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Sample records for achieve sustained erythroid

  1. Using Design To Achieve Sustainability

    EPA Science Inventory

    Sustainability is defined as meeting the needs of this generation without compromising the ability of future generations to meet their needs. This is a conditional statement that places the responsibility for achieving sustainability squarely in hands of designers and planners....

  2. Perlman receives Sustained Achievement Award

    NASA Astrophysics Data System (ADS)

    Petit, Charles; Perlman, David

    David Perlman was awarded the Sustained Achievement Award at the AGU Fall Meeting Honors Ceremony, which was held on December 10, 1997, in San Francisco, California. The award recognizes a journalist who has made significant, lasting, and consistent contributions to accurate reporting or writing on the geophysical sciences for the general public.

  3. Achieving sustainable cultivation of potatoes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Every phase of the production cycle impacts the sustainability of potato. Potato physiology determines how genetically encoded developmental attributes interact with local environmental conditions as modified through agricultural practice to produce a perishable crop. In this chapter we highlight ho...

  4. Activation of Stat 5b in erythroid progenitors correlates with the ability of ErbB to induce sustained cell proliferation.

    PubMed Central

    Mellitzer, G; Wessely, O; Decker, T; Meinke, A; Hayman, M J; Beug, H

    1996-01-01

    Self renewal of normal erythroid progenitors is induced by the receptor tyrosine kinase c-ErbB, whereas other receptors (c-Kit/Epo-R) regulate erythroid differentiation. To address possible mechanisms that could explain this selective activity of c-ErbB, we analyzed the ability of these receptors to activate the different members of the Stat transcription factor family. Ligand activation of c-ErbB induced the tyrosine phosphorylation, DNA-binding, and reporter gene transcription of Stat 5b in erythroblasts. In contrast, ligand activation of c-Kit was unable to induce any of these effects in the same cells. Activation of the erythropoietin receptor caused specific DNA-binding of Stat 5b, but failed to induce reporter gene transcription. These biochemical findings correlate perfectly with the selective ability of c-ErbB to cause sustained self renewal in erythroid progenitors. Images Fig. 1 Fig. 3 Fig. 4 PMID:8790376

  5. Achieving a sustainable service advantage.

    PubMed

    Coyne, K P

    1993-01-01

    Many managers believe that superior service should play little or no role in competitive strategy; they maintain that service innovations are inherently copiable. However, the author states that this view is too narrow. For a company to achieve a lasting service advantage, it must base a new service on a capability gap that competitors cannot or will not copy.

  6. Achieving and sustaining full employment.

    PubMed

    Rosen, S M

    1995-01-01

    Human rights and public health considerations provide strong support for policies that maximize employment. Ample historical and conceptual evidence supports the feasibility of full employment policies. New factors affecting the labor force, the rate of technological change, and the globalization of economic activity require appropriate policies--international as well as national--but do not invalidate the ability of modern states to apply the measures needed. Among these the most important include: (I) systematic reduction in working time with no loss of income, (2) active labor market policies, (3) use of fiscal and monetary measures to sustain the needed level of aggregate demand, (4) restoration of equal bargaining power between labor and capital, (5) social investment in neglected and outmoded infrastructure, (6) accountability of corporations for decisions to shift or reduce capital investment, (7) major reductions in military spending, to be replaced by socially needed and economically productive expenditures, (8) direct public sector job creation, (9) reform of monetary policy to restore emphasis on minimizing unemployment and promoting full employment. None are without precedent in modern economies. The obstacles are ideological and political. To overcome them will require intellectual clarity and effective advocacy. PMID:7499512

  7. Factors Contributing to Institutions Achieving Environmental Sustainability

    ERIC Educational Resources Information Center

    James, Matthew; Card, Karen

    2012-01-01

    Purpose: The purpose of this paper is to determine what factors contributed to three universities achieving environmental sustainability. Design/methodology/approach: A case study methodology was used to determine how each factor contributed to the institutions' sustainability. Site visits, fieldwork, document reviews, and interviews with…

  8. PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors

    PubMed Central

    Farrés, J; Llacuna, L; Martin-Caballero, J; Martínez, C; Lozano, J J; Ampurdanés, C; López-Contreras, A J; Florensa, L; Navarro, J; Ottina, E; Dantzer, F; Schreiber, V; Villunger, A; Fernández-Capetillo, O; Yélamos, J

    2015-01-01

    Erythropoiesis is a tightly regulated process in which multipotential hematopoietic stem cells produce mature red blood cells. Here we show that deletion of poly(ADP-ribose) polymerase-2 (PARP-2) in mice leads to chronic anemia at steady state, despite increased erythropoietin plasma levels, a phenomenon not observed in mice lacking PARP-1. Loss of PARP-2 causes shortened lifespan of erythrocytes and impaired differentiation of erythroid progenitors. In erythroblasts, PARP-2 deficiency triggers replicative stress, as indicated by the presence of micronuclei, the accumulation of γ-H2AX (phospho-histone H2AX) in S-phase cells and constitutive CHK1 and replication protein A phosphorylation. Transcriptome analyses revealed the activation of the p53-dependent DNA-damage response pathways in PARP-2-deficient cells, culminating in the upregulation of cell-cycle and cell death regulators, concomitant with G2/M arrest and apoptosis. Strikingly, while loss of the proapoptotic p53 target gene Puma restored hematocrit levels in the PARP-2-deficient mice, loss of the cell-cycle regulator and CDK inhibitor p21 leads to perinatal death by exacerbating impaired fetal liver erythropoiesis in PARP-2-deficient embryos. Although the anemia displayed by PARP-2-deficient mice is compatible with life, mice die rapidly when exposed to stress-induced enhanced hemolysis. Our results pinpoint an essential role for PARP-2 in erythropoiesis by limiting replicative stress that becomes essential in the absence of p21 and in the context of enhanced hemolysis, highlighting the potential effect that might arise from the design and use of PARP inhibitors that specifically inactivate PARP proteins. PMID:25501596

  9. ACHIEVING SUSTAINABILITY - FINAL STEPS IN A DYNAMIC DANCE

    EPA Science Inventory

    Achieving sustainability relies upon adequate metrics to evaluate the environment and guide decisions. Although adequate assessment is important to prescribing remedies, achieving a sustainable environment cannot be delayed. It must be achieved today as well as tomorrow so that t...

  10. Achieving true sustainability of zoo populations.

    PubMed

    Lacy, Robert C

    2013-01-01

    For the last 30 years, cooperative management of irreplaceable animal populations in zoos and aquariums has focused primarily on the goal of minimizing genetic decay within defined time frames, and large advances have been made in technologies to optimize genetic management of closed populations. However, recent analyses have shown that most zoo programs are not projected to meet their stated goals. This has been described as a lack of achieving "sustainability" of the populations, yet by definition a goal of managed decay is not a plan for sustainability. True sustainability requires management of the resource in manner that does not deplete its value for the future. Achieving such sustainability for many managed populations may require changing from managing isolated populations to managing populations that are part of a broader metapopulation, with carefully considered exchange between populations across a spectrum of ex situ to in situ. Managing zoo populations as components of comprehensive conservation strategies for the species will require research on determinants of various kinds of genetic, physiological, behavioral, and morphological variation and their roles in population viability, development of an array of management techniques and tools, training of population managers in metapopulation management and integrated conservation planning, and projections of impacts of management strategies on the viability of the captive populations and all populations that are interactively managed or affected. Such a shift in goals and methods would result in zoo population management being an ongoing part of species conservation rather than short-term or isolated from species conservation. Zoo Biol. 32:19-26, 2013. © 2012 Wiley Periodicals, Inc.

  11. Achieving true sustainability of zoo populations.

    PubMed

    Lacy, Robert C

    2013-01-01

    For the last 30 years, cooperative management of irreplaceable animal populations in zoos and aquariums has focused primarily on the goal of minimizing genetic decay within defined time frames, and large advances have been made in technologies to optimize genetic management of closed populations. However, recent analyses have shown that most zoo programs are not projected to meet their stated goals. This has been described as a lack of achieving "sustainability" of the populations, yet by definition a goal of managed decay is not a plan for sustainability. True sustainability requires management of the resource in manner that does not deplete its value for the future. Achieving such sustainability for many managed populations may require changing from managing isolated populations to managing populations that are part of a broader metapopulation, with carefully considered exchange between populations across a spectrum of ex situ to in situ. Managing zoo populations as components of comprehensive conservation strategies for the species will require research on determinants of various kinds of genetic, physiological, behavioral, and morphological variation and their roles in population viability, development of an array of management techniques and tools, training of population managers in metapopulation management and integrated conservation planning, and projections of impacts of management strategies on the viability of the captive populations and all populations that are interactively managed or affected. Such a shift in goals and methods would result in zoo population management being an ongoing part of species conservation rather than short-term or isolated from species conservation. Zoo Biol. 32:19-26, 2013. © 2012 Wiley Periodicals, Inc. PMID:22753040

  12. Perspectives on achieving sustainable energy production and use

    EPA Science Inventory

    The traditional definition of sustainability calls for polices and strategies that meet society's present needs without compromising the ability of future generations to meet their own needs. Achieving operational sustainability requires three critical elements: advances in scien...

  13. ACHIEVING SUSTAINABILITY THROUGH LIFE CYCLE STRATEGIES

    EPA Science Inventory

    Sustainability is, of course, not a recent concept. But our understanding of what it means and what we need to do to meet the challenge it presents continues to grow. Throughout the ages, nations have had to address the issue of harmony between the environment, society and the e...

  14. Language Teacher Action Research: Achieving Sustainability

    ERIC Educational Resources Information Center

    Edwards, Emily; Burns, Anne

    2016-01-01

    Action research (AR) is becoming increasingly popular in ELT contexts as a means of continuous professional development. The positive impacts of AR on language teacher development are well documented, but the important question of how those impacts can be sustained over time is virtually unexplored. Drawing on findings from a study of teachers in…

  15. Achieving scale strategies for sustained competitive performance.

    PubMed

    Grube, Mark E; Gish, Ryan S; Tkach, Sasha N

    2008-05-01

    Growth to achieve scale requires the following strategic initiatives: Having a clear understanding of what the organization is and what it wants to become. Ensuring a structured and rigorous growth process. Leveraging size to achieve benefits of scale. Recognizing the importance of physicians, ambulatory care, and primary care. Establishing and maintaining accountability as growth occurs.

  16. Sustaining School Achievement in California's Elementary Schools after State Monitoring

    ERIC Educational Resources Information Center

    McCabe, Molly

    2010-01-01

    This study examined the Academic Performance Index (API) and Adequate Yearly Progress (AYP) achievement trends between 2004 and 2006 of 58 California public elementary schools after exiting state monitoring and investigated practices for sustaining consistent achievement growth. Statistical methods were used to analyze statewide achievement trends…

  17. Sustaining Continued Acceleration in Reading Comprehension Achievement Following an Intervention

    ERIC Educational Resources Information Center

    Lai, Mei Kuin; McNaughton, Stuart; Timperley, Helen; Hsiao, Selena

    2009-01-01

    Schooling improvement initiatives have demonstrated that moderate but significant achievement gains are possible with well designed interventions, but there is little research into whether these gains can be sustained. The present study examines the extent to which acceleration in achievement made during a three-year literacy intervention and the…

  18. Achievement Effects of Sustained Silent Reading in a Middle School

    ERIC Educational Resources Information Center

    Sullivan, Mary Pinson

    2010-01-01

    The purpose of this study was to determine the reading achievement effects of a school-year-long program of sustained silent reading in a middle school. Students' scores on the Stanford Achievement Test, Ninth Edition across three years (2006, 2007, and 2008) were analyzed to test eleven null hypotheses. A 3 x 3 repeated measures factorial ANOVA…

  19. Recovery after disaster: achieving sustainable development, mitigation and equity.

    PubMed

    Berke, P R; Kartez, J; Wenger, D

    1993-06-01

    This paper reviews key findings and raises issues that are not fully addressed by the predominant disaster recovery literature. Achievement of equity, mitigation and sustainable development, particularly through local participation in redevelopment planning and institutional cooperation, is the central issue of the review. Previous research and past assumptions about the process by which communities rebuild after a disaster are reviewed. A conceptual model for understanding local disaster recovery efforts is then presented. The conceptual and practical significance of this model is then demonstrated by presenting case studies of local recovery experiences. Finally, conclusions on the current understanding of disaster redevelopment planning, as well as implications for public policy and future research are offered.

  20. DEVELOPMENT AND APPLICATION OF PLANNING PROCESS TO ACHIEVE SUSTAINABILITY

    EPA Science Inventory

    Concepts of sustainability are numerous, widely discussed, and necessary, but sustainability needs to be applied to development projects to succeed. However, few applications are made and their measures are unclear. Sustainability indicators are typically used as measures, but ...

  1. The role of marine reserves in achieving sustainable fisheries.

    PubMed

    Roberts, Callum M; Hawkins, Julie P; Gell, Fiona R

    2005-01-29

    Many fishery management tools currently in use have conservation value. They are designed to maintain stocks of commercially important species above target levels. However, their limitations are evident from continuing declines in fish stocks throughout the world. We make the case that to reverse fishery declines, safeguard marine life and sustain ecosystem processes, extensive marine reserves that are off limits to fishing must become part of the management strategy. Marine reserves should be incorporated into modern fishery management because they can achieve many things that conventional tools cannot. Only complete and permanent protection from fishing can protect the most sensitive habitats and vulnerable species. Only reserves will allow the development of natural, extended age structures of target species, maintain their genetic variability and prevent deleterious evolutionary change from the effects of fishing. Species with natural age structures will sustain higher rates of reproduction and will be more resilient to environmental variability. Higher stock levels maintained by reserves will provide insurance against management failure, including risk-prone quota setting, provided the broader conservation role of reserves is firmly established and legislatively protected. Fishery management measures outside protected areas are necessary to complement the protection offered by marine reserves, but cannot substitute for it.

  2. The role of marine reserves in achieving sustainable fisheries

    PubMed Central

    Roberts, Callum M.; Hawkins, Julie P.; Gell, Fiona R.

    2005-01-01

    Many fishery management tools currently in use have conservation value. They are designed to maintain stocks of commercially important species above target levels. However, their limitations are evident from continuing declines in fish stocks throughout the world. We make the case that to reverse fishery declines, safeguard marine life and sustain ecosystem processes, extensive marine reserves that are off limits to fishing must become part of the management strategy. Marine reserves should be incorporated into modern fishery management because they can achieve many things that conventional tools cannot. Only complete and permanent protection from fishing can protect the most sensitive habitats and vulnerable species. Only reserves will allow the development of natural, extended age structures of target species, maintain their genetic variability and prevent deleterious evolutionary change from the effects of fishing. Species with natural age structures will sustain higher rates of reproduction and will be more resilient to environmental variability. Higher stock levels maintained by reserves will provide insurance against management failure, including risk-prone quota setting, provided the broader conservation role of reserves is firmly established and legislatively protected. Fishery management measures outside protected areas are necessary to complement the protection offered by marine reserves, but cannot substitute for it. PMID:15713592

  3. Achieving and Maintaining Existing Building Sustainability Certification at Georgetown University

    ERIC Educational Resources Information Center

    Payant, Richard P.

    2013-01-01

    Sustainability is the promotion of high performance, healthful, energy-efficient, and environmentally stable buildings. Buildings intended for sustainable certification must meet guidelines developed by the Leadership in Energy and Environmental Design (LEED) of the U.S. Green Building Council. The problem is that LEED certification often fails to…

  4. Achieving Transformative Sustainability Learning: Engaging Head, Hands and Heart

    ERIC Educational Resources Information Center

    Sipos, Yona; Battisti, Bryce; Grimm, Kurt

    2008-01-01

    Purpose: The current UN Decade of Education for Sustainable Development echoes many scholars' calls to re-envision education for sustainability. Short of a complete overhaul of education, the paper seeks to propose learning objectives that can be integrated across existing curricula. These learning objectives are organized by head, hands and…

  5. Achieving sustainable plant disease management through evolutionary principles.

    PubMed

    Zhan, Jiasui; Thrall, Peter H; Burdon, Jeremy J

    2014-09-01

    Plants and their pathogens are engaged in continuous evolutionary battles and sustainable disease management requires novel systems to create environments conducive for short-term and long-term disease control. In this opinion article, we argue that knowledge of the fundamental factors that drive host-pathogen coevolution in wild systems can provide new insights into disease development in agriculture. Such evolutionary principles can be used to guide the formulation of sustainable disease management strategies which can minimize disease epidemics while simultaneously reducing pressure on pathogens to evolve increased infectivity and aggressiveness. To ensure agricultural sustainability, disease management programs that reflect the dynamism of pathogen population structure are essential and evolutionary biologists should play an increasing role in their design.

  6. Sustaining College Students' Persistence and Achievement through Exemplary Instructional Strategies

    ERIC Educational Resources Information Center

    Gentry, Ruben

    2014-01-01

    A "take it or leave it" attitude has no place in higher education. Society needs an educated citizenry to sustain and advance its technological and global mission. Too few students are entering college and even fewer than might reasonably be expected are graduating. Retention and graduation rates serve as key indicators of performance…

  7. Is Sustainability Achievable? Exploring the Limits of Sustainability with Model Systems

    EPA Science Inventory

    Successful implementation of sustainability ideas in ecosystem management requires a basic understanding of the often nonlinear and non-intuitive relationships amongst different dimensions of sustainability, particularly the systemwide implications of human actions. This basic un...

  8. An international waste convention: measures for achieving sustainable development.

    PubMed

    Meyers, Gary D; McLeod, Glen; Anbarci, Melanie A

    2006-12-01

    Waste is a by-product of economic growth. Consequently, economic growth presents challenges for sustainable resource management and development because continued economic growth implies continued growth in waste outputs. Poor management of waste results in the inappropriate depletion of natural resources and potentially adverse effects on the environment, health and the economy. It is unsustainable. This paper begins by outlining the magnitude of and the current response to the growth in the quantity of waste outputs. This is followed by a consideration of why the international response to date, including the Rio Declaration and Agenda 21, fails to address the issue adequately. The paper concludes with a discussion on why and how an international treaty or other measure could advance sustainable development by providing an appropriate framework within which to address the problem.

  9. Erythroid-specific expression of beta-globin by the sleeping beauty transposon for Sickle cell disease.

    PubMed

    Zhu, Jianhui; Kren, Betsy T; Park, Chang Won; Bilgim, Rasim; Wong, Phillip Y-P; Steer, Clifford J

    2007-06-12

    Sickle cell disease (SCD) results predominately from a single monogenic mutation that affects thousands of individuals worldwide. Gene therapy approaches have focused on using viral vectors to transfer wild-type beta- or gamma-globin transgenes into hematopoietic stem cells for long-term expression of the recombinant globins. In this study, we investigated the use of a novel nonviral vector system, the Sleeping Beauty (SB) transposon (Tn) to insert a wild-type beta-globin expression cassette into the human genome for sustained expression of beta-globin. We initially constructed a beta-globin expression vector composed of the hybrid cytomegalovirus (CMV) enhancer chicken beta-actin promoter (CAGGS) and full-length beta-globin cDNA, as well as truncated forms lacking either the 3' or 3' and 5' untranslated regions (UTRs), to optimize expression of beta-globin. Beta-globin with its 5' UTR was efficiently expressed from its cDNA in K-562 cells induced with hemin. However, expression was constitutive and not erythroid-specific. We then constructed cis SB-Tn-beta-globin plasmids using a minimal beta-globin gene driven by hybrid promoter IHK (human ALAS2 intron 8 erythroid-specific enhancer, HS40 core element from human alphaLCR, ankyrin-1 promoter), IHbetap (human ALAS2 intron 8 erythroid-specific enhancer, HS40 core element from human alphaLCR, beta-globin promoter), or HS3betap (HS3 core element from human betaLCR, beta-globin promoter) to establish erythroid-specific expression of beta-globin. Stable genomic insertion of the minimal gene and expression of the beta-globin transgene for >5 months at a level comparable to that of the endogenous gamma-globin gene were achieved using a SB-Tn beta-globin cis construct. Interestingly, erythroid-specific expression of beta-globin driven by IHK was regulated primarily at the translational level, in contrast to post-transcriptional regulation in non-erythroid cells. The SB-Tn system is a promising nonviral vector for efficient

  10. Achieving high sustained performance in an unstructured mesh CFD application

    SciTech Connect

    Keyes, D E; Anderson, W K; Gropp, W D; Kaushik, D K; Smith, B F

    1999-12-10

    This paper highlights a three-year project by an interdisciplinary team on a legacy F77 computational fluid dynamics code, with the aim of demonstrating that implicit unstructured grid simulations can execute at rates not far from those of explicit structured grid codes, provided attention is paid to data motion complexity and the reuse of data positioned at the levels of the memory hierarchy closest to the processor, in addition to traditional operation count complexity. The demonstration code is from NASA and the enabling parallel hardware and (freely available) software toolkit are from DOE, but the resulting methodology should be broadly applicable, and the hardware limitations exposed should allow programmers and vendors of parallel platforms to focus with greater encouragement on sparse codes with indirect addressing. This snapshot of ongoing work shows a performance of 15 microseconds per degree of freedom to steady-state convergence of Euler flow on a mesh with 2.8 million vertices using 3072 dual-processor nodes of ASCI Red, corresponding to a sustained floating-point rate of 0.227 Tflop/s.

  11. AKT induces erythroid-cell maturation of JAK2-deficient fetal liver progenitor cells and is required for Epo regulation of erythroid-cell differentiation.

    PubMed

    Ghaffari, Saghi; Kitidis, Claire; Zhao, Wei; Marinkovic, Dragan; Fleming, Mark D; Luo, Biao; Marszalek, Joseph; Lodish, Harvey F

    2006-03-01

    AKT serine threonine kinase of the protein kinase B (PKB) family plays essential roles in cell survival, growth, metabolism, and differentiation. In the erythroid system, AKT is known to be rapidly phosphorylated and activated in response to erythropoietin (Epo) engagement of Epo receptor (EpoR) and to sustain survival signals in cultured erythroid cells. Here we demonstrate that activated AKT complements EpoR signaling and supports erythroid-cell differentiation in wild-type and JAK2-deficient fetal liver cells. We show that erythroid maturation of AKT-transduced cells is not solely dependent on AKT-induced cell survival or proliferation signals, suggesting that AKT transduces also a differentiation-specific signal downstream of EpoR in erythroid cells. Down-regulation of expression of AKT kinase by RNA interference, or AKT activity by expression of dominant negative forms, inhibits significantly fetal liver-derived erythroid-cell colony formation and gene expression, demonstrating that AKT is required for Epo regulation of erythroid-cell maturation.

  12. The Failure of Non-Binding Declarations to Achieve University Sustainability: A Need for Accountability

    ERIC Educational Resources Information Center

    Bekessy, S. A.; Samson, K.; Clarkson, R. E.

    2007-01-01

    Purpose: This paper aims to assess the impact and value of non-binding agreements or declarations in achieving sustainability in universities. Design/methodology/approach: A case study of Royal Melbourne Institute of Technology (RMIT) University is presented, analysing the reasons for lack of progress towards sustainability and evaluating best…

  13. A TWO CENTURY HISTORY OF PACIFIC NORTHWEST SALMON: LESSONS LEARNED FOR ACHIEVING A SUSTAINABLE FUTURE

    EPA Science Inventory

    Achieving ecological sustainability is a daunting challenge. In the Pacific Northwest one of the most highly visible public policy debates concerns the future of salmon populations. Throughout the Pacific Northwest, many wild salmon stocks have declined and some have disappeare...

  14. The role of partnership functioning and synergy in achieving sustainability of innovative programmes in community care.

    PubMed

    Cramm, Jane M; Phaff, Sanne; Nieboer, Anna P

    2013-03-01

    This cross-sectional study (conducted in April-May 2011) explored associations between partnership functioning synergy and sustainability of innovative programmes in community care. The study sample consisted of 106 professionals (of 244 individuals contacted) participating in 21 partnerships that implemented different innovative community care programmes in Rotterdam, The Netherlands. Partnership functioning was evaluated by assessing leadership, resources administration and efficiency. Synergy was considered the proximal outcome of partnership functioning, which, in turn, influenced the achievement of programme sustainability. On a 5-point scale of increasing sustainability, mean sustainability scores ranged from 1.9 to 4.9. The results of the regression analysis demonstrated that sustainability was positively influenced by leadership (standardised regression coefficient β = 0.32; P < 0.001) and non-financial resources (β = 0.25; P = 0.008). No significant relationship was found between administration or efficiency and programme sustainability. Partnership synergy acted as a mediator for partnership functioning and significantly affected sustainability (β = 0.39; P < 0.001). These findings suggest that the sustainability of innovative programmes in community care is achieved more readily when synergy is created between partners. Synergy was more likely to emerge with boundary-spanning leaders, who understood and appreciated partners' different perspectives, and could bridge their diverse cultures and were comfortable sharing ideas, resources and power. In addition, the acknowledgement of and ability to use members' resources were found to be valuable in engaging partners' involvement and achieving synergy in community care partnerships.

  15. ERYTHROPOIETIN EFFECTS ON FETAL MOUSE ERYTHROID CELLS

    PubMed Central

    Chui, David H. K.; Djaldetti, Meir; Marks, Paul A.; Rifkind, Richard A.

    1971-01-01

    The effect of the hormone, erythropoietin, on cultures of erythroblasts derived from the livers of fetal C57BL/6J mice was examined. An increase both in the content and in the rate of synthesis of normal adult mouse globin chains was detected in hormone-treated cultures. The rate of protein synthesis by individual erythroblasts does not increase in response to the hormone, whereas the absolute number of hemoglobin-synthesizing cells does increase and accounts for the observed stimulation of hemoglobin synthesis. The principal effect of erythropoietin appears to be upon the population of immature erythroid precursor cells which persists in the presence of the hormone, the cells maintaining their ability to replicate, and their capacity to differentiate into hemoglobinizing erythroblasts. In the absence of hormone, already committed erythroblasts continue their development, but erythropoiesis is not sustained. PMID:5128349

  16. The Effects of Sustained Silent Reading on Reading Achievement and Reading Attitudes of Fourth Grade Students

    ERIC Educational Resources Information Center

    Gray, Holly Lynn

    2012-01-01

    This study tested the effects of a Sustained Silent Reading program on reading achievement and reading attitude. The study accessed scores from the DIBELS Oral Reading Fluency (Good, Kaminski, & Dill, 2007) to measure reading achievement. This measure was given before and after a twelve week period, during which the treatment group…

  17. Challenges to achievement of metal sustainability in our high-tech society

    SciTech Connect

    Izatt, Reed M.; Izatt, Steven R.; Bruening, Ronald L.; Izatt, Neil; Moyer, Bruce A

    2014-01-01

    Achievement of sustainability in metal life cycles from mining of virgin ore to consumer and industrial devices to end-of-life products requires greatly increased recycling and improved processing of metals. Electronic and other high-tech products containing precious, toxic, and specialty metals usually have short lifetimes and low recycling rates. Products containing these metals generally are incinerated, discarded as waste in landfills, or dismantled in informal recycling using crude and environmentally irresponsible procedures. Low metal recycling rates coupled with increasing demand for products containing them necessitate increased mining with attendant environmental, health, energy, water, and carbon-footprint consequences. In this tutorial review, challenges to achieving metal sustainability in present high-tech society are presented; health, environmental, and economic incentives for various stakeholders to improve metal sustainability are discussed; a case for technical improvements in separations technology, especially employing molecular recognition, is given; and global consequences of continuing on the present path are examined.

  18. Achieving Our Environmental Sustainability Goals: The Opportunities and Pitfalls of Applying Life Cycle Thinking

    EPA Science Inventory

    An increasing number of people around the world are beginning to realize that a systems approach, such as life cycle thinking, is necessary to truly achieve environmental sustainability. Without the holistic perspective that life cycle thinking provides, our actions risk leading ...

  19. Program Proposal: Certificates of Competence, Certificate of Achievement, Associate in Applied Science Degree in Sustainable Technology.

    ERIC Educational Resources Information Center

    Pezzoli, Jean A.; Ainsworth, Don

    This document proposes a program in sustainable technology at Maui Community College (Hawaii). This new career program would be designed to provide four Certificates of Competence, a Certificate of Achievement, and an Associate in Applied Science degree. The primary objectives of the program are to meet student, county, and state needs for…

  20. Influence of School Climate on Students' Achievement and Teachers' Productivity for Sustainable Development

    ERIC Educational Resources Information Center

    Adeogun, A. A.; Olisaemeka, Blessing U.

    2011-01-01

    The study covers ten secondary schools in Lagos State of Nigeria. The purpose is to ascertain the relationship between school climate and student achievements and teachers' productivity for sustainable development. A total sample of 150 respondents was taken. Ten principals, seven teachers and seven students were randomly picked per school. This…

  1. Sustained Silent Reading in Middle School and Its Impact on Students' Attitudes and Achievement

    ERIC Educational Resources Information Center

    Morgan, Margaret Peggy S.

    2013-01-01

    Sustained Silent Reading (SSR) is a period of time given to students to read self-selected materials during their school day. This study examines the effect of participation in a SSR program on reading attitudes and reading achievement of students as measured by the Adolescent Motivation to Read Profile (AMRP) and the Northwest Evaluation…

  2. Ecosystem management to achieve ecological sustainability: The case of South Florida

    NASA Astrophysics Data System (ADS)

    Harwell, Mark A.; Long, John F.; Bartuska, Ann M.; Gentile, John H.; Harwell, Christine C.; Myers, Victoria; Ogden, John C.

