proposed and explored. The large sample of fully reconstructed B events allows detailed studies of various CP violating decays with requisite statistics to confront the standard model. The CP physics potential of the proposed experiment is evaluated and compared with alternative approaches, such as symmetric e + e - B Factories and specialized hadron colliders

  2. SSC RIAR is the largest centre of research reactors

    International Nuclear Information System (INIS)

    Kalygin, V.V.

    1997-01-01

    The State Scientific Centre (SSC) ''Research Institute of Atomic Reactors'' (RIAR) is situated 100 km to the south-east from Moscow, in Dimitrovgrad, the Volga Region of the Russian Federation. SSC RIAR is the largest centre of research reactors in Russia. At present there are 5 types of reactor facilities in operation, including two NPP. One of the main tasks the Centre is the investigations on safety increase for power reactors. Broad international connections are available at the Institute. On the basis of the SSC RIAR during 3 years work has been done on the development of the branch training centre (TC) for the training of operation personnel of research and pilot reactors in Russia. (author). 3 tabs

  3. SSC RIAR is the largest centre of research reactors

    Energy Technology Data Exchange (ETDEWEB)

    Kalygin, V V [State Scientific Centre, Research Inst. of Atomic Reactors (Russian Federation)

    1997-10-01

    The State Scientific Centre (SSC) ``Research Institute of Atomic Reactors`` (RIAR) is situated 100 km to the south-east from Moscow, in Dimitrovgrad, the Volga Region of the Russian Federation. SSC RIAR is the largest centre of research reactors in Russia. At present there are 5 types of reactor facilities in operation, including two NPP. One of the main tasks the Centre is the investigations on safety increase for power reactors. Broad international connections are available at the Institute. On the basis of the SSC RIAR during 3 years work has been done on the development of the branch training centre (TC) for the training of operation personnel of research and pilot reactors in Russia. (author). 3 tabs.

  4. An engineering design network for SSC detector development

    International Nuclear Information System (INIS)

    DiGiacomo, N.J.

    1990-01-01

    The detector systems that are being proposed to exploit the capabilities of the SSC are of a scale and scope that will make them among the most complex devices ever built. To successfully design and build these systems over the next decade, the authors must make use of integrated state of the art computer aided engineering and design (CAE/CAD) tools that have been developed and employed in industry. The challenge is to made these tools and associated engineering resources available to the spectrum of institutions - large and small universities, industries and national labs - involved in SSC detector development in such a way that each may contribute and participate in the most effective manner. The authors believe that powerful workstations running sophisticated modeling, analysis and simulation software, linked by high speed data networks and governed by modern configuration management methods offer the ideal means of arriving at the optimum detector configuration for physics at the SSC

  5. A high gradient quadrupole magnet for the SSC

    International Nuclear Information System (INIS)

    Taylor, C.; Caspi, S.; Helm, M.; Mirk, K.; Peters, C.; Wandesforde, A.

    1987-01-01

    A quadrupole magnet for the SSC has been designed with a gradient of 234 T/m at 6500 A. Coil I.D. is 40 mm. The two-layer windings have 9 inner turns and 13 outer turns per pole with a wedge-shaped space in each layer. The 30-strand cable is identical to that used in the outer layer of the SSC dipole magnet. Interlocking aluminum alloy collars are compressed around the coil using a four-way press and are locked with four keys. The collared coil is supported and centered in a cold split iron yoke. A one-meter model was constructed and tested. Design details including quench behavior are presented. The quadrupole magnets proposed for the main SSC rings have a design gradient of 230 T/m. For one proposed 60 degree lattice cell, each 3-m long quad is separated by five 17-m long dipole magnets

  6. Preliminary design implications of SSC fixed-target operation

    International Nuclear Information System (INIS)

    Zisman, M.S.

    1984-06-01

    This paper covers some of the accelerator physics issues relevant to a possible fixed-target operating mode for the Superconducting Super Collider (SSC). In the brief time available, no attempt has been made to design this capability into the SSC. Rather, I have tried to evaluate what the performance of such a machine might be, and to indicate the hardware implications and extraction considerations that would be part of an actual design study. Where appropriate, parameters and properties of the present LBL design for the SSC have been used; these should be taken as being representative of the general class of small-aperture, high-field colliders being considered by the accelerator physics community. Thus, the numerical examples given here must ultimately be reexamined in light of the actual parameters of the particular accelerator being considered

  7. The SSC superconducting air core toroid design development

    International Nuclear Information System (INIS)

    Fields, T.; Carroll, A.; Chiang, I.H.; Frank, J.S.; Haggerty, J.; Littenberg, L.; Morse, W.; Strand, R.C.; Lau, K.; Weinstein, R.; McNeil, R.; Friedman, J.; Hafen, E.; Haridas, P.; Kendall, H.W.; Osborne, L.; Pless, I.; Rosenson, L.; Pope, B.; Jones, L.W.; Luton, J.N.; Bonanos, P.; Marx, M.; Pusateri, J.A.; Favale, A.; Gottesman, S.; Schneid, E.; Verdier, R.

    1990-01-01

    Superconducting air core toroids show great promise for use in a muon spectrometer for the SSC. Early studies by SUNY at Stony Brook funded by SSC Laboratory, have established the feasibility of building magnets of the required size. The toroid spectrometer consists of a central toroid with two end cap toroids. The configuration under development provides for muon trajectory measurement outside the magnetic volume. System level studies on support structure, assembly, cryogenic material selection, and power are performed. Resulting selected optimal design and assembly is described. 4 refs., 6 figs

  8. SSC Tenant Meeting: NASA Near Earth Network (NEN) Overview

    Science.gov (United States)

    Carter, David; Larsen, David; Baldwin, Philip; Wilson, Cristy; Ruley, LaMont

    2018-01-01

    The Near Earth Network (NEN) consists of globally distributed tracking stations that are strategically located throughout the world which provide Telemetry, Tracking, and Commanding (TTC) services support to a variety of orbital and suborbital flight missions, including Low Earth Orbit (LEO), Geosynchronous Earth Orbit (GEO), highly elliptical, and lunar orbits. Swedish Space Corporation (SSC), which is one of the NEN Commercial Service Provider, has provided the NEN with TTC services support from its Alaska, Hawaii, Chile and Sweden. The presentation will give an overview of the NEN and its support from SSC.

  9. Tevatron as an SSC prototype; experience versus predictions

    International Nuclear Information System (INIS)

    Johnson, R.P.

    1984-01-01

    Early machine experiments on the Tevatron which are relevant to the SSC are discussed. Despite the preliminary nature of the data, there have been some interesting observations which may influence the design of the SSC. In particular, comparisons of measured betatron tunes, chromaticities, and resonance line widths with those predicted from computer simulations using magnetic field measurements have been made; the predictability for low order phenomena seems acceptable. Coasting beam studies indicate long lifetime and lack of strong resonance driving terms. Low energy studies of beam behavior indicate that a dynamic range of a factor of 15 from injection to operation energy should be possible

  10. EMPACT: An alternative approach to a high PT SSC experiment

    International Nuclear Information System (INIS)

    Marx, M.; State Univ. of New York, Stony Brook, NY

    1989-05-01

    A survey of high P T detector concepts advanced for the SSC reveals two striking facts -- first, the scale of most detectors is set by the muon detection system; and second, that the performance of these muon systems is limited in comparison to electron or jet capabilities, either in resolution or in rapidity acceptance. I propose here an alternative concept for an SSC experiment which will provide enhanced muon performance at a level to that obtainable through calorimetric means for electrons and jets, while drastically reducing the tonnage of the experiment

  11. Heater induced quenches in SSC [Superconducting Super Collider] model dipoles

    International Nuclear Information System (INIS)

    Hassenzahl, W.V.

    1986-10-01

    A 1-m long SSC dipole constructed at the Lawrence Berkeley laboratory was subjected to a series of heater induced quenches to determine: axial quench propagation velocities, transverse quench propagation, and conductor temperature rise. Quenches were produced by 3 heaters at different locations in the magnet and at several currents. The results of these studies are described and are compared to previously published theoretical studies of quenches on the SSC dipoles. These results are shown to be in agreement with the calculations of the program ''QUENCH'', which includes an increase of the quench velocity during the first few milliseconds of the quench

  12. Radioactivation in ''quiet'' sections of the SSC [Superconducting Super Collider

    International Nuclear Information System (INIS)

    Cossairt, J.D.

    1987-10-01

    Estimation of induced radioactivity in the ''quiet'' sections of the SSC is approached using elementary methods. Estimates are given of total activity and residual dose rates on the surface of magnets in the quiet regions, as well as estimates of the activation of tunnel concrete. The residual radioactivity produced in the magnets and concrete walls of the ''quiet'' regions of the SSC are found to be quite small and of little radiological impact, but that simple scaling could yield results for more ''lossy'' regions

  13. Full length SSC R and D dipole magnet test results

    International Nuclear Information System (INIS)

    Strait, J.; Bleadon, M.; Brown, B.C.

    1989-03-01

    Four full scale SSC development dipole magnets have been tested for mechanical and quench behavior. Two are of a design similar to previous magnets but contain a number of improvements, including more uniform coil size, higher pre-stress and a redesigned inner-outer coil splice. One exceeds the SSC operating current on the second quench but the other appears to be limited by damaged superconductor to a lower current. The other two magnets are of alternate designs. One trains erratically and fails to reach a plateau and the other reaches plateau after four quenches. 12 refs., 4 figs

  14. Fixed target beauty physics from Tevatron to SSC (E771)

    International Nuclear Information System (INIS)

    Lau, K.

    1992-01-01

    The E771 beauty experiment at Fermilab is described. The Super Fixed Target Beauty Facility (SFT) proposal to perform fixed target beauty physics at the SSC is a natural evolution. The unique features of SFT include crystal channeling extraction from the SSC main ring, which allows the experiment to operate concurrently with the collider experiments. The slow extraction rate (≅2x10 8 protons/s) does not limit the lifetime of the stored beams. The proposed beauty spectrometer and its capability in CP violation studies are described. (author) 19 refs.; 2 figs.; 2 tabs

  15. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma.

    Science.gov (United States)

    Shan, Juanjuan; Shen, Junjie; Liu, Limei; Xia, Feng; Xu, Chuan; Duan, Guangjie; Xu, Yanmin; Ma, Qinghua; Yang, Zhi; Zhang, Qianzhen; Ma, Leina; Liu, Jia; Xu, Senlin; Yan, Xiaochu; Bie, Ping; Cui, Youhong; Bian, Xiu-wu; Qian, Cheng

    2012-09-01

    Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem-cell-related genes are preferentially overexpressed in a fraction of cancer cells of poorly differentiated tumors. However, it is not known whether or how these cancer cells contribute to tumor initiation and progression. Here, our data showed that increased expression of pluripotency transcription factor Nanog in cancer cells correlates with a worse clinical outcome in HCC. Using the Nanog promoter as a reporter system, we could successfully isolate a small subpopulation of Nanog-positive cells. We demonstrate that Nanog-positive cells exhibited enhanced ability of self-renewal, clonogenicity, and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). Nanog(Pos) CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. In addition, we found that Nanog(Pos) CSCs exhibited resistance to therapeutic agents (e.g., sorafenib and cisplatin) and have a high capacity for tumor invasion and metastasis. Knock-down expression of Nanog in Nanog(Pos) CSCs could decrease self-renewal accompanied with decreased expression of stem-cell-related genes and increased expression of mature hepatocyte-related genes. Overexpression of Nanog in Nanog(Neg) cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF receptor (IGF1R) were up-regulated in Nanog(Pos) CSCs. Knock-down expression of Nanog in Nanog(Pos) CSCs inhibited the expression of IGF1R, and overexpression of Nanog in Nanog(Neg) cells increased the expression of IGF1R. A specific inhibitor of IGF1R signaling could significantly inhibit self-renewal and Nanog expression, indicating that IGF1R signaling participated in Nanog-mediated self-renewal. These data indicate that Nanog could be a novel biomarker for CSCs in HCC, and that Nanog could play a crucial role in maintaining the self-renewal of CSCs through the IGF1R

  16. ERK inhibition promotes neuroectodermal precursor commitment by blocking self-renewal and primitive streak formation of the epiblast.

    Science.gov (United States)

    Yu, Yang; Wang, Xiaoxiao; Zhang, Xiaoxin; Zhai, Yanhua; Lu, Xukun; Ma, Haixia; Zhu, Kai; Zhao, Tongbiao; Jiao, Jianwei; Zhao, Zhen-Ao; Li, Lei

    2018-01-05

    Pluripotent stem cells hold great promise for regenerative medicine. However, before clinical application, reproducible protocols for pluripotent stem cell differentiation should be established. Extracellular signal-regulated protein kinase (ERK) signaling plays a central role for the self-renewal of epiblast stem cells (EpiSCs), but its role for subsequent germ layer differentiation is still ambiguous. We proposed that ERK could modulate differentiation of the epiblast. PD0325901 was used to inhibit ERK activation during the differentiation of embryonic stem cells and EpiSCs. Immunofluorescence, western blot analysis, real-time PCR and flow cytometry were used to detect germ layer markers and pathway activation. We demonstrate that the ERK phosphorylation level is lower in neuroectoderm of mouse E7.5 embryos than that in the primitive streak. ERK inhibition results in neural lineage commitment of epiblast. Mechanistically, PD0325901 abrogates the expression of primitive streak markers by β-catenin retention in the cytoplasm, and inhibits the expression of OCT4 and NANOG during EpiSC differentiation. Thus, EpiSCs differentiate into neuroectodermal lineage efficiently under PD0325901 treatment. These results suggest that neuroectoderm differentiation does not require extrinsic signals, supporting the default differentiation of neural lineage. We report that a single ERK inhibitor, PD0325901, can specify epiblasts and EpiSCs into neural-like cells, providing an efficient strategy for neural differentiation.

  17. Histone Methylation and microRNA-dependent Regulation of Epigenetic Activities in Neural Progenitor Self-Renewal and Differentiation.

    Science.gov (United States)

    Cacci, Emanuele; Negri, Rodolfo; Biagioni, Stefano; Lupo, Giuseppe

    2017-01-01

    Neural stem/progenitor cell (NSPC) self-renewal and differentiation in the developing and the adult brain are controlled by extra-cellular signals and by the inherent competence of NSPCs to produce appropriate responses. Stage-dependent responsiveness of NSPCs to extrinsic cues is orchestrated at the epigenetic level. Epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNA-mediated regulation control crucial aspects of NSPC development and function, and are also implicated in pathological conditions. While their roles in the regulation of stem cell fate have been largely explored in pluripotent stem cell models, the epigenetic signature of NSPCs is also key to determine their multipotency as well as their progressive bias towards specific differentiation outcomes. Here we review recent developments in this field, focusing on the roles of histone methylation marks and the protein complexes controlling their deposition in NSPCs of the developing cerebral cortex and the adult subventricular zone. In this context, we describe how bivalent promoters, carrying antagonistic epigenetic modifications, feature during multiple steps of neural development, from neural lineage specification to neuronal differentiation. Furthermore, we discuss the emerging cross-talk between epigenetic regulators and microRNAs, and how the interplay between these different layers of regulation can finely tune the expression of genes controlling NSPC maintenance and differentiation. In particular, we highlight recent advances in the identification of astrocyte-enriched microRNAs and their function in cell fate choices of NSPCs differentiating towards glial lineages.

  18. Single-Cell Analyses of ESCs Reveal Alternative Pluripotent Cell States and Molecular Mechanisms that Control Self-Renewal

    Directory of Open Access Journals (Sweden)

    Dmitri Papatsenko

    2015-08-01

    Full Text Available Analyses of gene expression in single mouse embryonic stem cells (mESCs cultured in serum and LIF revealed the presence of two distinct cell subpopulations with individual gene expression signatures. Comparisons with published data revealed that cells in the first subpopulation are phenotypically similar to cells isolated from the inner cell mass (ICM. In contrast, cells in the second subpopulation appear to be more mature. Pluripotency Gene Regulatory Network (PGRN reconstruction based on single-cell data and published data suggested antagonistic roles for Oct4 and Nanog in the maintenance of pluripotency states. Integrated analyses of published genomic binding (ChIP data strongly supported this observation. Certain target genes alternatively regulated by OCT4 and NANOG, such as Sall4 and Zscan10, feed back into the top hierarchical regulator Oct4. Analyses of such incoherent feedforward loops with feedback (iFFL-FB suggest a dynamic model for the maintenance of mESC pluripotency and self-renewal.

  19. Nuclear Factor Erythroid 2 Regulates Human HSC Self-Renewal and T Cell Differentiation by Preventing NOTCH1 Activation.

    Science.gov (United States)

    Di Tullio, Alessandro; Passaro, Diana; Rouault-Pierre, Kevin; Purewal, Sukhveer; Bonnet, Dominique

    2017-07-11

    Nuclear factor erythroid-derived 2 (NF-E2) has been associated with megakaryocyte maturation and platelet production. Recently, an increased in NF-E2 activity has been implicated in myeloproliferative neoplasms. Here, we investigate the role of NF-E2 in normal human hematopoiesis. Knockdown of NF-E2 in the hematopoietic stem and progenitor cells (HSPCs) not only reduced the formation of megakaryocytes but also drastically impaired hematopoietic stem cell activity, decreasing human engraftment in immunodeficient (NSG) mice. This phenotype is likely to be related to both increased cell proliferation (p21-mediated) and reduced Notch1 protein expression, which favors HSPC differentiation over self-renewal. Strikingly, although NF-E2 silencing in HSPCs did not affect their myeloid and B cell differentiation in vivo, it almost abrogated T cell production in primary hosts, as confirmed by in vitro studies. This effect is at least partly due to Notch1 downregulation in NF-E2-silenced HSPCs. Together these data reveal that NF-E2 is an important driver of human hematopoietic stem cell maintenance and T lineage differentiation. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.

    Science.gov (United States)

    He, Xi C; Zhang, Jiwang; Tong, Wei-Gang; Tawfik, Ossama; Ross, Jason; Scoville, David H; Tian, Qiang; Zeng, Xin; He, Xi; Wiedemann, Leanne M; Mishina, Yuji; Li, Linheng

    2004-10-01

    In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

  1. Rotator cuff tear state modulates self-renewal and differentiation capacity of human skeletal muscle progenitor cells.

    Science.gov (United States)

    Thomas, Kelsey A; Gibbons, Michael C; Lane, John G; Singh, Anshuman; Ward, Samuel R; Engler, Adam J

    2017-08-01

    Full thickness rotator cuff tendon (RCT) tears have long-term effects on RC muscle atrophy and fatty infiltration, with lasting damage even after surgical tendon repair. Skeletal muscle progenitor cells (SMPs) are critical for muscle repair in response to injury, but the inability of RC muscles to recover from chronic RCT tear indicates possible deficits in repair mechanisms. Here we investigated if muscle injury state was a crucial factor during human SMP expansion and differentiation ex vivo. SMPs were isolated from muscles in patients with no, partial-thickness (PT), or full-thickness (FT) RCT tears. Despite using growth factors, physiological niche stiffness, and muscle-mimetic extracellular matrix (ECM) proteins, we found that SMPs isolated from human RC muscle with RCT tears proliferated slower but fused into myosin heavy chain (MHC)-positive myotubes at higher rates than SMPs from untorn RCTs. Proteomic analysis of RC muscle tissue revealed shifts in muscle composition with pathology, as muscle from massive RCT tears had increased ECM deposition compared with no tear RC muscle. Together these data imply that the remodeled niche in a torn RCT primes SMPs not for expansion but for differentiation, thus limiting longer-term self-renewal necessary for regeneration after surgical repair. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1816-1823, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  2. DIDO as a Switchboard that Regulates Self-Renewal and Differentiation in Embryonic Stem Cells.

    Science.gov (United States)

    Fütterer, Agnes; de Celis, Jésus; Navajas, Rosana; Almonacid, Luis; Gutiérrez, Julio; Talavera-Gutiérrez, Amaia; Pacios-Bras, Cristina; Bernascone, Ilenia; Martin-Belmonte, Fernando; Martinéz-A, Carlos

    2017-04-11

    Transition from symmetric to asymmetric cell division requires precise coordination of differential gene expression. We show that embryonic stem cells (ESCs) mainly express DIDO3 and that their differentiation after leukemia inhibitory factor withdrawal requires DIDO1 expression. C-terminal truncation of DIDO3 (Dido3ΔCT) impedes ESC differentiation while retaining self-renewal; small hairpin RNA-Dido1 ESCs have the same phenotype. Dido3ΔCT ESC differentiation is rescued by ectopic expression of DIDO3, which binds the Dido locus via H3K4me3 and RNA POL II and induces DIDO1 expression. DIDO1, which is exported to cytoplasm, associates with, and is N-terminally phosphorylated by PKCiota. It binds the E3 ubiquitin ligase WWP2, which contributes to cell fate by OCT4 degradation, to allow expression of primitive endoderm (PE) markers. PE formation also depends on phosphorylated DIDO3 localization to centrosomes, which ensures their correct positioning for PE cell polarization. We propose that DIDO isoforms act as a switchboard that regulates genetic programs for ESC transition from pluripotency maintenance to promotion of differentiation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. FOXP3 inhibits cancer stem cell self-renewal via transcriptional repression of COX2 in colorectal cancer cells.

    Science.gov (United States)

    Liu, Shuo; Zhang, Cun; Zhang, Kuo; Gao, Yuan; Wang, Zhaowei; Li, Xiaoju; Cheng, Guang; Wang, Shuning; Xue, Xiaochang; Li, Weina; Zhang, Wei; Zhang, Yingqi; Xing, Xianghui; Li, Meng; Hao, Qiang

    2017-07-04

    Colon cancer stem cell (cCSC) is considered as the seed cell of colon cancer initiation and metastasis. Cyclooxygenase-2 (COX2), a downstream target of NFκB, is found to be essential in promoting cancer stem cell renewal. However, how COX2 is dysregulated in cCSCs is largely unknown. In this study, we found that the expression of transcription factor FOXP3 was much lower in the spheroids than that in the parental tumor cells. Overexpression of FOXP3 significantly decreased the numbers of spheres, reduced the side population. Accordingly, FOXP3 expression decreased the tumor size and weight in the xenograft model. The tumor inhibitory effects of FOXP3 were rarely seen when COX2 was additionally knocked down. Mechanically, FOXP3 transcriptionally repressed COX2 expression via interacting with and thus inhibiting p65 activity on the putative NFκB response elements in COX2 promoter. Taken together, we here revealed possible involvement of FOXP3 in regulating cCSC self-renewal via tuning COX2 expression, and thus providing a new target for the eradication of colon cancer stem cells.

  4. Nuclear Factor Erythroid 2 Regulates Human HSC Self-Renewal and T Cell Differentiation by Preventing NOTCH1 Activation

    Directory of Open Access Journals (Sweden)

    Alessandro Di Tullio

    2017-07-01

    Full Text Available Nuclear factor erythroid-derived 2 (NF-E2 has been associated with megakaryocyte maturation and platelet production. Recently, an increased in NF-E2 activity has been implicated in myeloproliferative neoplasms. Here, we investigate the role of NF-E2 in normal human hematopoiesis. Knockdown of NF-E2 in the hematopoietic stem and progenitor cells (HSPCs not only reduced the formation of megakaryocytes but also drastically impaired hematopoietic stem cell activity, decreasing human engraftment in immunodeficient (NSG mice. This phenotype is likely to be related to both increased cell proliferation (p21-mediated and reduced Notch1 protein expression, which favors HSPC differentiation over self-renewal. Strikingly, although NF-E2 silencing in HSPCs did not affect their myeloid and B cell differentiation in vivo, it almost abrogated T cell production in primary hosts, as confirmed by in vitro studies. This effect is at least partly due to Notch1 downregulation in NF-E2-silenced HSPCs. Together these data reveal that NF-E2 is an important driver of human hematopoietic stem cell maintenance and T lineage differentiation.

  5. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells

    Science.gov (United States)

    Kobayashi, Hideki; Butler, Jason M.; O'Donnell, Rebekah; Kobayashi, Mariko; Ding, Bi-Sen; Bonner, Bryant; Chiu, Vi K.; Nolan, Daniel J.; Shido, Koji; Benjamin, Laura; Rafii, Shahin

    2010-01-01

    Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34−Flt3− KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34−Flt3− KLS HSPCs with LT-HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the upregulation of angiocrine factors, with Akt–mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs. PMID:20972423

  6. The Satellite Cell Niche Regulates the Balance between Myoblast Differentiation and Self-Renewal via p53.

    Science.gov (United States)

    Flamini, Valentina; Ghadiali, Rachel S; Antczak, Philipp; Rothwell, Amy; Turnbull, Jeremy E; Pisconti, Addolorata

    2018-03-13

    Satellite cells are adult muscle stem cells residing in a specialized niche that regulates their homeostasis. How niche-generated signals integrate to regulate gene expression in satellite cell-derived myoblasts is poorly understood. We undertook an unbiased approach to study the effect of the satellite cell niche on satellite cell-derived myoblast transcriptional regulation and identified the tumor suppressor p53 as a key player in the regulation of myoblast quiescence. After activation and proliferation, a subpopulation of myoblasts cultured in the presence of the niche upregulates p53 and fails to differentiate. When satellite cell self-renewal is modeled ex vivo in a reserve cell assay, myoblasts treated with Nutlin-3, which increases p53 levels in the cell, fail to differentiate and instead become quiescent. Since both these Nutlin-3 effects are rescued by small interfering RNA-mediated p53 knockdown, we conclude that a tight control of p53 levels in myoblasts regulates the balance between differentiation and return to quiescence. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Wnt/β-catenin and LIF-Stat3 signaling pathways converge on Sp5 to promote mouse embryonic stem cell self-renewal.