    1996-07-01

    The ecosystems of South Florida are unique in the world. The defining features of the natural Everglades (large spatial scale, temporal patterns of water storage and sheetflow, and low nutrient levels) historically allowed a mosaic of habitats with characteristic animals. Massive hydrological alterations have halved the Everglades, and ecological sustainability requires fundamental changes in management. The US Man and the Biosphere Human-Dominated Systems Directorate is conducting a case study of South Florida using ecosystem management as a framework for exploring options for mutually dependent sustainability of society and the environment. A new methodology was developed to specify sustainability goals, characterize human factors affecting the ecosystem, and conduct scenario/consequence analyses to examine ecological and societal implications. South Florida has sufficient water for urban, agricultural, and ecological needs, but most water drains to the sea through the system of canals; thus, the issue is not competition for resources but storage and management of water. The goal is to reestablish the natural system for water quantity, timing, and distribution over a sufficient area to restore the essence of the Everglades. The societal sustainability in the Everglades Agricultural Area (EAA) is at risk because of soil degradation, vulnerability of sugar price supports, policies affecting Cuban sugar imports, and political/economic forces aligned against sugar production. One scenario suggested using the EAA for water storage while under private sugar production, thereby linking sustainability of the ecological system with societal sustainability. Further analyses are needed, but the US MAB project suggests achieving ecological sustainability consistent with societal sustainability may be feasible.

  3. Addressing China's grand challenge of achieving food security while ensuring environmental sustainability.

    PubMed

    Lu, Yonglong; Jenkins, Alan; Ferrier, Robert C; Bailey, Mark; Gordon, Iain J; Song, Shuai; Huang, Jikun; Jia, Shaofeng; Zhang, Fusuo; Liu, Xuejun; Feng, Zhaozhong; Zhang, Zhibin

    2015-02-01

    China's increasingly urbanized and wealthy population is driving a growing and changing demand for food, which might not be met without significant increase in agricultural productivity and sustainable use of natural resources. Given the past relationship between lack of access to affordable food and political instability, food security has to be given a high priority on national political agendas in the context of globalization. The drive for increased food production has had a significant impact on the environment, and the deterioration in ecosystem quality due to historic and current levels of pollution will potentially compromise the food production system in China. We discuss the grand challenges of not only producing more food but also producing it sustainably and without environmental degradation. In addressing these challenges, food production should be considered as part of an environmental system (soil, air, water, and biodiversity) and not independent from it. It is imperative that new ways of meeting the demand for food are developed while safeguarding the natural resources upon which food production is based. We present a holistic approach to both science and policy to ensure future food security while embracing the ambition of achieving environmental sustainability in China. It is a unique opportunity for China to be a role model as a new global player, especially for other emerging economies.

  4. Review: Balancing Limiting Factors and Economic Drivers to Achieve Sustainable Midwestern US Agricultural Residue Feedstock Supplies

    SciTech Connect

    Wally W. Wilhelm; J. Richard Hess; Douglas L. Karlen; David J. Muth; Jane M. F. Johnson; John M. Baker; Hero T. Gollany; Jeff M. Novak; Diane E. Stott; Gary E. Varvel

    2010-10-01

    Advanced biofuels will be developed using cellulosic feedstock rather than grain or oilseed crops that can also be used for food and feed. To be sustainable, these new agronomic production systems must be economically viable without degrading soil resources. This review examines six agronomic factors that collectively define many of the limits and opportunities for harvesting crop residue for biofuel feedstock. These six “limiting factors” are discussed in relationship to economic drivers associated with harvesting corn (Zea mays L.) stover as a potential cellulosic feedstock. The limiting factors include soil organic carbon, wind and water erosion, plant nutrient balance, soil water and temperature dynamics, soil compaction, and off-site environmental impacts. Initial evaluations using the Revised Universal Soil Loss Equation 2.0 (RUSLE2) show that a single factor analysis based on simply meeting tolerable soil loss might indicate stover could be harvested sustainably, but the same analysis based on maintaining soil organic carbon shows the practice to be non-sustainable. Modifying agricultural management to include either annual or perennial cover crops is shown to meet both soil erosion and soil carbon requirements. The importance of achieving high yields and planning in a holistic manner at the landscape scale are also shown to be crucial for balancing limitations and drivers associated with renewable bioenergy production.

  5. Addressing China's grand challenge of achieving food security while ensuring environmental sustainability.

    PubMed

    Lu, Yonglong; Jenkins, Alan; Ferrier, Robert C; Bailey, Mark; Gordon, Iain J; Song, Shuai; Huang, Jikun; Jia, Shaofeng; Zhang, Fusuo; Liu, Xuejun; Feng, Zhaozhong; Zhang, Zhibin

    2015-02-01

    China's increasingly urbanized and wealthy population is driving a growing and changing demand for food, which might not be met without significant increase in agricultural productivity and sustainable use of natural resources. Given the past relationship between lack of access to affordable food and political instability, food security has to be given a high priority on national political agendas in the context of globalization. The drive for increased food production has had a significant impact on the environment, and the deterioration in ecosystem quality due to historic and current levels of pollution will potentially compromise the food production system in China. We discuss the grand challenges of not only producing more food but also producing it sustainably and without environmental degradation. In addressing these challenges, food production should be considered as part of an environmental system (soil, air, water, and biodiversity) and not independent from it. It is imperative that new ways of meeting the demand for food are developed while safeguarding the natural resources upon which food production is based. We present a holistic approach to both science and policy to ensure future food security while embracing the ambition of achieving environmental sustainability in China. It is a unique opportunity for China to be a role model as a new global player, especially for other emerging economies. PMID:26601127

  6. Addressing China’s grand challenge of achieving food security while ensuring environmental sustainability

    PubMed Central

    Lu, Yonglong; Jenkins, Alan; Ferrier, Robert C.; Bailey, Mark; Gordon, Iain J.; Song, Shuai; Huang, Jikun; Jia, Shaofeng; Zhang, Fusuo; Liu, Xuejun; Feng, Zhaozhong; Zhang, Zhibin

    2015-01-01

    China’s increasingly urbanized and wealthy population is driving a growing and changing demand for food, which might not be met without significant increase in agricultural productivity and sustainable use of natural resources. Given the past relationship between lack of access to affordable food and political instability, food security has to be given a high priority on national political agendas in the context of globalization. The drive for increased food production has had a significant impact on the environment, and the deterioration in ecosystem quality due to historic and current levels of pollution will potentially compromise the food production system in China. We discuss the grand challenges of not only producing more food but also producing it sustainably and without environmental degradation. In addressing these challenges, food production should be considered as part of an environmental system (soil, air, water, and biodiversity) and not independent from it. It is imperative that new ways of meeting the demand for food are developed while safeguarding the natural resources upon which food production is based. We present a holistic approach to both science and policy to ensure future food security while embracing the ambition of achieving environmental sustainability in China. It is a unique opportunity for China to be a role model as a new global player, especially for other emerging economies. PMID:26601127

  7. What Is an Education for Sustainable Development Supposed to Achieve--A Question of What, How and Why

    ERIC Educational Resources Information Center

    Hofman, Maria

    2015-01-01

    This is a theoretical article to open the discussion of what an education for sustainable development is supposed to achieve and how teachers can help students to develop skills that might be needed in order to support a sustainable future. The focus in the article will be on education. As it is an article aiming to open this kind of discussion…

  8. Iron targeting to mitochondria in erythroid cells.

    PubMed

    Ponka, P; Sheftel, A D; Zhang, A-S

    2002-08-01

    Immature erythroid cells have an exceptionally high capacity to synthesize haem that is, at least in part, the result of the unique control of iron metabolism in these cells. In erythroid cells the vast majority of Fe released from endosomes must cross both the outer and the inner mitochondrial membranes to reach ferrochelatase, which inserts Fe into protoporphyrin IX. Based on the fact that Fe is specifically targeted into erythroid mitochondria, we have proposed that a transient mitochondria-endosome interaction is involved in Fe transfer to ferrochelatase [Ponka (1997) Blood 89, 1-25]. In this study, we examined whether the inhibition of endosome mobility within erythroid cells would decrease the rate of (59)Fe incorporation into haem. We found that, in reticulocytes, the myosin light-chain kinase inhibitor, wortmannin, and the calmodulin antagonist, W-7, caused significant inhibition of (59)Fe incorporation from (59)Fe-transferrin-labelled endosomes into haem. These results, together with confocal microscopy studies using transferrin and mitochondria labelled by distinct fluorescent markers, suggest that, in erythroid cells, endosome mobility, and perhaps their contact with mitochondria, plays an important role in a highly efficient utilization of iron for haem synthesis.

  9. The CACCC-Binding Protein KLF3/BKLF Represses a Subset of KLF1/EKLF Target Genes and Is Required for Proper Erythroid Maturation In Vivo

    PubMed Central

    Funnell, Alister P. W.; Norton, Laura J.; Mak, Ka Sin; Burdach, Jon; Artuz, Crisbel M.; Twine, Natalie A.; Wilkins, Marc R.; Power, Carl A.; Hung, Tzong-Tyng; Perdomo, José; Koh, Philip; Bell-Anderson, Kim S.; Orkin, Stuart H.; Fraser, Stuart T.; Perkins, Andrew C.; Pearson, Richard C. M.

    2012-01-01

    The CACCC-box binding protein erythroid Krüppel-like factor (EKLF/KLF1) is a master regulator that directs the expression of many important erythroid genes. We have previously shown that EKLF drives transcription of the gene for a second KLF, basic Krüppel-like factor, or KLF3. We have now tested the in vivo role of KLF3 in erythroid cells by examining Klf3 knockout mice. KLF3-deficient adults exhibit a mild compensated anemia, including enlarged spleens, increased red pulp, and a higher percentage of erythroid progenitors, together with elevated reticulocytes and abnormal erythrocytes in the peripheral blood. Impaired erythroid maturation is also observed in the fetal liver. We have found that KLF3 levels rise as erythroid cells mature to become TER119+. Consistent with this, microarray analysis of both TER119− and TER119+ erythroid populations revealed that KLF3 is most critical at the later stages of erythroid maturation and is indeed primarily a transcriptional repressor. Notably, many of the genes repressed by KLF3 are also known to be activated by EKLF. However, the majority of these are not currently recognized as erythroid-cell-specific genes. These results reveal the molecular and physiological function of KLF3, defining it as a feedback repressor that counters the activity of EKLF at selected target genes to achieve normal erythropoiesis. PMID:22711990

  10. Socially cooperative choices: An approach to achieving resource sustainability in the coastal zone

    NASA Astrophysics Data System (ADS)

    Crance, Colin; Draper, Dianne

    1996-03-01

    Achieving resource sustainability, particularly in the coastal zone, is complicated by a variety of interdependencies and trade-offs between economic, social, and ecological variables. Although trade-offs between each of these variables are important, this paper emphasizes the social components of resource management. In this regard a distinction is made between individual and cooperative choices. Individual choices frequently are made from a shortterm, self-interested perspective, whereas cooperative choices are made from a long-term, community and resource-sustainability perspective. Typically, when presented with a spectrum of resource management decisions, individuals have a tendency to act in a self-interested manner. Thus, cooperative benefits, such as reduced conflict and improved resource certainty, are not realized. An overview of selected aspects of social dilemma theory suggests that socially cooperative choice outcomes are attainable in coastal zone management by integrating structural and behavioral solutions in resource use decision making. Three barriers to successful integration of structural and behavioral solutions are identified as self-interest, mistrust, and variable perceptions of resource amenities. Examples from coastal zone management indicate that these barriers may be overcome using approaches such as scopereduction, co-management, community education, and local participation. The paper also provides comment on the potential benefits of integrating structural and behavioral solutions in international coastal zone management efforts.

  11. Untangling the debate surrounding strategies for achieving sustainable high coverage of insecticide-treated nets.

    PubMed

    Stevens, Warren

    2005-01-01

    On the question of how to achieve the goal of long-term high utilisation of insecticide-treated nets (ITNs), most protagonists fall into one of two camps: free distribution or market development. The 'free distribution' camp argue that given the health benefit to be gained and lives saved, not to mention the relative cost effectiveness of ITNs, such an intervention should be provided free and paid for by governments or donors. In addition, they argue that it is unrealistic to ask the poorest of the population, who are often the ones at most risk, to pay for an ITN, and this risks producing greater inequalities in health. The market advocates counter that free distribution compromises sustainability, both in terms of demand and supply. Firstly they argue that, without a price, people will be less inclined to value ITNs. In turn this could mean lower utilisation, and a lower inclination to replace such an asset at the end of its useful life. In addition, on the supply side, without a price there is little chance of a local market developing for ITNs, although this would be the surest way to ensure a sustainable supply. It is hard to argue with either viewpoint, as both have merit. This article considers three major issues in the debate, and attempts to draw policy conclusions.

  12. Charting the course for home health care quality: action steps for achieving sustainable improvement: conference proceedings.

    PubMed

    Feldman, Penny Hollander; Peterson, Laura E; Reische, Laurie; Bruno, Lori; Clark, Amy

    2004-12-01

    On June 30 and July 1, 2003, the first national meeting Charting the Course for Home Health Care Quality: Action Steps for Achieving Sustainable Improvement convened in New York City. The Center for Home Care Policy & Research of the Visiting Nurse Service of New York (VNSNY) hosted the meeting with support from the Robert Wood Johnson Foundation. Fifty-seven attendees from throughout the United States participated. The participants included senior leaders and managers and nurses working directly in home care today. The meeting's objectives were to: 1. foster dialogue among key constituents influencing patient safety and home care, 2. promote information-sharing across sectors and identify areas where more information is needed, and, 3. develop an agenda and strategy for moving forward. This article reports the meeting's proceedings.

  13. Achieving sustainability, quality and access: lessons from the world's largest revolving drug fund in Khartoum.

    PubMed

    Witter, S

    2007-01-01

    Ensuring a reliable and affordable supply of essential drugs to health facilities is one of the main challenges facing developing countries. This paper describes the revolving drug fund in Khartoum, which was set up in 1989 to improve access to high quality drugs across the State. An evaluation in 2004 showed that the fund has successfully managed a number of threats to its financial sustainability and has expanded its network of facilities, its range of products and its financial assets. It now supplies essential drugs to 3 million out of the 5 million population of Khartoum each year, at prices between 40% and 100% less than alternative sources. However, results illustrated the tension between achieving an efficient cost-recovery system and access for the poorest.

  14. Petit receives Robert C. Cowen Award for Sustained Achievement in Science Journalism: Citation

    NASA Astrophysics Data System (ADS)

    Rademacher, Horst

    2012-01-01

    Charles W. Petit, a veteran science writer, received the 2011 Robert C. Cowan Award for Sustained Achievement in Science Journalism at the AGU Fall Meeting Honors Ceremony, held on 7 December 2011 in San Francisco, Calif. Petit covered earthquakes for the San Francisco Chronicle during the 1980s and 1990s and has recently served as "head tracker" for the Knight Science Journalism Tracker, a Massachusetts Institute of Technology-based daily blog that compiles and critiques science reporting worldwide. Petit was previously honored by AGU in 2003 when he received the David Perlman Award for an article about a new finding in oceanography. The Cowan Award, named for a former science editor of the Christian Science Monitor, is given no more than every 2 years and recognizes a journalist who has made "significant, lasting, and consistent contributions to accurate reporting or writing" on the Earth and space sciences for the general public.

  15. Petit receives Robert C. Cowen Award for Sustained Achievement in Science Journalism: Response

    NASA Astrophysics Data System (ADS)

    Petit, Charles W.

    2012-01-01

    Charles W. Petit, a veteran science writer, received the 2011 Robert C. Cowan Award for Sustained Achievement in Science Journalism at the AGU Fall Meeting Honors Ceremony, held on 7 December 2011 in San Francisco, Calif. Petit covered earthquakes for the San Francisco Chronicle during the 1980s and 1990s and has recently served as "head tracker" for the Knight Science Journalism Tracker, a Massachusetts Institute of Technology-based daily blog that compiles and critiques science reporting worldwide. Petit was previously honored by AGU in 2003 when he received the David Perlman Award for an article about a new finding in oceanography. The Cowan Award, named for a former science editor of the Christian Science Monitor, is given no more than every 2 years and recognizes a journalist who has made "significant, lasting, and consistent contributions to accurate reporting or writing" on the Earth and space sciences for the general public.

  16. A novel role for nuclear factor-erythroid 2 in erythroid maturation by modulation of mitochondrial autophagy.

    PubMed

    Gothwal, Monika; Wehrle, Julius; Aumann, Konrad; Zimmermann, Vanessa; Gründer, Albert; Pahl, Heike L

    2016-09-01

    We have recently demonstrated that the transcription factor nuclear factor-erythroid 2, which is critical for erythroid maturation and globin gene expression, plays an important role in the pathophysiology of myeloproliferative neoplasms. Myeloproliferative neoplasm patients display elevated levels of nuclear factor-erythroid 2 and transgenic mice overexpressing the transcription factor develop myeloproliferative neoplasm, albeit, surprisingly without erythrocytosis. Nuclear factor-erythroid 2 transgenic mice show both a reticulocytosis and a concomitant increase in iron deposits in the spleen, suggesting both enhanced erythrocyte production and increased red blood cell destruction. We therefore hypothesized that elevated nuclear factor-erythroid 2 levels may lead to increased erythrocyte destruction by interfering with organelle clearance during erythroid maturation. We have previously shown that nuclear factor-erythroid 2 overexpression delays erythroid maturation of human hematopoietic stem cells. Here we report that increased nuclear factor-erythroid 2 levels also impede murine maturation by retarding mitochondrial depolarization and delaying mitochondrial elimination. In addition, ribosome autophagy is delayed in transgenics. We demonstrate that the autophagy genes NIX and ULK1 are direct novel nuclear factor-erythroid 2 target genes, as these loci are bound by nuclear factor-erythroid 2 in chromatin immunoprecipitation assays. Moreover, Nix and Ulk1 expression is increased in transgenic mice and in granulocytes from polycythemia vera patients. This is the first report implying a role for nuclear factor-erythroid 2 in erythroid maturation by affecting autophagy. PMID:27479815

  17. A novel role for nuclear factor-erythroid 2 in erythroid maturation by modulation of mitochondrial autophagy.

    PubMed

    Gothwal, Monika; Wehrle, Julius; Aumann, Konrad; Zimmermann, Vanessa; Gründer, Albert; Pahl, Heike L

    2016-09-01

    We have recently demonstrated that the transcription factor nuclear factor-erythroid 2, which is critical for erythroid maturation and globin gene expression, plays an important role in the pathophysiology of myeloproliferative neoplasms. Myeloproliferative neoplasm patients display elevated levels of nuclear factor-erythroid 2 and transgenic mice overexpressing the transcription factor develop myeloproliferative neoplasm, albeit, surprisingly without erythrocytosis. Nuclear factor-erythroid 2 transgenic mice show both a reticulocytosis and a concomitant increase in iron deposits in the spleen, suggesting both enhanced erythrocyte production and increased red blood cell destruction. We therefore hypothesized that elevated nuclear factor-erythroid 2 levels may lead to increased erythrocyte destruction by interfering with organelle clearance during erythroid maturation. We have previously shown that nuclear factor-erythroid 2 overexpression delays erythroid maturation of human hematopoietic stem cells. Here we report that increased nuclear factor-erythroid 2 levels also impede murine maturation by retarding mitochondrial depolarization and delaying mitochondrial elimination. In addition, ribosome autophagy is delayed in transgenics. We demonstrate that the autophagy genes NIX and ULK1 are direct novel nuclear factor-erythroid 2 target genes, as these loci are bound by nuclear factor-erythroid 2 in chromatin immunoprecipitation assays. Moreover, Nix and Ulk1 expression is increased in transgenic mice and in granulocytes from polycythemia vera patients. This is the first report implying a role for nuclear factor-erythroid 2 in erythroid maturation by affecting autophagy.

  18. A novel role for nuclear factor-erythroid 2 in erythroid maturation by modulation of mitochondrial autophagy

    PubMed Central

    Gothwal, Monika; Wehrle, Julius; Aumann, Konrad; Zimmermann, Vanessa; Gründer, Albert; Pahl, Heike L.

    2016-01-01

    We have recently demonstrated that the transcription factor nuclear factor-erythroid 2, which is critical for erythroid maturation and globin gene expression, plays an important role in the pathophysiology of myeloproliferative neoplasms. Myeloproliferative neoplasm patients display elevated levels of nuclear factor-erythroid 2 and transgenic mice overexpressing the transcription factor develop myeloproliferative neoplasm, albeit, surprisingly without erythrocytosis. Nuclear factor-erythroid 2 transgenic mice show both a reticulocytosis and a concomitant increase in iron deposits in the spleen, suggesting both enhanced erythrocyte production and increased red blood cell destruction. We therefore hypothesized that elevated nuclear factor-erythroid 2 levels may lead to increased erythrocyte destruction by interfering with organelle clearance during erythroid maturation. We have previously shown that nuclear factor-erythroid 2 overexpression delays erythroid maturation of human hematopoietic stem cells. Here we report that increased nuclear factor-erythroid 2 levels also impede murine maturation by retarding mitochondrial depolarization and delaying mitochondrial elimination. In addition, ribosome autophagy is delayed in transgenics. We demonstrate that the autophagy genes NIX and ULK1 are direct novel nuclear factor-erythroid 2 target genes, as these loci are bound by nuclear factor-erythroid 2 in chromatin immunoprecipitation assays. Moreover, Nix and Ulk1 expression is increased in transgenic mice and in granulocytes from polycythemia vera patients. This is the first report implying a role for nuclear factor-erythroid 2 in erythroid maturation by affecting autophagy. PMID:27479815

  19. Calcium Signaling Is Required for Erythroid Enucleation.

    PubMed

    Wölwer, Christina B; Pase, Luke B; Russell, Sarah M; Humbert, Patrick O

    2016-01-01

    Although erythroid enucleation, the property of erythroblasts to expel their nucleus, has been known for 7ore than a century, surprisingly little is known regarding the molecular mechanisms governing this unique developmental process. Here we show that similar to cytokinesis, nuclear extrusion requires intracellular calcium signaling and signal transduction through the calmodulin (CaM) pathway. However, in contrast to cytokinesis we found that orthochromatic erythroblasts require uptake of extracellular calcium to enucleate. Together these functional studies highlight a critical role for calcium signaling in the regulation of erythroid enucleation.

  20. Chronic erythroid hyperplasia and accelerated bone turnover.

    PubMed

    Weinstein, R S; Lutcher, C L

    Bone atrophy is generally thought to be the etiology of the decreased skeletal mass and fractures found in patients with ineffective hematopoiesis and associated erythroid hyperplasia. A bone biopsy from a patient with chronic erythroid hyperplasia and diffuse cortical osteopenia revealed a normal trabecular bone volume, excess osteoid, numerous osteoblasts, and increased osteoclastic resorptive surface. The increased fractional labeled surfaces and widely spaced double tetracycline labels indicated accelerated bone turnover, despite demonstrable iron deposits at the calcification front and cement lines and a low serum level of 25-hydroxyvitamin D. The relationship between the expanded marrow space and trabecular bone suggests that local marrow factors may be responsible for the rapid bone remodeling.

  1. Calcium Signaling Is Required for Erythroid Enucleation

    PubMed Central

    Russell, Sarah M.; Humbert, Patrick O.

    2016-01-01

    Although erythroid enucleation, the property of erythroblasts to expel their nucleus, has been known for 7ore than a century, surprisingly little is known regarding the molecular mechanisms governing this unique developmental process. Here we show that similar to cytokinesis, nuclear extrusion requires intracellular calcium signaling and signal transduction through the calmodulin (CaM) pathway. However, in contrast to cytokinesis we found that orthochromatic erythroblasts require uptake of extracellular calcium to enucleate. Together these functional studies highlight a critical role for calcium signaling in the regulation of erythroid enucleation. PMID:26731108

  2. Secondary Students' Reading Attitudes and Achievement in a Scaffolded Silent Reading Program versus Traditional Sustained Silent Reading

    ERIC Educational Resources Information Center

    West, Chandra Lorene

    2010-01-01

    This study explored the reading attitudes and achievement, as well as genre knowledge, of tenth, eleventh, and twelfth-grade students who participated in Scaffolded Silent Reading, Sustained Silent Reading, or a control group. The Reading and You attitude survey, Degrees of Reading Power achievement measure, and Genre Assessment were administered…

  3. Achieving and sustaining profound institutional change in healthcare: case study using neo-institutional theory.

    PubMed

    Macfarlane, Fraser; Barton-Sweeney, Cathy; Woodard, Fran; Greenhalgh, Trisha

    2013-03-01

    Change efforts in healthcare sometimes have an ambitious, whole-system remit and seek to achieve fundamental changes in norms and organisational culture rather than (or as well as) restructuring the service. Long-term evaluation of such initiatives is rarely undertaken. We report a secondary analysis of data from an evaluation of a profound institutional change effort in London, England, using a mixed-method longitudinal case study design. The service had received £15 million modernisation funding in 2004, covering multiple organisations and sectors and overseen by a bespoke management and governance infrastructure that was dismantled in 2008. In 2010-11, we gathered data (activity statistics, documents, interviews, questionnaires, site visits) and compared these with data from 2003 to 2008. Data analysis was informed by neo-institutional theory, which considers organisational change as resulting from the material-resource environment and three 'institutional pillars' (regulative, normative and cultural-cognitive), enacted and reproduced via the identities, values and activities of human actors. Explaining the long-term fortunes of the different components of the original programme and their continuing adaptation to a changing context required attention to all three of Scott's pillars and to the interplay between macro institutional structures and embedded human agency. The paper illustrates how neo-institutional theory (which is typically used by academics to theorise macro-level changes in institutional structures over time) can also be applied at a more meso level to inform an empirical analysis of how healthcare organisations achieve change and what helps or hinders efforts to sustain those changes. PMID:23415586

  4. Distinct foods with smaller unit would be an effective approach to achieve sustainable weight loss.

    PubMed

    Chang, Un Jae; Suh, Hyung Joo; Yang, Sun Ok; Hong, Yang Hee; Kim, Young Suk; Kim, Jin Man; Jung, Eun Young

    2012-01-01

    We studied the effects of food type and food unit size on food intake and satiety using fried rice mixed with Kimchi in healthy Korean young women (n=31). Amorphous fried rice (1st week), distinct large fried rice balls (100 g/unit, 2nd week) and distinct small fried rice balls (20 g/unit, 3rd week) were served in the same content and volume (500 g). Subjects ate significantly (p<.001) less distinct large fried rice balls (243.5 g) compared to amorphous fried rice (317.2 g). Despite consuming more amorphous fried rice, subjects did not feel significantly fuller after eating amorphous fried rice compared to distinct large fried rice balls. When distinct fried rice balls were served as smaller unit, subjects ate significantly less them (small unit; 190.6 g vs. large unit; 243.5 g, p<.01). Although subjects ate more distinct fried rice balls provided as large unit, they rated similar satiety and hunger levels for distinct small and distinct large fried rice balls. In conclusion, we propose that distinct foods with smaller unit would be an effective approach to achieve sustainable weight loss. PMID:22177403

  5. Sustainability.

    PubMed

    Chang, Chein-Chi; DiGiovanni, Kimberly; Mei, Ying; Wei, Li

    2016-10-01

    This review on Sustainability covers selected 2015 publications on the focus of Sustainability. It is divided into the following sections : • Sustainable water and wastewater utilities • Sustainable water resources management • Stormwater and green infrastructure • Sustainability in wastewater treatment • Life cycle assessment (LCA) applications • Sustainability and energy in wastewater industry, • Sustainability and asset management.

  6. Sustainability.

    PubMed

    Chang, Chein-Chi; DiGiovanni, Kimberly; Mei, Ying; Wei, Li

    2016-10-01

    This review on Sustainability covers selected 2015 publications on the focus of Sustainability. It is divided into the following sections : • Sustainable water and wastewater utilities • Sustainable water resources management • Stormwater and green infrastructure • Sustainability in wastewater treatment • Life cycle assessment (LCA) applications • Sustainability and energy in wastewater industry, • Sustainability and asset management. PMID:27620092

  7. Achieving and Sustaining Automated Health Data Linkages for Learning Systems: Barriers and Solutions

    PubMed Central

    Van Eaton, Erik G.; Devlin, Allison B.; Devine, Emily Beth; Flum, David R.; Tarczy-Hornoch, Peter

    2014-01-01

    challenges of idiosyncratic EHR implementations required each hospital to devote more IT resources than were predicted. Cost savings did not meet projections because of the increased IT resource requirements and a different source of lowered chart review costs. Discussion: CERTAIN succeeded in recruiting unaffiliated hospitals into the Automation Project to create an enhanced registry to achieve AHRQ goals. This case report describes several distinct barriers to central data aggregation for QI and CER across unaffiliated hospitals: (1) competition for limited on-site IT expertise, (2) concerns about data use for QI versus research, (3) restrictions on data automation to a defined subset of patients, and (4) unpredictable resource needs because of idiosyncrasies among unaffiliated hospitals in how EHR data are coded, stored, and made available for transmission—even between hospitals using the same vendor’s EHR. Therefore, even a fully optimized automation infrastructure would still not achieve complete automation. The Automation Project was unable to align sufficiently with internal hospital objectives, so it could not show a compelling case for sustainability. PMID:25848606

  8. Concepts for Life Cycle Cost Control Required to Achieve Space Transportation Affordability and Sustainability

    NASA Technical Reports Server (NTRS)

    Rhodes, Russel E.; Zapata, Edgar; Levack, Daniel J. H.; Robinson, John W.; Donahue, Benjamin B.

    2009-01-01

    Cost control must be implemented through the establishment of requirements and controlled continually by managing to these requirements. Cost control of the non-recurring side of life cycle cost has traditionally been implemented in both commercial and government programs. The government uses the budget process to implement this control. The commercial approach is to use a similar process of allocating the non-recurring cost to major elements of the program. This type of control generally manages through a work breakdown structure (WBS) by defining the major elements of the program. If the cost control is to be applied across the entire program life cycle cost (LCC), the approach must be addressed very differently. A functional breakdown structure (FBS) is defined and recommended. Use of a FBS provides the visibifity to allow the choice of an integrated solution reducing the cost of providing many different elements of like function. The different functional solutions that drive the hardware logistics, quantity of documentation, operational labor, reliability and maintainability balance, and total integration of the entire system from DDT&E through the life of the program must be fully defined, compared, and final decisions made among these competing solutions. The major drivers of recurring cost have been identified and are presented and discussed. The LCC requirements must be established and flowed down to provide control of LCC. This LCC control will require a structured rigid process similar to the one traditionally used to control weight/performance for space transportation systems throughout the entire program. It has been demonstrated over the last 30 years that without a firm requirement and methodically structured cost control, it is unlikely that affordable and sustainable space transportation system LCC will be achieved.

  9. Current guidelines for nut consumption are achievable and sustainable: a hazelnut intervention.

    PubMed

    Tey, S L; Brown, R; Chisholm, A; Gray, A; Williams, S; Delahunty, C

    2011-05-01

    Nuts are known for their hypocholesterolaemic properties; however, to achieve optimal health benefits, nuts must be consumed regularly and in sufficient quantity. It is therefore important to assess the acceptability of regular consumption of nuts. The present study examined the long-term effects of hazelnut consumption in three different forms on 'desire to consume' and 'overall liking'. A total of forty-eight participants took part in this randomised cross-over study with three dietary phases of 4 weeks: 30 g/d of whole, sliced and ground hazelnuts. 'Overall liking' was measured in a three-stage design: a pre- and post-exposure tasting session and daily evaluation over the exposure period. 'Desire to consume' hazelnuts was measured during the exposure period only. Ratings were measured on a 150 mm visual analogue scale. Mean ratings of 'desire to consume' were 92 (SD 35) mm for ground, 108 (SD 33) mm for sliced and 116 (SD 30) mm for whole hazelnuts. For 'overall liking', the mean ratings were 101 (SD 29) mm for ground, 110 (SD 32) mm for sliced and 118 (SD 30) mm for whole hazelnuts. Ground hazelnuts had significantly lower ratings than both sliced (P ≤ 0·034) and whole hazelnuts (P < 0·001), with no difference in ratings between sliced and whole hazelnuts (P ≥ 0·125). For each form of nut, ratings of 'overall liking' and 'desire to consume' were stable over the exposure period, indicating that not only did the participants like the nuts, but also they wished to continue eating them. Therefore, the guideline to consume nuts on a regular basis appears to be a sustainable behaviour to reduce CVD.

  10. Lipophilic nalmefene prodrugs to achieve a one-month sustained release.

    PubMed

    Gaekens, Tim; Guillaume, Michel; Borghys, Herman; De Zwart, Loeckie L; de Vries, Ronald; Embrechts, Roger C A; Vermeulen, An; Megens, Anton A H P; Leysen, Josée E; Herdewijn, Piet; Annaert, Pieter P; Atack, John R

    2016-06-28

    Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5-1.0ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2-0.3ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5-1.0ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene

  11. Achieving Campus Sustainability: Top-Down, Bottom-Up, or Neither?

    ERIC Educational Resources Information Center

    Brinkhurst, Marena; Rose, Peter; Maurice, Gillian; Ackerman, Josef Daniel

    2011-01-01

    Purpose: The dynamics of organizational change related to environmental sustainability on university campuses are examined in this article. Whereas case studies of campus sustainability efforts tend to classify leadership as either "top-down" or "bottom-up", this classification neglects consideration of the leadership roles of the institutional…

  12. In Pursuit of Sustained Achievement: A Case Study of One At-Risk School's Efforts to Change Behaviors

    ERIC Educational Resources Information Center

    Sorvig, Carol A.

    2010-01-01

    Sustained achievement remains out of reach for most Title I schools. While there are many programs and examples of schools touting improved performance, there are precious few that are able to maintain that improved performance over time. This case study examined the characteristics of changes made at one Colorado Title I elementary school that…

  13. The Sustainability of Reading Recovery Intervention on Reading Achievement of Students Identified as At-Risk for Early Reading Failure

    ERIC Educational Resources Information Center

    Harley, Anne J.

    2012-01-01

    The purpose of this study was to determine the impact and sustainability of successfully discontinued first grade Reading Recovery students as compared to non-Reading Recovery students in reading achievement measures as third graders. Schools are facing the unprecedented challenge to ensure reading success for all students by the end of second…

  14. Achieving a high-reliability organization through implementation of the ARCC model for systemwide sustainability of evidence-based practice.

    PubMed

    Melnyk, Bernadette Mazurek

    2012-01-01

    High-reliability health care organizations are those that provide care that is safe and one that minimizes errors while achieving exceptional performance in quality and safety. This article presents major concepts and characteristics of a patient safety culture and a high-reliability health care organization and explains how building a culture of evidence-based practice can assist organizations in achieving high reliability. The ARCC (Advancing Research and Clinical practice through close Collaboration) model for systemwide implementation and sustainability of evidence-based practice is highlighted as a key strategy in achieving high reliability in health care organizations.

  15. Perspectives on Federal Funding for State Health Care-Associated Infection Programs: Achievements, Barriers, and Implications for Sustainability.

    PubMed

    Ellingson, Katherine; McCormick, Kelly; Woodard, Tiffanee; Garcia-Williams, Amanda; Mendel, Peter; Kahn, Katherine; McDonald, Clifford; Jernigan, John; Sinkowitz-Cochran, Ronda

    2014-08-01

    In September 2009, federal funding for health care-associated infection (HAI) program development was dispersed through a cooperative agreement to 51 state and territorial health departments. From July to September 2011, 69 stakeholders from six states-including state health department employees, representatives from partner organizations, and health care facility employees-were interviewed to assess state HAI program achievements, implementation barriers, and strategies for sustainability. Respondents most frequently cited enhanced HAI surveillance as a program achievement and resource constraints as an implementation barrier. To sustain programs, respondents recommended ongoing support for HAI prevention activities, improved surveillance processes, and maintenance of partnerships. Findings suggest that state-level HAI program growth was achieved during the cooperative agreement but that maintenance of programs faces challenges.

  16. Endogenous K-ras signaling in erythroid differentiation.

    PubMed

    Zhang, Jing; Lodish, Harvey F

    2007-08-15

    K-ras is one of the most frequently mutated genes in virtually all types of human cancers. Using mouse fetal liver erythroid progenitors as a model system, we studied the role of endogenous K-ras signaling in erythroid differentiation. When oncogenic K-ras is expressed from its endogenous promoter, it hyperactivates cytokine-dependent signaling pathways and results in a partial block in erythroid differentiation. In erythroid progenitors deficient in K-ras, cytokine-dependent Akt activation is greatly reduced, leading to delays in erythroid differentiation. Thus, both loss- and gain-of-Kras functions affect erythroid differentiation through modulation of cytokine signaling. These results support the notion that in human cancer patients oncogenic Ras signaling might be controlled by antagonizing essential cytokines.

  17. Early Stage Design Decisions: The Way to Achieve Sustainable Buildings at Lower Costs

    PubMed Central

    Bragança, Luís; Vieira, Susana M.; Andrade, Joana B.

    2014-01-01

    The construction industry attempts to produce buildings with as lower environmental impact as possible. However, construction activities still greatly affect environment; therefore, it is necessary to consider a sustainable project approach based on its performance. Sustainability is an important issue to consider in design, not only due to environmental concerns but also due to economic and social matters, promoting architectural quality and economic advantages. This paper aims to identify the phases through which a design project should be developed, emphasising the importance and ability of earlier stages to influence sustainability, performance, and life cycle cost. Then, a selection of sustainability key indicators, able to be used at the design conceptual phase and able to start predicting environmental sustainability performance of buildings is presented. The output of this paper aimed to enable designers to compare and evaluate the consequences of different design solutions, based on preliminary data, and facilitate the collaboration between stakeholders and clients and eventually yield a sustainable and high performance building throughout its life cycle. PMID:24578630

  18. Significant increase in ecosystem C can be achieved with sustainable forest management in subtropical plantation forests.

    PubMed

    Wei, Xiaohua; Blanco, Juan A

    2014-01-01

    Subtropical planted forests are rapidly expanding. They are traditionally managed for intensive, short-term goals that often lead to long-term yield decline and reduced carbon sequestration capacity. Here we show how it is possible to increase and sustain carbon stored in subtropical forest plantations if management is switched towards more sustainable forestry. We first conducted a literature review to explore possible management factors that contribute to the potentials in ecosystem C in tropical and subtropical plantations. We found that broadleaves plantations have significantly higher ecosystem C than conifer plantations. In addition, ecosystem C increases with plantation age, and reaches a peak with intermediate stand densities of 1500-2500 trees ha⁻¹. We then used the FORECAST model to simulate the regional implications of switching from traditional to sustainable management regimes, using Chinese fir (Cunninghamia lanceolata) plantations in subtropical China as a study case. We randomly simulated 200 traditional short-rotation pure stands and 200 sustainably-managed mixed Chinese fir--Phoebe bournei plantations, for 120 years. Our results showed that mixed, sustainably-managed plantations have on average 67.5% more ecosystem C than traditional pure conifer plantations. If all pure plantations were gradually transformed into mixed plantations during the next 10 years, carbon stocks could rise in 2050 by 260.22 TgC in east-central China. Assuming similar differences for temperate and boreal plantations, if sustainable forestry practices were applied to all new forest plantation types in China, stored carbon could increase by 1,482.80 TgC in 2050. Such an increase would be equivalent to a yearly sequestration rate of 40.08 TgC yr⁻¹, offsetting 1.9% of China's annual emissions in 2010. More importantly, this C increase can be sustained in the long term through the maintenance of higher amounts of soil organic carbon and the production of timber products

  19. Significant Increase in Ecosystem C Can Be Achieved with Sustainable Forest Management in Subtropical Plantation Forests

    PubMed Central

    Wei, Xiaohua; Blanco, Juan A.

    2014-01-01

    Subtropical planted forests are rapidly expanding. They are traditionally managed for intensive, short-term goals that often lead to long-term yield decline and reduced carbon sequestration capacity. Here we show how it is possible to increase and sustain carbon stored in subtropical forest plantations if management is switched towards more sustainable forestry. We first conducted a literature review to explore possible management factors that contribute to the potentials in ecosystem C in tropical and subtropical plantations. We found that broadleaves plantations have significantly higher ecosystem C than conifer plantations. In addition, ecosystem C increases with plantation age, and reaches a peak with intermediate stand densities of 1500–2500 trees ha−1. We then used the FORECAST model to simulate the regional implications of switching from traditional to sustainable management regimes, using Chinese fir (Cunninghamia lanceolata) plantations in subtropical China as a study case. We randomly simulated 200 traditional short-rotation pure stands and 200 sustainably-managed mixed Chinese fir – Phoebe bournei plantations, for 120 years. Our results showed that mixed, sustainably-managed plantations have on average 67.5% more ecosystem C than traditional pure conifer plantations. If all pure plantations were gradually transformed into mixed plantations during the next 10 years, carbon stocks could rise in 2050 by 260.22 TgC in east-central China. Assuming similar differences for temperate and boreal plantations, if sustainable forestry practices were applied to all new forest plantation types in China, stored carbon could increase by 1,482.80 TgC in 2050. Such an increase would be equivalent to a yearly sequestration rate of 40.08 TgC yr−1, offsetting 1.9% of China’s annual emissions in 2010. More importantly, this C increase can be sustained in the long term through the maintenance of higher amounts of soil organic carbon and the production of timber

  20. In place of fear: aligning health care planning with system objectives to achieve financial sustainability.

    PubMed

    Birch, Stephen; Murphy, Gail Tomblin; MacKenzie, Adrian; Cumming, Jackie

    2015-04-01

    The financial sustainability of publicly funded health care systems is a challenge to policymakers in many countries as health care absorbs an ever increasing share of both national wealth and government spending. New technology, aging populations and increasing public expectations of the health care system are often cited as reasons why health care systems need ever increasing funding as well as reasons why universal and comprehensive public systems are unsustainable. However, increases in health care spending are not usually linked to corresponding increases in need for care within populations. Attempts to promote financial sustainability of systems such as limiting the range of services is covered or the groups of population covered may compromise their political sustainability as some groups are left to seek private cover for some or all services. In this paper, an alternative view of financial sustainability is presented which identifies the failure of planning and management of health care to reflect needs for care in populations and to integrate planning and management functions for health care expenditure, health care services and the health care workforce. We present a Health Care Sustainability Framework based on disaggregating the health care expenditure into separate planning components. Unlike other approaches to planning health care expenditure, this framework explicitly incorporates population health needs as a determinant of health care requirements, and provides a diagnostic tool for understanding the sources of expenditure increase.

  1. Disparities in achieving and sustaining viral suppression among a large cohort of HIV-infected persons in care - Washington, DC.

    PubMed

    Castel, Amanda D; Kalmin, Mariah M; Hart, Rachel L D; Young, Heather A; Hays, Harlen; Benator, Debra; Kumar, Princy; Elion, Richard; Parenti, David; Ruiz, Maria Elena; Wood, Angela; D'Angelo, Lawrence; Rakhmanina, Natella; Rana, Sohail; Bryant, Maya; Hebou, Annick; Fernández, Ricardo; Abbott, Stephen; Peterson, James; Wood, Kathy; Subramanian, Thilakavathy; Binkley, Jeffrey; Happ, Lindsey Powers; Kharfen, Michael; Masur, Henry; Greenberg, Alan E

    2016-11-01

    One goal of the HIV care continuum is achieving viral suppression (VS), yet disparities in suppression exist among subpopulations of HIV-infected persons. We sought to identify disparities in both the ability to achieve and sustain VS among an urban cohort of HIV-infected persons in care. Data from HIV-infected persons enrolled at the 13 DC Cohort study clinical sites between January 2011 and June 2014 were analyzed. Univariate and multivariate logistic regression were conducted to identify factors associated with achieving VS (viral load < 200 copies/ml) at least once, and Kaplan-Meier (KM) curves and Cox proportional hazards models were used to identify factors associated with sustaining VS and time to virologic failure (VL ≥ 200 copies/ml after achievement of VS). Among the 4311 participants, 95.4% were either virally suppressed at study enrollment or able to achieve VS during the follow-up period. In multivariate analyses, achieving VS was significantly associated with age (aOR: 1.04; 95%CI: 1.03-1.06 per five-year increase) and having a higher CD4 (aOR: 1.05, 95% CI 1.04-1.06 per 100 cells/mm(3)). Patients infected through perinatal transmission were less likely to achieve VS compared to MSM patients (aOR: 0.63, 95% CI 0.51-0.79). Once achieved, most participants (74.4%) sustained VS during follow-up. Blacks and perinatally infected persons were less likely to have sustained VS in KM survival analysis (log rank chi-square p ≤ .001 for both) compared to other races and risk groups. Earlier time to failure was observed among females, Blacks, publically insured, perinatally infected, those with longer standing HIV infection, and those with diagnoses of mental health issues or depression. Among this HIV-infected cohort, most people achieved and maintained VS; however, disparities exist with regard to patient age, race, HIV transmission risk, and co-morbid conditions. Identifying populations with disparate outcomes allows for appropriate targeting

  2. Hypoxia Alters Progression of the Erythroid Program

    PubMed Central

    Rogers, Heather M.; Yu, Xiaobing; Wen, Jie; Smith, Reginald; Fibach, Eitan; Noguchi, Constance Tom

    2008-01-01

    Hypoxia can induce erythropoiesis through regulated increase of erythropoietin (Epo) production. We investigated the direct influence of oxygen tension (pO2) in the physiologic range (2–8%) on erythroid progenitor cell differentiation using cultures of adult human hematopoietic progenitor cells exposed to decreasing (20 – 2%) pO2 and independent of variation in Epo levels. Decreases in Hb-containing cells were observed at the end of the culture period with decreasing pO2. This is due in part to a reduction in cell growth, and at 2% O2 a marked increase in cell toxicity. Analysis of the kinetics of cell differentiation showed an increase in the proportion of cells with glycophorin A expression and Hb accumulation at physiologic pO2. The cells were characterized by an early induction of γ-globin expression and a delay and reduction in peak levels of β-globin expression. Overall, fetal Hb and γ-globin expression were increased at physiologic pO2 but the increases were reduced at 2% O2 as cultures become cytotoxic. At reduced pO2, induction of EPO-receptor (EPO-R) by Epo was decreased and delayed, analogous to the delay in β-globin induction. The oxygen dependent reduction of EPO-R can account for the associated cytotoxicity at 2% O2. Epo induction of erythroid transcription factors, EKLF, GATA-1 and SCL/Tal-1, was also delayed and decreased at reduced pO2, consistent with lower levels of EPO-R and resultant Epo signaling. These changes in EPO-R and globin gene expression raise the possibility that the early increase of γ-globin is a consequence of reduced Epo signaling and a delay in induction of erythroid transcription factors. PMID:17936496

  3. Out of the wilderness? Achieving sustainable development within Scottish national parks.

    PubMed

    Barker, Adam; Stockdale, Aileen

    2008-07-01

    The introduction of national parks to Scotland represents a significant shift in the evolution of protected area management within the UK. Although the National Parks (Scotland) Act 2000 adopts the established national park aims of conservation and recreation, provisions are also made for advancing notions of sustainable development. This paper provides an assessment of the degree to which the Scottish national park model is likely to enable the realisation of multiple national park objectives. Five key areas are considered for analysis. These relate to management aims, institutional arrangements, implementation, democratic accountability and funding. The evaluation reveals that whilst management provisions have been established in accordance with international sustainable development guidelines, a number of concerns relating to operational processes remain.

  4. Bmi1 promotes erythroid development through regulating ribosome biogenesis

    PubMed Central

    Gao, Rui; Chen, Sisi; Kobayashi, Michihiro; Yu, Hao; Zhang, Yingchi; Wan, Yang; Young, Sara K.; Soltis, Anthony; Yu, Ming; Vemula, Sasidhar; Fraenkel, Ernest; Cantor, Alan; Antipin, Yevgeniy; Xu, Yang; Yoder, Mervin C.; Wek, Ronald C.; Ellis, Steven R.; Kapur, Reuben; Zhu, Xiaofan; Liu, Yan

    2015-01-01

    While Polycomb group protein Bmi1 is important for stem cell maintenance, its role in lineage commitment is largely unknown. We have identified Bmi1 as a novel regulator of erythroid development. Bmi1 is highly expressed in mouse erythroid progenitor cells and its deficiency impairs erythroid differentiation. BMI1 is also important for human erythroid development. Furthermore, we discovered that loss of Bmi1 in erythroid progenitor cells results in down-regulation of transcription of multiple ribosomal protein genes and impaired ribosome biogenesis. Bmi1 deficiency stabilizes p53 protein, leading to upregulation of p21 expression and subsequent G0/G1 cell cycle arrest. Genetic inhibition of p53 activity rescues the erythroid defects seen in the Bmi1 null mice, demonstrating that a p53-dependent mechanism underlies the pathophysiology of the anemia. Mechanistically, Bmi1 is associated with multiple ribosomal protein genes and may positively regulate their expression in erythroid progenitor cells. Thus, Bmi1 promotes erythroid development, at least in part through regulating ribosome biogenesis. Ribosomopathies are human disorders of ribosome dysfunction, including diamond blackfan anemia (DBA) and 5q- syndrome, in which genetic abnormalities cause impaired ribosome biogenesis, resulting in specific clinical phenotypes. We observed that BMI1 expression in human hematopoietic stem and progenitor cells (HSPCs) from patients with DBA is correlated with the expression of some ribosomal protein genes, suggesting that BMI1 deficiency may play a pathological role in DBA and other ribosomopathies. PMID:25385494

  5. Bmi1 promotes erythroid development through regulating ribosome biogenesis.

    PubMed

    Gao, Rui; Chen, Sisi; Kobayashi, Michihiro; Yu, Hao; Zhang, Yingchi; Wan, Yang; Young, Sara K; Soltis, Anthony; Yu, Ming; Vemula, Sasidhar; Fraenkel, Ernest; Cantor, Alan; Antipin, Yevgeniy; Xu, Yang; Yoder, Mervin C; Wek, Ronald C; Ellis, Steven R; Kapur, Reuben; Zhu, Xiaofan; Liu, Yan

    2015-03-01

    While Polycomb group protein Bmi1 is important for stem cell maintenance, its role in lineage commitment is largely unknown. We have identified Bmi1 as a novel regulator of erythroid development. Bmi1 is highly expressed in mouse erythroid progenitor cells and its deficiency impairs erythroid differentiation. BMI1 is also important for human erythroid development. Furthermore, we discovered that loss of Bmi1 in erythroid progenitor cells results in decreased transcription of multiple ribosomal protein genes and impaired ribosome biogenesis. Bmi1 deficiency stabilizes p53 protein, leading to upregulation of p21 expression and subsequent G0/G1 cell cycle arrest. Genetic inhibition of p53 activity rescues the erythroid defects seen in the Bmi1 null mice, demonstrating that a p53-dependent mechanism underlies the pathophysiology of the anemia. Mechanistically, Bmi1 is associated with multiple ribosomal protein genes and may positively regulate their expression in erythroid progenitor cells. Thus, Bmi1 promotes erythroid development, at least in part through regulating ribosome biogenesis. Ribosomopathies are human disorders of ribosome dysfunction, including Diamond-Blackfan anemia (DBA) and 5q- syndrome, in which genetic abnormalities cause impaired ribosome biogenesis, resulting in specific clinical phenotypes. We observed that BMI1 expression in human hematopoietic stem and progenitor cells from patients with DBA is correlated with the expression of some ribosomal protein genes, suggesting that BMI1 deficiency may play a pathological role in DBA and other ribosomopathies. PMID:25385494

  6. Transcriptome dynamics during human erythroid differentiation and development.

    PubMed

    Yang, Yadong; Wang, Hai; Chang, Kai-Hsin; Qu, Hongzhu; Zhang, Zhaojun; Xiong, Qian; Qi, Heyuan; Cui, Peng; Lin, Qiang; Ruan, Xiuyan; Yang, Yaran; Li, Yajuan; Shu, Chang; Li, Quanzhen; Wakeland, Edward K; Yan, Jiangwei; Hu, Songnian; Fang, Xiangdong

    2013-01-01

    To explore the mechanisms controlling erythroid differentiation and development, we analyzed the genome-wide transcription dynamics occurring during the differentiation of human embryonic stem cells (HESCs) into the erythroid lineage and development of embryonic to adult erythropoiesis using high throughput sequencing technology. HESCs and erythroid cells at three developmental stages: ESER (embryonic), FLER (fetal), and PBER (adult) were analyzed. Our findings revealed that the number of expressed genes decreased during differentiation, whereas the total expression intensity increased. At each of the three transitions (HESCs-ESERs, ESERs-FLERs, and FLERs-PBERs), many differentially expressed genes were observed, which were involved in maintaining pluripotency, early erythroid specification, rapid cell growth, and cell-cell adhesion and interaction. We also discovered dynamic networks and their central nodes in each transition. Our study provides a fundamental basis for further investigation of erythroid differentiation and development, and has implications in using ESERs for transfusion product in clinical settings.

  7. Sublethal radiation injury uncovers a functional transition during erythroid maturation

    PubMed Central

    Peslak, Scott A.; Wenger, Jesse; Bemis, Jeffrey C.; Kingsley, Paul D.; Frame, Jenna M.; Koniski, Anne D.; Chen, Yuhchyau; Williams, Jacqueline P.; McGrath, Kathleen E.; Dertinger, Stephen D.; Palis, James

    2012-01-01

    Objective Clastogenic injury of the erythroid lineage results in anemia, reticulocytopenia, and transient appearance of micronucleated reticulocytes (MN-RET). However, the MN-RET dose-response in murine models is only linear to 2 Gy total body irradiation (TBI) and paradoxically decreases at higher exposures, suggesting complex radiation effects on erythroid intermediates. To better understand this phenomenon, we investigated the kinetics and apoptotic response of the erythron to sublethal radiation injury. Materials and Methods We analyzed the response to 1 and 4 Gy TBI of erythroid progenitors and precursors using colony assays and imaging flow cytometry (IFC), respectively. We also investigated cell cycling and apoptotic gene expression of the steady-state erythron. Results Following 1 Gy TBI, erythroid progenitors and precursors were partially depleted. In contrast, essentially all bone marrow erythroid progenitors and precursors were lost within two days following 4 Gy irradiation. IFC analysis revealed preferential loss of phenotypic erythroid colony-forming units (CFU-E) and proerythroblasts immediately following sublethal irradiation. Furthermore, these populations underwent radiation-induced apoptosis, without changes in steady-state cellular proliferation, at much higher frequencies than later-stage erythroid precursors. Primary erythroid precursor maturation is associated with marked Bcl-xL upregulation and Bax and Bid down-regulation. Conclusions MN-RET loss following higher sublethal radiation exposures results from rapid depletion of erythroid progenitors and precursors. This injury reveals that CFU-E and proerythroblasts constitute a particularly proapoptotic compartment within the erythron. We conclude that the functional transition of primary proerythroblasts to later-stage erythroid precursors is characterized by a shift from a pro-apoptotic to an anti-apoptotic phenotype. PMID:21291953

  8. Before Sustainable Development Goals (SDG): why Nigeria failed to achieve the Millennium Development Goals (MDGs)

    PubMed Central

    Oleribe, Obinna Ositadimma; Taylor-Robinson, Simon David

    2016-01-01

    World leaders adopted the UN Millennium Declaration in 2000, which committed the nations of the world to a new global partnership, aimed at reducing extreme poverty and other time-bound targets, with a stated deadline of 2015. Fifteen years later, although significant progress has been made worldwide, Nigeria is lagging behind for a variety of reasons, including bureaucracy, poor resource management in the healthcare system, sequential healthcare worker industrial action, Boko Haram insurgency in the north of Nigeria and kidnappings in the south of Nigeria. The country needs to tackle these problems to be able to significantly advance with the new sustainable development goals (SDGs) by the 2030 target date. PMID:27795754

  9. Achieving Sustainability Goals for Urban Coasts in the US Northeast: Research Needs and Challenges

    NASA Technical Reports Server (NTRS)

    Close, Sarah L.; Montalto, Franco; Orton, Philip; Antoine, Adrienne; Peters, Danielle; Jones, Hunter; Parris, Adam; Blumberg, Alan

    2016-01-01

    In the wake of Hurricane Sandy and other recent extreme events, urban coastal communities in the northeast region of the United States are beginning or stepping up efforts to integrate climate adaptation and resilience into long-term coastal planning. Natural and nature-based shoreline strategies have emerged as essential components of coastal resilience and are frequently cited by practitioners, scientists, and the public for the wide range of ecosystem services they can provide. However, there is limited quantitative information associating particular urban shoreline design strategies with specific levels of ecosystem service provision, and research on this issue is not always aligned with decision context and decision-maker needs. Engagement between the research community, local government officials and sustainability practitioners, and the non-profit and private sectors can help bridge these gaps. A workshop to bring together these groups discussed research gaps and challenges in integrating ecosystem services into urban sustainability planning in the urban northeast corridor. Many themes surfaced repeatedly throughout workshop deliberations, including the challenges associated with ecosystem service valuation, the transferability of research and case studies within and outside the region, and the opportunity for urban coastal areas to be a focal point for education and outreach efforts related to ecosystem services.

  10. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene.

    PubMed

    Hutton, Guy; Chase, Claire

    2016-01-01

    Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of 'safely managed' water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs. PMID:27240389

  11. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene.

    PubMed

    Hutton, Guy; Chase, Claire

    2016-05-27

    Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of 'safely managed' water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs.

  12. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene

    PubMed Central

    Hutton, Guy; Chase, Claire

    2016-01-01

    Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of ‘safely managed’ water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs. PMID:27240389

  13. Sustained Acceleration of Achievement in Reading Comprehension: The New Zealand Experience

    ERIC Educational Resources Information Center

    Lai, Mei Kuin; McNaughton, Stuart; Amituanai-Toloa, Meaola; Turner, Rolf; Hsiao, Selena

    2009-01-01

    Schools with primarily indigenous and ethnic minorities in low socioeconomic areas have long been associated with low levels of achievement, particularly in literacy. This is true for New Zealand despite high levels of reading comprehension by international comparisons (e.g., PISA). Recent reviews of schooling improvement suggest small gains over…

  14. Sustaining Success toward Closing the Achievement Gap: A Case Study of One Urban High School

    ERIC Educational Resources Information Center

    Cabrera, Kimberly Elizabeth

    2010-01-01

    Since the introduction of the Coleman Report (1966), the focus on closing the achievement gap has been a critical component of educational policy for political leaders and field research by educators. The economic crisis which California and the nation at large currently face creates a challenging situation in attempting to narrow the gap.…

  15. Challenges to Achieving Sustainable Sanitation in Informal Settlements of Kigali, Rwanda

    PubMed Central

    Tsinda, Aime; Abbott, Pamela; Pedley, Steve; Charles, Katrina; Adogo, Jane; Okurut, Kenan; Chenoweth, Jonathan

    2013-01-01

    Like most cities in developing countries, Kigali is experiencing rapid urbanisation leading to an increase in the urban population and rapid growth in the size and number of informal settlements. More than 60% of the city’s population resides in these settlements, where they experience inadequate and poor quality urban services including sanitation. This article discusses the issues and constraints related to the provision of sustainable sanitation in the informal settlements in Kigali. Two informal settlements (Gatsata and Kimisagara) were selected for the study, which used a mixed method approach for data collection. The research found that residents experienced multiple problems because of poor sanitation and that the main barrier to improved sanitation was cost. Findings from this study can be used by the city authorities in the planning of effective sanitation intervention strategies for communities in informal settlements. PMID:24336021

  16. Rock on Cafe: achieving sustainable systems changes in school lunch programs.

    PubMed

    Johnston, Yvonne; Denniston, Ray; Morgan, Molly; Bordeau, Mark

    2009-04-01

    The rising rate of overweight poses a significant threat to the health of children. Because roughly one third of a child's dietary intake occurs during school hours and because both health and academic outcomes have been linked to children's nutrition, school nutrition policies and programs have been identified as a key area for intervention. This article describes the components, processes, and initial successes of a grassroots effort and innovative project to improve the nutritional quality of the School Lunch Program through a sustainable systems intervention and policy change across a regional area of upstate New York. The Rock on Cafe intervention was partially funded by the Steps to a Healthier New York program and promises to be a model for creating a school environment that supports healthy dietary behaviors among children.