    Science.gov (United States)

    Ye, Shoudong; Zhang, Dongming; Cheng, Fei; Wilson, Daniel; Mackay, Jeffrey; He, Kan; Ban, Qian; Lv, Feng; Huang, Saifei; Liu, Dahai; Ying, Qi-Long

    2016-01-15

    Activation of leukemia inhibitor factor (LIF)-Stat3 or Wnt/β-catenin signaling promotes mouse embryonic stem cell (mESC) self-renewal. A myriad of downstream targets have been identified in the individual signal pathways, but their common targets remain largely elusive. In this study, we found that the LIF-Stat3 and Wnt/β-catenin signaling pathways converge on Sp5 to promote mESC self-renewal. Forced Sp5 expression can reproduce partial effects of Wnt/β-catenin signaling but mimics most features of LIF-Stat3 signaling to maintain undifferentiated mESCs. Moreover, Sp5 is able to convert mouse epiblast stem cells into a naïve pluripotent state. Thus, Sp5 is an important component of the regulatory network governing mESC naïve pluripotency. © 2016. Published by The Company of Biologists Ltd.

  8. Searching for quark and lepton compositeness at the SSC

    International Nuclear Information System (INIS)

    Albright, C.H.; Bars, I.; Blumenfeld, B.

    1984-01-01

    We examine a variety of issues connected with searching for compositeness at the SSC. These include effects of resolution, alternative methods of looking for deviations from QCD predictions, advantages of polarized beams, and effects of compositeness on photon detection. We also consider how physics may look if the compositeness scale is as low as a few TeV. 17 refs

  9. Calculation of injection and extraction orbits for the IPCR SSC

    International Nuclear Information System (INIS)

    Goto, A.; Yano, Y.; Kishida, N.; Nakanishi, N.; Wada, T.

    1982-01-01

    Calculations of beam trajectories in the injection and extraction systems for the IPCR SSC were done and the characteristics of those elements were determined. Beam centering for single turn extraction by use of first harmonic fields were also studied. The rather simple conditions at the injection point for a well-centered acceleration orbit are also discussed

  10. Fermilab R and D test facility for SSC magnets

    International Nuclear Information System (INIS)

    Strait, J.; Bleadon, M.; Hanft, R.; Lamm, M.; McGuire, K.; Mantsch, P.; Mazur, P.O.; Orris, D.; Pachnik, J.

    1989-01-01

    The test facility used for R and D testing of full scale development dipole magnets for the SSC is described. The Fermilab Magnet Test Facility, originally built for production testing of Tevatron magnets, has been substantially modified to allow testing also of SSC magnets. Two of the original six test stands have been rebuilt to accommodate testing of SSC magnets at pressures between 1.3 Atm and 4 Atm and at temperatures between 1.8 K and 4.8 K and the power system has been modified to allow operation to at least 8 kA. Recent magnets have been heavily instrumented with voltage taps to allow detailed study of quench location and propagation and with strain gage based stress, force and motion transducers. A data acquisition system has been built with a capacity to read from each SSC test stand up to 220 electrical quench signals, 32 dynamic pressure, temperature and mechanical transducer signals during quench and up to 200 high precision, low time resolution, pressure, temperature and mechanical transducer signals. The quench detection and protection systems is also described. 23 refs., 4 figs. 2 tabs

  11. Cooldown and warmup computer simulations of the SSC ring

    International Nuclear Information System (INIS)

    Carcagno, R.H.; Schiesser, W.E.; Yuecel, A.

    1991-06-01

    The Superconducting Super Collider (SSC) consists of two stacked rings of superconducting magnets; each ring is about 86 km in circumference. The total mass to be cooled to liquid helium temperature amounts to about 1 x 10 8 kg, and the total helium inventory under nominal operating conditions (4.15 K and 4 atm) is about 2.8 x 10 5 kg. The cooldown and warmup process of a long string of magnets has to be well understood in order to design a cryogenic system that can satisfy the requirements of helium inventory handling, magnet temperature gradients, and process time for the different cooldown and warmup scenarios being planned for the SSC. A system that can be convincingly simulated can be understood, controlled, operated and improved in a systematic way. In this paper, we introduce two numerical models, a lumped model and a distributed model, for cooldown and warmup of the SSC ring, and present simulation results for an SSC string (4320 m long, or 1/20th of the full ring circumference). The models cover the temperature range between room and liquid helium temperature; the distributed model includes radial temperature distribution in the cold mass. Low temperature range simulations are particularly important to study inventory handling strategies because of the relationship between rapid changes in density and the system mass flow rate. 9 refs., 9 figs

  12. Probing the non-minimal Higgs sector at the SSC

    International Nuclear Information System (INIS)

    Gunion, J.F.; Haber, H.E.; Komamiya, S.; Yamamoto, H.; Barbaro-Galtieri, A.

    1987-11-01

    Non-minimal Higgs sectors occur in the Standard Model with more than one Higgs doublet, as well as in theories that go beyond the Standard Model. In this report, we discuss how Higgs search strategies must be altered, with respect to the Standard Model approaches, in order to probe the non-minimal Higgs sectors at the SSC

  13. Quench propagation across the copper wedges in SSC dipoles

    International Nuclear Information System (INIS)

    Ghosh, A.K.; Robins, K.E.; Sampson, W.B.

    1986-01-01

    The effect of copper wedges on quench propagation in SSC windings has been studied. The results indicate that the turn-to-turn quench transit time for conductors separated by an insulated copper wedge can be predicted with reasonable accuracy from the bulk quench properties and the mean wedge thickness

  14. Plans for industrial production of the SSC magnets

    International Nuclear Information System (INIS)

    Karpenko, V.N.; Rardin, D.C.

    1986-01-01

    The Universities Research Association through its Central Design Group is currently conducting research and development for the Department of Energy on a superconducting super collider (SSC). The proposed SSC is a device in which protons would be accelerated around a ring approximately 50 miles in circumference. The protons would be kept in their path by means of thousands of powerful superconducting magnets. Two such rings of magnets would be housed in a common underground tunnel, allowing groups of protons to be accelerated in opposite directions and collided, in order to study the fundamental nature of matter and energy. The magnet system is a major element of the SSC in terms of technical requirements, quantity of components and cost. In order to meet technical and production requirements imposed by this system early participation of industry is necessary. The program plans were developed with the objective to involve industry in the early stages of research and development of superconducting magnets, leading to cost effective processes of potential mass production of high quality accelerator magnets by industry. While a decision has not been made by the Department of Energy on whether or not to request construction of the SSC project, if such a request is made and the project is authorized and funded, it would lead to industrial manufacture of a large quantity of superconducting magnets

  15. Partial lifetime test of an SSC Collider dipole

    International Nuclear Information System (INIS)

    Wanderer, P.; Anerella, M.; Ganetis, G.

    1993-01-01

    Over a period of ten months, a 15 m-long, 50 mm-aperture superconducting SSC Collider dipole was taken through a series of thermal and power cycles to check for changes in performance. One quench below operating current was experienced during this period. Small changes in the coil preload and certain harmonics were observed

  16. Preaccident modeling of an LMFBR plant for SSC-L

    International Nuclear Information System (INIS)

    Agrawal, A.K.

    1976-12-01

    Physical models for various processes in preaccident or steady-state calculations for the entire liquid metal fast breeder reactor plant are described in this report. A computer program for this initialization phase was written to serve as the starting point for the transient version of the SSC-L code. All of the models and programming are applicable to the ''loop'' type plants

  17. Anti-proteinase 3 antibodies in diffuse systemic sclerosis (SSc with normotensive renal impairment: is it suggestive for an overlapping between SSc and idiopathic vasculitis?

    Directory of Open Access Journals (Sweden)

    V. Campanella

    2011-09-01

    Full Text Available Objective. To test the prevalence of anti-neutrophil cytoplasmic antibodies (ANCA in systemic sclerosis (SSc and to verify a possible association of ANCA with normotensive renal involvement in SSc. Patients and methods: 51 patients affected by SSc, 35 with diffuse scleroderma (dSSc and 16 with limited scleroderma (lSSc, were tested for ANCA by indirect immunofluorescence (IIF on human ethanol and formalin-acetone-fixed granulocytes (before and after DNase treatment, by conventional enzyme linked immuno-sorbent assay (ELISA and by capture-ELISA. Results. Six out of 51 selected SSc patients had ANCA by IIF (11.7% and five presented a perinuclear/nuclear atypical ANCA pattern. In all cases we only found anti-proteinase3 (aPR3 antibodies. All ANCA positive patients had diffuse form of SSc (17.1%, all were anti-Scl70 positive (aScl70, five patients had proteinuria, three had microscopic haematuria. All ANCA positive patients were normotensive with normal renin plasma levels, the mean erythrocyte sedimentation rate (ESR was higher in this group compared to the other SSc patients. Conclusions. Our study shows that aPR3 is not rare in dSSc. According to the clinical and serological findings and to the recent literature, we can hypothesise that when ANCA are found in SSc, an overlapping of scleroderma with systemic necrotizing vasculitis should be suspected.

  18. The B-MYB transcriptional network guides cell cycle progression and fate decisions to sustain self-renewal and the identity of pluripotent stem cells.

    Science.gov (United States)

    Zhan, Ming; Riordon, Daniel R; Yan, Bin; Tarasova, Yelena S; Bruweleit, Sarah; Tarasov, Kirill V; Li, Ronald A; Wersto, Robert P; Boheler, Kenneth R

    2012-01-01

    Embryonic stem cells (ESCs) are pluripotent and have unlimited self-renewal capacity. Although pluripotency and differentiation have been examined extensively, the mechanisms responsible for self-renewal are poorly understood and are believed to involve an unusual cell cycle, epigenetic regulators and pluripotency-promoting transcription factors. Here we show that B-MYB, a cell cycle regulated phosphoprotein and transcription factor critical to the formation of inner cell mass, is central to the transcriptional and co-regulatory networks that sustain normal cell cycle progression and self-renewal properties of ESCs. Phenotypically, B-MYB is robustly expressed in ESCs and induced pluripotent stem cells (iPSCs), and it is present predominantly in a hypo-phosphorylated state. Knockdown of B-MYB results in functional cell cycle abnormalities that involve S, G2 and M phases, and reduced expression of critical cell cycle regulators like ccnb1 and plk1. By conducting gene expression profiling on control and B-MYB deficient cells, ChIP-chip experiments, and integrative computational analyses, we unraveled a highly complex B-MYB-mediated transcriptional network that guides ESC self-renewal. The network encompasses critical regulators of all cell cycle phases and epigenetic regulators, pluripotency transcription factors, and differentiation determinants. B-MYB along with E2F1 and c-MYC preferentially co-regulate cell cycle target genes. B-MYB also co-targets genes regulated by OCT4, SOX2 and NANOG that are significantly associated with stem cell differentiation, embryonic development, and epigenetic control. Moreover, loss of B-MYB leads to a breakdown of the transcriptional hierarchy present in ESCs. These results coupled with functional studies demonstrate that B-MYB not only controls and accelerates cell cycle progression in ESCs it contributes to fate decisions and maintenance of pluripotent stem cell identity.

  19. Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice

    Directory of Open Access Journals (Sweden)

    Peng Zhang

    2016-06-01

    Full Text Available De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss as well as conditional deletion in osteoblasts and their progenitors led to significant bone loss and a markedly decreased number of bone marrow stromal cells (BMSCs compared with wild-type littermates. Asxl1−/− BMSCs displayed impaired self-renewal and skewed differentiation, away from osteoblasts and favoring adipocytes. RNA-sequencing analysis revealed altered expression of genes involved in cell proliferation, skeletal development, and morphogenesis. Furthermore, gene set enrichment analysis showed decreased expression of stem cell self-renewal gene signature, suggesting a role of Asxl1 in regulating the stemness of BMSCs. Importantly, re-introduction of Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1−/− BMSCs. Our study unveils a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development.

  20. Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice.

    Science.gov (United States)

    Zhang, Peng; Xing, Caihong; Rhodes, Steven D; He, Yongzheng; Deng, Kai; Li, Zhaomin; He, Fuhong; Zhu, Caiying; Nguyen, Lihn; Zhou, Yuan; Chen, Shi; Mohammad, Khalid S; Guise, Theresa A; Abdel-Wahab, Omar; Xu, Mingjiang; Wang, Qian-Fei; Yang, Feng-Chun

    2016-06-14

    De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss as well as conditional deletion in osteoblasts and their progenitors led to significant bone loss and a markedly decreased number of bone marrow stromal cells (BMSCs) compared with wild-type littermates. Asxl1(-/-) BMSCs displayed impaired self-renewal and skewed differentiation, away from osteoblasts and favoring adipocytes. RNA-sequencing analysis revealed altered expression of genes involved in cell proliferation, skeletal development, and morphogenesis. Furthermore, gene set enrichment analysis showed decreased expression of stem cell self-renewal gene signature, suggesting a role of Asxl1 in regulating the stemness of BMSCs. Importantly, re-introduction of Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1(-/-) BMSCs. Our study unveils a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. Lhx2 expression promotes self-renewal of a distinct multipotential hematopoietic progenitor cell in embryonic stem cell-derived embryoid bodies.

    Directory of Open Access Journals (Sweden)

    Lina Dahl

    Full Text Available The molecular mechanisms regulating the expansion of the hematopoietic system including hematopoietic stem cells (HSCs in the fetal liver during embryonic development are largely unknown. The LIM-homeobox gene Lhx2 is a candidate regulator of fetal hematopoiesis since it is expressed in the fetal liver and Lhx2(-/- mice die in utero due to severe anemia. Moreover, expression of Lhx2 in embryonic stem (ES cell-derived embryoid bodies (EBs can lead to the generation of HSC-like cell lines. To further define the role of this transcription factor in hematopoietic regulation, we generated ES cell lines that enabled tet-inducible expression of Lhx2. Using this approach we observed that Lhx2 expression synergises with specific signalling pathways, resulting in increased frequency of colony forming cells in developing EB cells. The increase in growth factor-responsive progenitor cells directly correlates to the efficiency in generating HSC-like cell lines, suggesting that Lhx2 expression induce self-renewal of a distinct multipotential hematopoietic progenitor cell in EBs. Signalling via the c-kit tyrosine kinase receptor and the gp130 signal transducer by IL-6 is necessary and sufficient for the Lhx2 induced self-renewal. While inducing self-renewal of multipotential progenitor cells, expression of Lhx2 inhibited proliferation of primitive erythroid precursor cells and interfered with early ES cell commitment, indicating striking lineage specificity of this effect.

  2. The SSC dipole: Its conceptual origin and early design history

    International Nuclear Information System (INIS)

    Dahl, P.F.

    1992-05-01

    The magnet system for the Superconducting Super Collider will likely remain the most ambitions-and challenging-application of superconducting technology for the foreseeable future. The centerpiece of the system is the behemoth collider dipole magnet. Its design, still evolving in its detailed features, dates from the mid-1980's when it emerged as the winter in an early technical showdown that occupied the fledgling SSC project. In the present report we chronicle the origins and chief milestones in the development of certain SSC dipole design concepts. Unfortunately, the chronicle must remain incomplete, with the design not yet frozen as we go to press and still subject to important modifications as the SSC Laboratory settles in near its future home in Ellis County, Texas, hard on the heels of a wide-ranging design review in the closing days of the SSC Central Design Group in (CDG) Berkeley. Be that as it may, in what follows we concentrate on the early years in an attempt to recapitulate the birth of the dipole, taking as our point of departure the SSC Reference Designs Study (RDS) of 1984. In Section 3 we touch on the background for the various RDS options, including ISABELLE/CBA and the Tevatron. In Section 4 the narrative focuses on the two final protagonists, a high-field cosine theta (cos θ) magnet and a low-field superferric magnet. Section 5 recounts the circumstances surrounding the selection of a particular magnet ''style'' for further development, and the ups and downs of the first model magnets. We conclude with a smattering of progress highlights in refining the design during the final push under the reign of the CDG. Beyond that, the ongoing chronicle must be left for others to amplify and complete

  3. The SSC dipole: Its conceptual origin and early design history

    International Nuclear Information System (INIS)

    Dahl, P.F.

    1990-06-01

    The magnet system for the Superconducting Super Collider will likely remain the most ambitious -- and challenging -- application of superconducting technology for the foreseeable future. The centerpiece of the system is the behemoth collider dipole magnet. Its design, still evolving in its detailed features, dates from the mid-1980's when it emerged as the winner in an early technical showdown that occupied the fledgling SSC project. However, some of its gross features can be traced back to three path-breaking superconducting accelerator initiatives under way a decade earlier -- on the East Coast, on the West Coast, and in the Midwest. Other features have a still earlier legacy. In the present report we chronicle the origins and chief milestones in the development of certain SSC dipole design concepts. Unfortunately, the chronicle must remain incomplete, with the design not yet frozen as we go to press and still subject to important modifications as the SSC Laboratory settles in near its future home in Ellis County, Texas, hard on the heels of a wide-ranging design review in the closing days of the SSC Central Design Group in (CDG) Berkeley. Be that as it may, in what follows we concentrate on the early years in an attempt to recapitulate the birth of the dipole, taking as our point of departure the SSC Reference Designs Study (RDS) of 1984. In Section 3 we touch on the background for the various RDS options, including ISABELLE/CBA and the Tevatron. In Section 4 the narrative focuses on the two final protagonists, a high-field cosine theta (cos θ) magnet and a low-field superferric magnet. Section 5 recounts the circumstances surrounding the selection of a particular magnet ''style'' for further development, and the ups and downs of the first model magnets. We conclude with a smattering of progress highlights in refining the design during the final push under the reign of the CDG

  4. Differential effects on cell motility, embryonic stem cell self-renewal and senescence by diverse Src kinase family inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Tamm, Christoffer, E-mail: christoffer.tamm@imbim.uu.se; Galito, Sara Pijuan, E-mail: sara.pijuan@imbim.uu.se; Anneren, Cecilia, E-mail: cecilia.anneren@imbim.uu.se

    2012-02-15

    The Src family of non-receptor tyrosine kinases (SFKs) has been shown to play an intricate role in embryonic stem (ES) cell maintenance. In the present study we have focused on the underlying molecular mechanisms responsible for the vastly different effects induced by various commonly used SFK inhibitors. We show that several diverse cell types, including fibroblasts completely lacking SFKs, cannot undergo mitosis in response to SU6656 and that this is caused by an unselective inhibition of Aurora kinases. In contrast, PP2 and PD173952 block motility immediately upon exposure and forces cells to grow in dense colonies. The subsequent halt in proliferation of fibroblast and epithelial cells in the center of the colonies approximately 24 h post-treatment appears to be caused by cell-to-cell contact inhibition rather than a direct effect of SFK kinase inhibition. Interestingly, in addition to generating more homogenous and dense ES cell cultures, without any diverse effect on proliferation, PP2 and PD173652 also promote ES cell self-renewal by reducing the small amount of spontaneous differentiation typically observed under standard ES cell culture conditions. These effects could not be mirrored by the use of Gleevec, a potent inhibitor of c-Abl and PDGFR kinases that are also inhibited by PP2. -- Highlights: Black-Right-Pointing-Pointer SFK inhibitor SU6656 induces senescence in mouse ES cells. Black-Right-Pointing-Pointer SU6656 inhibits mitosis in a SFK-independent manner via cross-selectivity for Aurora kinases. Black-Right-Pointing-Pointer SFK inhibitor PP2 impairs cell motility in various cell lines, including mouse ES cells. Black-Right-Pointing-Pointer Ensuing impeded motility, PP2 inhibits proliferation of various cells lines except for mouse ES cells. Black-Right-Pointing-Pointer SFK inhibitors PP2 and PD173952 impede spontaneous differentiation in standard mouse ES culture maintenance.

  5. Differential effects on cell motility, embryonic stem cell self-renewal and senescence by diverse Src kinase family inhibitors

    International Nuclear Information System (INIS)

    Tamm, Christoffer; Galitó, Sara Pijuan; Annerén, Cecilia

    2012-01-01

    The Src family of non-receptor tyrosine kinases (SFKs) has been shown to play an intricate role in embryonic stem (ES) cell maintenance. In the present study we have focused on the underlying molecular mechanisms responsible for the vastly different effects induced by various commonly used SFK inhibitors. We show that several diverse cell types, including fibroblasts completely lacking SFKs, cannot undergo mitosis in response to SU6656 and that this is caused by an unselective inhibition of Aurora kinases. In contrast, PP2 and PD173952 block motility immediately upon exposure and forces cells to grow in dense colonies. The subsequent halt in proliferation of fibroblast and epithelial cells in the center of the colonies approximately 24 h post-treatment appears to be caused by cell-to-cell contact inhibition rather than a direct effect of SFK kinase inhibition. Interestingly, in addition to generating more homogenous and dense ES cell cultures, without any diverse effect on proliferation, PP2 and PD173652 also promote ES cell self-renewal by reducing the small amount of spontaneous differentiation typically observed under standard ES cell culture conditions. These effects could not be mirrored by the use of Gleevec, a potent inhibitor of c-Abl and PDGFR kinases that are also inhibited by PP2. -- Highlights: ► SFK inhibitor SU6656 induces senescence in mouse ES cells. ► SU6656 inhibits mitosis in a SFK-independent manner via cross-selectivity for Aurora kinases. ► SFK inhibitor PP2 impairs cell motility in various cell lines, including mouse ES cells. ► Ensuing impeded motility, PP2 inhibits proliferation of various cells lines except for mouse ES cells. ► SFK inhibitors PP2 and PD173952 impede spontaneous differentiation in standard mouse ES culture maintenance.

  6. Electroweak and flavor physics: Implications for the SSC. Second annual SSCL spring conference

    International Nuclear Information System (INIS)

    1991-01-01

    This book is a collection of vugraphs for the papers given at the conference. The following topics are covered: neutrino physics and dark matter; solar neutrinos; kaon decays; future prospects in high energy physics (non SSC); bottom quark physics; status and physics aims of SSC; and SSC possibilities for B physics

  7. The sonic hedgehog signaling pathway maintains the cancer stem cell self-renewal of anaplastic thyroid cancer by inducing snail expression.

    Science.gov (United States)

    Heiden, Katherine B; Williamson, Ashley J; Doscas, Michelle E; Ye, Jin; Wang, Yimin; Liu, Dingxie; Xing, Mingzhao; Prinz, Richard A; Xu, Xiulong

    2014-11-01

    Cancer stem cells (CSCs) have been recently identified in thyroid neoplasm. Anaplastic thyroid cancer (ATC) contains a higher percentage of CSCs than well-differentiated thyroid cancer. The signaling pathways and the transcription factors that regulate thyroid CSC self-renewal remain poorly understood. The objective of this study is to use two ATC cell lines (KAT-18 and SW1736) as a model to study the role of the sonic hedgehog (Shh) pathway in maintaining thyroid CSC self-renewal and to understand its underlying molecular mechanisms. The expression and activity of aldehyde dehydrogenase (ALDH), a marker for thyroid CSCs, was analyzed by Western blot and ALDEFLUOR assay, respectively. The effect of three Shh pathway inhibitors (cyclopamine, HhAntag, GANT61), Shh, Gli1, Snail knockdown, and Gli1 overexpression on thyroid CSC self-renewal was analyzed by ALDEFLUOR assay and thyrosphere formation. The sensitivity of transfected KAT-18 cells to radiation was evaluated by a colony survival assay. Western blot analysis revealed that ALDH protein levels in five thyroid cancer cell lines (WRO82, a follicular thyroid cancer cell line; BCPAP and TPC1, two papillary thyroid cancer cell lines; KAT-18 and SW1736, two ATC cell lines) correlated with the percentage of the ALDH(High) cells as well as Gli1 and Snail expression. The Shh pathway inhibitors, Shh and Gli1 knockdown, in KAT-18 cells decreased thyroid CSC self-renewal and increased radiation sensitivity. In contrast, Gli1 overexpression led to increased thyrosphere formation, an increased percentage of ALDH(High) cells, and increased radiation resistance in KAT-18 cells. Inhibition of the Shh pathway by three specific inhibitors led to decreased Snail expression and a decreased number of ALDH(High) cells in KAT-18 and SW1736. Snail gene knockdown decreased the number of ALDH(High) cells in KAT-18 and SW1736 cells. The Shh pathway promotes the CSC self-renewal in ATC cell lines by Gli1-induced Snail expression.