  17. Challenges to achieving sustainable sanitation in informal settlements of Kigali, Rwanda.

    PubMed

    Tsinda, Aime; Abbott, Pamela; Pedley, Steve; Charles, Katrina; Adogo, Jane; Okurut, Kenan; Chenoweth, Jonathan

    2013-12-10

    Like most cities in developing countries, Kigali is experiencing rapid urbanisation leading to an increase in the urban population and rapid growth in the size and number of informal settlements. More than 60% of the city's population resides in these settlements, where they experience inadequate and poor quality urban services including sanitation. This article discusses the issues and constraints related to the provision of sustainable sanitation in the informal settlements in Kigali. Two informal settlements (Gatsata and Kimisagara) were selected for the study, which used a mixed method approach for data collection. The research found that residents experienced multiple problems because of poor sanitation and that the main barrier to improved sanitation was cost. Findings from this study can be used by the city authorities in the planning of effective sanitation intervention strategies for communities in informal settlements.

  18. Rock on Cafe: achieving sustainable systems changes in school lunch programs.

    PubMed

    Johnston, Yvonne; Denniston, Ray; Morgan, Molly; Bordeau, Mark

    2009-04-01

    The rising rate of overweight poses a significant threat to the health of children. Because roughly one third of a child's dietary intake occurs during school hours and because both health and academic outcomes have been linked to children's nutrition, school nutrition policies and programs have been identified as a key area for intervention. This article describes the components, processes, and initial successes of a grassroots effort and innovative project to improve the nutritional quality of the School Lunch Program through a sustainable systems intervention and policy change across a regional area of upstate New York. The Rock on Cafe intervention was partially funded by the Steps to a Healthier New York program and promises to be a model for creating a school environment that supports healthy dietary behaviors among children. PMID:19454756

  19. Transcription factor networks in erythroid cell and megakaryocyte development

    PubMed Central

    Doré, Louis C.

    2011-01-01

    Erythroid cells and megakaryocytes are derived from a common precursor, the megakaryocyte-erythroid progenitor. Although these 2 closely related hematopoietic cell types share many transcription factors, there are several key differences in their regulatory networks that lead to differential gene expression downstream of the megakaryocyte-erythroid progenitor. With the advent of next-generation sequencing and our ability to precisely define transcription factor chromatin occupancy in vivo on a global scale, we are much closer to understanding how these 2 lineages are specified and in general how transcription factor complexes govern hematopoiesis. PMID:21622645

  20. Erythroid Kruppel like factor: from fishing expedition to gourmet meal.

    PubMed

    Perkins, A

    1999-10-01

    Erythroid Kruppel like factor (EKLF) is the founding member of a family of transcription factors which are defined by the presence of three C-terminal C2H2-type zinc fingers. Since its discovery 6 years ago, the study of EKLF has been intense. In this review I will revisit the discovery of EKLF, and highlight recent advances in our understanding of how it interacts with other proteins to regulate erythroid gene transcription. The current knowledge of the biological role/s of EKLF in erythroid cell differentiation and globin gene switching are summarized.

  1. Does the law stymie the science? The role of law in achieving sustainable groundwater management

    NASA Astrophysics Data System (ADS)

    Allan, A.

    2012-04-01

    Legal frameworks for the management of groundwater evolved in an environment where scientific understanding of the resource was sketchy. As hydrogeological knowledge has improved over time, the law has often failed to catch up and enforcement of those laws that are in place has proved difficult. Consequently, groundwater in many countries is still managed by inadequate regimes that are unable to effectively integrate the impacts of land use management and surface water interactions. The Water Framework Directive and its associated Groundwater Directive require the integrated management of both ground and surface waters, but on a global level, this is unusual. Institutional frameworks often perpetuate this split, and the legal regime for the management of transboundary shared aquifers is a work in progress. Both national and international frameworks encourage a race to over-exploit groundwater resources. Symptomatic of the problems currently seen in groundwater management is a widespread inability to adapt to changing climate and environmental conditions. Users may be granted unchangeable rights of use in perpetuity, and the impacts of aquifer over-exploitation on dependent ecosystems may be ignored. There are therefore significant barriers to the application of existing science in many countries, and this seriously jeopardises efforts to sustainably manage groundwater. This presentation will assess current developments in the laws relating to the use of groundwater around the world, highlighting case studies from India, Australia and the USA, and assessing the implementation of the Groundwater Directive in selected European countries (in work derived from the EU-funded GENESIS project). It will also examine the legal architecture relating to international shared aquifers, and the extent to which it can cope with national groundwater use patterns that will shift in response to climate change and its consequences.

  2. Getting to Green: An Examination of the Relationship between Institutional Characteristics and Sustainability Achievement at Four-Year U.S. Based Colleges and Universities

    ERIC Educational Resources Information Center

    Miller, Justin

    2014-01-01

    This study presents an examination of how institutional characteristics might influence a four-year institution of higher education's achievement in sustainability, as measured by the Sustainability Tracking, Assessment, and Rating System (STARS). Specifically, it examined the potential role Carnegie classification, sector, location, number of…

  3. Quaternary Aquifer of the North China Plain-assessing and achieving groundwater resource sustainability

    NASA Astrophysics Data System (ADS)

    Foster, Stephen; Garduno, Hector; Evans, Richard; Olson, Doug; Tian, Yuan; Zhang, Weizhen; Han, Zaisheng

    The Quaternary Aquifer of the North China Plain is one of the world's largest aquifer systems and supports an enormous exploitation of groundwater, which has reaped large socio-economic benefits in terms of grain production, farming employment and rural poverty alleviation, together with urban and industrial water-supply provision. Both population and economic activity have grown markedly in the past 25 years. Much of this has been heavily dependent upon groundwater resource development, which has encountered increasing difficulties in recent years primarily as a result of aquifer depletion and related phenomena. This paper focuses upon the hydrogeologic and socio-economic diagnosis of these groundwater resource issues, and identifies strategies to improve groundwater resource sustainability. L'aquifère Quaternaire de la Plaine du Nord de la Chine est l'un des plus grands systèmes aquifères du monde; il permet une exploitation énorme d'eau souterraine, qui a permis des très importants bénéfices socio-économiques en terme de production de céréales, d'emplois ruraux et de réduction de la pauvreté rurale, en même temps que l'approvisionnement en eau potable et pour l'industrie. La population comme l'activité économique ont remarquablement augmenté au cours de ces 25 dernières années. Elles ont été sous la forte dépendance du développement de la ressource en eau souterraine, qui a rencontré des difficultés croissantes ces dernières années, du fait du rabattement de l'aquifère et des phénomènes associés. Cet article est consacré aux diagnostiques hydrogéologique et socio-économique des retombées de cette ressource en eau souterraine; il identifie les stratégies pour améliorer la pérennité des ressources en eau souterraine. El acuífero cuaternario de la Llanura Septentrional de China es uno de los mayores sistemas acuíferos del mundo y soporta una enorme explotación de su agua subterránea, las cuales han originado grandes

  4. Implementing the UN Decade of Education for Sustainable Development (DESD): achievements, open questions and strategies for the way forward

    NASA Astrophysics Data System (ADS)

    Pigozzi, Mary Joy

    2010-06-01

    This paper looks at the implementation of the DESD from a global perspective. It takes the position that quality education is fundamental for learning how to live sustainably, and that the DESD needs to be better positioned in the education landscape and conceived as a global social movement that must be fostered and nurtured for the well-being of humankind. It suggests that, while there has been progress, much remains to be achieved. Several key challenges are identified. With regard to overcoming these obstacles, it focuses on macro-level strategies that would allow the development of environments in which actions can take root and grow so that the work of the DESD endures beyond the decade itself. Finally, it suggests that there are some opportunities that can be seized to make the task ahead easier to accomplish.

  5. Strengthening the partnership between routine immunization and the global polio eradication initiative to achieve eradication and assure sustainability.

    PubMed

    Abdelwahab, Jalaa; Dietz, Vance; Eggers, Rudolf; Maher, Christopher; Olaniran, Marianne; Sandhu, Hardeep; Vandelaer, Jos

    2014-11-01

    Since the launch of the Global Polio Eradication Initiative (GPEI) in 1988, the number of polio endemic countries has declined from 125 to 3 in 2013. Despite this remarkable achievement, ongoing circulation of wild poliovirus in polio-endemic countries and the increase in the number of circulating vaccine-derived poliovirus cases, especially those caused by type 2, is a cause for concern. The Polio Eradication and Endgame Strategic Plan 2013-2018 (PEESP) was developed and includes 4 objectives: detection and interruption of poliovirus transmission, containment and certification, legacy planning, and a renewed emphasis on strengthening routine immunization (RI) programs. This is critical for the phased withdrawal of oral poliovirus vaccine, beginning with the type 2 component, and the introduction of a single dose of inactivated polio vaccine into RI programs. This objective has inspired renewed consideration of how the GPEI and RI programs can mutually benefit one another, how the infrastructure from the GPEI can be used to strengthen RI, and how a strengthened RI can facilitate polio eradication. The PEESP is the first GPEI strategic plan that places strong and clear emphasis on the necessity of improving RI to achieve and sustain global polio eradication.

  6. The SCL gene product: a positive regulator of erythroid differentiation.

    PubMed Central

    Aplan, P D; Nakahara, K; Orkin, S H; Kirsch, I R

    1992-01-01

    The SCL (tal-1, TCL5) gene is a member of the basic domain, helix-loop-helix (bHLH) class of putative transcription factors. We found that (i) the SCL promoter for exon Ia contains a potential recognition site for GATA-binding transcription factors, (ii) SCL mRNA is expressed in all erythroid tissues and cell lines examined, and (iii) SCL mRNA increases upon induced differentiation of murine erythroleukemia (MEL) cells, and inferred that SCL may play a physiologic role in erythroid differentiation. We used gel shift and transfection assays to demonstrate that the GATA motif in the SCL promoter binds GATA-1 (and GATA-2), and also mediates transcriptional transactivation. To identify a role for SCL in erythroid differentiation, we generated stable transfectants of MEL and K562 (a human chronic myelogenous leukemia cell line that can differentiate along the erythroid pathway) cells overexpressing wild-type, antisense or mutant SCL cDNA. Increasing the level of SCL expression in two independent MEL lines (F4-6 and C19, a 745 derivative) and K562 cells increased the rate of spontaneous (i.e. in the absence of inducer) erythroid differentiation. Conversely, induced differentiation was inhibited in MEL transfectants expressing either antisense SCL cDNA or a mutant SCL lacking the basic domain. Our experiments suggest that the SCL gene can be a target for the erythroid transcription factor GATA-1 and that the SCL gene product serves as a positive regulator of erythroid differentiation. Images PMID:1396592

  7. Hemozoin (malarial pigment) directly promotes apoptosis of erythroid precursors.

    PubMed

    Lamikanra, Abigail A; Theron, Michel; Kooij, Taco W A; Roberts, David J

    2009-12-24

    Severe malarial anemia is the most common syndrome of severe malaria in endemic areas. The pathophysiology of chronic malaria is characterised by a striking degree of abnormal development of erythroid precursors (dyserythropoiesis) and an inadequate erythropoietic response in spite of elevated levels of erythropoietin. The cause of dyserythropoiesis is unclear although it has been suggested that bone-marrow macrophages release cytokines, chemokines or lipo-peroxides after exposure to hemozoin, a crystalloid form of undigested heme moieties from malarial infected erythrocytes, and so inhibit erythropoiesis. However, we have previously shown that hemozoin may directly inhibit erythroid development in vitro and the levels of hemozoin in plasma from patients with malarial anemia and hemozoin within the bone marrow was associated with reduced reticulocyte response. We hypothesized that macrophages may reduce, not enhance, the inhibitory effect of hemozoin on erythropoiesis. In an in vitro model of erythropoiesis, we now show that inhibition of erythroid cell development by hemozoin isolated from P. falciparum is characterised by delayed expression of the erythroid markers and increased apoptosis of progenitor cells. Crucially, macrophages appear to protect erythroid cells from hemozoin, consistent with a direct contribution of hemozoin to the depression of reticulocyte output from the bone marrow in children with malarial anemia. Moreover, hemozoin isolated from P. falciparum in vitro inhibits erythroid development independently of inflammatory mediators by inducing apoptotic pathways that not only involve activation of caspase 8 and cleavage of caspase 3 but also loss of mitochondrial potential. Taken together these data are consistent with a direct effect of hemozoin in inducing apoptosis in developing erythroid cells in malarial anemia. Accumulation of hemozoin in the bone marrow could therefore result in inadequate reticulocytosis in children that have adequate

  8. CACCC and GATA-1 sequences make the constitutively expressed alpha-globin gene erythroid-responsive in mouse erythroleukemia cells.

    PubMed Central

    Ren, S; Li, J; Atweh, G F

    1996-01-01

    Although the human alpha-globin and beta-globin genes are co-regulated in adult life, they achieve the same end by very different mechanisms. For example, a transfected beta-globin gene is expressed in an inducible manner in mouse erythroleukemia (MEL) cells while a transfected alpha-globin gene is constitutively expressed at a high level in induced and uninduced MEL cells. Interestingly, when the alpha-globin gene is transferred into MEL cells as part of human chromosome 16, it is appropriately expressed in an inducible manner. We explored the basis for the lack of erythroid-responsiveness of the proximal regulatory elements of the human alpha-globin gene. Since the alpha-globin gene is the only functional human globin gene that lacks CACCC and GATA-1 motifs, we asked whether their addition to the alpha-globin promoter would make the gene erythroid-responsive in MEL cells. The addition of each of these binding sites to the alpha-globin promoter separately did not result in inducibility in MEL cells. However, when both sites were added together, the alpha-globin gene became inducible in MEL cells. This suggests that erythroid non-responsiveness of the alpha-globin gene results from the lack of erythroid binding sites and is not necessarily a function of the constitutively active, GC rich promoter. PMID:8628660

  9. Population Pharmacokinetics of Colistin Methanesulfonate in Rats: Achieving Sustained Lung Concentrations of Colistin for Targeting Respiratory Infections

    PubMed Central

    W. S. Yapa, Shalini; Li, Jian; Porter, Christopher J. H.; Nation, Roger L.

    2013-01-01

    Colistin methanesulfonate (CMS), the inactive prodrug of colistin, is administered by inhalation for the management of respiratory infections. However, limited pharmacokinetic data are available for CMS and colistin following pulmonary delivery. This study investigates the pharmacokinetics of CMS and colistin following intravenous (i.v.) and intratracheal (i.t.) administration in rats and determines the targeting advantage after direct delivery into the lungs. In addition to plasma, bronchoalveolar lavage (BAL) fluid was collected to quantify drug concentrations in lung epithelial lining fluid (ELF). The resulting data were analyzed using a population modeling approach in S-ADAPT. A three-compartment model described the disposition of both compounds in plasma following i.v. administration. The estimated mean clearance from the central compartment was 0.122 liters/h for CMS and 0.0657 liters/h for colistin. Conversion of CMS to colistin from all three compartments was required to fit the plasma data. The fraction of the i.v. dose converted to colistin in the systemic circulation was 0.0255. Two BAL fluid compartments were required to reflect drug kinetics in the ELF after i.t. dosing. A slow conversion of CMS (mean conversion time [MCTCMS] = 3.48 h) in the lungs contributed to high and sustained concentrations of colistin in ELF. The fraction of the CMS dose converted to colistin in ELF (fm,ELF = 0.226) was higher than the corresponding fractional conversion in plasma after i.v. administration. In conclusion, pulmonary administration of CMS achieves high and sustained exposures of colistin in lungs for targeting respiratory infections. PMID:23917323

  10. Pathogenesis of the erythroid failure in Diamond Blackfan anaemia.

    PubMed

    Sieff, Colin A; Yang, Jing; Merida-Long, Lilia B; Lodish, Harvey F

    2010-02-01

    Diamond Blackfan anaemia (DBA) is a severe congenital failure of erythropoiesis. Despite mutations in one of several ribosome protein genes, including RPS19, the cause of the erythroid specificity is still a mystery. We hypothesized that, because the chromatin of late erythroid cells becomes condensed and transcriptionally inactive prior to enucleation, the rapidly proliferating immature cells require very high ribosome synthetic rates. RNA biogenesis was measured in primary mouse fetal liver erythroid progenitor cells; during the first 24 h, cell number increased three to fourfold while, remarkably, RNA content increased sixfold, suggesting an accumulation of an excess of ribosomes during early erythropoiesis. Retrovirus infected siRNA RPS19 knockdown cells showed reduced proliferation but normal differentiation, and cell cycle analysis showed a G1/S phase delay. p53 protein was increased in the knockdown cells, and the mRNA level for p21, a transcriptional target of p53, was increased. Furthermore, we show that RPS19 knockdown decreased MYB protein, and Kit mRNA was reduced, as was the amount of cell surface KIT protein. Thus, in this small hairpin RNA murine model of DBA, RPS19 insufficient erythroid cells may proliferate poorly because of p53-mediated cell cycle arrest, and also because of decreased expression of the key erythroid signalling protein KIT.

  11. Altered Chromatin Occupancy of Master Regulators Underlies Evolutionary Divergence in the Transcriptional Landscape of Erythroid Differentiation

    PubMed Central

    Ulirsch, Jacob C.; Lacy, Jessica N.; An, Xiuli; Mohandas, Narla; Mikkelsen, Tarjei S.; Sankaran, Vijay G.

    2014-01-01

    Erythropoiesis is one of the best understood examples of cellular differentiation. Morphologically, erythroid differentiation proceeds in a nearly identical fashion between humans and mice, but recent evidence has shown that networks of gene expression governing this process are divergent between species. We undertook a systematic comparative analysis of six histone modifications and four transcriptional master regulators in primary proerythroblasts and erythroid cell lines to better understand the underlying basis of these transcriptional differences. Our analyses suggest that while chromatin structure across orthologous promoters is strongly conserved, subtle differences are associated with transcriptional divergence between species. Many transcription factor (TF) occupancy sites were poorly conserved across species (∼25% for GATA1, TAL1, and NFE2) but were more conserved between proerythroblasts and cell lines derived from the same species. We found that certain cis-regulatory modules co-occupied by GATA1, TAL1, and KLF1 are under strict evolutionary constraint and localize to genes necessary for erythroid cell identity. More generally, we show that conserved TF occupancy sites are indicative of active regulatory regions and strong gene expression that is sustained during maturation. Our results suggest that evolutionary turnover of TF binding sites associates with changes in the underlying chromatin structure, driving transcriptional divergence. We provide examples of how this framework can be applied to understand epigenomic variation in specific regulatory regions, such as the β-globin gene locus. Our findings have important implications for understanding epigenomic changes that mediate variation in cellular differentiation across species, while also providing a valuable resource for studies of hematopoiesis. PMID:25521328

  12. Beyond good intentions: The role of proactive coping in achieving sustained behavioural change in the context of diabetes management.

    PubMed

    Thoolen, Bart Johan; de Ridder, Denise; Bensing, Jozien; Gorter, Kees; Rutten, Guy

    2009-03-01

    This study examines the effectiveness of a brief self-management intervention to support patients recently diagnosed with type-2 diabetes to achieve sustained improvements in their self-care behaviours. Based on proactive coping, the intervention emphasizes the crucial role of anticipation and planning in maintaining self-care behaviours. In a randomised controlled trial among recent screen-detected patients, participants who received the intervention were compared with usual-care controls, examining changes in proximal outcomes (intentions, self-efficacy and proactive coping), self-care behaviour (diet, physical activity and medication) and weight over time (0, 3 and 12 months). Subsequently, the contribution of proactive coping in predicting maintenance of behavioural change was analysed using stepwise hierarchical regression analyses, controlling for baseline self-care behaviour, patient characteristics, and intentions and self-efficacy as measured after the course. The intervention was effective in improving proximal outcomes and behaviour with regard to diet and physical activity, resulting in significant weight loss at 12 months. Furthermore, proactive coping was a better predictor of long-term self-management than either intentions or self-efficacy. Proactive coping thus offers new insights into behavioural maintenance theory and can be used to develop effective self-management interventions. PMID:20204991

  13. Erythroid differentiation is augmented in Reelin-deficient K562 cells and homozygous reeler mice.

    PubMed

    Chu, Hui-Chun; Lee, Hsing-Ying; Huang, Yen-Shu; Tseng, Wei-Lien; Yen, Ching-Ju; Cheng, Ju-Chien; Tseng, Ching-Ping

    2014-01-01

    Reelin is an extracellular glycoprotein that is highly conserved in mammals. In addition to its expression in the nervous system, Reelin is present in erythroid cells but its function there is unknown. We report in this study that Reelin is up-regulated during erythroid differentiation of human erythroleukemic K562 cells and is expressed in the erythroid progenitors of murine bone marrow. Reelin deficiency promotes erythroid differentiation of K562 cells and augments erythroid production in murine bone marrow. In accordance with these findings, Reelin deficiency attenuates AKT phosphorylation of the Ter119(+)CD71(+) erythroid progenitors and alters the cell number and frequency of the progenitors at different erythroid differentiation stages. A regulatory role of Reelin in erythroid differentiation is thus defined. PMID:24239537

  14. The effect of mild agitation on in vitro erythroid development.

    PubMed

    Boehm, Daniela; Murphy, William G; Al-Rubeai, Mohamed

    2010-08-31

    The cultivation of erythroid cells at large scale would have to be performed in suitable bioreactors which would most likely employ some mode of agitation to ensure optimal mass and gas transfer and prevent culture inhomogeneity. The effect of low agitation at 15-20 rpm on ex vivo erythropoiesis of PB CD34+ derived cultures was investigated and found to have significant impact on erythroid development. Agitated cultures showed a reduced lag phase and increased cell expansion during the early stages of culture. Additionally, agitation accelerated erythroid differentiation as seen by the loss of early development markers, acquisition of late erythroid markers and premature cell cycle arrest, although not yielding higher fractions of terminally differentiated cells in comparison to stationary culture. However, agitation at 20 rpm led to significantly increased loss of cell viability after day 15 in culture, an effect that could be reduced by decreasing the agitation rate to 15 rpm. On the one hand these results imply that agitation may improve cell yields and reduce expensive cytokine-dependent early culture stages but on the other hand it might introduce the risk of increased cell death in large scale culture.

  15. TMEM14C is required for erythroid mitochondrial heme metabolism.

    PubMed

    Yien, Yvette Y; Robledo, Raymond F; Schultz, Iman J; Takahashi-Makise, Naoko; Gwynn, Babette; Bauer, Daniel E; Dass, Abhishek; Yi, Gloria; Li, Liangtao; Hildick-Smith, Gordon J; Cooney, Jeffrey D; Pierce, Eric L; Mohler, Kyla; Dailey, Tamara A; Miyata, Non; Kingsley, Paul D; Garone, Caterina; Hattangadi, Shilpa M; Huang, Hui; Chen, Wen; Keenan, Ellen M; Shah, Dhvanit I; Schlaeger, Thorsten M; DiMauro, Salvatore; Orkin, Stuart H; Cantor, Alan B; Palis, James; Koehler, Carla M; Lodish, Harvey F; Kaplan, Jerry; Ward, Diane M; Dailey, Harry A; Phillips, John D; Peters, Luanne L; Paw, Barry H

    2014-10-01

    The transport and intracellular trafficking of heme biosynthesis intermediates are crucial for hemoglobin production, which is a critical process in developing red cells. Here, we profiled gene expression in terminally differentiating murine fetal liver-derived erythroid cells to identify regulators of heme metabolism. We determined that TMEM14C, an inner mitochondrial membrane protein that is enriched in vertebrate hematopoietic tissues, is essential for erythropoiesis and heme synthesis in vivo and in cultured erythroid cells. In mice, TMEM14C deficiency resulted in porphyrin accumulation in the fetal liver, erythroid maturation arrest, and embryonic lethality due to profound anemia. Protoporphyrin IX synthesis in TMEM14C-deficient erythroid cells was blocked, leading to an accumulation of porphyrin precursors. The heme synthesis defect in TMEM14C-deficient cells was ameliorated with a protoporphyrin IX analog, indicating that TMEM14C primarily functions in the terminal steps of the heme synthesis pathway. Together, our data demonstrate that TMEM14C facilitates the import of protoporphyrinogen IX into the mitochondrial matrix for heme synthesis and subsequent hemoglobin production. Furthermore, the identification of TMEM14C as a protoporphyrinogen IX importer provides a genetic tool for further exploring erythropoiesis and congenital anemias.

  16. TMEM14C is required for erythroid mitochondrial heme metabolism

    PubMed Central

    Yien, Yvette Y.; Robledo, Raymond F.; Schultz, Iman J.; Takahashi-Makise, Naoko; Gwynn, Babette; Bauer, Daniel E.; Dass, Abhishek; Yi, Gloria; Li, Liangtao; Hildick-Smith, Gordon J.; Cooney, Jeffrey D.; Pierce, Eric L.; Mohler, Kyla; Dailey, Tamara A.; Miyata, Non; Kingsley, Paul D.; Garone, Caterina; Hattangadi, Shilpa M.; Huang, Hui; Chen, Wen; Keenan, Ellen M.; Shah, Dhvanit I.; Schlaeger, Thorsten M.; DiMauro, Salvatore; Orkin, Stuart H.; Cantor, Alan B.; Palis, James; Koehler, Carla M.; Lodish, Harvey F.; Kaplan, Jerry; Ward, Diane M.; Dailey, Harry A.; Phillips, John D.; Peters, Luanne L.; Paw, Barry H.

    2014-01-01

    The transport and intracellular trafficking of heme biosynthesis intermediates are crucial for hemoglobin production, which is a critical process in developing red cells. Here, we profiled gene expression in terminally differentiating murine fetal liver-derived erythroid cells to identify regulators of heme metabolism. We determined that TMEM14C, an inner mitochondrial membrane protein that is enriched in vertebrate hematopoietic tissues, is essential for erythropoiesis and heme synthesis in vivo and in cultured erythroid cells. In mice, TMEM14C deficiency resulted in porphyrin accumulation in the fetal liver, erythroid maturation arrest, and embryonic lethality due to profound anemia. Protoporphyrin IX synthesis in TMEM14C-deficient erythroid cells was blocked, leading to an accumulation of porphyrin precursors. The heme synthesis defect in TMEM14C-deficient cells was ameliorated with a protoporphyrin IX analog, indicating that TMEM14C primarily functions in the terminal steps of the heme synthesis pathway. Together, our data demonstrate that TMEM14C facilitates the import of protoporphyrinogen IX into the mitochondrial matrix for heme synthesis and subsequent hemoglobin production. Furthermore, the identification of TMEM14C as a protoporphyrinogen IX importer provides a genetic tool for further exploring erythropoiesis and congenital anemias. PMID:25157825

  17. The heme exporter Flvcr1 regulates expansion and differentiation of committed erythroid progenitors by controlling intracellular heme accumulation.

    PubMed

    Mercurio, Sonia; Petrillo, Sara; Chiabrando, Deborah; Bassi, Zuni Irma; Gays, Dafne; Camporeale, Annalisa; Vacaru, Andrei; Miniscalco, Barbara; Valperga, Giulio; Silengo, Lorenzo; Altruda, Fiorella; Baron, Margaret H; Santoro, Massimo Mattia; Tolosano, Emanuela

    2015-06-01

    Feline leukemia virus subgroup C receptor 1 (Flvcr1) encodes two heme exporters: FLVCR1a, which localizes to the plasma membrane, and FLVCR1b, which localizes to mitochondria. Here, we investigated the role of the two Flvcr1 isoforms during erythropoiesis. We showed that, in mice and zebrafish, Flvcr1a is required for the expansion of committed erythroid progenitors but cannot drive their terminal differentiation, while Flvcr1b contributes to the expansion phase and is required for differentiation. FLVCR1a-down-regulated K562 cells have defective proliferation, enhanced differentiation, and heme loading in the cytosol, while FLVCR1a/1b-deficient K562 cells show impairment in both proliferation and differentiation, and accumulate heme in mitochondria. These data support a model in which the coordinated expression of Flvcr1a and Flvcr1b contributes to control the size of the cytosolic heme pool required to sustain metabolic activity during the expansion of erythroid progenitors and to allow hemoglobinization during their terminal maturation. Consistently, reduction or increase of the cytosolic heme rescued the erythroid defects in zebrafish deficient in Flvcr1a or Flvcr1b, respectively. Thus, heme export represents a tightly regulated process that controls erythropoiesis.