  8. Organizational Self-Renewal

    DEFF Research Database (Denmark)

    Hedman, Jonas; Henningsson, Stefan; Selander, Lisen

    2012-01-01

    Recent research has acknowledged the key role of information systems (IS) in helping build sustainable organizations. Although many organizations have implemented strategies for increased sustainability, empirical evidence for the effects of such strategies is sparse, and the understanding...... from other sustainable initiatives, since they are re-enforcing each other. Third, Green IS initiatives can act as ‘motors’ towards eco-effectiveness, in bridging competing models of organizational effectiveness....

  9. Three-Dimensional Spatiotemporal Modeling of Colon Cancer Organoids Reveals that Multimodal Control of Stem Cell Self-Renewal is a Critical Determinant of Size and Shape in Early Stages of Tumor Growth.

    Science.gov (United States)

    Yan, Huaming; Konstorum, Anna; Lowengrub, John S

    2018-05-01

    We develop a three-dimensional multispecies mathematical model to simulate the growth of colon cancer organoids containing stem, progenitor and terminally differentiated cells, as a model of early (prevascular) tumor growth. Stem cells (SCs) secrete short-range self-renewal promoters (e.g., Wnt) and their long-range inhibitors (e.g., Dkk) and proliferate slowly. Committed progenitor (CP) cells proliferate more rapidly and differentiate to produce post-mitotic terminally differentiated cells that release differentiation promoters, forming negative feedback loops on SC and CP self-renewal. We demonstrate that SCs play a central role in normal and cancer colon organoids. Spatial patterning of the SC self-renewal promoter gives rise to SC clusters, which mimic stem cell niches, around the organoid surface, and drive the development of invasive fingers. We also study the effects of externally applied signaling factors. Applying bone morphogenic proteins, which inhibit SC and CP self-renewal, reduces invasiveness and organoid size. Applying hepatocyte growth factor, which enhances SC self-renewal, produces larger sizes and enhances finger development at low concentrations but suppresses fingers at high concentrations. These results are consistent with recent experiments on colon organoids. Because many cancers are hierarchically organized and are subject to feedback regulation similar to that in normal tissues, our results suggest that in cancer, control of cancer stem cell self-renewal should influence the size and shape in similar ways, thereby opening the door to novel therapies.

  10. Proinflammatory cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) suppresses satellite cell self-renewal through inversely modulating Notch and NF-κB signaling pathways.

    Science.gov (United States)

    Ogura, Yuji; Mishra, Vivek; Hindi, Sajedah M; Kuang, Shihuan; Kumar, Ashok

    2013-12-06

    Satellite cell self-renewal is an essential process to maintaining the robustness of skeletal muscle regenerative capacity. However, extrinsic factors that regulate self-renewal of satellite cells are not well understood. Here, we demonstrate that TWEAK cytokine reduces the proportion of Pax7(+)/MyoD(-) cells (an index of self-renewal) on myofiber explants and represses multiple components of Notch signaling in satellite cell cultures. The number of Pax7(+) cells is significantly increased in skeletal muscle of TWEAK knock-out (KO) mice compared with wild-type in response to injury. Furthermore, Notch signaling is significantly elevated in cultured satellite cells and in regenerating myofibers of TWEAK-KO mice. Forced activation of Notch signaling through overexpression of the Notch1 intracellular domain (N1ICD) rescued the TWEAK-mediated inhibition of satellite cell self-renewal. TWEAK also activates the NF-κB transcription factor in satellite cells and inhibition of NF-κB significantly improved the number of Pax7(+) cells in TWEAK-treated cultures. Furthermore, our results demonstrate that a reciprocal interaction between NF-κB and Notch signaling governs the inhibitory effect of TWEAK on satellite cell self-renewal. Collectively, our study demonstrates that TWEAK suppresses satellite cell self-renewal through activating NF-κB and repressing Notch signaling.

  11. The SSC and speculations on the future of proton machines

    International Nuclear Information System (INIS)

    Tigner, M.

    1987-01-01

    In the U.S. a high energy physics community exists, in concert with many expert coleagues abroad, have submitted to the U.S. DOE, extensive documentation about the conceptual design, status of the R and D, and cost estimates for the SSC. Those documents come to more well over 2,000 pages and are available to anyone who would like to read them. This group is reviewed extensively by the DOE and all the expert committees that can possibly be put together and they have all concurred that the SSC is technically feasible, that the hardware is essentially in hand, and the cost has been properly calculated. That having been completed, the community withdraws into the inner sanctum to take counsel amongst themselves and decide whether or not to put the findings in the FY1988 budget. The next signal is when the President submits his budget in late January of 1988

  12. Preliminary study of magnet design for an SSC

    International Nuclear Information System (INIS)

    Taylor, C.E.; Meuser, R.B.

    1983-08-01

    The overriding design consideration for the SSC magnets is that cost of the facility be minimized; at 8 T, approximately 40 km of bending magnets is required for each ring of a 20 TeV collider. We present some results of a parametric study of two-in-one, iron-core magnets for an SSC. These results are necessarily preliminary in nature, and are intended only to show some of the trade-offs for a wide range of the variables. We show also some results for a reference design that produces 6.5 T in the aperture at 4.4 K for a coil inside diameter of 40 mm. It is not to be inferred that we have established this to be an optimum in any sense

  13. Overview of the physics issues at the SSC

    International Nuclear Information System (INIS)

    Hinchliffe, I.

    1984-11-01

    This report presents an overview of physics issues at the SSC. It discusses the progress made at the DPF Summer Study on the Design and Utilization of the SSC and emphasizes the important problems which remain. The discussion of the physics issues is divided into Standard Model, by which is meant the combination of QCD and the Weinberg-Salam model, and Non-Standard Physics, which includes supersymmetry, technicolor, new gauge bosons, compositeness and all the more or less speculative ideas in which theorists like to indulge. Then the work on identification of final states which contain W's, Z's or heavy quarks is discussed, and the impact of this work on some proposed signals for new physics is considered. Finally, some of the areas in which more work is required are discussed. 110 references

  14. Subcooler assembly for SSC single magnet test program

    International Nuclear Information System (INIS)

    Wu, K.C.; Brown, D.P.; Sondericker, J.H.; Farah, Y.; Zantopp, D.; Nicoletti, A.

    1991-01-01

    A subcooler assembly has been designed, constructed and installed in the MAGCOOL magnet test area at Brookhaven National Laboratory. Since July 1989, it has been used for testing SSC magnets. This subcooler assembly and cryogenic system are the first of its kind ever built. Today, with more than 5000 hours of operating time, the subcooler has proved to be a reliable unit with individual components meeting design expectations. The lowest temperatures achieved with one SSC dipole are 3.0 K at the suction of the cold vacuum pump and 3.2 K at the return of the magnet. The system performs well in both steady state operation and during magnet quench, subcooling, cooldown and warmup. 4 refs., 7 figs

  15. Use of learning programs for SSC trigger strategy studies

    International Nuclear Information System (INIS)

    Clearwater, S.H.; Cleland, W.E.; Stern, E.G.

    1990-01-01

    In a novel application of the learning program RL, we are studying ways to develop the trigger for experiments at the SSC. Our initial study, which is still in progress, is to understand how to select top events from background, combining both cuts at the trigger level and in the off-line analysis. Our plan is to carry out these studies for a variety of reactions and thereby build up a comprehensive view of the trigger requirements for a calorimeter-based experiment at the SSC. Our initial results have shown that the learning program can find correlations and cuts that would be quite difficult to find using traditional methods. The program is expected to obtain cuts that are at least as good, if not better, than the the cuts found by traditional methods

  16. Electrical performance characteristics of the SSC Accelerator System String Test

    International Nuclear Information System (INIS)

    Robinson, W.; Burgett, W.; Dombeck, T.; Gannon, J.; Kraushaar, P.; McInturff, A.; Savord, T.; Tool, G.

    1993-05-01

    The string test facility was constructed to provide a development test bed for the arc regions of the Superconducting Super Collider (SSC). Significant effort has been devoted to the development and testing of superconducting magnets, spools, and accelerator control systems required for the SSC. The string test facility provides the necessary environment required to evaluate the operational performance of these components as they are configured as an accelerator lens in the collider. This discussion will review the results of high current testing of the string conducted to evaluate magnet element uniformity and compatibility, the splice resistance used to connect the magnets, and system response to various quench conditions. Performance results of the spools, energy bypass systems, energy dump, and the power supply system are also discussed

  17. Observations on LEP with a view to SSC

    International Nuclear Information System (INIS)

    Toohig, T.E.

    1984-01-01

    From 24-29 October 1984 a visit was made to the LEP project at CERN with a view to extracting from the LEP planning and experience what might be useful in planning an SSC. With a circumference of 26.7 km, in a reasonably densely-populated area outside the boundaries of the CERN site, LEP already faces most of the problems of environment, public relations, maintenance and operation that will be faced by an SSC project. Information is presented under the headings of: (1) radiation protection; (2) heating, ventilation, and airconditioning; (3) electrical power distribution; (4) LEP experiments/UA1, UA2; (5) civil; (6) infrastructure installation; (7) survey; (8) safety; and (9) LEP controls. Each report lists the CERN individuals who generously provided their insights and help

  18. Electrical performance characteristics of the SSC Accelerator System String Test

    International Nuclear Information System (INIS)

    Robinson, W.; Burgett, W.; Dombeck, T.; Gannon, J.; Kraushaar, P.; McInturff, A.; Savord, T.; Tool, G.

    1993-01-01

    The string test facility was constructed to provide a development test bed for the arc regions of the Superconducting Super Collider (SSC). Significant effort has been devoted to the development and testing of superconducting magnets, spools, and accelerator control systems required for the SSC. The string test facility provides the necessary environment required to evaluate the operational performance of these components as they are configured as an accelerator lens in the collider. This discussion will review the results of high current testing of the string conducted to evaluate magnet element uniformity and compatibility, the splice resistance used to connect the magnets, and system response to various quench conditions. Performance results of the spools, energy bypass systems, energy dump, and the power supply system are also discussed

  19. An automated coil winding machine for the SSC dipole magnets

    International Nuclear Information System (INIS)

    Kamiya, S.; Iwase, T.; Inoue, I.; Fukui, I.; Ishida, K.; Kashiwagi, S.; Sato, Y.; Yoshihara, T.; Yamamoto, S.; Johnson, E.; Gibson, C.

    1990-01-01

    The authors have finished the preliminary design of a fully automated coil winding machine that can be used to manufacture the large number of SSC dipole magnets. The machine aims to perform all coil winding operations including coil parts inserting without human operators at a high productive rate. The machine is composed of five industrial robots. In order to verify the design, they built a small winding machine using an industrial robot and successfully wound a 1 meter long coil using SSC dipole magnet wire. The basic design for the full length coil and the robot winding technique are described in this paper. A fully automated coil winding machine using standard industrial components would be very useful if duplicate production lines are used. 5 figs., 1 tab

  20. Development of pixel detectors for SSC vertex tracking

    International Nuclear Information System (INIS)

    Kramer, G.; Shapiro, S.L.; Arens, J.F.; Jernigan, J.G.; Skubic, P.

    1991-04-01

    A description of hybrid PIN diode arrays and a readout architecture for their use as a vertex detector in the SSC environment is presented. Test results obtained with arrays having 256 x 256 pixels, each 30 μm square, are also presented. The development of a custom readout for the SSC will be discussed, which supports a mechanism for time stamping hit pixels, storing their xy coordinates, and storing the analog information within the pixel. The peripheral logic located on the array, permits the selection of those pixels containing interesting data and their coordinates to be selectively read out. This same logic also resolves ambiguous pixel ghost locations and controls the pixel neighbor read out necessary to achieve high spatial resolution. The thermal design of the vertex tracker and the proposed signal processing architecture will also be discussed. 5 refs., 13 figs., 3 tabs

  1. Real time control of the SSC string magnets

    International Nuclear Information System (INIS)

    Calvo, O.; Flora, R.; MacPherson, M.

    1987-01-01

    The system described in this paper, called SECAR, was designed to control the excitation of a test string of magnets for the proposed Superconducting Super Collider (SSC) and will be used to upgrade the present Tevatron Excitation, Control and Regulation (TECAR) hardware and software. It resides in a VME orate and is controlled by a 68020/68881 based CPU running the application software under a real time operating system named VRTX

  2. Irradiation of fiber optics in the SSC tunnel

    International Nuclear Information System (INIS)

    Dickey, C.E.

    1990-03-01

    The salient question is not whether optical fiber will survive in the Super Conducting Supercollider (SSC) tunnel, but rather how long will it survive. Current estimates indicate that single mode fiber under ideal conditions will have an expected lifetime of at least 25 years. Future development of optical fiber will lead to longer service lifetimes and increased radiation hardness. But conservatively speaking, current production optical fibers can probably not be depended upon for more than 25 years of service even under ideal conditions

  3. SSC 40 mm cable results and 50 mm design discussions

    International Nuclear Information System (INIS)

    Christopherson, D.; Capone, D.; Hannaford, R.; Remsbottom, R.; Delashmit, R.; Jayakumar, R.J.; Snitchler, G.; Scanlan, R.; Royet, J.

    1991-01-01

    This paper presents a summary of the cable produced for the 1990 40 mm Dipole Program. The cable design parameters for the 50 mm Dipole Program are discussed, as well as portions of the SSC specification draft. Considerations leading to the final cable configuration and the results of preliminary trials are included. The first iteration of a strand mapping program to automate cable strand maps is introduced

  4. SSC 40 mm cable results and 50 mm design discussions

    International Nuclear Information System (INIS)

    Christopherson, D.; Capone, D.; Hannaford, R.; Remsbottom, R.; Jayakumar, R.; Snitchler, G.; Scanlan, R.; Royet, J.

    1990-09-01

    A summary of the cable produced for the 1990 40 mm Dipole Program is presented. The cable design parameters for the 50 mm Dipole Program are discussed, as well as portions of the SSC specification draft. Considerations leading to the final cable configuration and the results of preliminary trials are included. The first iteration of a strand mapping program to automate cable strand maps is introduced. 7 refs., 2 figs., 1 tab

  5. Total cross sections and elastic scattering at the SSC

    Energy Technology Data Exchange (ETDEWEB)

    Foley, K.J.

    1985-12-05

    The need is discussed of a special purpose detector for the measurement of elastic scattering at the SSC. The detector would cover as small a solid angle as is practical. Two techniques are described briefly to measure total cross sections at hadron storage rings. The direct method is to measure the interaction rate in an IR of known luminosity - a method that gets more difficult increasing energy. A second method is to use the optical theorem. 6 refs., 1 fig. (LEW)

  6. Wire scanner data analysis for the SSC Linac emittance measurement

    International Nuclear Information System (INIS)

    Yao, C.Y.; Hurd, J.W.; Sage, J.

    1993-07-01

    The wire scanners are designed in the SSC Linac for measurement of beam emittance at various locations. In order to obtain beam parameters from the scan signal, a data analysis program was developed that considers the problems of noise reduction, machine modeling, parameter fitting, and correction. This program is intended as a tool for Linac commissioning and also as part of the Linac control program. Some of the results from commissioning runs are presented

  7. Stress relaxation in SSC 50mm dipole coils

    International Nuclear Information System (INIS)

    Rogers, D.; Markley, F.

    1992-04-01

    We are measuring the stress relaxation of SSC 50mm outer coils with the goal of predicting how much of the coil prestress will be lost while the coils are warehoused between manufacture and cooldown. We manufacture 3 inch (76.2mm) long segments of coil with the same materials and techniques that have been used for prototype coils. We are running four simultaneous tests in an attempt to separate the contributions of the different coil materials. Test one is a completely insulated coil section where the insulation is the all polyamide system being tested at Brookhaven; test two is a wire stack insulated only with the normal Kapton overwrap; test three is a stack of bare cable; and test four is a completely insulated normal coil section. All, except for the bare cable, include the ground insulation. The insulated coil sections are carefully dried before loading and testing in order to eliminate stress changes due to varying moisture content. The temperature dependence of the stress relaxation is being studied separately. Three companion papers presented at this conference will be: (1) ''Temperature dependence of the viscoelastic properties of SSC coil insulation'' (2) ''Measurement of the elastic modulus of Kapton perpendicular to the plane of the film at room and cryogenic temperatures'' (3) ''Theoretical methods for creep and stress relaxation studies of SSC coil.''

  8. An update on passive correctors for the SSC dipole magnets

    International Nuclear Information System (INIS)

    Green, M.A.

    1991-05-01

    The concept of correction of the magnetization sextupole became a topic of discussion as soon as it was realized that superconductor magnetization could have a serious effect on the SSC beam during injection. Several methods of correction were proposed. These included (1) correction with active bore tube windings like those on the HERA machine which correct out magnetization sextupole and the sextupole due to iron saturation, (2) correction with persistent sextupole windings mounted on the bore tube (3) correction using passive superconductor (4) correction using ferromagnetic material, and (5) correction using oriented magnetized materials. This report deals with the use of passive superconductor to correct the magnetization sextupole. Two basic methods are explored in this report: (1) One can correct the magnetization sextupole by changing the diameter of the superconductor filaments in one or more blocks of the SSC dipole. (2) One can correct the magnetization sextupole and decapole by mounting passive superconducting wires on the inside of the SSC dipole coil bore. In addition, an assessment of the contribution of each conductor in the dipole to the magnetization sextupole and decapole is shown. 38 refs, 25 figs., 15 tabs

  9. Comparisons of processes and performance of SSC-VQP material

    International Nuclear Information System (INIS)

    Seuntjens, J.M.; Clark, F.Y.; Erdmann, M.J.; Coleman, E.S.; Jones, B.A.

    1994-01-01

    The Superconducting Super Collider's (SSC) cable Vendor Qualification Program (VQP) will end in FY 1993. At the time of this writing, all 8 vendors involved in this program have demonstrated capability to fabricate conductor which meets SSC specifications. The magnet vendors have hard choices to make in calendar year 1993 in deciding which cable vendors will make the production cable. It is well accepted that because of requirements of magnet uniformity, that only one vendor will be chosen for dipole Inner cable, one vendor for dipole Outer cable, and one vendor for quadrupole Outer cable. The production quantities are nominally 500, 500, and 200 metric tonnes, respectively. Among the many deciding factors are a technically sound production process, process control, and production quantity capability of each cable vendor. Qualified vendors will have proven their technical process and process control is adequate for production quantities. This paper is part of ongoing effort to provide technical information for the magnet vendor's decision making process. Some of the Phase IB process data is summarized as well as results of a portion of the materials characterization performed at the SSC Laboratory. Key process and final product parameters for each cable vendor are compared without identifying specific vendor's process detail

  10. Comparisons of processes and performance of SSC-VQP material

    International Nuclear Information System (INIS)

    Seuntjens, J.; Clark, F.; Erdmann, M.; Coleman, E.; Jones, B.

    1993-05-01

    The Superconducting Super Collider's (SSC) cable Vendor Qualification Program (VQP) will end in FY 1993. At the time of this writing, all 8 vendors involved in this program have demonstrated capability to fabricate conductor which meets SSC specifications. The magnet vendors have hard choices to make in calendar year 1993 in deciding which cable vendors will make the production cable. It is well accepted that because of requirements of magnet uniformity, that only one vendor will be chosen for dipole Inner cable, one vendor for dipole Outer cable, and one vendor for quadrupole Outer cable. The production quantities are nominally 500, 500, and 200 metric tonnes, respectively. Among the many deciding factors are a technically sound production process, process control, and production quantity capability of each cable vendor. Qualified vendors will have proven their technical process and process control is adequate for production quantities. This paper is part of ongoing effort to provide technical information for the magnet vendor's decision making process. Some of the Phase IB process data is summarized and well as results of a portion of the materials characterization performed at the SSC Laboratory. Key process and final product parameters for each cable vendor are compared without identifying specific vendor's process detail

  11. Evaluating advanced LMR [liquid metal reactor] reactivity feedbacks using SSC

    International Nuclear Information System (INIS)

    Slovik, G.C.; Van Tuyle, G.J.; Kennett, R.J.; Cheng, H.S.

    1988-01-01

    Analyses of the PRISM and SAFR Liquid Metal Reactors with SSC are discussed from a safety and licensing perspective. The PRISM and SAFR reactors with metal fuel are designed for inherent shutdown responses to loss-of-flow and loss-of-heat-sink events. The demonstration of this technology was performed by EBR-II during experiments in April 1986 by ANL (Planchon, et al.). Response to postulated TOPs (control rod withdrawal) are made acceptable largely by reducing reactivity swings, and therefore minimizing the size of possible ractivity insertions. Analyses by DOE and the contractors GE, RI, and ANL take credit for several reactivity feedback mechanisms during transient calculations. These feedbacks include Doppler, sodium density, and thermal expansion of the grid plates, the load pads, the fuel (axial) and the control rod which are now factored into the BNL SSC analyses. The bowing feedback mechanism is not presently modeled in the SSC due to its complexity and subsequent large uncertainty. The analysis is conservative by not taking credit for this negative feedback mechanism. Comparisons of BNL predictions with DOE contractors are provided

  12. Development of Radhard VLSI electronics for SSC calorimeters

    International Nuclear Information System (INIS)

    Dawson, J.W.; Nodulman, L.J.

    1989-01-01

    A new program of development of integrated electronics for liquid argon calorimeters in the SSC detector environment is being started at Argonne National Laboratory. Scientists from Brookhaven National Laboratory and Vanderbilt University together with an industrial participants are expected to collaborate in this work. Interaction rates, segmentation, and the radiation environment dictate that front-end electronics of SSC calorimeters must be implemented in the form of highly integrated, radhard, analog, low noise, VLSI custom monolithic devices. Important considerations are power dissipation, choice of functions integrated on the front-end chips, and cabling requirements. An extensive level of expertise in radhard electronics exists within the industrial community, and a primary objective of this work is to bring that expertise to bear on the problems of SSC detector design. Radiation hardness measurements and requirements as well as calorimeter design will be primarily the responsibility of Argonne scientists and our Brookhaven and Vanderbilt colleagues. Radhard VLSI design and fabrication will be primarily the industrial participant's responsibility. The rapid-cycling synchrotron at Argonne will be used for radiation damage studies involving response to neutrons and charged particles, while damage from gammas will be investigated at Brookhaven. 10 refs., 6 figs., 2 tabs

  13. CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.

    Directory of Open Access Journals (Sweden)

    Rouzbeh Taghizadeh

    2010-12-01

    Full Text Available A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported. The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+.We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal. Thus, the relationship between melanoma formation and ABCG2 and CXCR6 expression was investigated. Consistent with their non-metastatic character, unsorted IGR39 cells formed significantly smaller tumors than unsorted IGR37 cells. In addition, ABCG2+ cells produced tumors that had a 2-fold greater mass than tumors produced by unsorted cells or ABCG2- cells. CXCR6+ cells produced more aggressive tumors. CXCR6 identifies a more discrete subpopulation of cultured human melanoma cells with a more aggressive MCSC phenotype than cells selected on the basis of the ABCG2+ phenotype alone.The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment.

  14. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling

    Science.gov (United States)

    Wang, Linlin; Schulz, Thomas C.; Sherrer, Eric S.; Dauphin, Derek S.; Shin, Soojung; Nelson, Angelique M.; Ware, Carol B.; Zhan, Mei; Song, Chao-Zhong; Chen, Xiaoji; Brimble, Sandii N.; McLean, Amanda; Galeano, Maria J.; Uhl, Elizabeth W.; D'Amour, Kevin A.; Chesnut, Jonathan D.; Rao, Mahendra S.

    2007-01-01

    Despite progress in developing defined conditions for human embryonic stem cell (hESC) cultures, little is known about the cell-surface receptors that are activated under conditions supportive of hESC self-renewal. A simultaneous interrogation of 42 receptor tyrosine kinases (RTKs) in hESCs following stimulation with mouse embryonic fibroblast (MEF) conditioned medium (CM) revealed rapid and prominent tyrosine phosphorylation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R); less prominent tyrosine phosphorylation of epidermal growth factor receptor (EGFR) family members, including ERBB2 and ERBB3; and trace phosphorylation of fibroblast growth factor receptors. Intense IGF1R and IR phosphorylation occurred in the absence of MEF conditioning (NCM) and was attributable to high concentrations of insulin in the proprietary KnockOut Serum Replacer (KSR). Inhibition of IGF1R using a blocking antibody or lentivirus-delivered shRNA reduced hESC self-renewal and promoted differentiation, while disruption of ERBB2 signaling with the selective inhibitor AG825 severely inhibited hESC proliferation and promoted apoptosis. A simple defined medium containing an IGF1 analog, heregulin-1β (a ligand for ERBB2/ERBB3), fibroblast growth factor-2 (FGF2), and activin A supported long-term growth of multiple hESC lines. These studies identify previously unappreciated RTKs that support hESC proliferation and self-renewal, and provide a rationally designed medium for the growth and maintenance of pluripotent hESCs. PMID:17761519

  15. YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate Self-Renewal and Vascular Mimicry of Stem-Like Cells.

    Science.gov (United States)

    Bora-Singhal, Namrata; Nguyen, Jonathan; Schaal, Courtney; Perumal, Deepak; Singh, Sandeep; Coppola, Domenico; Chellappan, Srikumar

    2015-06-01

    Non-small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that stem-like cells contribute to the genesis and progression of NSCLC. Our results show that the transcriptional coactivator yes-associated protein 1 (YAP1), which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem-like cells from NSCLC and contributes to their self-renewal and ability to form angiogenic tubules. Inhibition of YAP1 by a small molecule or depletion of YAP1 by siRNAs suppressed self-renewal and vascular mimicry of stem-like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor, Sox2. YAP1 could transcriptionally induce Sox2 through a physical interaction with Oct4; Sox2 induction occurred independent of TEAD2 transcription factor, which is the predominant mediator of YAP1 functions. The binding of Oct4 to YAP1 could be detected in cell lines as well as tumor tissues; the interaction was elevated in NSCLC samples compared to normal tissue as seen by proximity ligation assays. YAP1 bound to Oct4 through the WW domain, and a peptide corresponding to this region could disrupt the interaction. Delivery of the WW domain peptide to stem-like cells disrupted the interaction and abrogated Sox2 expression, self-renewal, and vascular mimicry. Depleting YAP1 reduced the expression of multiple epithelial-mesenchymal transition genes and prevented the growth and metastasis of tumor xenografts in mice; overexpression of Sox2 in YAP1 null cells rescued these functions. These results demonstrate a novel regulation of stem-like functions by YAP1, through the modulation of Sox2 expression. © 2015 AlphaMed Press.

  16. Distinct and Cooperative Roles of amh and dmrt1 in Self-Renewal and Differentiation of Male Germ Cells in Zebrafish.

    Science.gov (United States)

    Lin, Qiaohong; Mei, Jie; Li, Zhi; Zhang, Xuemei; Zhou, Li; Gui, Jian-Fang

    2017-11-01

    Spermatogenesis is a fundamental process in male reproductive biology and depends on precise balance between self-renewal and differentiation of male germ cells. However, the regulative factors for controlling the balance are poorly understood. In this study, we examined the roles of amh and dmrt1 in male germ cell development by generating their mutants with Crispr/Cas9 technology in zebrafish. Amh mutant zebrafish displayed a female-biased sex ratio, and both male and female amh mutants developed hypertrophic gonads due to uncontrolled proliferation and impaired differentiation of germ cells. A large number of proliferating spermatogonium-like cells were observed within testicular lobules of the amh -mutated testes, and they were demonstrated to be both Vasa- and PH3-positive. Moreover, the average number of Sycp3- and Vasa-positive cells in the amh mutants was significantly lower than in wild-type testes, suggesting a severely impaired differentiation of male germ cells. Conversely, all the dmrt1 -mutated testes displayed severe testicular developmental defects and gradual loss of all Vasa-positive germ cells by inhibiting their self-renewal and inducing apoptosis. In addition, several germ cell and Sertoli cell marker genes were significantly downregulated, whereas a prominent increase of Insl3-positive Leydig cells was revealed by immunohistochemical analysis in the disorganized dmrt1 -mutated testes. Our data suggest that amh might act as a guardian to control the balance between proliferation and differentiation of male germ cells, whereas dmrt1 might be required for the maintenance, self-renewal, and differentiation of male germ cells. Significantly, this study unravels novel functions of amh gene in fish. Copyright © 2017 by the Genetics Society of America.

  17. Wnt/β-catenin signaling promotes self-renewal and inhibits the primed state transition in naïve human embryonic stem cells.

    Science.gov (United States)

    Xu, Zhuojin; Robitaille, Aaron M; Berndt, Jason D; Davidson, Kathryn C; Fischer, Karin A; Mathieu, Julie; Potter, Jennifer C; Ruohola-Baker, Hannele; Moon, Randall T

    2016-10-18

    In both mice and humans, pluripotent stem cells (PSCs) exist in at least two distinct states of pluripotency, known as the naïve and primed states. Our understanding of the intrinsic and extrinsic factors that enable PSCs to self-renew and to transition between different pluripotent states is important for understanding early development. In mouse embryonic stem cells (mESCs), Wnt proteins stimulate mESC self-renewal and support the naïve state. In human embryonic stem cells (hESCs), Wnt/β-catenin signaling is active in naïve-state hESCs and is reduced or absent in primed-state hESCs. However, the role of Wnt/β-catenin signaling in naïve hESCs remains largely unknown. Here, we demonstrate that inhibition of the secretion of Wnts or inhibition of the stabilization of β-catenin in naïve hESCs reduces cell proliferation and colony formation. Moreover, we show that addition of recombinant Wnt3a partially rescues cell proliferation in naïve hESCs caused by inhibition of Wnt secretion. Notably, inhibition of Wnt/β-catenin signaling in naïve hESCs did not cause differentiation. Instead, it induced primed hESC-like proteomic and metabolic profiles. Thus, our results suggest that naïve hESCs secrete Wnts that activate autocrine or paracrine Wnt/β-catenin signaling to promote efficient self-renewal and inhibit the transition to the primed state.

  18. Fascin Is Critical for the Maintenance of Breast Cancer Stem Cell Pool Predominantly via the Activation of the Notch Self-Renewal Pathway.

    Science.gov (United States)

    Barnawi, Rayanah; Al-Khaldi, Samiyah; Majed Sleiman, Ghida; Sarkar, Abdullah; Al-Dhfyan, Abdullah; Al-Mohanna, Falah; Ghebeh, Hazem; Al-Alwan, Monther

    2016-12-01

    An emerging dogma shows that tumors are initiated and maintained by a subpopulation of cancer cells that hijack some stem cell features and thus referred to as "cancer stem cells" (CSCs). The exact mechanism that regulates the maintenance of CSC pool remains largely unknown. Fascin is an actin-bundling protein that we have previously demonstrated to be a major regulator of breast cancer chemoresistance and metastasis, two cardinal features of CSCs. Here, we manipulated fascin expression in breast cancer cell lines and used several in vitro and in vivo approaches to examine the relationship between fascin expression and breast CSCs. Fascin knockdown significantly reduced stem cell-like phenotype (CD44 hi /CD24 lo and ALDH + ) and reversal of epithelial to mesenchymal transition. Interestingly, expression of the embryonic stem cell transcriptional factors (Oct4, Nanog, Sox2, and Klf4) was significantly reduced when fascin expression was down-regulated. Functionally, fascin-knockdown cells were less competent in forming colonies and tumorspheres, consistent with lower basal self-renewal activity and higher susceptibility to chemotherapy. Fascin effect on CSC chemoresistance and self-renewability was associated with Notch signaling. Activation of Notch induced the relevant downstream targets predominantly in the fascin-positive cells. Limiting-dilution xenotransplantation assay showed higher frequency of tumor-initiating cells in the fascin-positive group. Collectively, our data demonstrated fascin as a critical regulator of breast CSC pool at least partially via activation of the Notch self-renewal signaling pathway and modification of the expression embryonic transcriptional factors. Targeting fascin may halt CSCs and thus presents a novel therapeutic approach for effective treatment of breast cancer. Stem Cells 2016;34:2799-2813 Video Highlight: https://youtu.be/GxS4fJ_Ow-o. © 2016 AlphaMed Press.

  19. Radiation damage testing at the SSC [Superconducting Super Collider

    International Nuclear Information System (INIS)

    Chinowsky, W.; Thun, R.

    1990-06-01

    A Task Force on Radiation Damage Testing met at the SSC Laboratory on March 5--6, 1990. This Task Force was asked to assess the availability of appropriate facilities for radiation damage tests of SSC detector materials and components. The Task Force was also instructed to review the techniques and standards for conducting such tests. Semiconductors were considered separately from other detector materials. Radiation damage test of electronic devices generally require exposures to both ionizing radiation and neutrons, whereas non-electric components such as plastic scintillating materials, adhesives, cable insulation, and other organic polymers are adequately tested with ionizing radiation only. Test standards are discussed with respect to irradiation techniques, environmental factors, dosimetry, and mechanisms whereby various materials are damaged. It is emphasized that radiation sources should be chosen to duplicate as much as possible the expected SSC environment and that the effects from ionizing particles and from neutrons be investigated separately. Radiation damage tests at reactors must be designed with particular care complex spectra of neutrons and gamma rays are produced at such facilities. It is also essential to investigate dose-rate effects since they are known to be important in many cases. The required irradiations may last several months and are most easily carried out with dedicated radioactive sources. Environmental factors such as the presence of oxygen when testing plastic scintillators, or temperature when measuring semiconductor annealing effects, must also be taken into account. The importance of reliable dosimetry is stressed and suitable references cited. Finally, it is noted that an understanding of the mechanisms for radiation damage in semiconductor and other materials is important in planning irradiations and evaluating results

  20. The effects of electrospun substrate-mediated cell colony morphology on the self-renewal of human induced pluripotent stem cells.

    Science.gov (United States)

    Maldonado, Maricela; Wong, Lauren Y; Echeverria, Cristina; Ico, Gerardo; Low, Karen; Fujimoto, Taylor; Johnson, Jed K; Nam, Jin

    2015-05-01

    The development of xeno-free, chemically defined stem cell culture systems has been a primary focus in the field of regenerative medicine to enhance the clinical application of pluripotent stem cells (PSCs). In this regard, various electrospun substrates with diverse physiochemical properties were synthesized utilizing various polymer precursors and surface treatments. Human induced pluripotent stem cells (IPSCs) cultured on these substrates were characterized by their gene and protein expression to determine the effects of the substrate physiochemical properties on the cells' self-renewal, i.e., proliferation and the maintenance of pluripotency. The results showed that surface chemistry significantly affected cell colony formation via governing the colony edge propagation. More importantly, when surface chemistry of the substrates was uniformly controlled by collagen conjugation, the stiffness of substrate was inversely related to the sphericity, a degree of three dimensionality in colony morphology. The differences in sphericity subsequently affected spontaneous differentiation of IPSCs during a long-term culture, implicating that the colony morphology is a deciding factor in the lineage commitment of PSCs. Overall, we show that the capability of controlling IPSC colony morphology by electrospun substrates provides a means to modulate IPSC self-renewal. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. JMJD1C Ensures Mouse Embryonic Stem Cell Self-Renewal and Somatic Cell Reprogramming through Controlling MicroRNA Expression.

    Science.gov (United States)

    Xiao, Feng; Liao, Bing; Hu, Jing; Li, Shuang; Zhao, Haixin; Sun, Ming; Gu, Junjie; Jin, Ying

    2017-09-12

    The roles of histone demethylases (HDMs) for the establishment and maintenance of pluripotency are incompletely characterized. Here, we show that JmjC-domain-containing protein 1c (JMJD1C), an H3K9 demethylase, is required for mouse embryonic stem cell (ESC) self-renewal. Depletion of Jmjd1c leads to the activation of ERK/MAPK signaling and epithelial-to-mesenchymal transition (EMT) to induce differentiation of ESCs. Inhibition of ERK/MAPK signaling rescues the differentiation phenotype caused by Jmjd1c depletion. Mechanistically, JMJD1C, with the help of pluripotency factor KLF4, maintains ESC identity at least in part by regulating the expression of the miR-200 family and miR-290/295 cluster to suppress the ERK/MAPK signaling and EMT. Additionally, we uncover that JMJD1C ensures efficient generation and maintenance of induced pluripotent stem cells, at least partially through controlling the expression of microRNAs. Collectively, we propose an integrated model of epigenetic and transcriptional control mediated by the H3K9 demethylase for ESC self-renewal and somatic cell reprogramming. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Enhanced Hematopoietic Stem Cell Self-Renewal-Promoting Ability of Clonal Primary Mesenchymal Stromal/Stem cells Versus Their Osteogenic Progeny.

    Science.gov (United States)

    He, Qiling; Scott Swindle, Claude; Wan, Chao; Flynn, Robert J; Oster, Robert A; Chen, Dongquan; Zhang, Fengjie; Shu, Yinglan; Klug, Christopher A

    2017-02-01

    Long-term self-renewing hematopoietic stem cell (LT-HSC) homeostasis within the bone marrow (BM) of adult mammals is regulated by complex interactions between LT-HSC and a number of niche-associated cell types including mesenchymal stromal/stem cells (MSC), osteoblasts (OB), macrophage, and neuronal cells in close proximity with the vasculature. Here, we cloned and functionally characterized a murine BM MSC subpopulation that was uniformly Nestin + Lepr + Sca-1 + CD146 + and could be stably propagated with high colony-forming unit fibroblast re-cloning efficiency. MSC synergized with SCF and IL-11 to support a 20-fold expansion in true LT-HSC after 10-days of in vitro coculture. Optimal stimulation of LT-HSC expansion was minimally dependent on Notch signaling but was significantly enhanced by global inhibition of Wnt signaling. The self-renewal-promoting activity of MSC was progressively lost when MSC clones were differentiated into mature OB. This suggests that the stage of osteoblast development may significantly impact the ability of osteolineage cells to support LT-HSC homeostasis in vivo. Stem Cells 2017;35:473-484. © 2016 AlphaMed Press.

  3. Overview and status of beam instrumentation at the SSC

    International Nuclear Information System (INIS)

    Webber, R.C.

    1993-05-01

    An overview of beam instrumentation requirements at the SSC and a status report on work progress is given. Small transverse emittance beams, ranging in energy from 30 KeV to 20 TeV, must be commissioned, measured, and diagnosed. Instrumentation plans and current design and development efforts for BPMs and other systems are presented. Monitors and electronics soon to be delivered for use in the Linac are described. Design of the Linac systems has been done with requirements and applications in the synchrotron in mind and thus should provide a basis for design of much of that hardware. The useful commonality of design across the machines is discussed

  4. Conductor development for the Superconducting Super Collider (SSC)

    International Nuclear Information System (INIS)

    Gregory, E.

    1988-01-01

    This review investigates the developments in fine filamentary materials over the last three years and traces how the relations between the magnet requirements and property improvements have fashioned SSC conductor specifications. The review emphasizes factors that affect filament nonuniformity and the overall quality of the product. The elimination of proximity effect-induced coupling in SCC type conductors, by introducing small percentages of manganese into the copper between the filaments, is discussed. Modification of a Fermi kit has produced materials with improved critical current densities. The possibility of using this approach to make conductors for accelerator magnets is assessed

  5. Measurement of AC electrical characteristics of SSC superconducting dipole magnets

    International Nuclear Information System (INIS)

    Smedley, K.M.; Shafer, R.E.

    1992-01-01

    Experiments were conducted to measure the AC electrical characteristics of SSC superconducting dipole magnets over the frequency range of 0.1 Hz to 10 kHz. A magnet equivalent circuit representing the magnet DC inductance, eddy current losses, coil-to-ground and turn-to-turn capacitance, was synthesized from the experimental data. This magnet equivalent circuit can be used to predict the current ripple distribution along the superconducting magnet string and can provide dynamic information for the design of the collider current regulation loop

  6. High P/sub T/ detectors for the SSC

    International Nuclear Information System (INIS)

    Trilling, G.H.

    1987-11-01

    Summarized in this report is some of the work done at the recent Workshop on Experiments, Detectors, and Experimental Areas for the Supercollider held at Berkeley. The major goal was to develop an understanding of what complement of detectors would provide the capability for a well-balanced physics program at the SSC. Unlike earlier studies which had emphasized individual components such as tracking, calorimetry, etc., the intention was to focus on complete detectors. The particular detectors discussed in this paper are: the large solenoid detectors, the compact solenoid detectors, the non-magnetic detectors, the dipole detectors and muon detectors. 10 refs., 6 figs., 2 tabs

  7. A super fixed target beauty experiment at the SSC

    International Nuclear Information System (INIS)

    Spiegel, L.; Murphy, C.T.; Cox, B.; Arenton, M.; Conetti, S.; Corti, G.; Dukes, C.; Golovatyuk, V.; Lawry, T.; McManus, A.

    1993-01-01

    The observation and precision measurement of CP violation asymmetries and the phase of the CKM matrix is a major objective of B experiments at the SSC. The yields of reconstructed and tagged B decays and the various factors which minimize the dilution factors make measurements of CP asymmetries in the fixed target option known as the SFT more than competitive with much more expensive hadron collider experiments and significantly better than asymmetric e + e - B factories. Moreover, the superior time resolution possible in the SFT configuration allows a precision in the measurement of the CKM matrix element phases possible with the SFT option for various B decay modes

  8. Hadron identification in a fixed target experiment at the SSC

    International Nuclear Information System (INIS)

    Nelson, K.S.; Cox, B.

    1993-01-01

    This article presents the design criteria and expected performance of a hadron identification system in a fixed target experiment at the SSC. The proposed SFT spectrometer will be used as a model for the discussion. Two primary uses of hadron identification is a B physics experiment are flavor tagging and the rejection of background due to particle reflections in the reconstruction of exclusive decay modes. In the first case it is shown that use of kaons can increase substantially the number of events which can be tagged. In the latter case, decays in which particles are mis-identified can form a background to a desired decay mode

  9. Design features of the SSC [Superconducting Super Collider] dipole magnet

    International Nuclear Information System (INIS)

    Willen, E.; Cottingham, J.; Ganetis, G.

    1989-01-01

    The main ring dipole for the SSC is specified as a high performance magnet that is required to provide a uniform, 6.6 T field in a 4 cm aperture at minimum cost. These design requirements have been addressed in an R ampersand D program in which the coil design, coil mechanical support, yoke and shell structure, trim coil and beam tube design, and a variety of new instrumentation, have been developed. The design of the magnet resulting from this intensive R ampersand D program, including various measurements from both 1.8 m and 17 m long models, is reviewed. 7 refs., 3 figs

  10. SSC [Superconducting Super Collider] dipole coil production tooling

    International Nuclear Information System (INIS)

    Carson, J.A.; Barczak, E.J.; Bossert, R.C.; Brandt, J.S.; Smith, G.A.

    1989-03-01

    Superconducting Super Collider dipole coils must be produced to high precision to ensure uniform prestress and even conductor distribution within the collared coil assembly. Tooling is being prepared at Fermilab for the production of high precision 1M and 16.6M SSC dipole coils suitable for mass production. The design and construction methods builds on the Tevatron tooling and production experience. Details of the design and construction methods and measured coil uniformity of 1M coils will be presented. 4 refs., 10 figs

  11. Debunching and Capture in the LEB for the SSC

    Energy Technology Data Exchange (ETDEWEB)

    Mahale, N.; Furman, M.

    1991-05-01

    The authors present the details of the capture process in the Low Energy Booster (LEB) for the SSC. They consider only the longitudinal dynamics. Space charge forces are computed quasistatically. The beam pipe is considered to be perfectly conducting. With respect to maximizing the capture efficiency and minimizing the space charge tune spread, initial few milliseconds are very important. They present only the first few milliseconds of the cycle, during which space charge effects are significant. For the numerical simulation they use the code ESME.

  12. Beam diagnostic system for SSC on HIRFL central console

    International Nuclear Information System (INIS)

    Zhang Guixu; Wang Zhen; Huang Tuanhua

    1998-01-01

    The SSC ion beam diagnostic system on the console of HIRFL in institute of modern physics is presented. The information between console and diagnostic system can be transferred via DECnet communication. The central computer for HIRFL console is VAX-8350, the working computer of diagnostic system is changed from IBM PC/XT to COMPAQ 486, and the operating program is rewritten from FORTRAN to C. In order to communicate information, DECnet TTT function is put into both programs on the VAX and PC

  13. Initial results from 50mm short SSC dipoles at Fermilab

    International Nuclear Information System (INIS)

    Bossert, R.C.; Brandt, J.S.; Carson, J.A.; Coulter, K.; Delchamps, S.; Ewald, K.D.; Fulton, H.; Gonczy, I.; Gourlay, S.A.; Jaffery, T.S.; Kinney, W.; Koska, W.; Lamm, M.J.; Strait, J.B.; Wake, M.; Gordon, M.; Hassan, N.; Sims, R.; Winters, M.

    1991-03-01

    Several short model SSC 50 mm bore dipoles are being built and tested at Fermilab. Mechanical design of these magnets has been determined from experience involved in the construction and testing of 40 mm dipoles. Construction experience includes coil winding, curing and measuring, coil end part design and fabrication, ground insulation, instrumentation, collaring and yoke assembly. Fabrication techniques are explained and construction problems are discussed. Similarities and differences from the 40 mm dipole tooling and management components are outlined. Test results from the first models are presented. 19 refs., 12 figs

  14. Conclusions from the engineering subgroup of the SSC liquid argon calorimeter working group

    International Nuclear Information System (INIS)

    Bederede, D.; Cooper, W.; Mulholland, G.; Kroon, P.; Guryn, W.; Lobkowicz, F.; Mason, I.; Pohlen, J.; Schindler, R.H.; Scholle, E.A.; Watanabe, Y.; Watt, R.

    1990-01-01

    The SSC Calorimeter Workshop was organized to explore the feasibility of each calorimeter technology for use in a 4π detector at the SSC. The Liquid Argon Calorimeter group further subdivided into four subgroups; Hermeticity, Engineering, Module Details, and Electronics. This is the report of the Engineering Subgroup whose charge was to evaluate the cost, schedule, manpower, safety, and facilities requirements for the construction of a large liquid argon calorimeter for the SSC

  15. Upregulated expression of Nogo-A and NgR in an experimental model of focal microgyria regulates the migration, proliferation and self-renewal of subventricular zone neural progenitors

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Sixun; Shu, Haifeng; Yang, Tao; Huang, Haidong [Department of Neurosurgery, General Hospital of the People' s Liberation Army Chengdu Military Region, Chengdu, Sichuan, 610083 (China); Li, Song [Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037 (China); Zhao, Ziyi [Central Laboratory, Teaching Hospital of Chengdu University of Traditional Chinese Medicine, 610075 (China); Kuang, Yongqin, E-mail: kuangyongqin@163.com [Department of Neurosurgery, General Hospital of the People' s Liberation Army Chengdu Military Region, Chengdu, Sichuan, 610083 (China)

    2016-04-29

    Nogo-A and its receptor (NgR) were first described as myelin-associated inhibitors of neuronal regeneration in response to injury. In recent years, knowledge about the important role of the Nogo-A protein in several neuronal pathologies has grown considerably. Here, we employed a neonatal cortex freeze-lesion (NFL) model in neonatal rats and measured the expression of Nogo-A and NgR in the resulting cerebrocortical microdysgenesis 5–75 days after freezing injury. We observed marked upregulation of Nogo-A and NgR in protein levels. Furthermore, the migration of neural precursor cells (NPCs) derived from the subventricular zone (SVZ) toward the sits of injury was perturbed by treatment of NgR antagonist peptide NEP1-40. In vitro analysis showed that the knockdown of NgR by lentivirus-delivered siRNA promoted in axonal regeneration and SVZ-derived neural stem cell/progenitor cell (SVZ-NPCs) adhesion and migration, findings which were similar to the effects of NEP1-40. Taken together, our results indicate an important role for NgR in regulating the physiological processes of SVZ-NPCs. The observation of upregulated Nogo-A/NgR in lesion sites in the NFL model suggest that the effects of the perturbed Nogo-A are a key feature during the development and/or the progression of cortical malformation. - Highlights: • NFL model is an accurate experimental reproduction of focal microgyria of FCD. • The increase of the Nogo-A Levels occurs in response to freeze-induced focal lesioning. • Nogo-A/NgR may play a critical role for in the pathologic progression of FCD. • Nogo-A is associated with the migration, proliferation and self-renewal of SVZ-NPCs.

  16. A helium venting model for a SSC half cell

    International Nuclear Information System (INIS)

    Carcagno, R.H.; McAshan, M.S.; Schiesser, W.E.