  18. Sustain

    SciTech Connect

    2013-08-20

    Current building energy simulation technology requires excessive labor, time and expertise to create building energy models, excessive computational time for accurate simulations and difficulties with the interpretation of the results. These deficiencies can be ameliorated using modern graphical user interfaces and algorithms which take advantage of modern computer architectures and display capabilities. To prove this hypothesis, we developed an experimental test bed for building energy simulation. This novel test bed environment offers an easy-to-use interactive graphical interface, provides access to innovative simulation modules that run at accelerated computational speeds, and presents new graphics visualization methods to interpret simulation results. Our system offers the promise of dramatic ease of use in comparison with currently available building energy simulation tools. Its modular structure makes it suitable for early stage building design, as a research platform for the investigation of new simulation methods, and as a tool for teaching concepts of sustainable design. Improvements in the accuracy and execution speed of many of the simulation modules are based on the modification of advanced computer graphics rendering algorithms. Significant performance improvements are demonstrated in several computationally expensive energy simulation modules. The incorporation of these modern graphical techniques should advance the state of the art in the domain of whole building energy analysis and building performance simulation, particularly at the conceptual design stage when decisions have the greatest impact. More importantly, these better simulation tools will enable the transition from prescriptive to performative energy codes, resulting in better, more efficient designs for our future built environment.

  19. Sustain

    2013-08-20

    Current building energy simulation technology requires excessive labor, time and expertise to create building energy models, excessive computational time for accurate simulations and difficulties with the interpretation of the results. These deficiencies can be ameliorated using modern graphical user interfaces and algorithms which take advantage of modern computer architectures and display capabilities. To prove this hypothesis, we developed an experimental test bed for building energy simulation. This novel test bed environment offers an easy-to-use interactivemore » graphical interface, provides access to innovative simulation modules that run at accelerated computational speeds, and presents new graphics visualization methods to interpret simulation results. Our system offers the promise of dramatic ease of use in comparison with currently available building energy simulation tools. Its modular structure makes it suitable for early stage building design, as a research platform for the investigation of new simulation methods, and as a tool for teaching concepts of sustainable design. Improvements in the accuracy and execution speed of many of the simulation modules are based on the modification of advanced computer graphics rendering algorithms. Significant performance improvements are demonstrated in several computationally expensive energy simulation modules. The incorporation of these modern graphical techniques should advance the state of the art in the domain of whole building energy analysis and building performance simulation, particularly at the conceptual design stage when decisions have the greatest impact. More importantly, these better simulation tools will enable the transition from prescriptive to performative energy codes, resulting in better, more efficient designs for our future built environment.« less

  20. The role of DNA methylation in catechol-enhanced erythroid differentiation of K562 cells

    SciTech Connect

    Li, Xiao-Fei; Wu, Xiao-Rong; Xue, Ming; Wang, Yan; Wang, Jie; Li, Yang; Suriguga,; Zhang, Guang-Yao; Yi, Zong-Chun

    2012-11-15

    Catechol is one of phenolic metabolites of benzene in vivo. Catechol is also widely used in pharmaceutical and chemical industries. In addition, fruits, vegetables and cigarette smoke also contain catechol. Our precious study showed that several benzene metabolites (phenol, hydroquinone, and 1,2,4-benzenetriol) inhibited erythroid differentiation of K562 cells. In present study, the effect of catechol on erythroid differentiation of K562 cells was investigated. Moreover, to address the role of DNA methylation in catechol-induced effect on erythroid differentiation in K562 cells, methylation levels of erythroid-specific genes were analyzed by Quantitative MassARRAY methylation analysis platform. Benzidine staining showed that exposure to catechol enhanced hemin-induced hemoglobin accumulation in K562 cells in concentration- and time-dependent manners. The mRNA expression of erythroid specific genes, including α-globin, β-globin, γ-globin, erythroid 5-aminolevulinate synthase, erythroid porphobilinogen deaminase, and transcription factor GATA-1 genes, showed a significant concentration-dependent increase in catechol-treated K562 cells. The exposure to catechol caused a decrease in DNA methylation levels at a few CpG sites in some erythroid specific genes including α-globin, β-globin and erythroid porphobilinogen deaminase genes. These results indicated that catechol improved erythroid differentiation potency of K562 cells at least partly via up-regulating transcription of some erythroid related genes, and suggested that inhibition of DNA methylation might be involved in up-regulated expression of some erythroid related genes. -- Highlights: ► Catechol enhanced hemin-induced hemoglobin accumulation. ► Exposure to catechol resulted in up-regulated expression of erythroid genes. ► Catechol reduced methylation levels at some CpG sites in erythroid genes.

  1. Radioactive Waste Management - It's Role in contributing and achieving Sustainability. R1.13 The French strategy of waste management: technical and political dimensions of sustainability

    SciTech Connect

    Bazile, F.

    2007-07-01

    The sustainability of an energy policy depends on the manner in which it satisfies environmental, economical and social requirements. Nuclear energy is not an exception. The objectives of the future nuclear systems, as defined in the Generation IV International Forum, tend to optimize the ability of nuclear energy to satisfy sustainable development goals. In this regard, they involve strong commitments concerning waste management policy : five designs in six are based on a closed fuel cycle, in order to minimize the volume and radiotoxicity of final waste, and to recycle the fissile materials to save natural resources. Since its beginnings, the French civil nuclear programme has considered a long-term perspective and has developed spent fuel reprocessing. The French current industrial technology has already permitted to recycle 96% of spent fuel materials, to save 30% of natural resources, to reduce by 5 the amount of waste and to reduce by 10 the waste radiotoxicity, all these benefits for less than 6% of the kWh total cost. This strategy has always been criticized by the nuclear opponents, precisely because they saw that it was a sustainable way, and didn't accept to consider nuclear energy as a sustainable source of power. Two arguments were put forward these criticisms. First, the cost of reprocessing versus once-through cycle and second, the risk of proliferation induced by U-Pu partitioning process. These arguments were also invoked in international debates, and they have also been pleaded by the anti-nukes during the National Debate on HLLLW, at the end of 2005, preceding the vote of a new law in 2006 by the French parliament. Fortunately they have not convinced public opinion in France nor political decision-makers. A majority of people with no regard to technical background understand that recycling and saving the natural resources are sustainable principles. And, from a technical point of view, the 6% over cost does not seem significant considering the

  2. Survival and proliferative roles of erythropoietin beyond the erythroid lineage

    PubMed Central

    Noguchi, Constance Tom; Wang, Li; Rogers, Heather M.; Teng, Ruifeng; Jia, Yi

    2011-01-01

    Since the isolation and purification of erythropoietin (EPO) in 1977, the essential role of EPO for mature red blood cell production has been well established. The cloning and production of recombinant human EPO led to its widespread use in treating patients with anaemia. However, the biological activity of EPO is not restricted to regulation of erythropoiesis. EPO receptor (EPOR) expression is also found in endothelial, brain, cardiovascular and other tissues, although at levels considerably lower than that of erythroid progenitor cells. This review discusses the survival and proliferative activity of EPO that extends beyond erythroid progenitor cells. Loss of EpoR expression in mouse models provides evidence for the role of endogenous EPO signalling in nonhaematopoietic tissue during development or for tissue maintenance and/or repair. Determining the extent and distribution of receptor expression provides insights into the potential protective activity of erythropoietin in brain, heart and other nonhaematopoietic tissues. PMID:19040789

  3. Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation

    PubMed Central

    Hu, Wenqian; Yuan, Bingbing; Lodish, Harvey F.

    2014-01-01

    SUMMARY While we have considerable understanding of the transcriptional networks controlling mammalian cell differentiation, our knowledge of post-transcriptional regulatory events is very limited. Using differentiation of primary erythroid cells as a model, we show that the sequence-specific mRNA-binding protein Cpeb4 is strongly induced by the erythroid important transcription factors Gata1 and Tal1 and is essential for terminal erythropoiesis. By interacting with the translation initiation factor eIF3 Cpeb4 represses the translation of a large set of mRNAs, including its own mRNA. Thus transcriptional induction and translational repression combine to form a negative feedback loop to control Cpeb4 protein levels within a specific range that is required for terminal erythropoiesis. Our study provides an example of how translational control is integrated with transcriptional regulation to precisely control gene expression during mammalian cell differentiation. PMID:25220394

  4. Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation.

    PubMed

    Hu, Wenqian; Yuan, Bingbing; Lodish, Harvey F

    2014-09-29

    While we have considerable understanding of the transcriptional networks controlling mammalian cell differentiation, our knowledge of posttranscriptional regulatory events is very limited. Using differentiation of primary erythroid cells as a model, we show that the sequence-specific mRNA-binding protein Cpeb4 is strongly induced by the erythroid-important transcription factors Gata1 and Tal1 and is essential for terminal erythropoiesis. By interacting with the translation initiation factor eIF3, Cpeb4 represses the translation of a large set of mRNAs, including its own mRNA. Thus, transcriptional induction and translational repression combine to form a negative feedback loop to control Cpeb4 protein levels within a specific range that is required for terminal erythropoiesis. Our study provides an example of how translational control is integrated with transcriptional regulation to precisely control gene expression during mammalian cell differentiation.

  5. Haemoglobin biosynthesis site in rabbit embryo erythroid cells.

    PubMed

    Cianciarullo, Aurora M; Bertho, Alvaro L; Soares, Maurilio J; Hosoda, Tânia M; Nogueira-Silva, Simone; Beçak, Willy

    2003-01-01

    Properly metabolized globin synthesis and iron uptake are indispensable for erythroid cell differentiation and maturation. Mitochondrial participation is crucial in the process of haeme synthesis for cytochromes and haemoglobin. We studied the final biosynthesis site of haemoglobin using an ultrastructural approach, with erythroid cells obtained from rabbit embryos, in order to compare these results with those of animals treated with saponine or phenylhydrazine. Our results are similar to those obtained in assays with adult mammals, birds, amphibians, reptiles and fish, after induction of haemolytic anaemia. Therefore, the treatment did not interfere with the process studied, confirming our previous findings. Immunoelectron microscopy showed no labelling of mitochondria or other cellular organelles supposedly involved in the final biosynthesis of haemoglobin molecules, suggesting instead that it occurs free in the cytoplasm immediately after the liberation of haeme from the mitochondria, by electrostatic attraction between haeme and globin chains. PMID:12972280

  6. Down-regulation of Myc is essential for terminal erythroid maturation.

    PubMed

    Jayapal, Senthil Raja; Lee, Kian Leong; Ji, Peng; Kaldis, Philipp; Lim, Bing; Lodish, Harvey F

    2010-12-17

    Terminal differentiation of mammalian erythroid progenitors involves 4-5 cell divisions and induction of many erythroid important genes followed by chromatin and nuclear condensation and enucleation. The protein levels of c-Myc (Myc) are reduced dramatically during late stage erythroid maturation, coinciding with cell cycle arrest in G(1) phase and enucleation, suggesting possible roles for c-Myc in either or both of these processes. Here we demonstrate that ectopic Myc expression affects terminal erythroid maturation in a dose-dependent manner. Expression of Myc at physiological levels did not affect erythroid differentiation or cell cycle shutdown but specifically blocked erythroid nuclear condensation and enucleation. Continued Myc expression prevented deacetylation of several lysine residues in histones H3 and H4 that are normally deacetylated during erythroid maturation. The histone acetyltransferase Gcn5 was up-regulated by Myc, and ectopic Gcn5 expression partially blocked enucleation and inhibited the late stage erythroid nuclear condensation and histone deacetylation. When overexpressed at levels higher than the physiological range, Myc blocked erythroid differentiation, and the cells continued to proliferate in cytokine-free, serum-containing culture medium with an early erythroblast morphology. Gene expression analysis demonstrated the dysregulation of erythropoietin signaling pathway and the up-regulation of several positive regulators of G(1)-S cell cycle checkpoint by supraphysiological levels of Myc. These results reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells.

  7. Going Green: A Comparative Case Study of How Three Higher Education Institutions Achieved Progressive Measures of Environmental Sustainability

    ERIC Educational Resources Information Center

    James, Matthew R.

    2009-01-01

    Leal Filho, MacDermot, and Padgam (1996) contended that post-secondary institutions are well suited to take on leadership responsibilities for society's environmental protection. Higher education has the unique academic freedom to engage in critical thinking and bold experimentation in environmental sustainability (Cortese, 2003). Although…

  8. When wastewater has worth: Water reconditioning opportunities in the food industry to achieve sustainable food manufacturing (abstract)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A major sustainability goal of food processing wastewater (FPWW) management is to not only decrease environmental pollution but also utilize valuable co-products present in the FPWW. Many processed food products, especially those from fruits and vegetables, result in FPWW streams that contain compou...

  9. Institutional Incorporation of Screening, Brief Intervention, and Referral to Treatment (SBIRT) in Residency Training: Achieving a Sustainable Curriculum

    ERIC Educational Resources Information Center

    Scott, Denise M.; McLaurin-Jones, TyWanda; Brown, Fannie D.; Newton, Robin; Marshall, Vanessa J.; Kalu, Nnenna; Cain, Gloria E.; Taylor, Robert E.

    2012-01-01

    The success of implementing a screening, brief intervention and referral to treatment (SBIRT) program within a medical residency program for sustainability is contingent upon a well-crafted training curriculum that incorporates substance abuse education and clinical practice skills. The goal of the Howard University (HU) SBIRT program is to train…

  10. Implementing the UN Decade of Education for Sustainable Development (DESD): Achievements, Open Questions and Strategies for the Way Forward

    ERIC Educational Resources Information Center

    Pigozzi, Mary Joy

    2010-01-01

    This paper looks at the implementation of the DESD from a global perspective. It takes the position that quality education is fundamental for learning how to live sustainably, and that the DESD needs to be better positioned in the education landscape and conceived as a global social movement that must be fostered and nurtured for the well-being of…

  11. In vitro apoptotic cell death during erythroid differentiation.

    PubMed

    Zamai, L; Burattini, S; Luchetti, F; Canonico, B; Ferri, P; Melloni, E; Gonelli, A; Guidotti, L; Papa, S; Falcieri, E

    2004-03-01

    Erythropoiesis occurs in bone marrow and it has been shown that during in vivo erythroid differentiation some immature erythroblasts undergo apoptosis. In this regard, it is known that immature erythroblasts are FasL- and TRAIL-sensitive and can be killed by cells expressing these ligand molecules. In the present study, we have investigated the cell death phenomenon that occurs during a common unilineage model of erythroid development. Purified CD34+ human haemopoietic progenitors were cultured in vitro in the presence of SCF, IL-3 and erythropoietin. Their differentiation stages and apoptosis were followed by multiple technical approaches. Flow cytometric evaluation of surface and intracellular molecules revealed that glycophorin A appeared at day 3-4 of incubation and about 75% of viable cells co-expressed high density glycophorin A (Gly(bright)) and adult haemoglobin at day 14 of culture, indicating that this system reasonably recapitulates in vivo normal erythropoiesis. Interestingly, when mature (Gly(bright)) erythroid cells reached their higher percentages (day 14) almost half of cultured cells were apoptotic. Morphological studies indicated that the majority of dead cells contained cytoplasmic granular material typical of basophilic stage, and DNA analysis by flow cytometry and TUNEL reaction revealed nuclear fragmentation. These observations indicate that in vitro unilineage erythroid differentiation, as in vivo, is associated with apoptotic cell death of cells with characteristics of basophilic erythroblasts. We suggest that the interactions between different death receptors on immature basophilic erythroblasts with their ligands on more mature erythroblasts may contribute to induce apoptosis in vitro. PMID:15004520

  12. Neuraminidase enhances in vitro expansion of human erythroid progenitors.

    PubMed

    Bodivit, Gwellaouen; Chadebech, Philippe; Vigon, Isabelle; Yacia, Azzedine; Roziers, Nicolas Burin des; Pirenne, France; Fichelson, Serge

    2016-06-01

    In spite of recent key improvements, in vitro mass production of erythrocytes from human stem cells is still limited by difficulties in obtaining sufficient numbers of erythroid progenitors. In fact, such progenitors are as scarce in the bone marrow as in peripheral blood. We used a two-step culture model of human cord blood-derived erythroid progenitors in the presence or absence of high-purity neuraminidase, in a serum-free, defined culture medium. Granulocytic and megakaryocytic progenitor cell expansions were also studied. We show that significant enhancement of erythroid cell generation is obtained when CD34(+) human hematopoietic progenitors are cultured in the presence of neuraminidase. Interestingly, in so doing, expanded red cell progenitors remained erythropoietin-dependent for further expansion and survival, and cells thus generated displayed a normal phenotype. Moreover, the activity of neuraminidase on these cells can be reversed by simple cell washing. Finally, growth of cells of the other myeloid lineages (granulocytes and megakaryocytes) is either decreased or unchanged in the presence of neuraminidase. This specific feature of neuraminidase, that of stimulation of human red cell progenitor proliferation, provides a safe technique for producing greater numbers of in vitro-generated red blood cells for both basic research and transfusion use. PMID:27478075

  13. The Effects of Sustained Classroom-Embedded Teacher Professional Learning on Teacher Efficacy and Related Student Achievement

    ERIC Educational Resources Information Center

    Bruce, Catherine D.; Esmonde, Indigo; Ross, John; Dookie, Lesley; Beatty, Ruth

    2010-01-01

    This paper reports on the impact of a classroom-embedded professional learning (PL) program for mathematics teaching in two contrasting districts in Canada, and investigates the relationship between teacher efficacy and student achievement. Before the PL, District A had lower teacher efficacy and student achievement than District B, but after the…

  14. Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors.

    PubMed

    Harandi, Omid F; Hedge, Shailaja; Wu, Dai-Chen; McKeone, Daniel; Paulson, Robert F

    2010-12-01

    Acute anemic stress induces a systemic response designed to increase oxygen delivery to hypoxic tissues. Increased erythropoiesis is a key component of this response. Recovery from acute anemia relies on stress erythropoiesis, which is distinct from steady-state erythropoiesis. In this study we found that the bone morphogenetic protein 4-dependent (BMP4-dependent) stress erythropoiesis pathway was required and specific for erythroid short-term radioprotection following bone marrow transplantation. BMP4 signaling promoted the development of three populations of stress erythroid progenitors, which expanded in the spleen subsequent to bone marrow transplantation in mice. These progenitors did not correspond to previously identified bone marrow steady-state progenitors. The most immature population of stress progenitors was capable of self renewal while maintaining erythropoiesis without contribution to other lineages when serially transplanted into irradiated secondary and tertiary recipients. These data suggest that during the immediate post-transplant period, the microenvironment of the spleen is altered, which allows donor bone marrow cells to adopt a stress erythropoietic fate and promotes the rapid expansion and differentiation of stress erythroid progenitors. Our results also suggest that stress erythropoiesis may be manipulated through targeting the BMP4 signaling pathway to improve survival after injury. PMID:21060151

  15. Subtle distinct regulations of late erythroid molecular events by PI3K/AKT-mediated activation of Spi-1/PU.1 oncogene autoregulation loop.

    PubMed

    Breig, O; Théoleyre, O; Douablin, A; Baklouti, F

    2010-05-13

    Spi-1/PU.1 oncogene is downregulated as proerythroblasts undergo terminal differentiation. Insertion of the Friend virus upstream of the Spi-1/PU.1 locus leads to the constitutive upregulation of Spi-1/PU.1, and a subsequent block in the differentiation of the affected erythroblasts. We have shown that sustained overexpression of Spi-1/PU.1 also inhibits the erythroid splicing of protein 4.1R exon 16, irrespective of chemical induction of differentiation. Here, we show a positive feedback loop that couples constitutive phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling to high expression of Spi-1/PU.1 in Friend erythroleukemia cells. Inhibition of PI3K/AKT results in Spi-1/PU.1 downregulation in a stepwise manner and induces cell differentiation. Chromatin immunoprecipitation assays further supported the positive autoregulatory effect of Spi-1/PU.1. Mutational analysis indicated that Ser41, but not Ser148, is necessary for Spi-1/PU.1-mediated repression of hemoglobin expression, whereas both Ser residues are required for Spi-1/PU.1 inhibition of the erythroid splicing event. We further show that inhibition of the erythroid transcriptional and splicing events are strictly dependent on distinct Spi-1/PU.1 phosphorylation modifications rather than Spi-1/PU.1 expression level per se. Our data further support the fact that Spi-1/PU.1 inhibits 4.1R erythroid splicing through two different pathways, and bring new insights into the extracellular signal impact triggered by erythropoietin on late erythroid regulatory program, including pre-mRNA splicing.

  16. Sustainable energy for all. Technical report of task force 1 in support of the objective to achieve universal access to modern energy services by 2030

    SciTech Connect

    Birol, Fatih

    2012-04-15

    The UN Secretary General established the Sustainable Energy for All initiative in order to guide and support efforts to achieve universal access to modern energy, rapidly increase energy efficiency, and expand the use of renewable energies. Task forces were formed involving prominent energy leaders and experts from business, government, academia and civil society worldwide. The goal of the Task Forces is to inform the implementation of the initiative by identifying challenges and opportunities for achieving its objectives. This report contains the findings of Task Force One which is dedicated to the objective of achieving universal access to modern energy services by 2030. The report shows that universal energy access can be realized by 2030 with strong, focused actions set within a coordinated framework.

  17. Erythroid-Specific Expression of LIN28A Is Sufficient for Robust Gamma-Globin Gene and Protein Expression in Adult Erythroblasts

    PubMed Central

    Byrnes, Colleen; Kaushal, Megha; Rabel, Antoinette; Tumburu, Laxminath; Allwardt, Joshua M.; Miller, Jeffery L.

    2015-01-01

    Increasing fetal hemoglobin (HbF) levels in adult humans remains an active area in hematologic research. Here we explored erythroid-specific LIN28A expression for its effect in regulating gamma-globin gene expression and HbF levels in cultured adult erythroblasts. For this purpose, lentiviral transduction vectors were produced with LIN28A expression driven by erythroid-specific gene promoter regions of the human KLF1 or SPTA1 genes. Transgene expression of LIN28A with a linked puromycin resistance marker was restricted to the erythroid lineage as demonstrated by selective survival of erythroid colonies (greater than 95% of all colonies). Erythroblast LIN28A over-expression (LIN28A-OE) did not significantly affect proliferation or inhibit differentiation. Greater than 70% suppression of total let-7 microRNA levels was confirmed in LIN28A-OE cells. Increases in gamma-globin mRNA and protein expression with HbF levels reaching 30–40% were achieved. These data suggest that erythroblast targeting of LIN28A expression is sufficient for increasing fetal hemoglobin expression in adult human erythroblasts. PMID:26675483

  18. Sustainable Communities: A Lens for Envisioning and Achieving a Community-Based Culture of Social and Ecological Peace

    ERIC Educational Resources Information Center

    Verhagen, Frans C.

    2014-01-01

    One of the obstacles to dealing with the social and ecological crises that obstruct the achievement of a culture of peace is silo thinking in global governance. A unidimensional mode of planning, silo thinking leads to decisions based on the area of expertise of a particular agency or intergovernmental organization and fails to recognize linkages…

  19. Hype, harmony and human factors: applying user-centered design to achieve sustainable telehealth program adoption and growth.

    PubMed

    Rossos, P G; St-Cyr, O; Purdy, B; Toenjes, C; Masino, C; Chmelnitsky, D

    2015-01-01

    Despite decades of international experience with the use of information and communication technologies in healthcare delivery, widespread telehealth adoption remains limited and progress slow. Escalating health system challenges related to access, cost and quality currently coincide with rapid advancement of affordable and reliable internet based communication technologies creating unprecedented opportunities and incentives for telehealth. In this paper, we will describe how Human Factors Engineering (HFE) and user-centric elements have been incorporated into the establishment of telehealth within a large academic medical center to increase acceptance and sustainability. Through examples and lessons learned we wish to increase awareness of HFE and its importance in the successful implementation, innovation and growth of telehealth programs.

  20. Moving Toward Universal Health Coverage (UHC) to Achieve Inclusive and Sustainable Health Development: Three Essential Strategies Drawn From Asian Experience

    PubMed Central

    Xu, Ye; Huang, Cheng; Colón-Ramos, Uriyoán

    2015-01-01

    Binagwaho and colleagues’ perspective piece provided a timely reflection on the experience of Rwanda in achieving the Millennium Development Goals (MDGs) and a proposal of 5 principles to carry forward in post-2015 health development. This commentary echoes their viewpoints and offers three lessons for health policy reforms consistent with these principles beyond 2015. Specifically, we argue that universal health coverage (UHC) is an integrated solution to advance the global health development agenda, and the three essential strategies drawn from Asian countries’ health reforms toward UHC are: (1) Public financing support and sequencing health insurance expansion by first extending health insurance to the extremely poor, vulnerable, and marginalized population are critical for achieving UHC; (2) Improved quality of delivered care ensures supply-side readiness and effective coverage; (3) Strategic purchasing and results-based financing creates incentives and accountability for positive changes. These strategies were discussed and illustrated with experience from China and other Asian economies. PMID:26673477

  1. miR-150 inhibits terminal erythroid proliferation and differentiation

    PubMed Central

    Sun, Zhiwei; Wang, Ye; Han, Xu; Zhao, Xielan; Peng, Yuanliang; Li, Yusheng; Peng, Minyuan; Song, Jianhui; Wu, Kunlu; Sun, Shumin; Zhou, Weihua; Qi, Biwei; Zhou, Chufan; Chen, Huiyong; An, Xiuli; Liu, Jing

    2015-01-01

    MicroRNAs (miRNAs), a class of small non-coding linear RNAs, have been shown to play a crucial role in erythropoiesis. To evaluate the indispensable role of constant suppression of miR-150 during terminal erythropoiesis, we performed miR-150 gain- and loss-of-function experiments on hemin-induced K562 cells and EPO-induced human CD34+ cells. We found that forced expression of miR-150 suppresses commitment of hemoglobinization and CD235a labeling in both cell types. Erythroid proliferation is also inhibited via inducing apoptosis and blocking the cell cycle when miR-150 is overexpressed. In contrast, miR-150 inhibition promotes terminal erythropoiesis. 4.1 R gene is a new target of miR-150 during terminal erythropoiesis, and its abundance ensures the mechanical stability and deformability of the membrane. However, knockdown of 4.1 R did not affect terminal erythropoiesis. Transcriptional profiling identified more molecules involved in terminal erythroid dysregulation derived from miR-150 overexpression. These results shed light on the role of miR-150 during human terminal erythropoiesis. This is the first report highlighting the relationship between miRNA and membrane protein and enhancing our understanding of how miRNA works in the hematopoietic system. PMID:26543232

  2. Achieving Sustainability in a Semi-Arid Basin in Northwest Mexico through an Integrated Hydrologic-Economic-Institutional Model

    NASA Astrophysics Data System (ADS)

    Munoz-Hernandez, A.; Mayer, A. S.

    2008-12-01

    The hydrologic systems in Northwest Mexico are at risk of over exploitation due to poor management of the water resources and adverse climatic conditions. The purpose of this work is to create and Integrated Hydrologic-Economic-Institutional Model to support future development in the Yaqui River basin, well known by its agricultural productivity, by directing the water management practices toward sustainability. The Yaqui River basin is a semi-arid basin with an area of 72,000 square kilometers and an average precipitation of 527 mm per year. The primary user of water is agriculture followed by domestic use and industry. The water to meet user demands comes from three reservoirs constructed, in series, along the river. The main objective of the integrated simulation-optimization model is to maximize the economic benefit within the basin, subject to physical and environmental constraints. Decision variables include the water allocation to major users and reservoirs as well as aquifer releases. Economic and hydrologic (including the interaction of the surface water and groundwater) simulation models were both included in the integrated model. The surface water model refers to a rainfall-runoff model created, calibrated, and incorporated into a MATLAB code that estimates the monthly storage in the main reservoirs by solving a water balance. The rainfall-runoff model was coupled with a groundwater model of the Yaqui Valley which was previously developed (Addams, 2004). This model includes flow in the main canals and infiltration to the aquifer. The economic benefit of water for some activities such as agricultural use, domestic use, hydropower generation, and environmental value was determined. Sensitivity analysis was explored for those parameters that are not certain such as price elasticities or population growth. Different water allocation schemes were created based on climate change, climate variability, and socio-economic scenarios. Addams L. 2004. Water resource

  3. Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors

    PubMed Central

    Canli, Özge; Alankuş, Yasemin B.; Grootjans, Sasker; Vegi, Naidu; Hültner, Lothar; Hoppe, Philipp S.; Schroeder, Timm; Vandenabeele, Peter; Bornkamm, Georg W.

    2016-01-01

    Maintaining cellular redox balance is vital for cell survival and tissue homoeostasis because imbalanced production of reactive oxygen species (ROS) may lead to oxidative stress and cell death. The antioxidant enzyme glutathione peroxidase 4 (Gpx4) is a key regulator of oxidative stress–induced cell death. We show that mice with deletion of Gpx4 in hematopoietic cells develop anemia and that Gpx4 is essential for preventing receptor-interacting protein 3 (RIP3)-dependent necroptosis in erythroid precursor cells. Absence of Gpx4 leads to functional inactivation of caspase 8 by glutathionylation, resulting in necroptosis, which occurs independently of tumor necrosis factor α activation. Although genetic ablation of Rip3 normalizes reticulocyte maturation and prevents anemia, ROS accumulation and lipid peroxidation in Gpx4-deficient cells remain high. Our results demonstrate that ROS and lipid hydroperoxides function as not-yet-recognized unconventional upstream signaling activators of RIP3-dependent necroptosis. PMID:26463424

  4. Reduction of erythroid progenitors in protein-energy malnutrition.

    PubMed

    Borelli, Primavera; Blatt, Solange; Pereira, Juliana; de Maurino, Beatriz Beutler; Tsujita, Maristela; de Souza, Ana Cristina; Xavier, José Guilherme; Fock, Ricardo Ambrósio

    2007-02-01

    Protein-energy malnutrition is a syndrome in which anaemia together with multivitamin and mineral deficiency may be present. The pathophysiological mechanisms involved have not, however, yet been completely elucidated. The aim of the present study was to evaluate the pathophysiological processes that occur in this anaemia in animals that were submitted to protein-energy malnutrition, in particular with respect to Fe concentration and the proliferative activity of haemopoietic cells. For this, histological, histochemical, cell culture and immunophenotyping techniques were used. Two-month-old male Swiss mice were submitted to protein-energy malnutrition with a low-protein diet (20 g/kg) compared with control diet (400 g/kg). When the experimental group had attained a 20 % loss of their original body weight, the animals from both groups received, intravenously, 20 IU erythropoietin every other day for 14 d. Malnourished animals showed a decrease in red blood cells, Hb concentration and reticulocytopenia, as well as severe bone marrow and splenic atrophy. The results for serum Fe, total Fe-binding capacity, transferrin and erythropoietin in malnourished animals were no different from those of the control animals. Fe reserves in the spleen, liver and bone marrow were found to be greater in the malnourished animals. The mixed colony-forming unit assays revealed a smaller production of granulocyte-macrophage colony-forming units, erythroid burst-forming units, erythroid colony-forming units and CD45, CD117, CD119 and CD71 expression in the bone marrow and spleen cells of malnourished animals. These findings suggest that, in this protein-energy malnutrition model, anaemia is not caused by Fe deficiency or erythropoietin deficiency, but is a result of ineffective erythropoiesis.