    1991-01-01

    When a Superconducting Super Collider (SSC) dipole magnet quenches, the quench protection system will intentionally quench other magnets in the half cell. The result is that the stored energy of all of these quenched magnets will be absorbed equally among them. These simultaneous quenches produce heat, which diffuses from the magnet coils to the main helium (He) coolant channels and thereby eventually causes an increase in the He pressure. When the quench is detected, vent valves open to minimize the He pressure increase and thus prevent damage to the magnets. The performance of the He venting system has been modeled and simulated to establish whether the venting will take place as required. The model consists of partial differential equation energy balances written radially for the magnet coils, collar, and yoke; and ordinary differential equations of energy and mass balance written for the He in the magnets and relief header. The basic algorithm is the numerical method of lines, with finite difference approximation of the spatial derivatives, and time integration by LSODES. Simulation results are presented for an SSC half cell of the Accelerator Systems String Test (ASST) facility. The results are also compared with recent string quench measurements performed at the Fermilab String Test Facility

  17. Report of the workshop on realistic SSC lattices

    International Nuclear Information System (INIS)

    1985-10-01

    A workshop was held at the SSC Central Design Group from May 29 to June 4, 1985, on topics relating to the lattice of the SSC. The workshop marked a shift of emphasis from the investigation of simplified test lattices to the development of a realistic lattice suitable for the conceptual design report. The first day of the workshop was taken up by reviews of accelerator system requirements, of the reference design solutions for these requirements, of lattice work following the reference design, and of plans for the workshop. The work was divided among four working groups. The first, chaired by David Douglas, concerned the arcs of regular cells. The second group, which studied the utility insertions, was chaired by Beat Leemann. The third group, under David E. Johnson, concerned itself with the experimental insertions, dispersion suppressors, and phase trombones. The fourth group, responsible for global lattice considerations and the design of a new realistic lattice example, was led by Ernest Courant. The papers resulting from this workshop are roughly divided into three sets: those relating to specific lattice components, to complete lattices, and to other topics. Among the salient accomplishments of the workshop were additions to and optimization of lattice components, especially those relating to lattices using 1-in-1 magnets, either horizontally or vertically separated, and the design of complete lattice examples. Selected papers are indexed separately for inclusion in the Energy Science and Technology Database

  18. Parallel processing at the SSC: The fact and the fiction

    International Nuclear Information System (INIS)

    Bourianoff, G.; Cole, B.

    1991-10-01

    Accurately modelling the behavior of particles circulating in accelerators is a computationally demanding task. The particle tracking code currently in use at SSC is based upon a ''thin element'' analysis (TEAPOT). In this model each magnet in the lattice is described by a thin element at which the particle experiences an impulsive kick. Each kick requires approximately 200 floating point operations (''FLOP''). For the SSC collider lattice consisting of 10 4 elements, performing a tracking of study for a set of 100 particles for 10 7 turns would require 2 x 10 15 FLOPS. Even on a machine capable of 100 MFLOP/sec (MFLOPS), this would require 2 x 10 7 seconds, and many such runs are necessary. It should be noted that the accuracy with which the kicks are to be calculated is important: the large number of iterations involved will magnify the effects of small errors. The inability of current computational resources to effectively perform the full calculation motivates the migration of this calculation to the most powerful computers available. A survey of the current research into new technologies for superconducting reveals that the supercomputers of the future will be parallel in nature. Further, numerous such machines exist today, and are being used to solve other difficult problems. Thus it seems clear that it is not early to begin developing the capability to develop tracking codes for parallel architectures. This report discusses implementing parallel processing on the SCC

  19. Self-renewal and differentiation capabilities are variable between human embryonic stem cell lines I3, I6 and BG01V

    Directory of Open Access Journals (Sweden)

    Rao Mahendra S

    2009-06-01

    Full Text Available Abstract Background A unique and essential property of embryonic stem cells is the ability to self-renew and differentiate into multiple cell lineages. However, the possible differences in proliferation and differentiation capabilities among independently-derived human embryonic stem cells (hESCs are not well known because of insufficient characterization. To address this question, a side-by-side comparison of 1 the ability to maintain an undifferentiated state and to self-renew under standard conditions; 2 the ability to spontaneously differentiate into three primary embryonic germ lineages in differentiating embryoid bodies; and 3 the responses to directed neural differentiation was made between three NIH registered hES cell lines I3 (TE03, I6 (TE06 and BG01V. Lines I3 and I6 possess normal XX and a normal XY karyotype while BG01V is a variant cell line with an abnormal karyotype derived from the karyotypically normal cell line BG01. Results Using immunocytochemistry, flow cytometry, qRT-PCR and MPSS, we found that all three cell lines actively proliferated and expressed similar "stemness" markers including transcription factors POU5F1/Oct3/4 and NANOG, glycolipids SSEA4 and TRA-1-81, and alkaline phosphatase activity. All cell lines differentiated into three embryonic germ lineages in embryoid bodies and into neural cell lineages when cultured in neural differentiation medium. However, a profound variation in colony morphology, growth rate, BrdU incorporation, and relative abundance of gene expression in undifferentiated and differentiated states of the cell lines was observed. Undifferentiated I3 cells grew significantly slower but their differentiation potential was greater than I6 and BG01V. Under the same neural differentiation-promoting conditions, the ability of each cell line to differentiate into neural progenitors varied. Conclusion Our comparative analysis provides further evidence for similarities and differences between three h

  20. Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion.

    Science.gov (United States)

    Kent, David G; Li, Juan; Tanna, Hinal; Fink, Juergen; Kirschner, Kristina; Pask, Dean C; Silber, Yvonne; Hamilton, Tina L; Sneade, Rachel; Simons, Benjamin D; Green, Anthony R

    2013-01-01

    Recent descriptions of significant heterogeneity in normal stem cells and cancers have altered our understanding of tumorigenesis, emphasizing the need to understand how single stem cells are subverted to cause tumors. Human myeloproliferative neoplasms (MPNs) are thought to reflect transformation of a hematopoietic stem cell (HSC) and the majority harbor an acquired V617F mutation in the JAK2 tyrosine kinase, making them a paradigm for studying the early stages of tumor establishment and progression. The consequences of activating tyrosine kinase mutations for stem and progenitor cell behavior are unclear. In this article, we identify a distinct cellular mechanism operative in stem cells. By using conditional knock-in mice, we show that the HSC defect resulting from expression of heterozygous human JAK2V617F is both quantitative (reduced HSC numbers) and qualitative (lineage biases and reduced self-renewal per HSC). The defect is intrinsic to individual HSCs and their progeny are skewed toward proliferation and differentiation as evidenced by single cell and transplantation assays. Aged JAK2V617F show a more pronounced defect as assessed by transplantation, but mice that transform reacquire competitive self-renewal ability. Quantitative analysis of HSC-derived clones was used to model the fate choices of normal and JAK2-mutant HSCs and indicates that JAK2V617F reduces self-renewal of individual HSCs but leaves progenitor expansion intact. This conclusion is supported by paired daughter cell analyses, which indicate that JAK2-mutant HSCs more often give rise to two differentiated daughter cells. Together these data suggest that acquisition of JAK2V617F alone is insufficient for clonal expansion and disease progression and causes eventual HSC exhaustion. Moreover, our results show that clonal expansion of progenitor cells provides a window in which collaborating mutations can accumulate to drive disease progression. Characterizing the mechanism(s) of JAK2V617F

  1. RNA-Binding Protein L1TD1 Interacts with LIN28 via RNA and is Required for Human Embryonic Stem Cell Self-Renewal and Cancer Cell Proliferation

    OpenAIRE

    Närvä, Elisa; Rahkonen, Nelly; Emani, Maheswara Reddy; Lund, Riikka; Pursiheimo, Huha-Pekka; Nästi, Juuso; Autio, Reija; Rasool, Omid; Denessiouk, Konstantin; Lähdesmäki, Harri; Rao, Anjana; Lahesmaa, Ritta

    2012-01-01

    Human embryonic stem cells (hESC) have a unique capacity to self-renew and differentiate into all the cell types found in human body. Although the transcriptional regulators of pluripotency are well studied, the role of cytoplasmic regulators is still poorly characterized. Here, we report a new stem cell-specific RNA-binding protein L1TD1 (ECAT11, FLJ10884) required for hESC self-renewal and cancer cell proliferation. Depletion of L1TD1 results in immediate downregulation of OCT4 and NANOG. F...

  2. Current Approaches to the Treatment of Systemic-Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH).

    Science.gov (United States)

    Sobanski, Vincent; Launay, David; Hachulla, Eric; Humbert, Marc

    2016-02-01

    Pulmonary arterial hypertension (PAH) is a severe condition causing significant morbidity and mortality in patients with systemic sclerosis (SSc). Despite the use of specific treatments, SSc-PAH survival remains poorer than in idiopathic PAH (IPAH). Recent therapeutic advances in PAH show a lower magnitude of response in SSc-PAH and a higher risk of adverse events, as compared to IPAH. The multifaceted underlying mechanisms and the multisystem nature of SSc probably explain part of the worse outcomes in SSc-PAH compared to IPAH. This review describes the current management of SSc-PAH with an emphasis on the impact of the different organ involvements in the prognosis and treatment response. An earlier detection of PAH and a better characterization of the clinical phenotypes of SSc-PAH are warranted in clinical practice and future trials. Determinants of prognosis, surrogate markers of clinical improvement or worsening, and relevance of the common endpoints used in clinical trials should be evaluated in this specific population. A multidisciplinary approach in expert referral centers is mandatory for SSc-PAH management.

  3. Is transverse feedback necessary for the SSC emittance preservation? (Vibration noise analysis and feedback parameters optimization)

    International Nuclear Information System (INIS)

    Parkhomchuk, V.V.; Shiltsev, V.D.

    1993-06-01

    The paper considers the Superconducting Super Collider (SSC) site ground motion measurements as well as data from accelerators worldwide about noises that worsen beam performance. Unacceptably fast emittance growth due to these noises is predicted for the SSC. A transverse feedback system was found to be the only satisfactory alternative to prevent emittance decay. Optimization of the primary feedback parameters was done

  4. Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells.

    Science.gov (United States)

    Hayashi, Yohei; Caboni, Laura; Das, Debanu; Yumoto, Fumiaki; Clayton, Thomas; Deller, Marc C; Nguyen, Phuong; Farr, Carol L; Chiu, Hsiu-Ju; Miller, Mitchell D; Elsliger, Marc-André; Deacon, Ashley M; Godzik, Adam; Lesley, Scott A; Tomoda, Kiichiro; Conklin, Bruce R; Wilson, Ian A; Yamanaka, Shinya; Fletterick, Robert J

    2015-04-14

    NANOG (from Irish mythology Tír na nÓg) transcription factor plays a central role in maintaining pluripotency, cooperating with OCT4 (also known as POU5F1 or OCT3/4), SOX2, and other pluripotency factors. Although the physiological roles of the NANOG protein have been extensively explored, biochemical and biophysical properties in relation to its structural analysis are poorly understood. Here we determined the crystal structure of the human NANOG homeodomain (hNANOG HD) bound to an OCT4 promoter DNA, which revealed amino acid residues involved in DNA recognition that are likely to be functionally important. We generated a series of hNANOG HD alanine substitution mutants based on the protein-DNA interaction and evolutionary conservation and determined their biological activities. Some mutant proteins were less stable, resulting in loss or decreased affinity for DNA binding. Overexpression of the orthologous mouse NANOG (mNANOG) mutants failed to maintain self-renewal of mouse embryonic stem cells without leukemia inhibitory factor. These results suggest that these residues are critical for NANOG transcriptional activity. Interestingly, one mutant, hNANOG L122A, conversely enhanced protein stability and DNA-binding affinity. The mNANOG L122A, when overexpressed in mouse embryonic stem cells, maintained their expression of self-renewal markers even when retinoic acid was added to forcibly drive differentiation. When overexpressed in epiblast stem cells or human induced pluripotent stem cells, the L122A mutants enhanced reprogramming into ground-state pluripotency. These findings demonstrate that structural and biophysical information on key transcriptional factors provides insights into the manipulation of stem cell behaviors and a framework for rational protein engineering.

  5. An important role for adenine, cholera toxin, hydrocortisone and triiodothyronine in the proliferation, self-renewal and differentiation of limbal stem cells in vitro.

    Science.gov (United States)

    Yu, Min; Bojic, Sanja; Figueiredo, Gustavo S; Rooney, Paul; de Havilland, Julian; Dickinson, Anne; Figueiredo, Francisco C; Lako, Majlinda

    2016-11-01

    The cornea is a self-renewing tissue located at the front of the eye. Its transparency is essential for allowing light to focus onto the retina for visual perception. The continuous renewal of corneal epithelium is supported by limbal stem cells (LSCs) which are located in the border region between conjunctiva and cornea known as the limbus. Ex vivo expansion of LSCs has been successfully applied in the last two decades to treat patients with limbal stem cell deficiency (LSCD). Various methods have been used for their expansion, yet the most widely used culture media contains a number of ingredients derived from animal sources which may compromise the safety profile of human LSC transplantation. In this study we sought to understand the role of these components namely adenine, cholera toxin, hydrocortisone and triiodothyronine with the aim of re-defining a safe and GMP compatible minimal media for the ex vivo expansion of LSCs on human amniotic membrane. Our data suggest that all four components play a critical role in maintaining LSC proliferation and promoting LSC self-renewal. However removal of adenine and triiodothyronine had a more profound impact and led to LSC differentiation and loss of viability respectively, suggesting their essential role for ex vivo expansion of LSCs. Replacement of each of the components with GMP-grade reagents resulted in equal growth to non-GMP grade media, however an enhanced differentiation of LSCs was observed, suggesting that additional combinations of GMP grade reagents need to be tested to achieve similar or better level of LSC maintenance in the same manner as the traditional LSC media. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  6. EphA4 Regulates the Balance between Self-Renewal and Differentiation of Radial Glial Cells and Intermediate Neuronal Precursors in Cooperation with FGF Signaling.

    Directory of Open Access Journals (Sweden)

    Qingfa Chen

    Full Text Available In mouse cerebral corticogenesis, neurons are generated from radial glial cells (RGCs or from their immediate progeny, intermediate neuronal precursors (INPs. The balance between self-renewal of these neuronal precursors and specification of cell fate is critical for proper cortical development, but the signaling mechanisms that regulate this progression are poorly understood. EphA4, a member of the receptor tyrosine kinase superfamily, is expressed in RGCs during embryogenesis. To illuminate the function of EphA4 in RGC cell fate determination during early corticogenesis, we deleted Epha4 in cortical cells at E11.5 or E13.5. Loss of EphA4 at both stages led to precocious in vivo RGC differentiation toward neurogenesis. Cortical cells isolated at E14.5 and E15.5 from both deletion mutants showed reduced capacity for neurosphere formation with greater differentiation toward neurons. They also exhibited lower phosphorylation of ERK and FRS2α in the presence of FGF. The size of the cerebral cortex at P0 was smaller than that of controls when Epha4 was deleted at E11.5 but not when it was deleted at E13.5, although the cortical layers were formed normally in both mutants. The number of PAX6-positive RGCs decreased at later developmental stages only in the E11.5 Epha4 deletion mutant. These results suggest that EphA4, in cooperation with an FGF signal, contributes to the maintenance of RGC self-renewal and repression of RGC differentiation through the neuronal lineage. This function of EphA4 is especially critical and uncompensated in early stages of corticogenesis, and thus deletion at E11.5 reduces the size of the neonatal cortex.

  7. CHIR99021 promotes self-renewal of mouse embryonic stem cells by modulation of protein-encoding gene and long intergenic non-coding RNA expression

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Yongyan [College of Veterinary Medicine, Northwest A and F University, Yangling 712100, Shaanxi (China); Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A and F University, Yangling 712100, Shaanxi (China); Ai, Zhiying [Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A and F University, Yangling 712100, Shaanxi (China); College of Life Sciences, Northwest A and F University, Yangling 712100, Shaanxi (China); Yao, Kezhen [College of Veterinary Medicine, Northwest A and F University, Yangling 712100, Shaanxi (China); Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A and F University, Yangling 712100, Shaanxi (China); Cao, Lixia; Du, Juan; Shi, Xiaoyan [Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A and F University, Yangling 712100, Shaanxi (China); College of Life Sciences, Northwest A and F University, Yangling 712100, Shaanxi (China); Guo, Zekun, E-mail: gzk@nwsuaf.edu.cn [College of Veterinary Medicine, Northwest A and F University, Yangling 712100, Shaanxi (China); Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A and F University, Yangling 712100, Shaanxi (China); Zhang, Yong, E-mail: zhylab@hotmail.com [College of Veterinary Medicine, Northwest A and F University, Yangling 712100, Shaanxi (China); Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A and F University, Yangling 712100, Shaanxi (China)

    2013-10-15

    Embryonic stem cells (ESCs) can proliferate indefinitely in vitro and differentiate into cells of all three germ layers. These unique properties make them exceptionally valuable for drug discovery and regenerative medicine. However, the practical application of ESCs is limited because it is difficult to derive and culture ESCs. It has been demonstrated that CHIR99021 (CHIR) promotes self-renewal and enhances the derivation efficiency of mouse (m)ESCs. However, the downstream targets of CHIR are not fully understood. In this study, we identified CHIR-regulated genes in mESCs using microarray analysis. Our microarray data demonstrated that CHIR not only influenced the Wnt/β-catenin pathway by stabilizing β-catenin, but also modulated several other pluripotency-related signaling pathways such as TGF-β, Notch and MAPK signaling pathways. More detailed analysis demonstrated that CHIR inhibited Nodal signaling, while activating bone morphogenetic protein signaling in mESCs. In addition, we found that pluripotency-maintaining transcription factors were up-regulated by CHIR, while several developmental-related genes were down-regulated. Furthermore, we found that CHIR altered the expression of epigenetic regulatory genes and long intergenic non-coding RNAs. Quantitative real-time PCR results were consistent with microarray data, suggesting that CHIR alters the expression pattern of protein-encoding genes (especially transcription factors), epigenetic regulatory genes and non-coding RNAs to establish a relatively stable pluripotency-maintaining network. - Highlights: • Combined use of CHIR with LIF promotes self-renewal of J1 mESCs. • CHIR-regulated genes are involved in multiple pathways. • CHIR inhibits Nodal signaling and promotes Bmp4 expression to activate BMP signaling. • Expression of epigenetic regulatory genes and lincRNAs is altered by CHIR.

  8. CHIR99021 promotes self-renewal of mouse embryonic stem cells by modulation of protein-encoding gene and long intergenic non-coding RNA expression

    International Nuclear Information System (INIS)

    Wu, Yongyan; Ai, Zhiying; Yao, Kezhen; Cao, Lixia; Du, Juan; Shi, Xiaoyan; Guo, Zekun; Zhang, Yong

    2013-01-01

    Embryonic stem cells (ESCs) can proliferate indefinitely in vitro and differentiate into cells of all three germ layers. These unique properties make them exceptionally valuable for drug discovery and regenerative medicine. However, the practical application of ESCs is limited because it is difficult to derive and culture ESCs. It has been demonstrated that CHIR99021 (CHIR) promotes self-renewal and enhances the derivation efficiency of mouse (m)ESCs. However, the downstream targets of CHIR are not fully understood. In this study, we identified CHIR-regulated genes in mESCs using microarray analysis. Our microarray data demonstrated that CHIR not only influenced the Wnt/β-catenin pathway by stabilizing β-catenin, but also modulated several other pluripotency-related signaling pathways such as TGF-β, Notch and MAPK signaling pathways. More detailed analysis demonstrated that CHIR inhibited Nodal signaling, while activating bone morphogenetic protein signaling in mESCs. In addition, we found that pluripotency-maintaining transcription factors were up-regulated by CHIR, while several developmental-related genes were down-regulated. Furthermore, we found that CHIR altered the expression of epigenetic regulatory genes and long intergenic non-coding RNAs. Quantitative real-time PCR results were consistent with microarray data, suggesting that CHIR alters the expression pattern of protein-encoding genes (especially transcription factors), epigenetic regulatory genes and non-coding RNAs to establish a relatively stable pluripotency-maintaining network. - Highlights: • Combined use of CHIR with LIF promotes self-renewal of J1 mESCs. • CHIR-regulated genes are involved in multiple pathways. • CHIR inhibits Nodal signaling and promotes Bmp4 expression to activate BMP signaling. • Expression of epigenetic regulatory genes and lincRNAs is altered by CHIR

  9. High-resolution molecular validation of self-renewal and spontaneous differentiation in adipose-tissue derived human mesenchymal stem cells cultured in human platelet lysate

    Science.gov (United States)

    Dudakovic, Amel Dudakovic; Camilleri, Emily; Riester, Scott M.; Lewallen, Eric A.; Kvasha, Sergiy; Chen, Xiaoyue; Radel, Darcie J.; Anderson, Jarett M.; Nair, Asha A.; Evans, Jared M.; Krych, Aaron J.; Smith, Jay; Deyle, David R.; Stein, Janet L.; Stein, Gary S.; Im, Hee-Jeong; Cool, Simon M.; Westendorf, Jennifer J.; Kakar, Sanjeev; Dietz, Allan B.; van Wijnen, Andre J.

    2014-01-01

    Improving the effectiveness of adipose-tissue derived human mesenchymal stromal/stem cells (AMSCs) for skeletal therapies requires a detailed characterization of mechanisms supporting cell proliferation and multi-potency. We investigated the molecular phenotype of AMSCs that were either actively proliferating in platelet lysate or in a basal non-proliferative state. Flow cytometry combined with high-throughput RNA sequencing (RNASeq) and RT-qPCR analyses validate that AMSCs express classic mesenchymal cell surface markers (e.g., CD44, CD73/NT5E, CD90/THY1 and CD105/ENG). Expression of CD90 is selectively elevated at confluence. Self-renewing AMSCs express a standard cell cycle program that successively mediates DNA replication, chromatin packaging, cyto-architectural enlargement and mitotic division. Confluent AMSCs preferentially express genes involved in extracellular matrix (ECM) formation and cellular communication. For example, cell cycle-related biomarkers (e.g., cyclins E2 and B2, transcription factor E2F1) and histone-related genes (e.g., H4, HINFP, NPAT) are elevated in proliferating AMSCs, while ECM genes are strongly upregulated (>10 fold) in quiescent AMSCs. AMSCs also express pluripotency genes (e.g., POU5F1, NANOG, KLF4) and early mesenchymal markers (e.g., NES, ACTA2) consistent with their multipotent phenotype. Strikingly, AMSCs modulate expression of WNT signaling components and switch production of WNT ligands (from WNT5A/WNT5B/WNT7B to WNT2/WNT2B), while up-regulating WNT-related genes (WISP2, SFRP2 and SFRP4). Furthermore, post-proliferative AMSCs spontaneously express fibroblastic, osteogenic, chondrogenic and adipogenic biomarkers when maintained in confluent cultures. Our findings validate the biological properties of self-renewing and multi-potent AMSCs by providing high-resolution quality control data that support their clinical versatility. PMID:24905804

  10. High molecular weight FGF2 isoforms demonstrate canonical receptor-mediated activity and support human embryonic stem cell self-renewal

    Directory of Open Access Journals (Sweden)

    Denis Kole

    2017-05-01

    Full Text Available Basic fibroblast growth factor (FGF2 is a highly pleiotropic member of a large family of growth factors with a broad range of activities, including mitogenesis and angiogenesis (Ornitz et al., 1996; Zhang et al., 2006, and it is known to be essential for maintenance of balance between survival, proliferation, and self-renewal in human pluripotent stem cells (Eiselleova et al., 2009; Zoumaro-Djayoon et al., 2011. A single FGF2 transcript can be translated into five FGF2 protein isoforms, an 18 kDa low molecular weight (LMW isoform and four larger high molecular weight (HMW isoforms (Arese et al., 1999; Arnaud et al., 1999. As they are not generally secreted, high molecular weight (HMW FGF2 isoforms have predominantly been investigated intracellularly; only a very limited number of studies have investigated their activity as extracellular factors. Here we report over-expression, isolation, and biological activity of all recombinant human FGF2 isoforms. We show that HMW FGF2 isoforms can support self-renewal of human embryonic stem cells (hESCs in vitro. Exogenous supplementation with HMW FGF2 isoforms also activates the canonical FGFR/MAPK pathway and induces mitogenic activity in a manner similar to that of the 18 kDa FGF2 isoform. Though all HMW isoforms, when supplemented exogenously, are able to recapitulate LMW FGF2 activity to some degree, it appears that certain isoforms tend to do so more poorly, demonstrating a lesser functional response by several measures. A better understanding of isoform-specific FGF2 effects will lead to a better understanding of developmental and pathological FGF2 signaling.

  11. Variable-field permanent-magnet quadrupole for the SSC

    International Nuclear Information System (INIS)

    Barlow, D.B.; Kraus, R.H. Jr.; Martinez, R.P.; Meyer, R.E.

    1994-01-01

    A set of compact variable-field permanent-magnet quadrupoles have been designed, fabricated, and tested for use in the SSC linac matching section. The quadrupoles have 24 mm-diameter apertures and 40 mm-long poles. The hybrid (permanent-magnet and iron) design, uses a fixed core of magnet material (NdFeB) and iron (C-1006) surrounded by a rotating ring of the same magnet material and iron. The quadrupole gradient-length product can be smoothly varied from a minimum of 0.7 T up to a maximum of 4.3 T by a 90 degree rotation of the outer ring of iron and magnet material

  12. Application of multiple timestep integration method in SSC

    International Nuclear Information System (INIS)

    Guppy, J.G.

    1979-01-01

    The thermohydraulic transient simulation of an entire LMFBR system is, by its very nature, complex. Physically, the entire plant consists of many subsystems which are coupled by various processes and/or components. The characteristic integration timesteps for these processes/components can vary over a wide range. To improve computing efficiency, a multiple timestep scheme (MTS) approach has been used in the development of the Super System Code (SSC). In this paper: (1) the partitioning of the system and the timestep control are described, and (2) results are presented showing a savings in computer running time using the MTS of as much as five times the time required using a single timestep scheme

  13. A medical facility proposal to use the SSC linac

    International Nuclear Information System (INIS)

    Funk, L.W.

    1994-01-01

    A consortium organized by the Texas National Research Laboratory Commission under a Department of Energy grant proposes to build and operate a Regional Medical Technology Center to function as a combined medical radioisotope production complex and proton cancer therapy facility using the Linear Accelerator (Linac) assets of the Superconducting Super Collider (SSC). The radioisotope production complex will serve as a domestic source of radioisotopes critically needed by the U.S. pharmaceutical industry and nuclear medicine facilities throughout North America. Presently, more than 70 percent of radioisotopes used in U.S. nuclear medicine procedures are produced outside the country. The Center's state-of-the-art proton cancer therapy facility will serve the Central United States, providing advanced capabilities and augmenting facilities in California and Massachusetts. Long-term, it is anticipated that the RMTC also will stimulate nuclear medicine research, advance medical diagnostic technologies, and generate new industrial applications for linear accelerator technology

  14. A medical facility proposal to use the SSC linac

    International Nuclear Information System (INIS)

    Funk, L.W.

    1995-01-01

    A consortium organized by the Texas National Research Laboratory Commission (TNRLC) under a Department of Energy (DOE) grant proposes to build and operate a Regional Medical Technology Center (RMTC) to function as a combined medical radioisotope production complex and proton cancer therapy facility using the linear accelerator (linac) assets of the cancelled Superconducting Super Collider (SSC). The radioisotope production complex will serve as a domestic source of radioisotopes critically needed by the U.S. pharmaceutical industry and nuclear medicine facilities throughout North America. Presently, more than 70 percent of radioisotopes used in U.S. nuclear medicine procedures are produced outside the country. The Center's state-of-the-art proton cancer therapy facility will serve the Central United States, providing advanced capabilities and augmenting facilities in California and Massachusetts. Long-term, it is anticipated that the RMTC also will stimulate nuclear medicine research, advance medical diagnostic technologies, and generate new industrial applications of linear accelerator technology. (orig.)

  15. A medical facility proposal to use the SSC linac

    Science.gov (United States)

    Warren Funk, L.

    1995-05-01

    A consortium organized by the Texas National Research Laboratory Commission (TNRLC) under a Department of Energy (DOE) grant proposes to build and operate a Regional Medical Technology Center (RMTC) to function as a combined medical radioisotope production complex and proton cancer therapy facility using the linear accelerator (linac) assets of the cancelled Superconducting Super Collider (SSC). The radioisotope production complex will serve as a domestic source of radioisotopes critically needed by the U.S. pharmaceutical industry and nuclear medicine facilities throughout North America. Presently, more than 70 percent of radioisotopes used in U.S. nuclear medicine procedures are produced outside the country. The Center's state-of-the-art proton cancer therapy facility will serve the Central United States, providing advanced capabilities and augmenting facilities in California and Massachusetts. Long-term, it is anticipated that the RMTC also will stimulate nuclear medicine research, advance medical diagnostic technologies, and generate new industrial applications of linear accelerator technology.

  16. Performance of field measuring probes for SSC magnets

    International Nuclear Information System (INIS)

    Thomas, R.; Ganetis, G.; Herrera, J.; Hogue, R.; Jain, A.; Louie, W.; Marone, A.; Wanderer, P.

    1994-01-01

    Several years of experience have been acquired on the operation of probes (open-quotes molesclose quotes) constructed for the measurement of the multipole components of the magnetic fields of SSC magnets. The field is measured by rotating coils contained in a 2.4-m long tube that is pulled through the aperture of the magnet by an external device - the transporter. In addition to the measuring coils, the tube contains motors for rotating the coil and a system for sensing local vertical using gravity sensors to provide an absolute reference for the field measurements. The authors describe the steps that must be taken in order to ensure accurate, repeatable measurements; the design changes that have been motivated by difficulties encountered (noise, vibration, variations in temperature); and other performance issues. The mechanical interface between the probe and the beam tube of the magnet is also described

  17. Performance of field measuring probes for SSC magnets

    International Nuclear Information System (INIS)

    Thomas, R.; Ganetis, G.; Herrera, J.; Hogue, R.; Jain, A.; Louie, W.; Marone, A.; Wanderer, P.

    1993-01-01

    Several years of experience have been acquired on the operation of probes (''moles'') constructed for the measurement of the multipole components of the magnetic fields of SSC magnets. The field is measured by rotating coils contained in a 2.4-m long tube that is pulled through the aperture of the magnet by an external device-the transporter. In addition to the measuring coils, the tube contains motors for rotating the coil and a system for sensing local vertical using gravity sensors to provide an absolute reference for the field measurements. We describe the steps that must be taken in order to ensure accurate, repeatable measurements; the design changes that have been motivated by difficulties encountered (noise, vibration, variations in temperature); and other performance issues. The mechanical interface between the probe and the hewn tube of the magnet is also described

  18. Overview and status of RF systems for the SSC Linac

    International Nuclear Information System (INIS)

    Mynk, J.; Grippe, J.; Cutler, R.I.; Rodriguez, R.

    1993-05-01

    The Superconducting Super Collider (SSC) Linear Accelerator (Linac) produces a 600-MeV, 35-μs, H-beam at a 10-Hz repetition rate. The beam is accelerated by a series of RF cavities. These consist of a Radio Frequency Quadrupole (RFQ), two bunchers, and four Drift Tube Linac (DTL) tanks at 427.617 MHz, and two bunchers, nine side-coupled Linac modules, and an energy compressor at 1282.851 MHz. The RFQ amplifier and the low-frequency buncher cavity amplifiers use gridded tubes, while the other cavities use klystron amplifier systems. The RF control system consists of a reference line and cavity feedback and feedforward loops for each amplifier. The RF amplifier system for each of these accelerator cavities is described, and the current status of each system is presented

  19. Simulation of quenches in SSC magnets with passive quench protection

    International Nuclear Information System (INIS)

    Koepke, K.

    1985-06-01

    The relative ease of protecting an SSC magnet following a quench and the implications of quench protection on magnet reliability and operation are necessary inputs in a rational magnet selection process. As it appears likely that the magnet selection will be made prior to full scale prototype testing, an alternative means is required to ascertain the surviveability of contending magnet types. This paper attempts to provide a basis for magnet selection by calculating the peak expected quench temperatures in the 3 T Design C magnet and the 6 T Design D magnet as a function of magnet length. A passive, ''cold diode'' protection system has been assumed. The relative merits of passive versus active protection systems have been discussed in a previous report. It is therefore assumed that - given the experience gained from the Tevatron system - that an active quench protection system can be employed to protect the magnets in the eventuality of unreliable cold diode function

  20. Scintillating fiber detector development for the SSC: Annual progress report

    International Nuclear Information System (INIS)

    Ruchti, R.C.

    1989-01-01

    During the past year, considerable effort has been applied to the development of scintillating fiber detectors in several areas: new scintillation liquids and studies of their fluorescence properties; new fluorescent dyes based on non-intramolecular proton transfer; new dyes based on intramolecular proton transfer; incorporation of these new dyes in plastic (polystyrene) and liquid scintillation solutions; development of small cross section glass capillaries for the containment of liquid scintillators; studies of waveguide characteristics; studies of image intensifier phosphor screen characteristics; initial steps to form a collaboration to study and develop appropriate new properties of the Solid State Photomultiplier; construction of a new laboratory at Notre Dame to enhance our capabilities for further measurements and studies; and organization of and execution of a Workshop on Scintillating Fiber Detector Development for the SSC, held at Fermilab, November 14--16, 1988

  1. Collider Physics: SDC/SSC liquified fiber calorimetry

    International Nuclear Information System (INIS)

    White, J.T.; Huson, F.R.

    1992-01-01

    Most effort was directed toward the D-Zero experiment at Fermilab. Over 3 pb -1 of high-quality physics data have been obtained. Analysis of the results (wino-zino physics, squark physics), D-zero data acquisition systems efforts, and level-1 and level-2 trigger work are described. Other work concerned detector development for use at the SSC. This technology consists of using liquid scintillator-filled tubes as scintillating fibers for a ''calorimeter.'' The key issues were to demonstrate that the liquid fibers were sufficiently rad-hard and to demonstrate that fibers with sufficiently long attenuation length could be found to satisfy the resolution requirements; both constraints could be satisfied

  2. Rad-hard electronics study for SSC detectors

    International Nuclear Information System (INIS)

    Ekenberg, T.; Dawson, J.; Stevens, A.; Haberichter, W.

    1991-01-01

    The radiation environment in a SSC detector operating at a luminosity of 10 33 cm -2 s -1 will put stringent requirements on radiation hardness of the electronics. Over the expected 10 year life-time of a large detector, ionizing radiation doses of up to 20 MRad and neutron fluences of 10 16 neutrons/cm 2 are projected. At a luminosity of 10 34 cm -2 s -1 even higher total doses are expected. the effect of this environment have been simulated by exposing CMOS/bulk and CMOS/SOS devices from monolithic processes to neutrons and ionizing radiation. leakage currents, noise variations, and DC characteristics have been measured before and after exposure in order to evaluate the effects of the irradiations. As expected the device characteristics remained virtually unchanged by neutron irradiation, while ionizing radiation caused moderate degradation of performance. 5 refs., 6 figs

  3. A novel bridge coupler for SSC coupled cavity linac

    International Nuclear Information System (INIS)

    Yao, C.G.; Chang, C.R.; Funk, W.

    1992-01-01

    A novel magnetically coupled multi-cavity bridge coupler is proposed for SSC Coupled-Cavity-Linac (CCL). The bridge coupler is a five cell disc-loaded waveguide with a small central aperture used for measurement and two large curved coupling slots near the edge on each disc. The two coupling slots on the adjacent disc are rotated 90 degrees in orientation to reduce the direct coupling. This type of structure is capable of producing very large coupling (>10% in our longest bridge coupler). Also because of the small opening on the discs, the high-order-modes are very far (> 300 MHz) above the operating mode. Thus for long bridge couplers, the magnetic coupled structure should provide maximum coupling with minimum mode mixing problems. In this paper both physics and engineering issues of this new bridge coupler are presented. (Author) 5 refs., 2 tabs., 6 figs

  4. Variable-field permanent magnet quadrupole for the SSC

    International Nuclear Information System (INIS)

    Barlow, D.B.; Kraus, R.H. Jr.; Martinez, R.P.; Meyer, R.E.

    1993-01-01

    A set of compact variable-field permanent-magnet quadrupoles have been designed, fabricated, and tested for use In the SSC linac matching section. The quadrupoles have 24 mm-diameter apertures and 40 mm-long poles. The hybrid (permanent-magnet and iron) design, uses a fixed core of magnet material (NdFeB) and iron (C-1006) surrounded by a rotating ring of the same magnet material and iron. The quadrupole gradient-length product can be smoothly varied from a minimum of 0.7 T up to a maximum, of 4.3 T by a 90 degrees rotation of the outer ring of iron and magnet material

  5. New technique for wiring SSC superconducting sextupole corrector coils

    International Nuclear Information System (INIS)

    Leon, B.

    1985-01-01

    There exists in the electronics industry, a technology for the manufacture of printed circuit (PC) boards which is directly transferable into the creation of highly controlled coils, such as the SSC sextupole superconducting corrector coils. This technology, which uses a process of laying down insulated wire in highly controlled patterns has heretofore been confined exclusively to the manufacture of high density printed circuit (PC) boards, possibly due to an ignorance of its utility in the field of precision winding of coils. This ability to fix wires in a well defined location can be used to produce precision wound coils in a very cost-effective manner. These coils may be superior in quality to conventionally made coils. Before describing what can be created with this technology, it is necessary to take a look at this coil winding process, the MULTIWIRE process, and the industry which has utilized this technology

  6. A new technique for wiring SSC superconducting sextupole corrector coils

    International Nuclear Information System (INIS)

    Leon, B.

    1985-01-01

    There exists in the electronics industry, a technology for the manufacture of printed circuit (PC) boards which is directly transferable into the creation of highly controlled coils, such as the SSC sextupole superconducting corrector coils. This technology, which uses a process of laying down insulated wire in highly controlled patterns, has heretofore been confined excusively to the manufacture of high density printed circuit (PC) boards, possibly due to an ignorance of its utility in the field of precision winding of coils. This ability to fix wires in a well defined location can be used to produce precision wound coils in a very cost-effective manner. These coils may be superior in quality to conventionally made coils. Before describing what can be created with this technology, it is necessary to take a look at this coil winding process, the MULTIWIRE process, and the industry which has utilized this technology

  7. Coil and iron design for SSC 50 mm magnet

    International Nuclear Information System (INIS)

    Gupta, R.C.; Kahn, S.A.; Morgan, G.H.

    1990-01-01

    In this paper we present the design of the two dimensional coil and iron cross section, referred to as DSX201/W6733, for the 50 mm aperture dipole magnet being built at the Brookhaven National Laboratory for the Superconducting Super Collider (SSC). The computed values of the allowed field harmonics as a function of current, the quench performance predictions, the stored energy calculations, the effect of random errors on the coil placement and the Lorentz forces on the coil will be presented. The yoke has been optimized to reduce iron saturation effects on the field harmonics. We shall present the summary of this design which will include the expected overall performance of this cross section. 4 refs., 8 figs., 12 tabs

  8. Winding mandrel design for the wide cable SSC dipole

    International Nuclear Information System (INIS)

    Morgan, G.H.; Greene, A.; Jochen, G.; Morgillo, A.

    1990-01-01

    The 50 mm coil i.d. SSC dipole magnets use wider cables to give a greater operational margin between quench field and operating field. The cable used for the inner coil has 30 strands of the same size (0.808 mm) instead of 23 and the outer has 36 strands of the same size (0.648 mm) instead of 30 and the cable widths are increased in proportion. Although the coil inner diameter has been increased from 40 mm, the coil ends are noticeably harder to wind. This report describes the computational and experimental effort to design winding mandrels or center posts for the constant-perimeter ends. 1 ref., 2 figs., 2 tabs

  9. A development environment for the SSC control system

    International Nuclear Information System (INIS)

    Murray, Doug; Martinsen, Garth; Wang, Judy

    1994-01-01

    The SSC is developing a design environment for control system development within the context of EPICS. The environment is aimed at developers of applications using the EPICS Input/Output Controller (IOC). The unique aspect of this effort is our emphasis on providing a simple and intuitive development environment compared with tools currently available. Our most important goal in this effort has been to hide the complexity of EPICS IOC development from the developers. This paper describes two tools which are under development; The Function Block Editor (FBE) and the State Machine Editor (SME). The FBE provides a visual editing environment for graphically describing control processes as a set of related functional blocks. The configuration of functional blocks is then translated into IOC records and executed. SME allows the user to visually construct a sequence using a notation we are modeling after Grafcet [1]. State machines are translated into EPICS State Notation Language programs and executed. Future extensions will be described. ((orig.))

  10. Evaluation of the radiosensitivity of acute myeloblastic leukaemia progenitor cells by culture methods exploring self-renewal. Evaluation de la radiosensibilite des progeniteurs de leucemie aigue myeloblastique par des methodes de culture explorant ou non l'autorenouvellement

    Energy Technology Data Exchange (ETDEWEB)

    Cowen, D; Richaud, P; Landriau, S; Lagarde, P; Gualde, N [Fondation Bergonie, 33 - Bordeaux (France); Boiron, J M [Hopital du Haut-Leveque, 33 - Pessac (France); Mahon, F X; Belloc, F [Hopital Regional, 33 - Bordeaux (France); Reiffers, J [Hopital du Haut-Leveque, 33 - Pessac (France) Hopital Regional, 33 - Bordeaux (France)

    1993-01-01

    The progenitor cells of acute myeloblastic leukaemia (AML) are usually cultured in methylcellulose which selects for terminal dividing cells. Suspension cultures have been developed because they reflect self-renewal: the exponential growth of the progenitors of AML cultured in suspension is due to self-renewal. We have compared the radiosensitivity of the progenitors of AML grown either in methylcellulose alone or first in suspension for 7 days before being plated in methylcellulose. Cells were harvested from leukaemic bone marrows at the moment of diagnosis. The myeloblastic lineage of the colonies was assessed by morphological, cytochemical and immunophenotypic analysis and by the use of growth factors which do not stimulate T-lymphocytes. The cell-cycle distribution of leukaemic blasts was comparable for all the samples. This method enabled aggressive leukaemias to be selected. The radiosensitivity showed wide variations from one patient to another (Do ranging from 0.35 to 2.6 Gy) whichever culture method used. The progenitor cells capable of self-renewal were more radiosensitive (Mean Do 0.9[+-]0.4 Gy) than terminal dividing cells (Mean Do = 1.35[+-]0.5 Gy). In two cases, a shoulder was found in the initial part of the cell-survival curves of cells capable of self-renewal. The shape of the curves was better fitted by the linear quadratic model with very low values of [alpha]/[beta], suggesting a reduced antileukaemic effect in case of fractionation.

  11. A Regulatory Network Involving β-Catenin, e-Cadherin, PI3k/Akt, and Slug Balances Self-Renewal and Differentiation of Human Pluripotent Stem Cells In Response to Wnt Signaling.

    Science.gov (United States)

    Huang, Tyng-Shyan; Li, Li; Moalim-Nour, Lilian; Jia, Deyong; Bai, Jian; Yao, Zemin; Bennett, Steffany A L; Figeys, Daniel; Wang, Lisheng

    2015-05-01

    The mechanisms underlying disparate roles of the canonical Wnt signaling pathway in maintaining self-renewal or inducing differentiation and lineage specification in embryonic stem cells (ESCs) are not clear. In this study, we provide the first demonstration that self-renewal versus differentiation of human ESCs (hESCs) in response to Wnt signaling is predominantly determined by a two-layer regulatory circuit involving β-catenin, E-cadherin, PI3K/Akt, and Slug in a time-dependent manner. Short-term upregulation of β-catenin does not lead to the activation of T-cell factor (TCF)-eGFP Wnt reporter in hESCs. Instead, it enhances E-cadherin expression on the cell membrane, thereby enhancing hESC self-renewal through E-cadherin-associated PI3K/Akt signaling. Conversely, long-term Wnt activation or loss of E-cadherin intracellular β-catenin binding domain induces TCF-eGFP activity and promotes hESC differentiation through β-catenin-induced upregulation of Slug. Enhanced expression of Slug leads to a further reduction of E-cadherin that serves as a β-catenin "sink" sequestering free cytoplasmic β-catenin. The formation of such a framework reinforces hESCs to switch from a state of temporal self-renewal associated with short-term Wnt/β-catenin activation to definitive differentiation. Stem Cells 2015;33:1419-1433. © 2015 AlphaMed Press.

  12. Genome Wide Association Studies (GWAS Identify QTL on SSC2 and SSC17 Affecting Loin Peak Shear Force in Crossbred Commercial Pigs.

    Directory of Open Access Journals (Sweden)

    Chunyan Zhang

    Full Text Available Of all the meat quality traits, tenderness is considered the most important with regard to eating quality and market value. In this study we have utilised genome wide association studies (GWAS for peak shear force (PSF of loin muscle as a measure of tenderness for 1,976 crossbred commercial pigs, genotyped for 42,721 informative SNPs using the Illumina PorcineSNP60 Beadchip. Four 1 Mb genomic regions, three on SSC2 (at 4 Mb, 5 Mb and 109 Mb and one on SSC17 (at 20 Mb, were detected which collectively explained about 15.30% and 3.07% of the total genetic and phenotypic variance for PSF respectively. Markers ASGA0008566, ASGA0008695, DRGA0003285 and ASGA0075615 in the four regions were strongly associated with the effects. Analysis of the reference genome sequence in the region with the most important SNPs for SSC2_5 identified FRMD8, SLC25A45 and LTBP3 as potential candidate genes for meat tenderness on the basis of functional annotation of these genes. The region SSC2_109 was close to a previously reported candidate gene CAST; however, the very weak LD between DRGA0003285 (the best marker representing region SSC2_109 and CAST indicated the potential for additional genes which are distinct from, or interact with, CAST to affect meat tenderness. Limited information of known genes in regions SSC2_109 and SSC17_20 restricts further analysis. Re-sequencing of these regions for informative animals may help to resolve the molecular architecture and identify new candidate genes and causative mutations affecting this trait. These findings contribute significantly to our knowledge of the genomic regions affecting pork shear force and will potentially lead to new insights into the molecular mechanisms regulating meat tenderness.

  13. IGF-1R Promotes Symmetric Self-Renewal and Migration of Alkaline Phosphatase+ Germ Stem Cells through HIF-2α-OCT4/CXCR4 Loop under Hypoxia

    Directory of Open Access Journals (Sweden)

    Yung-Che Kuo

    2018-02-01

    Full Text Available Summary: Hypoxia cooperates with endocrine signaling to maintain the symmetric self-renewal proliferation and migration of embryonic germline stem cells (GSCs. However, the lack of an appropriate in vitro cell model has dramatically hindered the understanding of the mechanism underlying this cooperation. Here, using a serum-free system, we demonstrated that hypoxia significantly induced the GSC mesenchymal transition, increased the expression levels of the pluripotent transcription factor OCT4 and migration-associated proteins (SDF-1, CXCR4, IGF-1, and IGF-1R, and activated the cellular expression and translocalization of the CXCR4-downstream proteins ARP3/pFAK. The underlying mechanism involved significant IGF-1/IGF-1R activation of OCT4/CXCR4 expression through HIF-2α regulation. Picropodophyllin-induced inhibition of IGF-1R phosphorylation significantly suppressed hypoxia-induced SDF-1/CXCR4 expression and cell migration. Furthermore, transactivation between IGF-1R and CXCR4 was involved. In summary, we demonstrated that niche hypoxia synergistically cooperates with its associated IGF-1R signaling to regulate the symmetric division (self-renewal proliferation and cell migration of alkaline phosphatase-positive GSCs through HIF-2α-OCT4/CXCR4 during embryogenesis. : In this article, Huang and colleagues demonstrate that niche hypoxia promotes symmetric self-renewal proliferation and migration of PGC-like CD49f+AP+GSCs through IGF-IR regulation. Using a serum-free culture system, the crosstalk between IGF-1R and CXCR4 signaling was discovered. This work demonstrated that embryonic hypoxia synergistically cooperated with IGF-1R signaling to regulate the symmetric self-renewal and migration of PGC-like GSCs through a HIF-2α–OCT4/CXCR4 loop. Keywords: hypoxia, niche, germline stem cells, self-renewal, migration, IGF-1R, HIF-2α, OCT4, SDF-1, CXCR4

  14. Best practices: Strategic stigma change (SSC): five principles for social marketing campaigns to reduce stigma.

    Science.gov (United States)

    Corrigan, Patrick W

    2011-08-01

    This column describes strategic stigma change (SSC), which comprises five principles and corresponding practices developed as a best practice to erase prejudice and discrimination associated with mental illness and promote affirming behaviors and social inclusion. SSC principles represent more than ten years of insights from the National Consortium on Stigma and Empowerment. The principles, which are centered on consumer contact that is targeted, local, credible, and continuous, were developed to inform the growth of large-scale social marketing campaigns supported by governments and nongovernmental organizations. Future social marketing efforts to address stigma and the need for evidence to determine SSC's penetration and impact are also discussed.

  15. Controlling the crossing angle in the SSC [Superconducting Super Collider

    International Nuclear Information System (INIS)

    Garren, A.A.; Johnson, D.E.

    1989-04-01

    The colliding beams in the SSC must cross at a small angle, so that when the bunches pass each other away from the interaction point (IP), they are sufficiently separated to avoid disruptive beam-beam forces. However, the crossing angle is so small that the adjacent quadrupoles must be common to both beams. Only after passing through four common quadrupoles on each side of the IP, are the beams split by vertical dipoles into separate beamlines. In order to make the closed orbits of the two beams cross at a definite angle at the IP (within a range up to 150 μrad), a series of correction dipoles are placed in the insertions. If these dipoles are excited in such a way as to control the closed orbits alone, the dispersion will be mismatched, reaching values of up to 50 cm in the arcs. This mismatch is due to the closed orbit displacements in the interaction region (IR) quadrupoles, causing them to act as bending magnets. Therefore, both the closed orbit and dispersion must be matched simultaneously. Solutions to this problem are presented. 6 figs

  16. SSC collider quadrupole cold mass design and development

    International Nuclear Information System (INIS)

    Farrell, R.A.; Murray, F.S.; Jonas, P.A.; Mischler, W.R.; Blecher, L.