  5. Long noncoding RNA-mediated anti-apoptotic activity in murine erythroid terminal differentiation.

    PubMed

    Hu, Wenqian; Yuan, Bingbing; Flygare, Johan; Lodish, Harvey F

    2011-12-15

    Long noncoding RNAs (lncRNAs) are differentially expressed under both normal and pathological conditions, implying that they may play important biological functions. Here we examined the expression of lncRNAs during erythropoiesis and identified an erythroid-specific lncRNA with anti-apoptotic activity. Inhibition of this lncRNA blocks erythroid differentiation and promotes apoptosis. Conversely, ectopic expression of this lncRNA can inhibit apoptosis in mouse erythroid cells. This lncRNA represses expression of Pycard, a proapoptotic gene, explaining in part the inhibition of programmed cell death. These findings reveal a novel layer of regulation of cell differentiation and apoptosis by a lncRNA.

  6. Erythropoietin-induced acute erythroid leukemia-like picture: a potential pitfall.

    PubMed

    Moharram, Laila; Kamal, Nazmi; Al Sukhun, Sana; Sughayer, Maher A

    2014-03-01

    A 31-year-old male patient presented with fever and pancytopenia. He was diagnosed as a case of chronic anemia since early childhood. The etiology of the anemia was not known. The patient was transfusion dependent, and he had been maintained on erythropoietin for three years prior to admission. A bone marrow examination revealed prominent proliferation of immature and dysplastic erythroid precursors. Acute erythroid leukemia of the pure erythroid subtype was suspected. However, because of the history of erythropoietin therapy a definite diagnosis was not made. On follow-up one month later, the marrow changes had reversed to normal.

  7. Predictors and outcomes of sustained, intermittent or never achieving remission in patients with recent onset inflammatory polyarthritis: results from the Norfolk Arthritis Register

    PubMed Central

    Cook, Michael J.; Diffin, Janet; Scirè, Carlo A.; Lunt, Mark; MacGregor, Alex J.; Symmons, Deborah P. M.

    2016-01-01

    Objectives. Early remission is the current treatment strategy for patients with inflammatory polyarthritis (IP) and RA. Our objective was to identify baseline factors associated with achieving remission: sustained (SR), intermittent (IR) or never (NR) over a 5-year period in patients with early IP. Methods. Clinical and demographic data of patients with IP recruited to the Norfolk Arthritis Register (NOAR) were obtained at baseline and years 1, 2, 3 and 5. Remission was defined as no tender or swollen joints (out of 51). Patients were classified as NR or PR, respectively, if they were in remission at: no assessment or ⩾3 consecutive assessments after baseline, and IR otherwise. Ordinal regression and a random effects model, respectively, were used to examine the association between baseline factors, remission group and HAQ scores over time. Results. A total of 868 patients (66% female) were included. Of these, 54%, 34% and 12% achieved NR, IR and SR, respectively. In multivariate analysis, female sex (odds ratio, OR 0.47, 95% CI: 0.35, 0.63), higher tender joint count (OR = 0.94, 95% CI: 0.93, 0.96), higher HAQ (OR = 0.59, 95% CI: 0.48, 0.74), being obese (OR = 0.70, 95% CI: 0.50, 0.99), hypertensive (OR = 0.67, 95% CI: 0.50, 0.90) or depressed (OR = 0.74, 95% CI: 0.55, 1.00) at baseline were independent predictors of being in a lower remission group. IR and SR were associated with lower HAQ scores over time and lower DAS28 at year 5. Conclusion. Women with higher tender joint count and disability at baseline, depression, obesity and hypertension were less likely to achieve remission. This information could help when stratifying patients for more aggressive therapy. PMID:27220594

  8. Gene expression profiling of human erythroid progenitors by micro-serial analysis of gene expression.

    PubMed

    Fujishima, Naohito; Hirokawa, Makoto; Aiba, Namiko; Ichikawa, Yoshikazu; Fujishima, Masumi; Komatsuda, Atsushi; Suzuki, Yoshiko; Kawabata, Yoshinari; Miura, Ikuo; Sawada, Ken-ichi

    2004-10-01

    We compared the expression profiles of highly purified human CD34+ cells and erythroid progenitor cells by micro-serial analysis of gene expression (microSAGE). Human CD34+ cells were purified from granulocyte colony-stimulating factor-mobilized blood stem cells, and erythroid progenitors were obtained by cultivating these cells in the presence of stem cell factor, interleukin 3, and erythropoietin. Our 10,202 SAGE tags allowed us to identify 1354 different transcripts appearing more than once. Erythroid progenitor cells showed increased expression of LRBA, EEF1A1, HSPCA, PILRB, RANBP1, NACA, and SMURF. Overexpression of HSPCA was confirmed by real-time polymerase chain reaction analysis. MicroSAGE revealed an unexpected preferential expression of several genes in erythroid progenitor cells in addition to the known functional genes, including hemoglobins. Our results provide reference data for future studies of gene expression in various hematopoietic disorders, including myelodysplastic syndrome and leukemia.

  9. Particle-induced erythropoietin-independent effects of erythroid precursor cells in murine bone marrow.

    PubMed

    Ploemacher, R E; van Soest, P L; Wagemaker, G; van 't Hull, E

    1979-09-01

    A possible regulatory action of phagocytic cells on erythropoiesis was investigated by infusion of inert polystyrene latex particles (LAT). LAT appeared to induce changes in the femoral content of erythroid progenitor cells. These changes were most pronounced in primitive erythroid progenitor cells (BFUe) and appeared to be gradually damped in more differentiated populations (CFUe and erythroblasts). LAT did not influence granulocyte/macrophage progenitor cells (CFUc). The effects of LAT could not be attributed to changes in the systemic erythropoietin (EP) concentration. Administration of dexamethason nullified the effect of low doses of LAT, suggesting that phagocytosis of the particles is essential to the observed effects. Erythroid burst formation was previously found to be dependent on a bone marrow associated activity, termed BFA (burst feeder activity). BFA acts as an in vitro inducer of EP-responsiveness in BFUe. In this study it was found that LAT-induced changes in femoral erythroid progenitor cell content were characteristically preceded by corresponding changes in BFA. It was concluded that BFA-associated cells probably play a role in vivo in the early differentiation of erythroid progenitor cells. The present data are interpreted as direct in vivo evidence supporting a two-step regulatory model operating in erythropoiesis and provide evidence that phagocytic cells are a component of the erythroid haemopoietic inductive micro-environment. PMID:519701

  10. Repression by RB1 characterizes genes involved in the penultimate stage of erythroid development.

    PubMed

    Zhang, Ji; Loyd, Melanie R; Randall, Mindy S; Morris, John J; Shah, Jayesh G; Ney, Paul A

    2015-01-01

    Retinoblastoma-1 (RB1), and the RB1-related proteins p107 and p130, are key regulators of the cell cycle. Although RB1 is required for normal erythroid development in vitro, it is largely dispensable for erythropoiesis in vivo. The modest phenotype caused by RB1 deficiency in mice raises questions about redundancy within the RB1 family, and the role of RB1 in erythroid differentiation. Here we show that RB1 is the major pocket protein that regulates terminal erythroid differentiation. Erythroid cells lacking all pocket proteins exhibit the same cell cycle defects as those deficient for RB1 alone. RB1 has broad repressive effects on gene transcription in erythroid cells. As a group, RB1-repressed genes are generally well expressed but downregulated at the final stage of erythroid development. Repression correlates with E2F binding, implicating E2Fs in the recruitment of RB1 to repressed genes. Merging differential and time-dependent changes in expression, we define a group of approximately 800 RB1-repressed genes. Bioinformatics analysis shows that this list is enriched for terms related to the cell cycle, but also for terms related to terminal differentiation. Some of these have not been previously linked to RB1. These results expand the range of processes potentially regulated by RB1, and suggest that a principal role of RB1 in development is coordinating the events required for terminal differentiation. PMID:26397180

  11. Force Dependent Changes in Non-Erythroid Spectrin and Ankyrins

    NASA Astrophysics Data System (ADS)

    Degaga, Eleni; Forstner, Martin

    2012-02-01

    Mechanotransduction in cells describes the process by which external physical stimuli are converted into biochemical activity and plays an important role in many biological functions on both the cell and tissue level. However, the specific mechanisms by which mechanical forces lead to particular molecular and cellular responses are much less understood. We investigate the changes in non-erythroid spectrin and ankyrins as a result of equi-biaxial strain application to live cells in culture. Specifically, we focus on the spectrins' role in the ubiquitination process - a vital process in the regulation of protein degradation- of spectrin and ankyrins. We utilize immune-fluorescence staining and fluorescent fusion proteins for quantitative fluorescence imaging as well as biochemical methods to measure changes in of cell's spectrin and ankyrin content. Protein expression levels and localization between cells exposed to mechanical stimuli of different temporal and spatial profiles are compared. In addition, the threshold behavior of cell proliferation - as measured by number densities - of a variety of cell types as a function of mechano-stimulation is investigated.

  12. Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.

    PubMed

    Latagliata, Roberto; Montagna, Chiara; Porrini, Raffaele; Di Veroli, Ambra; Leonetti, Sabrina Crescenzi; Niscola, Pasquale; Ciccone, Fabrizio; Spadea, Antonio; Breccia, Massimo; Maurillo, Luca; Rago, Angela; Spirito, Francesca; Cedrone, Michele; De Muro, Marianna; Montanaro, Marco; Andriani, Alessandro; Bagnato, Antonino; Montefusco, Enrico; Alimena, Giuliana

    2016-06-01

    At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase (FP-MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP-MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1-43.1) with median ferritin values of 1415 ng/mL (IR 1168-1768). Extra-hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6 months of treatment), after a median treatment period of 15.4 months (IR 8.1-22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000 ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3 months) rise of Hb levels >1.5 g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP-MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients.

  13. Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.

    PubMed

    Latagliata, Roberto; Montagna, Chiara; Porrini, Raffaele; Di Veroli, Ambra; Leonetti, Sabrina Crescenzi; Niscola, Pasquale; Ciccone, Fabrizio; Spadea, Antonio; Breccia, Massimo; Maurillo, Luca; Rago, Angela; Spirito, Francesca; Cedrone, Michele; De Muro, Marianna; Montanaro, Marco; Andriani, Alessandro; Bagnato, Antonino; Montefusco, Enrico; Alimena, Giuliana

    2016-06-01

    At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase (FP-MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP-MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1-43.1) with median ferritin values of 1415 ng/mL (IR 1168-1768). Extra-hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6 months of treatment), after a median treatment period of 15.4 months (IR 8.1-22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000 ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3 months) rise of Hb levels >1.5 g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP-MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients. PMID:26277477

  14. Myc Inhibits p27-Induced Erythroid Differentiation of Leukemia Cells by Repressing Erythroid Master Genes without Reversing p27-Mediated Cell Cycle Arrest▿ ‡

    PubMed Central

    Acosta, Juan C.; Ferrándiz, Nuria; Bretones, Gabriel; Torrano, Verónica; Blanco, Rosa; Richard, Carlos; O'Connell, Brenda; Sedivy, John; Delgado, M. Dolores; León, Javier

    2008-01-01

    Inhibition of differentiation has been proposed as an important mechanism for Myc-induced tumorigenesis, but the mechanisms involved are unclear. We have established a genetically defined differentiation model in human leukemia K562 cells by conditional expression of the cyclin-dependent kinase (Cdk) inhibitor p27 (inducible by Zn2+) and Myc (activatable by 4-hydroxy-tamoxifen). Induction of p27 resulted in erythroid differentiation, accompanied by Cdk inhibition and G1 arrest. Interestingly, activation of Myc inhibited p27-mediated erythroid differentiation without affecting p27-mediated proliferation arrest. Microarray-based gene expression indicated that, in the presence of p27, Myc blocked the upregulation of several erythroid-cell-specific genes, including NFE2, JUNB, and GATA1 (transcription factors with a pivotal role in erythropoiesis). Moreover, Myc also blocked the upregulation of Mad1, a transcriptional antagonist of Myc that is able to induce erythroid differentiation. Cotransfection experiments demonstrated that Myc-mediated inhibition of differentiation is partly dependent on the repression of Mad1 and GATA1. In conclusion, this model demonstrates that Myc-mediated inhibition of differentiation depends on the regulation of a specific gene program, whereas it is independent of p27-mediated cell cycle arrest. Our results support the hypothesis that differentiation inhibition is an important Myc tumorigenic mechanism that is independent of cell proliferation. PMID:18838534

  15. Hydroxymethylcytosine and demethylation of the γ-globin gene promoter during erythroid differentiation

    PubMed Central

    Ruiz, Maria Armila; Rivers, Angela; Ibanez, Vinzon; Vaitkus, Kestis; Mahmud, Nadim; DeSimone, Joseph; Lavelle, Donald

    2015-01-01

    The mechanism responsible for developmental stage-specific regulation of γ-globin gene expression involves DNA methylation. Previous results have shown that the γ-globin promoter is nearly fully demethylated during fetal liver erythroid differentiation and partially demethylated during adult bone marrow erythroid differentiation. The hypothesis that 5-hydroxymethylcytosine (5hmC), a known intermediate in DNA demethylation pathways, is involved in demethylation of the γ-globin gene promoter during erythroid differentiation was investigated by analyzing levels of 5-methylcytosine (5mC) and 5hmC at a CCGG site within the 5′ γ-globin gene promoter region in FACS-purified cells from baboon bone marrow and fetal liver enriched for different stages of erythroid differentiation. Our results show that 5mC and 5hmC levels at the γ-globin promoter are dynamically modulated during erythroid differentiation with peak levels of 5hmC preceding and/or coinciding with demethylation. The Tet2 and Tet3 dioxygenases that catalyze formation of 5hmC are expressed during early stages of erythroid differentiation and Tet3 expression increases as differentiation proceeds. In baboon CD34+ bone marrow-derived erythroid progenitor cell cultures, γ-globin expression was positively correlated with 5hmC and negatively correlated with 5mC at the γ-globin promoter. Supplementation of culture media with Vitamin C, a cofactor of the Tet dioxygenases, reduced γ-globin promoter DNA methylation and increased γ-globin expression when added alone and in an additive manner in combination with either DNA methyltransferase or LSD1 inhibitors. These results strongly support the hypothesis that the Tet-mediated 5hmC pathway is involved in developmental stage-specific regulation of γ-globin expression by mediating demethylation of the γ-globin promoter. PMID:25932923

  16. Neonatal CD71+ erythroid cells do not modify murine sepsis mortality

    PubMed Central

    Wynn, James L.; Scumpia, Philip O.; Stocks, Blair T.; Romano-Keeler, Joann; Alrifai, Mhd Wael; Liu, Jin-Hua; Kim, Annette S.; Alford, Catherine E.; Matta, Pranathi; Weitkamp, Jörn-Hendrik; Moore, Daniel J.

    2015-01-01

    Sepsis is a major cause of neonatal mortality and morbidity worldwide. A recent report suggested murine neonatal host defense against infection could be compromised by immunosuppressive CD71+ erythroid splenocytes. We examined the impact of CD71+ erythroid splenocytes on murine neonatal mortality to endotoxin challenge or polymicrobial sepsis and characterized circulating CD71+ erythroid (CD235a+) cells in human neonates. Adoptive transfer or antibody-mediated reduction of neonatal CD71+ erythroid splenocytes did not alter murine neonatal survival to endotoxin challenge or polymicrobial sepsis challenge. Ex vivo immunosuppression of stimulated adult CD11b+ cells was not limited to neonatal splenocytes as it also occurred with adult and neonatal bone marrow. Animals treated with anti-CD71 antibody showed reduced splenic bacterial load following bacterial challenge compared to isotype-treated mice. However, adoptive transfer of enriched CD71+ erythroid splenocytes to CD71+-reduced animals did not reduce bacterial clearance. Human CD71+CD235a+ cells were common among cord blood mononuclear cells and were shown to be reticulocytes. In summary, a lack of effect on murine survival to polymicrobial sepsis following adoptive transfer or diminution of CD71+ erythroid splenocytes under these experimental conditions suggests the impact of these cells on neonatal infection risk and progression may be limited. An unanticipated immune priming effect of anti-CD71 antibody treatment was likely responsible for the reported enhanced bacterial clearance, rather than a reduction of immunosuppressive CD71+ erythroid splenocytes. In humans, the well-described rapid decrease in circulating reticulocytes after birth suggests they may have a limited role in reducing inflammation secondary to microbial colonization. PMID:26101326

  17. Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.

    PubMed

    Shan, Yuxi; Cortopassi, Gino

    2016-01-01

    Mitochondrial iron-sulfur cluster (ISC) biogenesis provides iron-sulfur cofactors to several mitochondrial proteins, but the extent to which ISC biogenesis regulates hematopoiesis has been unclear. The blood disease Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis, and the disease overlaps with the gene Hspa9/Mortalin in multiple ways: the HSPA9 locus maps to 5q31.2 that is frequently deleted in human MDS; mutant Hspa9 causes zebrafish MDS; and Hspa9 knockdown mice have decreased hematopoiesis. We show here that HSPA9 functions in mitochondrial ISC biogenesis, and is required for erythroid differentiation. HSPA9 interacts with and stabilizes the mitochondrial ISC biogenesis proteins frataxin, Nfs1, ISCU, and Nfu. MDS-causing mutations in HSPA9 protein change its interactions with ISC biogenesis proteins. Depletion of HSPA9 decreases aconitase activity, which requires an ISC at its active site, but not that of the non-ISC requiring malate dehydrogenase, and increases IRP1 binding activity. In erythroid cell lines, Hspa9 depletion inhibited erythroid differentiation, post-transcriptionally regulating the expression of Alas2 and FeCH, as expected through known ISC control of the IRE response elements in these genes. By contrast, the Alas2 open reading frame rescued the Hspa9-dependent defect in erythroid differentiation, but not when uncoupled from its 5'-IRE sequence. Thus, Hspa9 depletion causes a mitochondrial ISC deficit, altering IRP1-IRE binding and FeCH stability, which consequently inhibits Alas2 translation, heme synthesis, and erythroid differentiation, i.e.: Hspa9->ISC->IRP/IRE->Alas2->heme synthesis->erythroid differentiation. Thus Hspa9 regulates erythroid differentiation through ISC cluster assembly, providing a pathophysiological mechanism for an MDS subtype characterized by HSPA9 haploinsufficiency, and suggests hemin and other pharmacological stimulators of ISC synthesis as potential routes to therapy.

  18. Functional erythroid promoters created by interaction of the transcription factor GATA-1 with CACCC and AP-1/NFE-2 elements.

    PubMed Central

    Walters, M; Martin, D I

    1992-01-01

    We have investigated interactions between the erythroid transcription factor GATA-1 and factors binding two cis-acting elements commonly linked to GATA sites in erythroid control elements. GATA-1 is present at all stages of erythroid differentiation, is necessary for erythropoiesis, and binds sites in all erythroid control elements. However, minimal promoters containing GATA-1 sites are inactive when tested in erythroid cells. Based on this observation, two erythroid cis elements, here termed CACCC and AP-1/NFE-2, were linked to GATA sites in minimal promoters. None of the elements linked only to a TATA box created an active promoter, but GATA sites linked to either CACCC or AP-1/NFE-2 elements formed strong erythroid promoters. A mutation of T to C at position -175 in the gamma-globin promoter GATA site, associated with hereditary persistence of fetal hemoglobin (HPFH), increased expression of these promoters in both fetal and adult cells. A construct bearing the beta-globin CACCC element was more active in adult and less active in fetal erythroid cells, when compared with the gamma-globin CACCC element. These studies suggest that erythroid control elements are formed by the interactions of at least three transcription factors, none of which functions alone. Images PMID:1438231

  19. β-Globin-Expressing Definitive Erythroid Progenitor Cells Generated from Embryonic and Induced Pluripotent Stem Cell-Derived Sacs.

    PubMed

    Fujita, Atsushi; Uchida, Naoya; Haro-Mora, Juan J; Winkler, Thomas; Tisdale, John

    2016-06-01

    Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a potential alternative source for red blood cell transfusion. However, when using traditional methods with embryoid bodies, ES cell-derived erythroid cells predominantly express embryonic type ɛ-globin, with lesser fetal type γ-globin and very little adult type β-globin. Furthermore, no β-globin expression is detected in iPS cell-derived erythroid cells. ES cell-derived sacs (ES sacs) have been recently used to generate functional platelets. Due to its unique structure, we hypothesized that ES sacs serve as hemangioblast-like progenitors capable to generate definitive erythroid cells that express β-globin. With our ES sac-derived erythroid differentiation protocol, we obtained ∼120 erythroid cells per single ES cell. Both primitive (ɛ-globin expressing) and definitive (γ- and β-globin expressing) erythroid cells were generated from not only ES cells but also iPS cells. Primitive erythropoiesis is gradually switched to definitive erythropoiesis during prolonged ES sac maturation, concurrent with the emergence of hematopoietic progenitor cells. Primitive and definitive erythroid progenitor cells were selected on the basis of glycophorin A or CD34 expression from cells within the ES sacs before erythroid differentiation. This selection and differentiation strategy represents an important step toward the development of in vitro erythroid cell production systems from pluripotent stem cells. Further optimization to improve expansion should be required for clinical application. Stem Cells 2016;34:1541-1552.

  20. Qualitative and quantitative comparison of the proteome of erythroid cells differentiated from human iPSCs and adult erythroid cells by multiplex TMT labelling and nanoLC-MS/MS.

    PubMed

    Trakarnsanga, Kongtana; Wilson, Marieangela C; Griffiths, Rebecca E; Toye, Ashley M; Carpenter, Lee; Heesom, Kate J; Parsons, Steve F; Anstee, David J; Frayne, Jan

    2014-01-01

    Induced pluripotent stem cells (iPSC) are an attractive progenitor source for the generation of in vitro blood products. However, before iPSC-derived erythroid cells can be considered for therapeutic use their similarity to adult erythroid cells must be confirmed. We have analysed the proteome of erythroid cells differentiated from the iPSC fibroblast derived line (C19) and showed they express hallmark RBC proteins, including all those of the ankyrin and 4.1R complex. We next compared the proteome of erythroid cells differentiated from three iPSC lines (C19, OCE1, OPM2) with that of adult and cord blood progenitors. Of the 1989 proteins quantified <3% differed in level by 2-fold or more between the different iPSC-derived erythroid cells. When compared to adult cells, 11% of proteins differed in level by 2-fold or more, falling to 1.9% if a 5-fold threshold was imposed to accommodate slight inter-cell line erythropoietic developmental variation. Notably, the level of >30 hallmark erythroid proteins was consistent between the iPSC lines and adult cells. In addition, a sub-population (10-15%) of iPSC erythroid cells in each of the iPSC lines completed enucleation. Aberrant expression of some cytoskeleton proteins may contribute to the failure of the majority of the cells to enucleate since we detected some alterations in cytoskeletal protein abundance. In conclusion, the proteome of erythroid cells differentiated from iPSC lines is very similar to that of normal adult erythroid cells, but further work to improve the induction of erythroid cells in existing iPSC lines or to generate novel erythroid cell lines is required before iPSC-derived red cells can be considered suitable for transfusion therapy.

  1. JAK-STAT and AKT pathway-coupled genes in erythroid progenitor cells through ontogeny

    PubMed Central

    2012-01-01

    Background It has been reported that the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway regulates erythropoietin (EPO)-induced survival, proliferation, and maturation of early erythroid progenitors. Erythroid cell proliferation and survival have also been related to activation of the JAK-STAT pathway. The goal of this study was to observe the function of EPO activation of JAK-STAT and PI3K/AKT pathways in the development of erythroid progenitors from hematopoietic CD34+ progenitor cells, as well as to distinguish early EPO target genes in human erythroid progenitors during ontogeny. Methods Hematopoietic CD34+ progenitor cells, isolated from fetal and adult hematopoietic tissues, were differentiated into erythroid progenitor cells. We have used microarray analysis to examine JAK-STAT and PI3K/AKT related genes, as well as broad gene expression modulation in these human erythroid progenitor cells. Results In microarray studies, a total of 1755 genes were expressed in fetal liver, 3844 in cord blood, 1770 in adult bone marrow, and 1325 genes in peripheral blood-derived erythroid progenitor cells. The erythroid progenitor cells shared 1011 common genes. Using the Ingenuity Pathways Analysis software, we evaluated the network pathways of genes linked to hematological system development, cellular growth and proliferation. The KITLG, EPO, GATA1, PIM1 and STAT3 genes represent the major connection points in the hematological system development linked genes. Some JAK-STAT signaling pathway-linked genes were steadily upregulated throughout ontogeny (PIM1, SOCS2, MYC, PTPN11), while others were downregulated (PTPN6, PIAS, SPRED2). In addition, some JAK-STAT pathway related genes are differentially expressed only in some stages of ontogeny (STATs, GRB2, CREBB). Beside the continuously upregulated (AKT1, PPP2CA, CHUK, NFKB1) and downregulated (FOXO1, PDPK1, PIK3CG) genes in the PI3K-AKT signaling pathway, we also observed intermittently regulated gene expression

  2. The fibronectin receptor on mammalian erythroid precursor cells: characterization and developmental regulation

    PubMed Central

    1986-01-01

    The plasma membrane of murine erythro-leukemia (MEL) cells contains a 140-kD protein that binds specifically to fibronectin. A 125I-labeled 140-kD protein from surface-labeled uninduced MEL cells was specifically bound by an affinity matrix that contained the 115-kD cell binding fragment of fibronectin, and specifically eluted by a synthetic peptide that has cell attachment-promoting activity. The loss of this protein during erythroid differentiation was correlated with loss of cellular adhesion to fibronectin. Both MEL cells and reticulocytes attached to the same site on fibronectin as do fibroblasts since adhesion of erythroid cells to fibronectin was specifically blocked by a monoclonal antibody directed against the cell-binding fragment of fibronectin and by a synthetic peptide containing the Arg-Gly-Asp-Ser sequence found in the cell-binding fragment of fibronectin. Erythroid cells attached specifically to surfaces coated either with the 115-kD cell-binding fragment of fibronectin or with the synthetic peptide- albumin complex. Thus, the erythroid 140-kD protein exhibits several properties in common with those described for the fibronectin receptor of fibroblasts. We propose that loss or modification of this protein at the cell surface is responsible for the loss of cellular adhesion to fibronectin during erythroid differentiation. PMID:2935541

  3. Stress Granules contribute to α-globin homeostasis in differentiating erythroid cells

    PubMed Central

    Ghisolfi, Laura; Dutt, Shilpee; McConkey, Marie E.; Ebert, Benjamin L.; Anderson, Paul

    2012-01-01

    Hemoglobin is the major biosynthetic product of developing erythroid cells. Assembly of hemoglobin requires the balanced production of globin protein and the oxygen-carrying heme moiety. The heme-regulated inhibitor kinase (HRI) participates in this process by phosphorylating eIF2α and inhibiting the translation of globin protein when levels of free heme are limiting. HRI is also activated in erythroid cells subjected to oxidative stress. Phospho-eIF2α-mediated translational repression induces the assembly of stress granules (SG), cytoplasmic foci that harbor untranslated mRNAs and promote the survival of cells subjected to adverse environmental conditions. We have found that differentiating erythroid, but not myelomonocytic or megakaryocytic, murine and human progenitor cells assemble SGs, in vitro and in vivo. Targeted knockdown of HRI or G3BP, a protein required for SG assembly, inhibits spontaneous and arsenite-induced assembly of SGs in erythroid progenitor cells. This is accompanied by reduced globin production and increased apoptosis suggesting that G3BP+ SGs facilitate the survival of developing erythroid cells. PMID:22452989

  4. Inactivation of 3-hydroxybutyrate dehydrogenase 2 delays zebrafish erythroid maturation by conferring premature mitophagy

    PubMed Central

    Davuluri, Gangarao; Song, Ping; Liu, Zhuoming; Wald, David; Sakaguchi, Takuya F.; Devireddy, L.