    1992-01-01

    Approximately 1,664 focussing and defocussing superconducting quadrupoles are required for the two SSC collider rings. Collider quadruple magnets (CQMS) must satisfy stringent performance, reliability, life and low cost criteria. Performance requirements include field uniformity, training, quench, tracking, thermal cycling and alignment. The CQM cold mass design presented incorporates lessons IGC and Alsthom Intermagnetics S.A. (AISA), our joint venture with GEC-Alsthom, learned in the design, development and manufacture of 500 MRI, 160 high-field custom and 126 HERA quadruple superconducting magnets. This baseline design reflects careful quantitative assessment of coil winding placement and collar material, evaluation of field uniformity and mechanical performance of the magnet coil ends using 3-D modeling and analysis, and considers tolerance and process variability. Selected CQM cold mass design highlights and a proposed prototype development program that allows incorporation of test feedback into the design to minimize risk are detailed in this paper. This information may be helpful to SSCL in the design and development of prototype CQM'S

  17. Design of the SSC medium-beta Interaction Regions

    International Nuclear Information System (INIS)

    Nosochkov, Y.M.

    1993-06-01

    In the SSC design the 87.12 km long collider lattice consists of two 35.28 km identical arcs located on the North and South sides of the machine and two 8.28 km clusters placed on the West and on the East. Each cluster contains two Interaction Regions (IRs), the Utility section and the interconnect sections between them. According to present plans the goal for the optics in the East IRs is to provide for a high value of the luminosity and, hence, for a low β at the Interaction Point (IP). The West IRs are aimed at providing for a large space for detector which can be achieved at the cost of higher value of the β and lower luminosity. The optics of each IR are based on the same optical configuration which gives an opportunity to use mostly identical quadrupoles and dipoles in four IRs. Trivial modification of the central region in this basic configuration allows for a wide range of values for detector free space from L = 20 m to L = 90 m, suitable for the experiments in both clusters. L denotes here the distance between the IP and the nearest magnetic element of the machine. In this paper we briefly review the current design of the so-called medium-β IR optics with a large free space for detector of L = 90 m, which could be used in the West cluster

  18. Field measuring probe for SSC [Superconducting Super Collider] magnets

    International Nuclear Information System (INIS)

    Ganetis, G.; Herrera, J.; Hogue, R.; Skaritka, J.; Wanderer, P.; Willen, E.

    1987-03-01

    The field probe developed for measuring the field in SSC dipole magnets is an adaptation of the rotating tangential coil system in use at Brookhaven for several years. Also known as the MOLE, it is a self-contained room-temperature mechanism that is pulled through the aperture of the magnet with regular stops to measure the local field. Several minutes are required to measure the field at each point. The probe measures the multipole components of the field as well as the field angle relative to gravity. The sensitivity of the coil and electronics is such that the field up to the full 6.6 T excitation of the magnet as well as the field when warm with only 0.01 T excitation can be measured. Tethers are attached to both ends of the probe to carry electrical connections and to supply dry nitrogen to the air motors that rotate the tangential windings as well as the gravity sensor. A small computer is attached to the probe for control and for data collection, analysis and storage. Digital voltmeters are used to digitize the voltages from the rotating coil and several custom circuits control motor speeds in the probe. The overall diameter of the probe is approximately 2 cm and its length is 2.4 m; the field sensitive windings are 0.6 m in length

  19. Electrical characteristics of long strings of SSC superconducting dipoles

    International Nuclear Information System (INIS)

    Shafer, R.E.; Smedley, K.M.

    1992-01-01

    Because long strings of series-connected superconducting magnets have no dc resistance and low ac losses, the string behaves like a shorted transmission line. The string is thus resonant at multiple half-wavelengths unless damped by the inclusion of resistors that couple to the LdI/dt voltage across the magnet inductance. Based on the measured ac characteristics of individual magnets, it is possible to predict the electrical properties of long strings of magnets for a variety of damping resistors. These strings can be simulated using an analytic representation in FORTRAN (using complex-number notation) or a discrete-component equivalent-circuit modelling program (e.g., SPICE). Various electrical parameters, including characteristic impedance, signal velocity, induced power-supply ripple current, attenuation lengths, and driving-point impedances, can be predicted, and the damping resistor value can be optimized. Comparisons will be made to measurements on a long string of superconducting Tevatron magnets, and some predictions will be made for the SSC collider magnet system

  20. A liquid nitrogen temperature SSC [Superconducting Super Collider

    International Nuclear Information System (INIS)

    McAshan, M.S.; VanderArend, P.

    1987-04-01

    Under the assumption that new developments in the science of superconductivity will lead to dipole magnets suitable for the SSC that have the same properties with regard to field, field quality, size and cost as those in the present conception of the collider, but operating at 77 K rather than 4.35 K; the initial cost of the collider facility is found to be less by $213 M out of the $2,000 M actual construction cost for the collider technical systems and the conventional facilities estimated in the Conceptual Design Report. EDI and contingency is not included in these figures. Operation at the higher temperature is not, however, an unequivocal advantage. The beam line vacuum system in the 77 K case presents problems that will require a larger magnet aperture for satisfactory solution. The costs of this together with the cost of the development and construction of the new vacuum system required is estimated to be $156 M. The net capital cost saving associated with the higher temperature operation is thus found to be $57 M or about 3% of the estimated cost. In addition it is estimated that the operating cost of the facility will under conditions be less by $27.5 M per year in the steady-state including an allowance for the greater availability of the simpler cryogenic system. 14 refs., 1 fig., 4 tabs

  1. Two dimensional magnetic field calculations for the SSC dipole magnets

    International Nuclear Information System (INIS)

    Krefta, M.P.; Pavlik, D.

    1991-01-01

    In this work two-dimensional methods are used to calculate the magnetic fields throughout the cross section of a SSC dipole magnet. Analytic techniques, which are based on closed form solutions to the defining field equations, are used to calculate the multipole content for any specified conductor positioning. The method is extended to investigate the effects of radial slots or keyways in the iron yoke. The multipole components of field, directly attributable to the slots or keyways, are examined as a function of size and location. It is shown that locating the slots or keyways at the magnet pole centers has a large effect on the multipole components; whereas, locating the keyways between the magnet poles has little effect on any of the multipoles. The investigation of nonlinear effects such as ferromagnetic saturation or superconductor magnetization relies on the use of numerical methods such as the finite element method. The errors associated with these codes are explained in terms of numerical round-off, spatial discretization error and the representation of distant boundaries. A method for increasing the accuracy of the multipole calculation from finite element solutions is set forth. It is shown that calculated multipole coefficients are sensitive to boundary conditions external to the cold mass during conditions of magnetic saturation

  2. A room-temperature liquid calorimeter prototype for the SSC

    International Nuclear Information System (INIS)

    Brandenburg, G.W.; Geer, S.H.; Oliver, J.; Sadowski, E.; Theriot, D.

    1990-01-01

    Calorimeters will be an extremely important part of SSC detectors as they have been in existing collider detectors. The main issues that need to be addressed are: (1) energy resolution of jets and electrons, (2) segmentation, (3) hermiticity, (4) response time, and (5) radiation resistance. An attractive possibility on all these counts is the use of room-temperature liquids together with uranium, as pioneered by UA1. The authors are planning a prototype calorimeter which consists of a sealed vessel containing both the radiator plates and the readout pads. This geometry has been appropriately named the swimming pool design. The general mechanical starting point is similar to the SLD liquid argon calorimeters. The points they wish to address are the following: (1) Simple and reliable modular construction techniques, (2) Satisfactory electrical connections with minimal geometric impact, (3) The necessity of isolating radiator plates and liquid to maintain purity, (4) What materials can be immersed without compromising the liquid purity. The design and construction of the swimming pool electromagnetic calorimeter prototype is being carried out at the Harvard High Energy Physics Laboratory. This is one of the first attempts to build a full-scale prototype of such a design

  3. Automatic beam centering at the SSC interaction regions

    International Nuclear Information System (INIS)

    Joestlein, H.

    1984-01-01

    In the SSC interaction regions, the two colliding beams, each only a few microns in size, will have to be centered and maintained in good alignment over many hours, in order to provide the maximum possible luminosity and to minimize off-center beam-beam focussing effects. It is unlikely that sufficiently good alignment can be achieved without some kind of active feedback system, based on the beam-beam interaction rate. This memo describes such a system. In the proposed scheme, one of the beams is moved continuously and in a circular fashion about its mean transverse position. The radius of this motion is approximately 0.01 of the rms beam size at the interaction point. The motion is achieved with two sets of crossed high frequency dipole magnets, one on each side of the interaction region, suitably phased. As a consequence of this motion, the beam-beam interaction rate is modulated in synchronism with the beam motion when the beams are not centered on one another. The amplitude and phase of this modulation yields information on the magnitude and direction of the misalignment between the beams, allowing continuous display and automatic correction of any misalignment

  4. Qualification of technical personnel for employment during construction and operation of the SSC

    International Nuclear Information System (INIS)

    Johnson, C.D.; Wolf, L.J.

    1991-01-01

    In the early stages of the SSC design it became apparent that construction will have a significant impact on post-secondary technical/vocational education in Texas. Present estimates are that from 2,000 to 3,000 employees will be needed in the traditional fields of civil, mechanical, electrical technology, computers as well as exotic technologies such as cryogenics and high vacuum. In this paper an on-going project is described which is directed toward assuring that graduates of Texas post-secondary technical and vocational education programs will be competitive for employment in these jobs. The project involves development of SSC pedagogical material at a level appropriate to the students, education of teachers about the SSC and development of delivery systems for education about the SSC

  5. Proceedings of the international workshop on solenoidal detectors for the SSC

    International Nuclear Information System (INIS)

    Abe, Fumio; Hasegawa, Katsuo

    1990-07-01

    This issue is the collection of the papers presented at the International Workshop on solenoidal detectors for the Superconducting Super Collider (SSC). The 48 of the presented papers are indexed individually. (J.P.N.)

  6. Increasing NASA SSC Range Safety by Developing the Framework to Monitor Airspace and Enforce Restrictions

    Data.gov (United States)

    National Aeronautics and Space Administration — The NASA John C. Stennis Space Center (SSC) Office of Safety and Mission Assurance (SMA) has a safety concern associated with unauthorized aircraft entering...

  7. A full-acceptance detector for SSC physics at low and intermediate mass scales

    International Nuclear Information System (INIS)

    Bjorken, J.D.

    1992-01-01

    The author of this paper is interested in seeing the proposed detector and physics measurements done at the SSC. It should be clear that the author views this subject as important enough to warrant the effort going into producing this tome. It should also be clear that nothing will happen unless members of the experimental community come forward and do real work to see whether the ideas contained herein are sound and that the physics is indeed worth a dedicated effort at the SSC. Therefore this paper is directed more toward the experimental community than the SSC Laboratory. However, since initial encouragement (or discouragement) by the laboratory is evidently very important, this paper also contains specific requests addressed to the SSC Laboratory

  8. Detection of H0 → γγ at the SSC

    International Nuclear Information System (INIS)

    Barter, C.; Partridge, R.; Bay, A.; Spadafora, A.; Whitaker, S.; Abashian, A.; Kass, R.

    1989-01-01

    This paper explores the prospects for using the SSC to find an intermediate mass Higgs boson through its decay to two photons. Monte Carlo studies of the signal and various backgrounds are performed to determine the required detector parameters

  9. Performance evaluation of concrete bridge decks reinforced with MMFX and SSC rebars.

    Science.gov (United States)

    2006-01-01

    This report investigates the performance of bridge decks reinforced with stainless steel clad (SSC) and micro-composite multistructural formable steel (MMFX) rebars. The two-span Galloway Road Bridge on route CR5218 over North Elkhorn Creek in Scott ...

  10. Mechanical and electromagnetic design of the SSC QSE101 quadrupole ends

    International Nuclear Information System (INIS)

    Orrell, D.; Nobrega, F.; Lilly, J.; Snitchler, G.; Jayakumar, J.; Venkatraman, V.; Brandt, J.S.

    1992-01-01

    The SSC collider magnets feature grouped ends in which cables of a particular coil remain stacked together as they are bent around the end. Methods have been developed to form the ends in such a way that mechanical stresses are lowered and field quality is optimized. This paper discusses techniques of end turn design and presents calculations of harmonics and peak fields for the SSC quadrupole QSE101

  11. Mechanical and electromagnetic design of the SSC QSE101 quadrupole ends

    International Nuclear Information System (INIS)

    Orrell, D.; Nobrega, F.; Lilly, J.; Snitchler, G.; Jayakumar, J.; Venkatraman, V.; Brandt, J.S.

    1991-06-01

    The SSC collider magnets feature grouped ends in which cables of a particular coil remain stacked together as they are gent around the end. methods have been developed to form the ends in such a way that mechanical stresses are lowered and field quality is optimized. This paper discusses techniques of end turn design and presents calculations of harmonics and peak fields for the SSC quadrupole QSE101. 5 refs., 9 figs

  12. EVALUATING THE EFFECTIVENESS OF TEACHING METHODS USED FOR GCE AND SSC LEVELS

    OpenAIRE

    Bhatti, Muhammad Safdar; Mukhtar, Rafia; Bajwa, Shahla

    2017-01-01

    Thepresent research focuses on comparative study of the Secondary SchoolCertificate (SSC) and the General Certificate of Education-Ordinary level(GCE-O level) English language course to trace out the problems andshortcomings of the curriculum objectives and teaching methods. The objectivesof the study were to analyze the objectives of teaching English of SSC and GCEO-level to critically review the teaching methodologies of both the courses.The population of the study comprised of all the teac...

  13. Design and analysis of the SSC [Superconducting Super Collider] dipole magnet suspension system

    International Nuclear Information System (INIS)

    Nicol, T.H.; Niemann, R.C.; Gonczy, J.D.

    1989-03-01

    The design of the suspension system for Superconducting Super Collider (SSC) dipole magnets has been driven by rigorous thermal and structural requirements. The current system, designed to meet those requirements, represents a significant departure from previous superconducting magnet suspension system designs. This paper will present a summary of the design and analysis of the vertical and lateral suspension as well as the axial anchor system employed in SSC dipole magnets. 5 refs., 9 figs., 4 tabs

  14. Magnetic field measurements of full length 50 mm aperture SSC dipole magnets at Fermilab

    International Nuclear Information System (INIS)

    Strait, J.; Bossert, R.; Carson, J.; Delchamps, S.W.; Gourlay, S.; Hanft, R.; Koska, W.; Kuchnir, M.; Lamm, M.J.; Mazur, P.O.; Mokhtarani, A.; Orris, D.; Ozelis, J.; Wake, M.; Devred, A.; DiMarco, J.; Kuzminski, J.; Puglisi, M.; Tompkins, J.C.; Yu, Y.; Zhao, Y.; Zheng, H.; Ogitsu, T.

    1992-09-01

    Thirteen 16 m long, 50 mm aperture SSC dipole magnets, designed jointly by Fermilab, Brookhaven National Laboratory, Lawrence Berkeley Laboratory and the SSC Laboratory, have been built at Fermilab. The first nine magnets have been fully tested to date. The allowed harmonics are systematically shifted from zero by amounts larger than the specification. The unallowed harmonics, with the exception of the skew sextupole, are consistent with zero. The magnet-to-magnet RMS variation of all harmonics is much smaller than the specification

  15. Trend of telomerase activity change during human iPSC self-renewal and differentiation revealed by a quartz crystal microbalance based assay

    Science.gov (United States)

    Zhou, Yitian; Zhou, Ping; Xin, Yinqiang; Wang, Jie; Zhu, Zhiqiang; Hu, Ji; Wei, Shicheng; Ma, Hongwei

    2014-11-01

    Telomerase plays an important role in governing the life span of cells for its capacity to extend telomeres. As high activity of telomerase has been found in stem cells and cancer cells specifically, various methods have been developed for the evaluation of telomerase activity. To overcome the time-consuming procedures and complicated manipulations of existing methods, we developed a novel method named Telomeric Repeat Elongation Assay based on Quartz crystal microbalance (TREAQ) to monitor telomerase activity during the self-renewal and differentiation of human induced pluripotent stem cells (hiPSCs). TREAQ results indicated hiPSCs possess invariable telomerase activity for 11 passages on Matrigel and a steady decline of telomerase activity when differentiated for different periods, which is confirmed with existing golden standard method. The pluripotency of hiPSCs during differentiation could be estimated through monitoring telomerase activity and compared with the expression levels of markers of pluripotency gene via quantitative real time PCR. Regular assessment for factors associated with pluripotency or stemness was expensive and requires excessive sample consuming, thus TREAQ could be a promising alternative technology for routine monitoring of telomerase activity and estimate the pluripotency of stem cells.

  16. MicroRNA-302/367 Cluster Governs hESC Self-Renewal by Dually Regulating Cell Cycle and Apoptosis Pathways

    Directory of Open Access Journals (Sweden)

    Zhonghui Zhang

    2015-04-01

    Full Text Available miR-302/367 is the most abundant miRNA cluster in human embryonic stem cells (hESCs and can promote somatic cell reprogramming. However, its role in hESCs remains poorly understood. Here, we studied functional roles of the endogenous miR-302/367 cluster in hESCs by employing specific TALE-based transcriptional repressors. We revealed that miR-302/367 cluster dually regulates hESC cell cycle and apoptosis in dose-dependent manner. Gene profiling and functional studies identified key targets of the miR-302/367 cluster in regulating hESC self-renewal and apoptosis. We demonstrate that in addition to its role in cell cycle regulation, miR-302/367 cluster conquers apoptosis by downregulating BNIP3L/Nix (a BH3-only proapoptotic factor and upregulating BCL-xL expression. Furthermore, we show that butyrate, a natural compound, upregulates miR-302/367 cluster expression and alleviates hESCs from apoptosis induced by knockdown of miR-302/367 cluster. In summary, our findings provide new insights in molecular mechanisms of how miR-302/367 cluster regulates hESCs.

  17. Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance

    Science.gov (United States)

    Mohammed, Maryam K.; Shao, Connie; Wang, Jing; Wei, Qiang; Wang, Xin; Collier, Zachary; Tang, Shengli; Liu, Hao; Zhang, Fugui; Huang, Jiayi; Guo, Dan; Lu, Minpeng; Liu, Feng; Liu, Jianxiang; Ma, Chao; Shi, Lewis L.; Athiviraham, Aravind; He, Tong-Chuan; Lee, Michael J.

    2016-01-01

    Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities, including cell proliferation, calcium homeostasis, and cell polarity. The role of Wnt signaling in control of cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway, which is the best characterized among the multiple Wnt signaling branches. The past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway, as many new components of Wnt signaling have been identified and linked to signaling regulation, stem cell functions, and adult tissue homeostasis. Additionally, a substantial body of evidence links Wnt signaling to tumorigenesis of many cancer types and implicates it in the development of cancer drug resistance. Thus, a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current therapy. This review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and disease. We begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness, tumorigenesis, and cancer drug resistance. Ultimately, we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance. PMID:27077077

  18. Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC

    Directory of Open Access Journals (Sweden)

    Mimmi S. Ballard

    2015-10-01

    Full Text Available Tissue homeostasis requires somatic stem cell maintenance; however, mechanisms regulating this process during organogenesis are not well understood. Here, we identify asymmetrically renewing basal and luminal stem cells in the mammary end bud. We demonstrate that SLIT2/ROBO1 signaling regulates the choice between self-renewing asymmetric cell divisions (ACDs and expansive symmetric cell divisions (SCDs by governing Inscuteable (mInsc, a key member of the spindle orientation machinery, through the transcription factor Snail (SNAI1. Loss of SLIT2/ROBO1 signaling increases SNAI1 in the nucleus. Overexpression of SNAI1 increases mInsc expression, an effect that is inhibited by SLIT2 treatment. Increased mInsc does not change cell proliferation in the mammary gland (MG but instead causes more basal cap cells to divide via SCD, at the expense of ACD, leading to more stem cells and larger outgrowths. Together, our studies provide insight into how the number of mammary stem cells is regulated by the extracellular cue SLIT2.

  19. Identification of a Dynamic Core Transcriptional Network in t(8;21 AML that Regulates Differentiation Block and Self-Renewal

    Directory of Open Access Journals (Sweden)

    Anetta Ptasinska

    2014-09-01

    Full Text Available Oncogenic transcription factors such as RUNX1/ETO, which is generated by the chromosomal translocation t(8;21, subvert normal blood cell development by impairing differentiation and driving malignant self-renewal. Here, we use digital footprinting and chromatin immunoprecipitation sequencing (ChIP-seq to identify the core RUNX1/ETO-responsive transcriptional network of t(8;21 cells. We show that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind to identical DNA sites in a mutually exclusive fashion. Perturbation of this equilibrium in t(8;21 cells by RUNX1/ETO depletion leads to a global redistribution of transcription factor complexes within preexisting open chromatin, resulting in the formation of a transcriptional network that drives myeloid differentiation. Our work demonstrates on a genome-wide level that the extent of impaired myeloid differentiation in t(8;21 is controlled by the dynamic balance between RUNX1/ETO and RUNX1 activities through the repression of transcription factors that drive differentiation.

  20. HTR8/SVneo Cells Display Trophoblast Progenitor Cell-Like Characteristics Indicative of Self-Renewal, Repopulation Activity, and Expression of “Stemness-” Associated Transcription Factors

    Directory of Open Access Journals (Sweden)

    Maja Weber

    2013-01-01

    Full Text Available Introduction. JEG3 is a choriocarcinoma—and HTR8/SVneo a transformed extravillous trophoblast—cell line often used to model the physiologically invasive extravillous trophoblast. Past studies suggest that these cell lines possess some stem or progenitor cell characteristics. Aim was to study whether these cells fulfill minimum criteria used to identify stem-like (progenitor cells. In summary, we found that the expression profile of HTR8/SVneo (CDX2+, NOTCH1+, SOX2+, NANOG+, and OCT- is distinct from JEG3 (CDX2+ and NOTCH1+ as seen only in human-serum blocked immunocytochemistry. This correlates with HTR8/SVneo’s self-renewal capacities, as made visible via spheroid formation and multi-passagability in hanging drops protocols paralleling those used to maintain embryoid bodies. JEG3 displayed only low propensity to form and reform spheroids. HTR8/SVneo spheroids migrated to cover and seemingly repopulate human chorionic villi during confrontation cultures with placental explants in hanging drops. We conclude that HTR8/SVneo spheroid cells possess progenitor cell traits that are probably attained through corruption of “stemness-” associated transcription factor networks. Furthermore, trophoblastic cells are highly prone to unspecific binding, which is resistant to conventional blocking methods, but which can be alleviated through blockage with human serum.

  1. PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact.

    Science.gov (United States)

    Lee, Byung-Chul; Kim, Hyung-Sik; Shin, Tae-Hoon; Kang, Insung; Lee, Jin Young; Kim, Jae-Jun; Kang, Hyun Kyoung; Seo, Yoojin; Lee, Seunghee; Yu, Kyung-Rok; Choi, Soon Won; Kang, Kyung-Sun

    2016-05-27

    Mesenchymal stem cells (MSCs) possess unique immunomodulatory abilities. Many studies have elucidated the clinical efficacy and underlying mechanisms of MSCs in immune disorders. Although immunoregulatory factors, such as Prostaglandin E2 (PGE2), and their mechanisms of action on immune cells have been revealed, their effects on MSCs and regulation of their production by the culture environment are less clear. Therefore, we investigated the autocrine effect of PGE2 on human adult stem cells from cord blood or adipose tissue, and the regulation of its production by cell-to-cell contact, followed by the determination of its immunomodulatory properties. MSCs were treated with specific inhibitors to suppress PGE2 secretion, and proliferation was assessed. PGE2 exerted an autocrine regulatory function in MSCs by triggering E-Prostanoid (EP) 2 receptor. Inhibiting PGE2 production led to growth arrest, whereas addition of MSC-derived PGE2 restored proliferation. The level of PGE2 production from an equivalent number of MSCs was down-regulated via gap junctional intercellular communication. This cell contact-mediated decrease in PGE2 secretion down-regulated the suppressive effect of MSCs on immune cells. In conclusion, PGE2 produced by MSCs contributes to maintenance of self-renewal capacity through EP2 in an autocrine manner, and PGE2 secretion is down-regulated by cell-to-cell contact, attenuating its immunomodulatory potency.

  2. HTR8/SVneo cells display trophoblast progenitor cell-like characteristics indicative of self-renewal, repopulation activity, and expression of "stemness-" associated transcription factors.

    Science.gov (United States)

    Weber, Maja; Knoefler, Ilka; Schleussner, Ekkehard; Markert, Udo R; Fitzgerald, Justine S

    2013-01-01

    JEG3 is a choriocarcinoma--and HTR8/SVneo a transformed extravillous trophoblast--cell line often used to model the physiologically invasive extravillous trophoblast. Past studies suggest that these cell lines possess some stem or progenitor cell characteristics. Aim was to study whether these cells fulfill minimum criteria used to identify stem-like (progenitor) cells. In summary, we found that the expression profile of HTR8/SVneo (CDX2+, NOTCH1+, SOX2+, NANOG+, and OCT-) is distinct from JEG3 (CDX2+ and NOTCH1+) as seen only in human-serum blocked immunocytochemistry. This correlates with HTR8/SVneo's self-renewal capacities, as made visible via spheroid formation and multi-passagability in hanging drops protocols paralleling those used to maintain embryoid bodies. JEG3 displayed only low propensity to form and reform spheroids. HTR8/SVneo spheroids migrated to cover and seemingly repopulate human chorionic villi during confrontation cultures with placental explants in hanging drops. We conclude that HTR8/SVneo spheroid cells possess progenitor cell traits that are probably attained through corruption of "stemness-" associated transcription factor networks. Furthermore, trophoblastic cells are highly prone to unspecific binding, which is resistant to conventional blocking methods, but which can be alleviated through blockage with human serum.