    2016-01-01

    Mitochondria are the site of iron utilization, wherein imported iron is incorporated into heme or iron–sulfur clusters. Previously, we showed that a cytosolic siderophore, which resembles a bacterial siderophore, facilitates mitochondrial iron import in eukaryotes, including zebrafish. An evolutionarily conserved 3-hydroxy butyrate dehydrogenase, 3-hydroxy butyrate dehydrogenase 2 (Bdh2), catalyzes a rate-limiting step in the biogenesis of the eukaryotic siderophore. We found that inactivation of bdh2 in developing zebrafish embryo results in heme deficiency and delays erythroid maturation. The basis for this erythroid maturation defect is not known. Here we show that bdh2 inactivation results in mitochondrial dysfunction and triggers their degradation by mitophagy. Thus, mitochondria are prematurely lost in bdh2-inactivated erythrocytes. Interestingly, bdh2-inactivated erythroid cells also exhibit genomic alterations as indicated by transcriptome analysis. Reestablishment of bdh2 restores mitochondrial function, prevents premature mitochondrial degradation, promotes erythroid development, and reverses altered gene expression. Thus, mitochondrial communication with the nucleus is critical for erythroid development. PMID:26929344

  5. Identification of CD13+CD36+ cells as a common progenitor for erythroid and myeloid lineages in human bone marrow

    PubMed Central

    Chen, Ling; Gao, Zhigang; Zhu, Jianqiong; Rodgers, Griffin P.

    2008-01-01

    Objective To identify bi-potential precursor cells of erythroid and myeloid development in human bone marrow. Materials and Methods Cells co-expressing CD13 and CD36 (CD13+CD36+) were investigated by analyzing cell surface marker expression during erythroid development (induced with a combination of cytokines plus erythropoietin [EPO]), or myeloid development (induced with the same cocktail of cytokines plus granulocyte-colony stimulating factor [G-CSF]) of bone marrow derived CD133 cells in liquid cultures. CD13+CD36+ subsets were also isolated on the 14th day of cultures and further evaluated for their hematopoietic clonogenic capacity in methylcellulose. Results Colony-forming analysis of sorted CD13+CD36+ cells of committed erythroid and myeloid lineages demonstrated that these cells were able to generate erythroid, granulocyte, and mixed erythroid –granulocyte colonies. In contrast, CD13+CD36− or CD13−CD36+ cells exclusively committed to granulocyte/monocyte or erythroid colonies, respectively, but failed to form mixed erythroid –granulocyte colonies; no colonies were detected in CD13−CD36− cells with lineage-supporting cytokines. In addition, our data confirmed that EPO induced both erythroid and myeloid commitment, while G-CSF only supported the differentiation of the myeloid lineage. Conclusions The present data identify some CD13+CD36+ cells as bi-potential precursors of erythroid and myeloid commitment in normal hematopoiesis. They provide a physiological explanation for the cell identification of myeloid and erythroid lineages observed in hematopoietic diseases. This unique fraction of CD13+CD36+ cells may be useful for further studies on regulating erythroid and myeloid differentiation during normal and malignant hematopoiesis. PMID:17588473

  6. Non-random subcellular distribution of variant EKLF in erythroid cells

    PubMed Central

    Quadrini, Karen J.; Gruzglin, Eugenia; Bieker, James J.

    2008-01-01

    EKLF protein plays a prominent role during erythroid development as a nuclear transcription factor. Not surprisingly, exogenous EKLF quickly localizes to the nucleus. However, using two different assays we have unexpectedly found that a substantial proportion of endogenous EKLF resides in the cytoplasm at steady state in all erythroid cells examined. While EKLF localization does not appear to change during either erythroid development or terminal differentiation, we find that the protein displays subtle yet distinct biochemical and functional differences depending on which subcellular compartment it is isolated from, with PEST sequences possibly playing a role in these differences. Localization is unaffected by inhibition of CRM1 activity and the two populations are not differentiated by stability. Heterokaryon assays demonstrate that EKLF is able to shuttle out of the nucleus although its nuclear re-entry is rapid. These studies suggest there is an unexplored role for EKLF in the cytoplasm that is separate from its well-characterized nuclear function. PMID:18329016

  7. A Chemical Screening Approach to Identify Novel Key Mediators of Erythroid Enucleation

    PubMed Central

    Wölwer, Christina B.; Pase, Luke B.; Pearson, Helen B.; Gödde, Nathan J.; Lackovic, Kurt; Huang, David C. S.; Russell, Sarah M.; Humbert, Patrick O.

    2015-01-01

    Erythroid enucleation is critical for terminal differentiation of red blood cells, and involves extrusion of the nucleus by orthochromatic erythroblasts to produce reticulocytes. Due to the difficulty of synchronizing erythroblasts, the molecular mechanisms underlying the enucleation process remain poorly understood. To elucidate the cellular program governing enucleation, we utilized a novel chemical screening approach whereby orthochromatic cells primed for enucleation were enriched ex vivo and subjected to a functional drug screen using a 324 compound library consisting of structurally diverse, medicinally active and cell permeable drugs. Using this approach, we have confirmed the role of HDACs, proteasomal regulators and MAPK in erythroid enucleation and introduce a new role for Cyclin-dependent kinases, in particular CDK9, in this process. Importantly, we demonstrate that when coupled with imaging analysis, this approach provides a powerful means to identify and characterize rate limiting steps involved in the erythroid enucleation process. PMID:26569102

  8. Non-random subcellular distribution of variant EKLF in erythroid cells

    SciTech Connect

    Quadrini, Karen J.; Gruzglin, Eugenia; Bieker, James J.

    2008-04-15

    EKLF protein plays a prominent role during erythroid development as a nuclear transcription factor. Not surprisingly, exogenous EKLF quickly localizes to the nucleus. However, using two different assays we have unexpectedly found that a substantial proportion of endogenous EKLF resides in the cytoplasm at steady state in all erythroid cells examined. While EKLF localization does not appear to change during either erythroid development or terminal differentiation, we find that the protein displays subtle yet distinct biochemical and functional differences depending on which subcellular compartment it is isolated from, with PEST sequences possibly playing a role in these differences. Localization is unaffected by inhibition of CRM1 activity and the two populations are not differentiated by stability. Heterokaryon assays demonstrate that EKLF is able to shuttle out of the nucleus although its nuclear re-entry is rapid. These studies suggest there is an unexplored role for EKLF in the cytoplasm that is separate from its well-characterized nuclear function.

  9. The VP1u Receptor Restricts Parvovirus B19 Uptake to Permissive Erythroid Cells

    PubMed Central

    Leisi, Remo; Von Nordheim, Marcus; Ros, Carlos; Kempf, Christoph

    2016-01-01

    Parvovirus B19 (B19V) is a small non-enveloped virus and known as the causative agent for the mild childhood disease erythema infectiosum. B19V has an extraordinary narrow tissue tropism, showing only productive infection in erythroid precursor cells in the bone marrow. We recently found that the viral protein 1 unique region (VP1u) contains an N-terminal receptor-binding domain (RBD), which mediates the uptake of the virus into cells of the erythroid lineage. To further investigate the role of the RBD in connection with a B19V-unrelated capsid, we chemically coupled the VP1u of B19V to the bacteriophage MS2 capsid and tested the internalization capacity of the bioconjugate on permissive cells. In comparison, we studied the cellular uptake and infection of B19V along the erythroid differentiation. The results showed that the MS2-VP1u bioconjugate mimicked the specific internalization of the native B19V into erythroid precursor cells, which further coincides with the restricted infection profile. The successful mimicry of B19V uptake demonstrates that the RBD in the VP1u is sufficient for the endocytosis of the viral capsid. Furthermore, the recombinant VP1u competed with B19V uptake into permissive cells, thus excluding a significant alternative uptake mechanism by other receptors. Strikingly, the VP1u receptor appeared to be expressed only on erythropoietin-dependent erythroid differentiation stages that also provide the necessary intracellular factors for a productive infection. Taken together, these findings suggest that the VP1u binds to a yet-unknown erythroid-specific cellular receptor and thus restricts the virus entry to permissive cells. PMID:27690083

  10. Upstream Distal Regulatory Elements Contact the Lmo2 Promoter in Mouse Erythroid Cells

    PubMed Central

    Bhattacharya, Anandi; Chen, Chih-Yu; Ho, Sara; Mitchell, Jennifer A.

    2012-01-01

    The Lim domain only 2 (Lmo2) gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Several distal regulatory elements have been identified upstream of the Lmo2 gene in the human and mouse genomes that are capable of enhancing reporter gene expression in erythroid cells and may be responsible for the high level transcription of Lmo2 in the erythroid lineage. In this study we investigate how these elements regulate transcription of Lmo2 and whether or not they function cooperatively in the endogenous context. Chromosome conformation capture (3C) experiments show that chromatin-chromatin interactions exist between upstream regulatory elements and the Lmo2 promoter in erythroid cells but that these interactions are absent from kidney where Lmo2 is transcribed at twelve fold lower levels. Specifically, long range chromatin-chromatin interactions occur between the Lmo2 proximal promoter and two broad regions, 3–31 and 66–105 kb upstream of Lmo2, which we term the proximal and distal control regions for Lmo2 (pCR and dCR respectively). Each of these regions is bound by several transcription factors suggesting that multiple regulatory elements cooperate in regulating high level transcription of Lmo2 in erythroid cells. Binding of CTCF and cohesin which support chromatin loops at other loci were also found within the dCR and at the Lmo2 proximal promoter. Intergenic transcription occurs throughout the dCR in erythroid cells but not in kidney suggesting a role for these intergenic transcripts in regulating Lmo2, similar to the broad domain of intergenic transcription observed at the human β-globin locus control region. Our data supports a model in which the dCR functions through a chromatin looping mechanism to contact and enhance Lmo2 transcription specifically in erythroid cells. Furthermore, these chromatin loops are supported by the cohesin complex recruited to both CTCF and transcription factor bound regions. PMID

  11. Stimulated stromal cells induce gamma-globin gene expression in erythroid cells via nitric oxide production

    PubMed Central

    Čokić, Vladan P.; Beleslin-Čokić, Bojana B.; Smith, Reginald D.; Economou, Antaeus P.; Wahl, Larry M.; Noguchi, Constance T.; Schechter, Alan N.

    2009-01-01

    Objective We have previously shown that nitric oxide (NO) is involved in the hydroxyurea-induced increase of gamma-globin gene expression in cultured human erythroid progenitor cells and that hydroxyurea increases NO production in endothelial cells via endothelial NO synthase (NOS). We have now expanded those studies to demonstrate that the stimulation of gamma-globin gene expression is also mediated by NOS induction in stromal cells within the bone marrow microenvironment. Materials and Methods Using NO analyzer, we measured NO production in endothelial and macrophage cell cultures. In co-culture studies of erythroid and stromal cells we measured globin gene expression during stimulation by NO inducers. Results Hydroxyurea (30–100 μM) induced NOS-dependent production of NO in human macrophages (up to 1.2 μM). Co-culture studies of human macrophages with erythroid progenitor cells also resulted in induction of gamma-globin mRNA expression (up to 3 fold) in the presence of hydroxyurea. NOS-dependent stimulation of NO by lipopolysaccharide (up to 0.6 μM) has been observed in human macrophages. We found that lipopolysaccharide and interferon-gamma together increased gamma-globin gene expression (up to 2 fold) in human macrophage/erythroid cell co-cultures. Co-culture of human bone marrow endothelial cells with erythroid progenitor cells also induced gamma-globin mRNA expression (2.4 fold) in the presence of hydroxyurea (40 μM). Conclusion These results demonstrate an arrangement by which NO and fetal hemoglobin inducers may stimulate globin genes in erythroid cells via the common paracrine effect of bone marrow stromal cells. PMID:19576950

  12. Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor.

    PubMed Central

    Blobel, G A; Sieff, C A; Orkin, S H

    1995-01-01

    High-dose estrogen administration induces anemia in mammals. In chickens, estrogens stimulate outgrowth of bone marrow-derived erythroid progenitor cells and delay their maturation. This delay is associated with down-regulation of many erythroid cell-specific genes, including alpha- and beta-globin, band 3, band 4.1, and the erythroid cell-specific histone H5. We show here that estrogens also reduce the number of erythroid progenitor cells in primary human bone marrow cultures. To address potential mechanisms by which estrogens suppress erythropoiesis, we have examined their effects on GATA-1, an erythroid transcription factor that participates in the regulation of the majority of erythroid cell-specific genes and is necessary for full maturation of erythrocytes. We demonstrate that the transcriptional activity of GATA-1 is strongly repressed by the estrogen receptor (ER) in a ligand-dependent manner and that this repression is reversible in the presence of 4-hydroxytamoxifen. ER-mediated repression of GATA-1 activity occurs on an artificial promoter containing a single GATA-binding site, as well as in the context of an intact promoter which is normally regulated by GATA-1. GATA-1 and ER bind to each other in vitro in the absence of DNA. In coimmunoprecipitation experiments using transfected COS cells, GATA-1 and ER associate in a ligand-dependent manner. Mapping experiments indicate that GATA-1 and the ER form at least two contacts, which involve the finger region and the N-terminal activation domain of GATA-1. We speculate that estrogens exert effects on erythropoiesis by modulating GATA-1 activity through protein-protein interaction with the ER. Interference with GATA-binding proteins may be one mechanism by which steroid hormones modulate cellular differentiation. PMID:7760810

  13. Spatio-temporal optimization of agricultural practices to achieve a sustainable development at basin level; framework of a case study in Colombia

    NASA Astrophysics Data System (ADS)

    Uribe, Natalia; corzo, Gerald; Solomatine, Dimitri

    2016-04-01

    The flood events present during the last years in different basins of the Colombian territory have raised questions on the sensitivity of the regions and if this regions have common features. From previous studies it seems important features in the sensitivity of the flood process were: land cover change, precipitation anomalies and these related to impacts of agriculture management and water management deficiencies, among others. A significant government investment in the outreach activities for adopting and promoting the Colombia National Action Plan on Climate Change (NAPCC) is being carried out in different sectors and regions, having as a priority the agriculture sector. However, more information is still needed in the local environment in order to assess were the regions have this sensitivity. Also the continuous change in one region with seasonal agricultural practices have been pointed out as a critical information for optimal sustainable development. This combined spatio-temporal dynamics of crops cycle in relation to climate change (or variations) has an important impact on flooding events at basin areas. This research will develop on the assessment and optimization of the aggregated impact of flood events due to determinate the spatio-temporal dynamic of changes in agricultural management practices. A number of common best agricultural practices have been identified to explore their effect in a spatial hydrological model that will evaluate overall changes. The optimization process consists on the evaluation of best performance in the agricultural production, without having to change crops activities or move to other regions. To achieve this objectives a deep analysis of different models combined with current and future climate scenarios have been planned. An algorithm have been formulated to cover the parametric updates such that the optimal temporal identification will be evaluated in different region on the case study area. Different hydroinformatics

  14. First-line cART regimen impacts the course of CD8+ T-cell counts in HIV-infected patients that achieve sustained undetectable viral load.

    PubMed Central

    Poizot-Martin, Isabelle; Allavena, Clotilde; Delpierre, Cyrille; Duvivier, Claudine; Obry-Roguet, Véronique; Cano, Carla E.; Guillouet de Salvador, Francine; Rey, David; Dellamonica, Pierre; Cheret, Antoine; Cuzin, Lise; Katlama, Christine; Cabié, André; Hoen, Bruno

    2016-01-01

    Abstract The aim of the study was to investigate the impact of first-line combined antiretroviral therapy (cART) regimen on the course of CD8+ T-cell counts in human immunodeficiency virus (HIV)-infected patients. A retrospective observational study conducted on the French DAT’AIDS Cohort of HIV-infected patients. We selected 605 patients initiating a first-line cART between 2002 and 2009, and which achieved a sustained undetectable HIV plasma viral load (pVL) for at least 12 months without cART modification. The evolution of CD8+ T-cell counts according to cART regimen was assessed. CD8+ T-cell counts were assessed in 572 patients treated with 2NRTIs+1PI/r (n= 297), 2NRTIs+1NNRTI (n= 207) and 3NRTIs (n= 68). In multivariate analysis, after 12 months of follow-up, the 3NRTIs regimen was associated with a significantly smaller decrease of CD8+ T-cell count compared with NNRTI-containing regimens (–10.2 cells/μL in 3NRTIs vs –105.1 cells/μL; P=0.02) but not compared with PI-containing regimens (10.2 vs –60.9 cells/μL; P=0.21). After 24 months, the 3NRTIs regimen was associated with a smaller decrease of CD8+ T-cell count and % compared with PI/r- and NNRTI-containing regimens (0.2 in 3NRTIs vs –9.9 with PI/r-regimens, P=0.001, and vs –11.1 with NNRTI-regimens, p < 0.0001). A focus analysis on 11 patients treated with an INSTI-containing cART regimen during the study period showed after 12 months of follow-up, a median decrease of CD8+ T-cell count of –155 [inter quartile range: –302; –22] cells/μL. Our data highlight the fact that cART regimens have differential effects on CD8 pool down regulation. PMID:27741125

  15. Dysplastic changes in erythroid precursors as a manifestation of lead poisoning: report of a case and review of literature.

    PubMed

    Lv, Chenglan; Xu, Yueyi; Wang, Jing; Shao, Xiaoyan; Ouyang, Jian; Li, Juan

    2015-01-01

    Dysplastic changes in erythroid precursors occur not only in patients with hematologic diseases, but also those with other diseases. Here, we report on a patient that presented with dysplastic changes in erythroid precursors due to lead poisoning from the intake of Chinese folk remedies.

  16. Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation.

    PubMed

    Li, Ying; Schulz, Vincent P; Deng, Changwang; Li, Guangyao; Shen, Yong; Tusi, Betsabeh K; Ma, Gina; Stees, Jared; Qiu, Yi; Steiner, Laurie A; Zhou, Lei; Zhao, Keji; Bungert, Jörg; Gallagher, Patrick G; Huang, Suming

    2016-09-01

    The modulation of chromatin structure is a key step in transcription regulation in mammalian cells and eventually determines lineage commitment and differentiation. USF1/2, Setd1a and NURF complexes interact to regulate chromatin architecture in erythropoiesis, but the mechanistic basis for this regulation is hitherto unknown. Here we showed that Setd1a and NURF complexes bind to promoters to control chromatin structural alterations and gene activation in a cell context dependent manner. In human primary erythroid cells USF1/2, H3K4me3 and the NURF complex were significantly co-enriched at transcription start sites of erythroid genes, and their binding was associated with promoter/enhancer accessibility that resulted from nucleosome repositioning. Mice deficient for Setd1a, an H3K4 trimethylase, in the erythroid compartment exhibited reduced Ter119/CD71 positive erythroblasts, peripheral blood RBCs and hemoglobin levels. Loss of Setd1a led to a reduction of promoter-associated H3K4 methylation, inhibition of gene transcription and blockade of erythroid differentiation. This was associated with alterations in NURF complex occupancy at erythroid gene promoters and reduced chromatin accessibility. Setd1a deficiency caused decreased associations between enhancer and promoter looped interactions as well as reduced expression of erythroid genes such as the adult β-globin gene. These data indicate that Setd1a and NURF complexes are specifically targeted to and coordinately regulate erythroid promoter chromatin dynamics during erythroid lineage differentiation. PMID:27141965

  17. Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation

    PubMed Central

    Li, Ying; Schulz, Vincent P.; Deng, Changwang; Li, Guangyao; Shen, Yong; Tusi, Betsabeh K.; Ma, Gina; Stees, Jared; Qiu, Yi; Steiner, Laurie A.; Zhou, Lei; Zhao, Keji; Bungert, Jörg; Gallagher, Patrick G.; Huang, Suming

    2016-01-01

    The modulation of chromatin structure is a key step in transcription regulation in mammalian cells and eventually determines lineage commitment and differentiation. USF1/2, Setd1a and NURF complexes interact to regulate chromatin architecture in erythropoiesis, but the mechanistic basis for this regulation is hitherto unknown. Here we showed that Setd1a and NURF complexes bind to promoters to control chromatin structural alterations and gene activation in a cell context dependent manner. In human primary erythroid cells USF1/2, H3K4me3 and the NURF complex were significantly co-enriched at transcription start sites of erythroid genes, and their binding was associated with promoter/enhancer accessibility that resulted from nucleosome repositioning. Mice deficient for Setd1a, an H3K4 trimethylase, in the erythroid compartment exhibited reduced Ter119/CD71 positive erythroblasts, peripheral blood RBCs and hemoglobin levels. Loss of Setd1a led to a reduction of promoter-associated H3K4 methylation, inhibition of gene transcription and blockade of erythroid differentiation. This was associated with alterations in NURF complex occupancy at erythroid gene promoters and reduced chromatin accessibility. Setd1a deficiency caused decreased associations between enhancer and promoter looped interactions as well as reduced expression of erythroid genes such as the adult β-globin gene. These data indicate that Setd1a and NURF complexes are specifically targeted to and coordinately regulate erythroid promoter chromatin dynamics during erythroid lineage differentiation. PMID:27141965

  18. Dysplastic changes in erythroid precursors as a manifestation of lead poisoning: report of a case and review of literature

    PubMed Central

    Lv, Chenglan; Xu, Yueyi; Wang, Jing; Shao, Xiaoyan; Ouyang, Jian; Li, Juan

    2015-01-01

    Dysplastic changes in erythroid precursors occur not only in patients with hematologic diseases, but also those with other diseases. Here, we report on a patient that presented with dysplastic changes in erythroid precursors due to lead poisoning from the intake of Chinese folk remedies. PMID:25755780

  19. Direct demonstration of the human parvovirus in erythroid progenitor cells infected in vitro.

    PubMed Central

    Young, N; Harrison, M; Moore, J; Mortimer, P; Humphries, R K

    1984-01-01

    The human parvovirus (HPV), the cause of transient aplastic crisis of hereditary hemolytic anemia, has been shown to be cytotoxic for erythroid progenitor cells and its presence in these cells demonstrated by morphologic techniques. A relatively pure population of progenitors, isolated by removal of immature erythroid bursts from primary culture, was the target of the virus infection. Infected cells failed to proliferate in secondary culture. Using a monoclonal antibody to HPV, specific fluorescence was demonstrated in a minority of cells 24-48 h after infection with virus. Infected cells examined by electron microscopy showed marked toxic ultrastructural alterations and parvovirus-like particles in crystalline arrays in the nucleus. Images PMID:6392340

  20. Challenges facing the elimination of sleeping sickness in west and central Africa: sustainable control of animal trypanosomiasis as an indispensable approach to achieve the goal.

    PubMed

    Simo, Gustave; Rayaisse, Jean Baptiste

    2015-12-16

    African trypanosomiases are infectious diseases caused by trypanosomes. African animal trypanosomiasis (AAT) remains an important threat for livestock production in some affected areas whereas human African trypanosomiasis (HAT) is targeted for elimination in 2020. In West and Central Africa, it has been shown that the parasites causing these diseases can coexist in the same tsetse fly or the same animal. In such complex settings, the control of these diseases must be put in the general context of trypanosomiasis control or "one health" concept where the coordination of control operations will be beneficial for both diseases. In this context, implementing control activities on AAT will help to sustain HAT control. It will also have a positive impact on animal health and economic development of the regions. The training of inhabitants on how to implement and sustain vector control tools will enable a long-term sustainability of control operations that will lead to the elimination of HAT and AAT.

  1. Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders.

    PubMed

    Wakabayashi, Aoi; Ulirsch, Jacob C; Ludwig, Leif S; Fiorini, Claudia; Yasuda, Makiko; Choudhuri, Avik; McDonel, Patrick; Zon, Leonard I; Sankaran, Vijay G

    2016-04-19

    Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptionalcis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders.

  2. Erythropoietin-independent regeneration of erythroid progenitor cells following multiple injections of hydroxyurea.

    PubMed

    Wagemaker, G; Visser, T P

    1980-09-01

    It wa shown previously that colony formation in vitro by early erythroid progenitor cells (BFUe) requires sequential stimulation with a specific glycoprotein termed BFA and erythropoietin (EP). The action exerted by BFA was characterized as induction of proliferation in BFUe resulting after several cell divisions in EP-responsive progeny. The present study is directed at detection of EP-independent regulation of erythroid progenitor cells in vivo. Haemopoietic regeneration was induced by multiple administrations of hydroxyurea (HU). The femoral regeneration patterns of haemopoietic stem cells (CFUs), granulocyte/macrophage progenitor cells (CFUgm) and erythroid progenitor cells (BFUe, day 3 BFUe and CFUe) were studied in hypertransfused mice in comparison to nontransfused controls. The results show that (1) the phase of exponential regeneration of none of the cell populations studied is affected by hypertransfusion; (2) each of these cell populations exhibit a distinct regeneration pattern, indicating that they behave as separate functional entities; and (3) the three erythroid cell populations are suppressed by hypertransfusion in the post-exponential phase of regeneration in contrast to CFUs and CFUgm. The results support a two-regulator model of erythropoiesis. PMID:7459981

  3. Establishment of Immortalized Human Erythroid Progenitor Cell Lines Able to Produce Enucleated Red Blood Cells

    PubMed Central

    Kurita, Ryo; Suda, Noriko; Sudo, Kazuhiro; Miharada, Kenichi; Hiroyama, Takashi; Miyoshi, Hiroyuki; Tani, Kenzaburo; Nakamura, Yukio

    2013-01-01

    Transfusion of red blood cells (RBCs) is a standard and indispensable therapy in current clinical practice. In vitro production of RBCs offers a potential means to overcome a shortage of transfusable RBCs in some clinical situations and also to provide a source of cells free from possible infection or contamination by microorganisms. Thus, in vitro production of RBCs may become a standard procedure in the future. We previously reported the successful establishment of immortalized mouse erythroid progenitor cell lines that were able to produce mature RBCs very efficiently. Here, we have developed a reliable protocol for establishing immortalized human erythroid progenitor cell lines that are able to produce enucleated RBCs. These immortalized cell lines produce functional hemoglobin and express erythroid-specific markers, and these markers are upregulated following induction of differentiation in vitro. Most importantly, these immortalized cell lines all produce enucleated RBCs after induction of differentiation in vitro, although the efficiency of producing enucleated RBCs remains to be improved further. To the best of our knowledge, this is the first demonstration of the feasibility of using immortalized human erythroid progenitor cell lines as an ex vivo source for production of enucleated RBCs. PMID:23533656

  4. Imaging Flow Cytometry for the Study of Erythroid Cell Biology and Pathology

    PubMed Central

    Samsel, Leigh; McCoy, J Philip

    2015-01-01

    Erythroid cell maturation and diseases affecting erythrocytes are frequently accompanied by morphologic and immunophenotypic changes to these cells. In the past, these changes have been assessed primarily through the use of manual microscopy, which substantially limits the statistical rigor, throughput, and objectivity of these studies. Imaging flow cytometry provides a technology to examine both the morphology of cells as well as to quantify the staining intensity and signal distribution of numerous fluorescent markers on a cell-by-cell basis with high throughput in a statistically robust manner, and thus is ideally suited to studying erythroid cell biology. To date imaging flow cytometry has been used to study erythrocytes in three areas: 1) erythroid cell maturation, 2) sickle cell disease, and 3) infectious diseases such as malaria. In the maturation studies, imaging flow cytometry can closely recapitulate known stages of maturation and has led to the identification of a new population of erythroid cell precursors. In sickle cell disease, imaging flow cytometry provides a robust method to quantify sickled erythrocytes and to identify cellular aggregates linked to morbidities, and in malaria, imaging flow cytometry has been used to screen for new chemotherapeutic agents. These studies have demonstrated the value of imaging flow cytometry for investigations of erythrocyte biology and pathology. PMID:25858229

  5. Histones to the cytosol: exportin 7 is essential for normal terminal erythroid nuclear maturation.

    PubMed

    Hattangadi, Shilpa M; Martinez-Morilla, Sandra; Patterson, Heide Christine; Shi, Jiahai; Burke, Karly; Avila-Figueroa, Amalia; Venkatesan, Srividhya; Wang, Junxia; Paulsen, Katharina; Görlich, Dirk; Murata-Hori, Maki; Lodish, Harvey F

    2014-09-18

    Global nuclear condensation, culminating in enucleation during terminal erythropoiesis, is poorly understood. Proteomic examination of extruded erythroid nuclei from fetal liver revealed a striking depletion of most nuclear proteins, suggesting that nuclear protein export had occurred. Expression of the nuclear export protein, Exportin 7 (Xpo7), is highly erythroid-specific, induced during erythropoiesis, and abundant in very late erythroblasts. Knockdown of Xpo7 in primary mouse fetal liver erythroblasts resulted in severe inhibition of chromatin condensation and enucleation but otherwise had little effect on erythroid differentiation, including hemoglobin accumulation. Nuclei in Xpo7-knockdown cells were larger and less dense than normal and accumulated most nuclear proteins as measured by mass spectrometry. Strikingly,many DNA binding proteins such as histones H2A and H3 were found to have migrated into the cytoplasm of normal late erythroblasts prior to and during enucleation, but not in Xpo7-knockdown cells. Thus, terminal erythroid maturation involves migration of histones into the cytoplasm via a process likely facilitated by Xpo7.

  6. Homeodomain-interacting protein kinase 2 plays an important role in normal terminal erythroid differentiation.

    PubMed

    Hattangadi, Shilpa M; Burke, Karly A; Lodish, Harvey F

    2010-06-10

    Gene-targeting experiments report that the homeodomain-interacting protein kinases 1 and 2, Hipk1 and Hipk2, are essential but redundant in hematopoietic development because Hipk1/Hipk2 double-deficient animals exhibit severe defects in hematopoiesis and vasculogenesis, whereas the single knockouts do not. These serine-threonine kinases phosphorylate and consequently modify the functions of several important hematopoietic transcription factors and cofactors. Here we show that Hipk2 knockdown alone plays a significant role in terminal fetal liver erythroid differentiation. Hipk1 and Hipk2 are highly induced during primary mouse fetal liver erythropoiesis. Specific knockdown of Hipk2 inhibits terminal erythroid cell proliferation (explained in part by impaired cell-cycle progression as well as increased apoptosis) and terminal enucleation as well as the accumulation of hemoglobin. Hipk2 knockdown also reduces the transcription of many genes involved in proliferation and apoptosis as well as important, erythroid-specific genes involved in hemoglobin biosynthesis, such as alpha-globin and mitoferrin 1, demonstrating that Hipk2 plays an important role in some but not all aspects of normal terminal erythroid differentiation.