  3. Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1.

    Science.gov (United States)

    Li, Fengyin; He, Bing; Ma, Xiaoke; Yu, Shuyang; Bhave, Rupali R; Lentz, Steven R; Tan, Kai; Guzman, Monica L; Zhao, Chen; Xue, Hai-Hui

    2017-09-07

    Effective treatment of chronic myelogenous leukemia (CML) largely depends on the eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map, we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34 + stem/progenitor cells. Mechanistically, PGE1 acted on the EP4 receptor and repressed Fosb and Fos AP-1 factors in a β-catenin-independent manner. Misoprostol, an FDA-approved EP4 agonist, conferred similar protection against CML. These findings suggest that activation of this PGE1-EP4 pathway specifically targets CML LSCs and that the combination of PGE1/misoprostol with conventional tyrosine-kinase inhibitors could provide effective therapy for CML. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway.

    Science.gov (United States)

    Ho, Lena; Tan, Shawn Y X; Wee, Sheena; Wu, Yixuan; Tan, Sam J C; Ramakrishna, Navin B; Chng, Serene C; Nama, Srikanth; Szczerbinska, Iwona; Sczerbinska, Iwona; Chan, Yun-Shen; Avery, Stuart; Tsuneyoshi, Norihiro; Ng, Huck Hui; Gunaratne, Jayantha; Dunn, N Ray; Reversade, Bruno

    2015-10-01

    ELABELA (ELA) is a peptide hormone required for heart development that signals via the Apelin Receptor (APLNR, APJ). ELA is also abundantly secreted by human embryonic stem cells (hESCs), which do not express APLNR. Here we show that ELA signals in a paracrine fashion in hESCs to maintain self-renewal. ELA inhibition by CRISPR/Cas9-mediated deletion, shRNA, or neutralizing antibodies causes reduced hESC growth, cell death, and loss of pluripotency. Global phosphoproteomic and transcriptomic analyses of ELA-pulsed hESCs show that it activates PI3K/AKT/mTORC1 signaling required for cell survival. ELA promotes hESC cell-cycle progression and protein translation and blocks stress-induced apoptosis. INSULIN and ELA have partially overlapping functions in hESC medium, but only ELA can potentiate the TGFβ pathway to prime hESCs toward the endoderm lineage. We propose that ELA, acting through an alternate cell-surface receptor, is an endogenous secreted growth factor in human embryos and hESCs that promotes growth and pluripotency. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. SSCTRK: A particle tracking code for the SSC

    International Nuclear Information System (INIS)

    Ritson, D.

    1990-07-01

    While many indirect methods are available to evaluate dynamic aperture there appears at this time to be no reliable substitute to tracking particles through realistic machine lattices for a number of turns determined by the storage times. Machine lattices are generated by ''Monte Carlo'' techniques from the expected rms fabrication and survey errors. Any given generated machine can potentially be a lucky or unlucky fluctuation from the average. Therefore simulation to serve as a predictor of future performance must be done for an ensemble of generated machines. Further, several amplitudes and momenta are necessary to predict machine performance. Thus to make Monte Carlo type simulations for the SSC requires very considerable computer resources. Hitherto, it has been assumed that this was not feasible, and alternative indirect methods have been proposed or tried to answer the problem. We reexamined the feasibility of using direct computation. Previous codes have represented lattices by a succession of thin elements separated by bend-drifts. With ''kick-drift'' configurations, tracking time is linear in the multipole order included, and the code is symplectic. Modern vector processors simultaneously handle a large number of cases in parallel. Combining the efficiencies of kick drift tracking with vector processing, in fact, makes realistic Monte Carlo simulation entirely feasible. SSCTRK uses the above features. It is structured to have a very friendly interface, a very wide latitude of choice for cases to be run in parallel, and, by using pure FORTRAN 77, to interchangeably run on a wide variety of computers. We describe in this paper the program structure operational checks and results achieved

  6. SC1 Promotes MiR124-3p Expression to Maintain the Self-Renewal of Mouse Embryonic Stem Cells by Inhibiting the MEK/ERK Pathway.

    Science.gov (United States)

    Wei, Qing; Liu, Hongliang; Ai, Zhiying; Wu, Yongyan; Liu, Yingxiang; Shi, Zhaopeng; Ren, Xuexue; Guo, Zekun

    2017-01-01

    Self-renewal is one of the most important features of embryonic stem (ES) cells. SC1 is a small molecule modulator that effectively maintains the self-renewal of mouse ES cells in the absence of leukemia inhibitory factor (LIF), serum and feeder cells. However, the mechanism by which SC1 maintains the undifferentiated state of mouse ES cells remains unclear. In this study, microarray and small RNA deep-sequencing experiments were performed on mouse ES cells treated with or without SC1 to identify the key genes and microRNAs that contributed to self-renewal. SC1 regulates the expressions of pluripotency and differentiation factors, and antagonizes the retinoic acid (RA)-induced differentiation in the presence or absence of LIF. SC1 inhibits the MEK/ERK pathway through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and pathway reporting experiments. Small RNA deep-sequencing revealed that SC1 significantly modulates the expression of multiple microRNAs with crucial functions in ES cells. The expression of miR124-3p is upregulated in SC1-treated ES cells, which significantly inhibits the MEK/ERK pathway by targeting Grb2, Sos2 and Egr1. SC1 enhances the self-renewal capacity of mouse ES cells by modulating the expression of key regulatory genes and pluripotency-associated microRNAs. SC1 significantly upregulates miR124-3p expression to further inhibit the MEK/ ERK pathway by targeting Grb2, Sos2 and Egr1. © 2017 The Author(s). Published by S. Karger AG, Basel.

  7. Essential role of miR-200c in regulating self-renewal of breast cancer stem cells and their counterparts of mammary epithelium

    International Nuclear Information System (INIS)

    Feng, Zhong-Ming; Qiu, Jun; Chen, Xie-Wan; Liao, Rong-Xia; Liao, Xing-Yun; Zhang, Lu-Ping; Chen, Xu; Li, Yan; Chen, Zheng-Tang; Sun, Jian-Guo

    2015-01-01

    Breast cancer stem cells (BCSCs) have been reported as the origin of breast cancer and the radical cause of drug resistance, relapse and metastasis in breast cancer. BCSCs could be derived from mutated mammary epithelial stem cells (MaSCs). Therefore, comparing the molecular differences between BCSCs and MaSCs may clarify the mechanism underlying breast carcinogenesis and the targets for gene therapy. Specifically, the distinct miRNome data of BCSCs and MaSCs need to be analyzed to find out the key miRNAs and reveal their roles in regulating the stemness of BCSCs. MUC1 − ESA + cells were isolated from normal mammary epithelial cell line MCF-10A by fluorescence-activated cell sorting (FACS) and tested for stemness by clonogenic assay and multi-potential differentiation experiments. The miRNA profiles of MaSCs, BCSCs and breast cancer MCF-7 cells were compared to obtain the candidate miRNAs that may regulate breast tumorigenesis. An miRNA consecutively upregulated from MaSCs to BCSCs to MCF-7 cells, miR-200c, was chosen to determine its role in regulating the stemness of BCSCs and MaSCs in vitro and in vivo. Based on bioinformatics, the targets of miR-200c were validated by dual-luciferase report system, western blot and rescue experiments. In a 2-D clonogenic assay, MUC1 − ESA + cells gave rise to multiple morphological colonies, including luminal colonies, myoepithelial colonies and mixed colonies. The clonogenic potential of MUC1 − ESA + (61.5 ± 3.87 %) was significantly higher than that of non-stem MCF-10A cells (53.5 ± 3.42 %) (P < 0.05). In a 3-D matrigel culture, MUC1 − ESA + cells grew into mammospheres with duct-like structures. A total of 12 miRNAs of interest were identified, 8 of which were upregulated and 4 downregulated in BCSCs compared with MaSCs. In gain- and lost-of-function assays, miR-200c was sufficient to inhibit the self-renewal of BCSCs and MaSCs in vitro and the growth of BCSCs in vivo. Furthermore, miR-200c negatively regulated

  8. Protective effects of a preparation(hemoHIM) of herb mixture on self-renewal tissues and immune system in whole body irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hae-Ran; Oh, Heon; Jo, Sung-Kee [Korea Atomic Energy Research Institute, Daejon (Korea, Republic of); Kim, Sung-Ho [Chonnam National Univ., Kwangju (Korea, Republic of); Yee, Sung-Tae [Sunchon National Univ., Sunchon (Korea, Republic of)

    2002-07-01

    A preparation (HemoHIM) of herb mixture was designed to protect the gastrointestine and hematopoietic organs and to promote recovery of the immune system against radiation damage. The mixture of 3 edible medicinal herbs (Angelica gagantis Radix, etc.) was decocted with hot water and the extract was fractionated with ethanol. The preparation HemoHIM was made up with addition of ethanol- insoluble fraction yielded from one half of the total water extract to the other half of the total water extract. In vitro, lymphocytes were protected by HemoHIM, its polysaccharide and ethanol fractions against radiation. The proliferation of lymphocytes and bone marrow cells by HemoHIM was due to its polysaccharide fraction. In mice administered with the preparation (HemoHIM) before gamma- irradiation, the jejunal crypt survival was increased and the apoptosis of crypt cells was decreased. HemoHIM administration increased the survival of bone marrow stem cells and promoted the repopulation of blood cells following irradiation. In the analysis of the repopulated lymphocyte subsets, B cells were firstly regenerated and then T cells were recovered in mice administrated with HemoHIM. The antibody production against T-dependent antigen DNP-KLH was augmented by HemoHIM in irradiated mice. These results indicated that HemoHIM, a preparation of the herb mixture, protected the stem cells of self-renewal tissues and hematopoietic organs and promoted recovery of the immune system against radiation damage. Since the preparation of herb mixture is a relatively nontoxic natural product, it might be a useful modifier for prevention and control of radiation damages.

  9. Radioprotective effects of a preparation (HemoHIM) of herb mixture on self-renewal tissues and immune system in mice

    Energy Technology Data Exchange (ETDEWEB)

    Jo, Sung Kee; Park, Hae Ran; Jung, Uhee; Oh, Heon [KAERI, Taejon (Korea, Republic of); Kim, Sung Ho [Chonnam National Univ. Seoul (Korea, Republic of); Yee, Sung Tae [Sunchon National Univ., Seoul (Korea, Republic of)

    2004-07-01

    A preparation (HemoHIM) of herb mixture was designed to protect the gastrointestine and hematopoietic organs and to promote recovery of the immune system against radiation damage. The mixture of 3 edible medicinal herbs was decocted with hot water and the extract was fractionated with ethanol. The preparation HemoHIM was made up with addition of ethanol-insoluble fraction to the total water extract. In vitro, HemoHIM, its polysaccharide and ethanol fractions protected lymphocytes against radiation and scavenged hydroxyl radicals. The proliferation of lymphocytes and bone marrow cells by HemoHIM was due to its polysaccharide fraction. In mice administered with the preparation (HemoHIM) before gamma-irradiation the jejunal crypt survival was increased and the apoptosis of crypt cells was decreased. HemoHIM administration increased the survival of bone marrow stem cells and promoted the repopulation of blood cells following irradiation. In the analysis of the repopulated lymphocyte subsets, B cells were firstly regenerated and then T cells were recovered in mice administrated with HemoHIM. The antibody production against T-dependent antigen DNP-KLH was augmented by HemoHIM in irradiated mice. Finally, oral or intraperitoneal administration of HemoHIM augmented the 30 day survival rate after irradiation. These results indicated that HemoHIM, a preparation of the herb mixture, protected the stem cells of self-renewal tissues and hematopoietic organs and promoted recovery of the immune system against radiation damage, thus increasing the survival following lethal irradiation. Since the preparation of herb mixture is a relatively nontoxic natural product, it might be a useful modifier for prevention and control of radiation damages.

  10. Optimization of culture conditions to support long-term self-renewal of buffalo (Bubalus bubalis) embryonic stem cell-like cells.

    Science.gov (United States)

    Sharma, Ruchi; George, Aman; Kamble, Nitin Manchindra; Singh, Karn Pratap; Chauhan, Manmohan Singh; Singla, Suresh Kumar; Manik, Radhey Sham; Palta, Prabhat

    2011-12-01

    A culture system capable of sustaining self-renewal of buffalo embryonic stem (ES) cell-like cells in an undifferentiated state over a long period of time was developed. Inner cell masses were seeded on KO-DMEM+15% KO-serum replacer on buffalo fetal fibroblast feeder layer. Supplementation of culture medium with 5 ng/mL FGF-2 and 1000 IU/mL mLIF gave the highest (p<0.05) rate of primary colony formation. The ES cell-like cells' colony survival rate and increase in colony size were highest (p<0.05) following supplementation with FGF-2 and LIF compared to other groups examined. FGF-2 supplementation affected the quantitative expression of NANOG, SOX-2, ACTIVIN A, BMP 4, and TGFβ1, but not OCT4 and GREMLIN. Supplementation with SU5402, an FGFR inhibitor (≥20 μM) increased (p<0.05) the percentage of colonies that differentiated. FGFR1-3 and ERK1, K-RAS, E-RAS, and SHP-2, key signaling intermediates of FGF signaling, were detected in ES cell-like cells. Under culture conditions described, three ES cell lines were derived that, to date, have been maintained for 135, 95, and 85 passages for over 27, 19, and 17 months, respectively, whereas under other conditions examined, ES cell-like cells did not survive beyond passage 10. The ES cell-like cells were regularly monitored for expression of pluripotency markers and their potency to form embryoid bodies.

  11. Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells.

    Science.gov (United States)

    Peng, Hui; Kasada, Atsuo; Ueno, Masaya; Hoshii, Takayuki; Tadokoro, Yuko; Nomura, Naho; Ito, Chiaki; Takase, Yusuke; Vu, Ha Thi; Kobayashi, Masahiko; Xiao, Bo; Worley, Paul F; Hirao, Atsushi

    2018-01-01

    The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) senses a cell's energy status and environmental levels of nutrients and growth factors. In response, mTORC1 mediates signaling that controls protein translation and cellular metabolism. Although mTORC1 plays a critical role in hematopoiesis, it remains unclear which upstream stimuli regulate mTORC1 activity in the context of hematopoietic stem cells (HSC) maintenance in vivo. In this study, we investigated the function of Rheb, a critical regulator of mTORC1 activity controlled by the PI3K-AKT-TSC axis, both in HSC maintenance in mice at steady-state and in HSC-derived hematopoiesis post-transplantation. In contrast to the severe hematopoietic dysfunction caused by Raptor deletion, which completely inactivates mTORC1, Rheb deficiency in adult mice did not show remarkable hematopoietic failure. Lack of Rheb caused abnormalities in myeloid cells but did not have impact on hematopoietic regeneration in mice subjected to injury by irradiation. As previously reported, Rheb deficiency resulted in defective HSC-derived hematopoiesis post-transplantation. However, while Raptor is essential for HSC competitiveness in vivo, Rheb is dispensable for HSC maintenance under physiological conditions, indicating that the PI3K-AKT-TSC pathway does not contribute to mTORC1 activity for sustaining HSC self-renewal activity at steady-state. Thus, the various regulatory elements that impinge upstream of mTORC1 activation pathways are differentially required for HSC homeostasis in vivo. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Performance of the MAGCOOL-subcooler cryogenic system after SSC quadrupole quenches

    International Nuclear Information System (INIS)

    Wu, K.C.

    1993-01-01

    The subcooler assembly installed in the MAGCOOL magnet test area at Brookhaven National Laboratory has been used for testing SSC dipoles, quadrupoles and a spool piece since 1989. A detailed description of the system, its steady state capacity and the performance after quenches of a 50 mm SSC dipole were given. Subsequent studies on low current quenches of the SSC dipoles and quenches of the RHIC dipoles were also carried out. In this paper, the performance of the subcooler after quenches of the SSC quadrupole QCC404 is presented. Pressures, temperatures and flow rates in the magnet cooling loop after magnet quenches are given as a function of time. The cooling rates and total energy removed by cooling during quench recovery have been calculated for quench currents between 2000 and 7952 amperes. Because the inductance of the quadrupole is about one tenth that of a SSC dipole, the stored energy released is small and the impact on the system is mild. The cooling loop pressure never exceeds 12 atmospheres and the cryogenic system recovers in less than 15 minutes. As in all past studies, the peak pressure and temperature in the magnet cooling loop are linearly proportional to the energy released during a quench and excellent agreement between the total cooling provided and the magnetic stored energy is found

  13. Sawtooth-wave prebuncher with dual-gaps in Linac injector for HIRFL-SSC

    Science.gov (United States)

    Zhang, Xiaohu; Yuan, Youjin; Xia, Jiawen; Yin, Xuejun; Jin, Peng; Xu, Zhe; Du, Heng; Li, Zhongshan; Qiao, Jian; Wang, Kedong

    2018-01-01

    An RFQ structure is normally composed of radial matcher, shaper, gentle buncher and accelerator section with changing cell geometry. Bunching is started in the shaper, and adiabatic bunching is done in gentle buncher section. The beam preforms from DC beam to bunch beam through the RFQ and the longitudinal emittance for the ions linacs is defined initially in the RFQ, in which the beam bunch has been shaped. In the present SSC-Linac injector, an RFQ has been designed to accelerate the continuous beam from 3.728 keV/u to 143 keV/u. The heavy ions beam is injected into the SSC (Separated Sector Cyclotron) with the kinetic energy of 1.025 MeV/u after four IH DTLs. The rf frequency of the SSC is 13.417 MHz, and the frequency of the heavy ions RFQ is set to four times of the rf frequency of the SSC. In order to increase the longitudinal capture efficiency of the SSC and suppress the longitudinal emittance at the exit of RFQ, an external MHB (Multi-Harmonics Buncher) is proposed in front of the RFQ. The fundamental frequency of the MHB is the same as the rf frequency of the cyclotron. The scheme of dual-gaps prebuncher with the sawtooth waveform is firstly carried out through multi-harmonics synthetic technology. The multi-particle beam dynamic simulations of the MHB have been done by the BEAMPATH code.

  14. Theoretical methods for creep and stress relaxation studies of SSC coil

    International Nuclear Information System (INIS)

    McAdams, J.; Markley, F.

    1992-04-01

    Extrapolation of laboratory measurements of SSC coil properties to the actual construction of SSC magnets requires mathematical models of the experimental data. A variety of models were used to approximate the data collected from creep and stress relaxation experiments performed on Kapton film and SSC coil samples. The coefficients for these mathematical models were found by performing a least-squares fit via the program MINUIT. Once the semiempirical expressions for the creep data were found, they were converted to expressions for stress relaxation using an approximate I pn of the Laplace integral relating the two processes. The data sets from creep experiments were also converted directly to stress relaxation data by numeric integration. Both of these methods allow comparison of data from two different methods of measuring viscoelastic properties. Three companion papers presented at this conference will present: Stress relaxation in SSC 50mm dipole coil. Measurement of the elastic modulus of Kapton perpendicular to the plane of the film at room and cryogenic temperatures. Temperature dependence of the viscoelastic properties of SSC coil insulation (Kapton)

  15. Test results from recent 1.8-m SSC [Superconducting Super Collider] model dipoles

    International Nuclear Information System (INIS)

    Wanderer, P.; Cottingham, J.G.; Dahl, P.

    1988-01-01

    We report results from four 1.8 m-long dipoles built as part of the Superconducting Super Collider (SSC) RandD program. Except for length, these models have the features of the SSC design, which is based on a two-layer cosine theta coil with 4 cm aperture. As compared to the 17 m design length SSC dipoles, these 1.8 m magnets are a faster and more economical way of testing design changes in field shape, conductor support in the coil straight-section and ends, etc. The four magnets reported here all reach fields in excess of 7.5T with little training and have excellent field shape. 10 refs., 2 figs., 3 tabs

  16. Coherent production of {epsilon}{sup +} particles in crystal using proton beam from SSC

    Energy Technology Data Exchange (ETDEWEB)

    Okorokov, V.V.; Dubin, A.Yu. [ITER, Moscow, (Russian Federation)

    1995-05-01

    The unique possibilities of the SSC can be ideally used for a new generation of coherent generation experiments with relativistic protons which require 20 Tev energy of the incident beam. The availability of 20 Tev proton beam at SSC allows new experiments on coherent production of {var_epsilon}{sup +} particle by relativistic proton in crystal. Experiment carried out at low energies can now be extended with protons in very narrow energy region (resonance energy, which easy can be calculated) using the new accelerator facilities at SSC. We propose to study coherent production via the Coulomb field of the cristal atoms to excite the transition p + {gamma}{implies} {var_epsilon} {sup +} (1189).

  17. Modelling formation of new radiation belts and response to ULF oscillations following March 24, 1991 SSC

    International Nuclear Information System (INIS)

    Hudson, M.K.; Kotelnikov, A.D.; Li, X.; Lyon, J.G.; Roth, I.; Temerin, M.; Wygant, J.R.; Blake, J.B.; Gussenhoven, M.S.; Yumoto, K.; Shiokawa, K.

    1996-01-01

    The rapid formation of a new proton radiation belt at L≅2.5 following the March 24, 1991 Storm Sudden Commencement (SSC) observed at the CRRES satellite is modelled using a relativistic guiding center test particle code. The new radiation belt formed on a time scale shorter than the drift period of eg. 20 MeV protons. The SSC is modelled by a bipolar electric field and associated compression and relaxation in the magnetic field, superimposed on a background dipole magnetic field. The source population consists of solar protons that populated the outer magnetosphere during the solar proton event that preceeded the SSC and trapped inner zone protons. The simulations show that both populations contribute to drift echoes in the 20 endash 80 MeV range measured by the Aerospace instrument and in lower energy channels of the Protel instrument on CRRES, while primary contribution to the newly trapped population is from solar protons. Proton acceleration by the SSC differs from electron acceleration in two notable ways: different source populations contribute and nonrelativistic conservation of the first adiabatic invariant leads to greater energization of protons for a given decrease in L than for relativistic electrons. Model drift echoes, energy spectra and flux distribution in L at the time of injection compare well with CRRES observations. On the outbound pass, ∼2 hours after the SSC, the broad spectral peak of the new radiation belt extends to higher energies (20 endash 40 MeV) than immediately after formation. Electron flux oscillations observed at this later time are attributed to post-SSC impulses evident in ground magnetograms, while two minute period ULF oscillations also evident in CRRES field data appear to be cavity modes in the inner magnetosphere. copyright 1996 American Institute of Physics

  18. Rats

    Directory of Open Access Journals (Sweden)

    Alexey Kondrashov

    2012-01-01

    Full Text Available We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol-free Alibernet red wine extract (AWE and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY and spontaneously hypertensive rats (SHRs. Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR.

  19. Bipolar and unipolar tests of 1.5m model SSC collider dipole magnets at Fermilab

    International Nuclear Information System (INIS)

    Lamm, M.J.; Ozelis, J.P.; Coulter, K.J.; Delchamps, S.; Jaffery, T.S.; Kinney, W.; Koska, W.; Strait, J.; Wake, M.; Fortunato, D.; Johnson, D.E.

    1991-05-01

    Tests have been performed at Fermilab on 1.5 m magnetic length model SSC collider dipoles using both bipolar and unipolar ramp cycles. Hysteresis energy loss due to superconductor and iron magnetization and eddy currents is measured and compared as a function of various ramp parameters. Additionally, magnetic field measurements have been performed for both unipolar and bipolar ramp cycles. Measurements such as these will be used to estimate the heat load during collider injection for the SSC High Energy Booster dipoles. 9 refs., 4 figs

  20. Correction of magnetization sextupole and decapole in a 5 centimeter bore SSC dipole using passive superconductor

    International Nuclear Information System (INIS)

    Green, M.A.

    1991-05-01

    Higher multipoles due to magnetization of the superconductor in four and five centimeter bore Superconducting Super Collider (SSC) superconducting dipole magnets have been observed. The use of passive superconductor to correct out the magnetization sextupole has been demonstrated on two dipoles built by the Lawrence Berkeley Laboratory (LBL). This reports shows how passive correction can be applied to the five centimeter SSC dipoles to remove sextupole and decapole caused by magnetization of the dipole superconductor. Two passive superconductor corrector options will be presented. The change in magnetization sextupole and decapole due to flux creep decay of the superconductor during injection can be partially compensated for using the passive superconductor. 9 refs; 5 figs