  7. Histones to the cytosol: exportin 7 is essential for normal terminal erythroid nuclear maturation

    PubMed Central

    Martinez-Morilla, Sandra; Patterson, Heide Christine; Shi, Jiahai; Burke, Karly; Avila-Figueroa, Amalia; Venkatesan, Srividhya; Wang, Junxia; Paulsen, Katharina; Görlich, Dirk; Murata-Hori, Maki; Lodish, Harvey F.

    2014-01-01

    Global nuclear condensation, culminating in enucleation during terminal erythropoiesis, is poorly understood. Proteomic examination of extruded erythroid nuclei from fetal liver revealed a striking depletion of most nuclear proteins, suggesting that nuclear protein export had occurred. Expression of the nuclear export protein, Exportin 7 (Xpo7), is highly erythroid-specific, induced during erythropoiesis, and abundant in very late erythroblasts. Knockdown of Xpo7 in primary mouse fetal liver erythroblasts resulted in severe inhibition of chromatin condensation and enucleation but otherwise had little effect on erythroid differentiation, including hemoglobin accumulation. Nuclei in Xpo7-knockdown cells were larger and less dense than normal and accumulated most nuclear proteins as measured by mass spectrometry. Strikingly, many DNA binding proteins such as histones H2A and H3 were found to have migrated into the cytoplasm of normal late erythroblasts prior to and during enucleation, but not in Xpo7-knockdown cells. Thus, terminal erythroid maturation involves migration of histones into the cytoplasm via a process likely facilitated by Xpo7. PMID:25092175

  8. Hepatocyte growth factor induces proliferation and differentiation of multipotent and erythroid hemopoietic progenitors

    PubMed Central

    1994-01-01

    Hepatocyte growth factor (HGF) is a mesenchymal derived growth factor known to induce proliferation and "scattering" of epithelial and endothelial cells. Its receptor is the tyrosine kinase encoded by the c- MET protooncogene. Here we show that highly purified recombinant HGF stimulates hemopoietic progenitors to form colonies in vitro. In the presence of erythropoietin, picomolar concentrations of HGF induced the formation of erythroid burst-forming unit colonies from CD34-positive cells purified from human bone marrow, peripheral blood, or umbilical cord blood. The growth stimulatory activity was restricted to the erythroid lineage. HGF also stimulated the formation of multipotent CFU- GEMM colonies. This effect is synergized by stem cell factor, the ligand of the tyrosine kinase receptor encoded by the c-KIT protooncogene, which is active on early hemopoietic progenitors. By flow cytometry analysis, the receptor for HGF was found to be expressed on the cell surface in a fraction of CD34+ progenitors. Moreover, in situ hybridization experiments showed that HGF receptor mRNA is highly expressed in embryonic erythroid cells (megaloblasts). HGF mRNA was also found to be produced in the embryonal liver. These data show that HGF plays a direct role in the control of proliferation and differentiation of erythroid progenitors, and they suggest that it may be one of the long-sought mediators of paracrine interactions between stromal and hemopoietic cells within the hemopoietic microenvironment. PMID:7528222

  9. Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders.

    PubMed

    Wakabayashi, Aoi; Ulirsch, Jacob C; Ludwig, Leif S; Fiorini, Claudia; Yasuda, Makiko; Choudhuri, Avik; McDonel, Patrick; Zon, Leonard I; Sankaran, Vijay G

    2016-04-19

    Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptionalcis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders. PMID:27044088

  10. Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus

    PubMed Central

    Byrska-Bishop, Marta; VanDorn, Daniel; Campbell, Amy E.; Betensky, Marisol; Arca, Philip R.; Yao, Yu; Gadue, Paul; Costa, Fernando F.; Nemiroff, Richard L.; Blobel, Gerd A.; French, Deborah L.; Hardison, Ross C.; Weiss, Mitchell J.; Chou, Stella T.

    2015-01-01

    Germline GATA1 mutations that result in the production of an amino-truncated protein termed GATA1s (where s indicates short) cause congenital hypoplastic anemia. In patients with trisomy 21, similar somatic GATA1s-producing mutations promote transient myeloproliferative disease and acute megakaryoblastic leukemia. Here, we demonstrate that induced pluripotent stem cells (iPSCs) from patients with GATA1-truncating mutations exhibit impaired erythroid potential, but enhanced megakaryopoiesis and myelopoiesis, recapitulating the major phenotypes of the associated diseases. Similarly, in developmentally arrested GATA1-deficient murine megakaryocyte-erythroid progenitors derived from murine embryonic stem cells (ESCs), expression of GATA1s promoted megakaryopoiesis, but not erythropoiesis. Transcriptome analysis revealed a selective deficiency in the ability of GATA1s to activate erythroid-specific genes within populations of hematopoietic progenitors. Although its DNA-binding domain was intact, chromatin immunoprecipitation studies showed that GATA1s binding at specific erythroid regulatory regions was impaired, while binding at many nonerythroid sites, including megakaryocytic and myeloid target genes, was normal. Together, these observations indicate that lineage-specific GATA1 cofactor associations are essential for normal chromatin occupancy and provide mechanistic insights into how GATA1s mutations cause human disease. More broadly, our studies underscore the value of ESCs and iPSCs to recapitulate and study disease phenotypes. PMID:25621499

  11. Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

    PubMed Central

    Wakabayashi, Aoi; Ulirsch, Jacob C.; Ludwig, Leif S.; Fiorini, Claudia; Yasuda, Makiko; Choudhuri, Avik; McDonel, Patrick; Zon, Leonard I.; Sankaran, Vijay G.

    2016-01-01

    Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders. PMID:27044088

  12. Probing Conformational Stability and Dynamics of Erythroid and Nonerythroid Spectrin: Effects of Urea and Guanidine Hydrochloride

    PubMed Central

    Patra, Malay; Mukhopadhyay, Chaitali; Chakrabarti, Abhijit

    2015-01-01

    We have studied the conformational stability of the two homologous membrane skeletal proteins, the erythroid and non-erythroid spectrins, in their dimeric and tetrameric forms respectively during unfolding in the presence of urea and guanidine hydrochloride (GuHCl). Fluorescence and circular dichroism (CD) spectroscopy have been used to study the changes of intrinsic tryptophan fluorescence, anisotropy, far UV-CD and extrinsic fluorescence of bound 1-anilinonapthalene-8-sulfonic acid (ANS). Chemical unfolding of both proteins were reversible and could be described as a two state transition. The folded erythroid spectrin and non-erythroid spectrin were directly converted to unfolded monomer without formation of any intermediate. Fluorescence quenching, anisotropy, ANS binding and dynamic light scattering data suggest that in presence of low concentrations of the denaturants (up-to 1M) hydrogen bonding network and van der Waals interaction play a role inducing changes in quaternary as well as tertiary structures without complete dissociation of the subunits. This is the first report of two large worm like, multi-domain proteins obeying twofold rule which is commonly found in small globular proteins. The free energy of stabilization (ΔGuH20) for the dimeric spectrin has been 20 kcal/mol lesser than the tetrameric from. PMID:25617632

  13. Mito-protective autophagy is impaired in erythroid cells of aged mtDNA-mutator mice.

    PubMed

    Li-Harms, XiuJie; Milasta, Sandra; Lynch, John; Wright, Christopher; Joshi, Aashish; Iyengar, Rekha; Neale, Geoffrey; Wang, Xi; Wang, Yong-Dong; Prolla, Tomas A; Thompson, James E; Opferman, Joseph T; Green, Douglas R; Schuetz, John; Kundu, Mondira

    2015-01-01

    Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocytic anemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome-mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wild-type and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease.

  14. Eafs Control Erythroid Cell Fate by Regulating c-myb Expression through Wnt Signaling

    PubMed Central

    Ma, Xufa; Liu, Jing-Xia

    2013-01-01

    ELL associated factor 1 and ELL associated factor 2 (EAF1/2 factors) are reported to play important roles in tumor suppression and embryogenesis. Our previous studies showed that eaf factors mediated effective convergence and extension (C&E) movements and modulated mesoderm and neural patterning by regulating both non-canonical and canonical Wnt signaling in the early embryonic process. In this study, through knockdown of both eaf1 and eaf2 in embryos, we found that differentiation of primary erythroid cells was blocked, but hematopoietic precursor cells maintained in eafs morphants. Co-injection of c-myb-MO rescued the erythroid differentiation in eafs morphants, as indicated by the restored expression of the erythroid-specific gene, βe3 globin. In addition, low dosage of c-myb effectively blocked the βe3 globin expression in embryos, and did not affect the expression of markers of hematopoietic progenitor cells and other mesoderm, which was similar to the phenotypes we observed in eafs morphants. We also revealed that knockdown Wnt signaling by transiently inducing dn-Tcf in embryos at the bud stage down-regulated the increased c-myb to normal level and also restored βe3 globin expression in eafs morphants. Our evidence points to a novel role for eaf factors in controlling erythroid cell fate by regulating c-Myb expression through canonic Wnt signaling. PMID:23717633

  15. Depletion of glutamine enhances sodium butyrate-induced erythroid differentiation of K562 cells.

    PubMed

    Canh Hiep, Nguyen; Kinohira, Seiko; Furuyama, Kazumichi; Taketani, Shigeru

    2012-12-01

    Human erytholeukemia K562 cells are induced to differentiate along the erythroid lineage by a variety of chemical compounds, including hemin, sodium butyrate and 1-β-d-arabinofuranosylcytosine. We have investigated the induction of erythroid differentiation of K562 cells by glutamine depletion. When K562 cells were cultured in glutamine-minus medium, the induction of hemoglobin synthesis, accompanied by those of heme-biosynthetic enzymes and erythroid transcriptional factors, was observed. This induction was dependent on the temporally marked decrease of intracellular level of glutathione, followed by the marked activation of p38MAPK and SAPK/JNK, but not ERK. Under glutamine-deficient conditions, the treatment of K562 cells with sodium butyrate resulted in the marked enhancement of the induction of heme biosynthesis. Glutamine depletion also accelerated the expressions of erythroid-related factors including α-globin and heme-biosynthetic enzymes, GATA-1 and NF-E2, in sodium butyrate-induced K562 cells. The transcriptional activity of β-globin gene promoter-reporter was markedly enhanced by these treatments, indicating that glutamine deficiency in combination with sodium butyrate treatment gives high efficiency of chemical-induced differentiation in the hematopoiesis process.

  16. Cytoplasmic Poly(A) Binding Protein C4 Serves a Critical Role in Erythroid Differentiation

    PubMed Central

    Kini, Hemant K.; Kong, Jian

    2014-01-01

    The expression of an mRNA is strongly impacted by its 3′ poly(A) tail and associated poly(A)-binding proteins (PABPs). Vertebrates encode six PABP isoforms that vary in abundance, distribution, developmental control, and subcellular localization. Here we demonstrate that the minor PABP isoform PABPC4 is expressed in erythroid cells and impacts the steady-state expression of a subset of erythroid mRNAs. Motif analyses reveal a high-value AU-rich motif in the 3′ untranslated regions (UTRs) of PABPC4-impacted mRNAs. This motif enhances the association of PABPC4 with mRNAs containing critically shortened poly(A) tails. This association may serve to protect a subset of mRNAs from accelerated decay. Finally, we demonstrate that selective depletion of PABPC4 in an erythroblast cell line inhibits terminal erythroid maturation with corresponding alterations in the erythroid gene expression. These observations lead us to conclude that PABPC4 plays an essential role in posttranscriptional control of a major developmental pathway. PMID:24469397

  17. Translational control mediated by hnRNP K links NMHC IIA to erythroid enucleation.

    PubMed

    Naarmann-de Vries, Isabel S; Brendle, Annika; Bähr-Ivacevic, Tomi; Benes, Vladimir; Ostareck, Dirk H; Ostareck-Lederer, Antje

    2016-03-15

    Post-transcriptional regulation is crucial for structural and functional alterations in erythropoiesis. Enucleation of erythroid progenitors precedes reticulocyte release into circulation. In enucleated cells, reticulocyte 15-lipoxygenase (r15-LOX, also known as ALOX15) initiates mitochondria degradation. Regulation of r15-LOX mRNA translation by hnRNP K determines timely r15-LOX synthesis in terminal maturation. K562 cells induced for erythroid maturation recapitulate enucleation and mitochondria degradation. HnRNP K depletion from maturing K562 cells results in enhanced enucleation, which even occurs independently of maturation. We performed RIP-Chip analysis to identify hnRNP K-interacting RNAs comprehensively. Non-muscle myosin heavy chain (NMHC) IIA (also known as MYH9) mRNA co-purified with hnRNP K from non-induced K562 cells, but not from mature cells. NMHC IIA protein increase in erythroid maturation at constant NMHC IIA mRNA levels indicates post-transcriptional regulation. We demonstrate that binding of hnRNP K KH domain 3 to a specific sequence element in the NMHC IIA mRNA 3'UTR mediates translation regulation in vitro Importantly, elevated NMHC IIA expression results in erythroid-maturation-independent enucleation as shown for hnRNP K depletion. Our data provide evidence that hnRNP-K-mediated regulation of NMHC IIA mRNA translation contributes to the control of enucleation in erythropoiesis. PMID:26823606

  18. Ldb1-nucleated transcription complexes function as primary mediators of global erythroid gene activation

    PubMed Central

    Li, LiQi; Freudenberg, Johannes; Cui, Kairong; Dale, Ryan; Song, Sang-Hyun; Dean, Ann; Zhao, Keji

    2013-01-01

    Erythropoiesis is dependent on the lineage-specific transcription factors Gata1, Tal1, and Klf1. Several erythroid genes have been shown to require all 3 factors for their expression, suggesting that they function synergistically; however, there is little direct evidence for widespread cooperation. Gata1 and Tal1 can assemble within higher-order protein complexes (Ldb1 complexes) that include the adapter molecules Lmo2 and Ldb1. Ldb1 proteins are capable of coassociation, and long-range Ldb1-mediated oligomerization of enhancer- and promoter-bound Ldb1 complexes has been shown to be required for β-globin gene expression. In this study, we generated a genomewide map of Ldb1 complex binding sites that revealed widespread binding at erythroid genes and at known erythroid enhancer elements. Ldb1 complex binding sites frequently colocalized with Klf1 binding sites and with consensus binding motifs for other erythroid transcription factors. Transcriptomic analysis demonstrated a strong correlation between Ldb1 complex binding and Ldb1 dependency for gene expression and identified a large cohort of genes coregulated by Ldb1 complexes and Klf1. Together, these results provide a foundation for defining the mechanism and scope of Ldb1 complex activity during erythropoiesis. PMID:23610375

  19. Transgene Insertion in Proximity to thec-myb Gene Disrupts Erythroid-Megakaryocytic Lineage Bifurcation▿

    PubMed Central

    Mukai, Harumi Y.; Motohashi, Hozumi; Ohneda, Osamu; Suzuki, Norio; Nagano, Masumi; Yamamoto, Masayuki

    2006-01-01

    The nuclear proto-oncogene c-myb plays crucial roles in the growth, survival, and differentiation of hematopoietic cells. We established three lines of erythropoietin receptor-transgenic mice and found that one of them exhibited anemia, thrombocythemia, and splenomegaly. These abnormalities were independent of the function of the transgenic erythropoietin receptor and were observed exclusively in mice harboring the transgene homozygously, suggesting transgenic disruption of a certain gene. The transgene was inserted 77 kb upstream of the c-myb gene, and c-Myb expression was markedly decreased in megakaryocyte/erythrocyte lineage-restricted progenitors (MEPs) of the homozygous mutant mice. In the bone marrows and spleens of the mutant mice, numbers of megakaryocytes were increased and numbers of erythroid progenitors were decreased. These abnormalities were reproducible in vitro in a coculture assay of MEPs with OP9 cells but eliminated by the retroviral expression of c-Myb in MEPs. The erythroid/megakaryocytic abnormalities were reconstituted in mice in vivo by transplantation of mutant mouse bone marrow cells. These results demonstrate that the transgene insertion into the c-myb gene far upstream regulatory region affects the gene expression at the stage of MEPs, leading to an imbalance between erythroid and megakaryocytic cells, and suggest that c-Myb is an essential regulator of the erythroid-megakaryocytic lineage bifurcation. PMID:16940183

  20. Effects of THAP11 on Erythroid Differentiation and Megakaryocytic Differentiation of K562 Cells

    PubMed Central

    Kong, Xiang-Zhen; Yin, Rong-Hua; Ning, Hong-Mei; Zheng, Wei-Wei; Dong, Xiao-Ming; Yang, Yang; Xu, Fei-Fei; Li, Jian-Jie; Zhan, Yi-Qun; Yu, Miao; Ge, Chang-Hui; Zhang, Jian-Hong; Chen, Hui; Li, Chang-Yan; Yang, Xiao-Ming

    2014-01-01

    Hematopoiesis is a complex process regulated by sets of transcription factors in a stage-specific and context-dependent manner. THAP11 is a transcription factor involved in cell growth, ES cell pluripotency, and embryogenesis. Here we showed that THAP11 was down-regulated during erythroid differentiation but up-regulated during megakaryocytic differentiation of cord blood CD34+ cells. Overexpression of THAP11 in K562 cells inhibited the erythroid differentiation induced by hemin with decreased numbers of benzidine-positive cells and decreased mRNA levels of α-globin (HBA) and glycophorin A (GPA), and knockdown of THAP11 enhanced the erythroid differentiation. Conversely, THAP11 overexpression accelerated the megakaryocytic differentiation induced by phorbol myristate acetate (PMA) with increased percentage of CD41+ cells, increased numbers of 4N cells, and elevated CD61 mRNA levels, and THAP11 knockdown attenuated the megakaryocytic differentiation. The expression levels of transcription factors such as c-Myc, c-Myb, GATA-2, and Fli1 were changed by THAP11 overexpression. In this way, our results suggested that THAP11 reversibly regulated erythroid and megakaryocytic differentiation. PMID:24637716

  1. RESTORATION PLUS: A COLLABORATIVE ENVIRONMENTAL PROTECTION AGENCY RESEARCH PROGRAM TO DEVELOP AND EVALUATE ECOSYSTEM RESTORATION AND MANAGEMENT OPTIONS TO ACHIEVE ECOLOGICALLY AND ECONOMICALLY SUSTAINABLE SOLUTIONS

    EPA Science Inventory

    The U.S. Environmental Protection Agency (U.S. EPA) is evaluating ecosystem restoration and management techniques to ensure they create sustainable solutions for degraded watersheds. The ORD/NRMRL initiated the Restoration Plus (RePlus) program in 2002, which emphasizes collabora...

  2. RESTORATION PLUS: A COLLABORATIVE RESEARCH PROGRAM TO DEVELOP AND EVALUATE ECOSYSTEM RESTORATION AND MANAGEMENT OPTIONS TO ACHIEVE ECOLOGICALLY AND ECONOMICALLY SUSTAINABLE SOLUTIONS

    EPA Science Inventory

    EPA is evaluating ecosystem restoration and management techniques to ensure they create sustainable solutions for degraded watersheds. ORD NRMRL initiated the Restoration Plus (RePlus) program in 2002 to a) evaluate ecosystem restoration and management options, b) assess the non-...

  3. Selective erythroid replacement in murine beta-thalassemia using fetal hematopoietic stem cells.

    PubMed Central

    Bethel, C. A.; Murugesh, D.; Harrison, M. R.; Mohandas, N.; Rubin, E. M.

    1993-01-01

    We have explored the application of fetal hematopoietic stem cell (HSC) transplants for cellular replacement in a murine model of beta-thalassemia. Liver-derived HSCs from nonthalassemic syngeneic murine fetal donors were transplanted into nonirradiated neonatal beta-thalassemic recipients. Significant erythrocyte chimerism (9-27%) was demonstrated in the majority of recipients at 1 month and remained stable or increased (up to 55%) during long-term follow-up in almost all cases. Chimeras had improved phenotypes, as evidenced by decreased reticulocyte counts, increased mean erythrocyte deformability, and decreased iron deposits in comparison to controls. To investigate whether the high degree of peripheral blood chimerism was predominantly a feature of erythroid elements or was a general feature of all hematopoietic elements, chimeras were created using donor HSCs "tagged" with a DNA transgene. Whereas donor hemoglobin comprised > 30% of total hemoglobin, nucleated tagged nonerythroid donor cells comprised < 1% of peripheral blood elements. Explanations for the observed selective increase in erythroid chimerism include longer survival of normal donor red cells compared to that of thalassemic red cells and the effective maturation of the donor erythroid elements in the bone marrow in chimeric animals. The latter explanation bears consideration because it is consistent with the process of ineffective erythropoiesis, well documented to occur in thalassemia, in which the majority of thalassemic erythroid cells are destroyed during erythropoiesis prior to release from the bone marrow. Overall, these data demonstrate the potential for significant erythroid chimerism and suggest that fetal HSC transplantation may play a significant role in future treatment. Images Fig. 1 Fig. 4 Fig. 7 PMID:7980734

  4. Selective erythroid replacement in murine beta-thalassemia using fetal hematopoietic stem cells.

    PubMed

    Bethel, C A; Murugesh, D; Harrison, M R; Mohandas, N; Rubin, E M

    1993-11-01

    We have explored the application of fetal hematopoietic stem cell (HSC) transplants for cellular replacement in a murine model of beta-thalassemia. Liver-derived HSCs from nonthalassemic syngeneic murine fetal donors were transplanted into nonirradiated neonatal beta-thalassemic recipients. Significant erythrocyte chimerism (9-27%) was demonstrated in the majority of recipients at 1 month and remained stable or increased (up to 55%) during long-term follow-up in almost all cases. Chimeras had improved phenotypes, as evidenced by decreased reticulocyte counts, increased mean erythrocyte deformability, and decreased iron deposits in comparison to controls. To investigate whether the high degree of peripheral blood chimerism was predominantly a feature of erythroid elements or was a general feature of all hematopoietic elements, chimeras were created using donor HSCs "tagged" with a DNA transgene. Whereas donor hemoglobin comprised > 30% of total hemoglobin, nucleated tagged nonerythroid donor cells comprised < 1% of peripheral blood elements. Explanations for the observed selective increase in erythroid chimerism include longer survival of normal donor red cells compared to that of thalassemic red cells and the effective maturation of the donor erythroid elements in the bone marrow in chimeric animals. The latter explanation bears consideration because it is consistent with the process of ineffective erythropoiesis, well documented to occur in thalassemia, in which the majority of thalassemic erythroid cells are destroyed during erythropoiesis prior to release from the bone marrow. Overall, these data demonstrate the potential for significant erythroid chimerism and suggest that fetal HSC transplantation may play a significant role in future treatment.

  5. Erythroid differentiation of human induced pluripotent stem cells is independent of donor cell type of origin

    PubMed Central

    Dorn, Isabel; Klich, Katharina; Arauzo-Bravo, Marcos J.; Radstaak, Martina; Santourlidis, Simeon; Ghanjati, Foued; Radke, Teja F.; Psathaki, Olympia E.; Hargus, Gunnar; Kramer, Jan; Einhaus, Martin; Kim, Jeong Beom; Kögler, Gesine; Wernet, Peter; Schöler, Hans R.; Schlenke, Peter; Zaehres, Holm

    2015-01-01

    Epigenetic memory in induced pluripotent stem cells, which is related to the somatic cell type of origin of the stem cells, might lead to variations in the differentiation capacities of the pluripotent stem cells. In this context, induced pluripotent stem cells from human CD34+ hematopoietic stem cells might be more suitable for hematopoietic differentiation than the commonly used fibroblast-derived induced pluripotent stem cells. To investigate the influence of an epigenetic memory on the ex vivo expansion of induced pluripotent stem cells into erythroid cells, we compared induced pluripotent stem cells from human neural stem cells and human cord blood-derived CD34+ hematopoietic stem cells and evaluated their potential for differentiation into hematopoietic progenitor and mature red blood cells. Although genome-wide DNA methylation profiling at all promoter regions demonstrates that the epigenetic memory of induced pluripotent stem cells is influenced by the somatic cell type of origin of the stem cells, we found a similar hematopoietic induction potential and erythroid differentiation pattern of induced pluripotent stem cells of different somatic cell origin. All human induced pluripotent stem cell lines showed terminal maturation into normoblasts and enucleated reticulocytes, producing predominantly fetal hemoglobin. Differences were only observed in the growth rate of erythroid cells, which was slightly higher in the induced pluripotent stem cells derived from CD34+ hematopoietic stem cells. More detailed methylation analysis of the hematopoietic and erythroid promoters identified similar CpG methylation levels in the induced pluripotent stem cell lines derived from CD34+ cells and those derived from neural stem cells, which confirms their comparable erythroid differentiation potential. PMID:25326431

  6. Narrowing the Achievement Gap and Sustaining Success: A Qualitative Study of the Norms, Practices, and Programs of a Successful High School with Urban Characteristics

    ERIC Educational Resources Information Center

    Senesac, Donald Raymond

    2010-01-01

    The academic achievement gap is the manifestation of differential learning outcomes for students typified by membership in an ethnic minority sub group or economically disadvantaged sub group. Addressing the achievement gap has become vital for the nation as a whole, and even more critical for the state of California because the majority of…

  7. The role of catechol-O-methyltransferase in catechol-enhanced erythroid differentiation of K562 cells

    SciTech Connect

    Suriguga,; Li, Xiao-Fei; Li, Yang; Yu, Chun-Hong; Li, Yi-Ran; Yi, Zong-Chun

    2013-12-15

    Catechol is widely used in pharmaceutical and chemical industries. Catechol is also one of phenolic metabolites of benzene in vivo. Our previous study showed that catechol improved erythroid differentiation potency of K562 cells, which was associated with decreased DNA methylation in erythroid specific genes. Catechol is a substrate for the catechol-O-methyltransferase (COMT)-mediated methylation. In the present study, the role of COMT in catechol-enhanced erythroid differentiation of K562 cells was investigated. Benzidine staining showed that exposure to catechol enhanced hemin-induced hemoglobin accumulation and induced mRNA expression of erythroid specific genes in K562 cells. Treatment with catechol caused a time- and concentration-dependent increase in guaiacol concentration in the medium of cultured K562 cells. When COMT expression was knocked down by COMT shRNA expression in K562 cells, the production of guaiacol significantly reduced, and the sensitivity of K562 cells to cytotoxicity of catechol significantly increased. Knockdown of COMT expression by COMT shRNA expression also eliminated catechol-enhanced erythroid differentiation of K562 cells. In addition, the pre-treatment with methyl donor S-adenosyl-L-methionine or its demethylated product S-adenosyl-L-homocysteine induced a significant increase in hemin-induced Hb synthesis in K562 cells and the mRNA expression of erythroid specific genes. These findings indicated that O-methylation catalyzed by COMT acted as detoxication of catechol and involved in catechol-enhanced erythroid differentiation of K562 cells, and the production of S-adenosyl-L-homocysteine partly explained catechol-enhanced erythroid differentiation. - Highlights: • Catechol enhanced hemin-induced hemoglobin accumulation. • COMT-catalyzed methylation acted as detoxication of catechol. • COMT involved in catechol-enhanced erythroid differentiation.

  8. Sustainable Development

    NASA Astrophysics Data System (ADS)

    Schmandt, Jurgen; Ward, C. H.; Marilu Hastings, Assisted By

    2000-04-01

    Demographers predict that the world population will double during the first half of the 21st century before it will begin to level off. In this volume, a group of prominent authors examine what societal changes must occur to meet this challenge to the natural environment and the transformational changes that we must experience to achieve sustainability. Frances Cairncross, Herman E. Daly, Stephen H. Schneider and others provide a broad discussion of sustainable development. They detail economic and environmental, as well as spiritual and religious, corporate and social, scientific and political factors. Sustainable Development: The Challenge of Transition offers many insightful policy recommendations about how business, government, and individuals must change their current values, priorities, and behavior to meet present and future challenges. It will appeal to scholars and decision makers interested in global change, environmental policy, population growth, and sustainable development, and also to corporate environmental managers.

  9. Three Years Sustained Complete Remission Achieved in a Primary Refractory ALK-Positive Anaplastic T Large Cell Lymphoma Treated with Crizotinib

    PubMed Central

    Mahuad, Carolina Valeria; Repáraz, María de los Ángeles Vicente; Zerga, Marta E.; Aizpurua, María Florencia; Casali, Claudia; Garate, Gonzalo

    2016-01-01

    The prognosis of the primary refractory anaplastic lymphoma kinase (ALK+) anaplastic T large cell lymphoma is ominous. The identification of molecular targets with potential to drive oncogenesis remains a cornerstone for the designing of new selective cancer therapies. Crizotinib is a selective ATP-competitive inhibitor for ALK, approved for its use in lung cancer with rearrangements on ALK gene. The reported cases describe the use of crizotinib as a bridging strategy prior to allotransplantation; there are no reported prolonged survivals under monotherapy with Crizotinib. We report a case of a primary refractory ALK+ anaplastic large-cell lymphoma that sustains complete response after 3 years of crizotinib monotherapy. PMID:27441079

  10. Three Years Sustained Complete Remission Achieved in a Primary Refractory ALK-Positive Anaplastic T Large Cell Lymphoma Treated with Crizotinib.

    PubMed

    Mahuad, Carolina Valeria; Repáraz, María de Los Ángeles Vicente; Zerga, Marta E; Aizpurua, María Florencia; Casali, Claudia; Garate, Gonzalo

    2016-06-28

    The prognosis of the primary refractory anaplastic lymphoma kinase (ALK+) anaplastic T large cell lymphoma is ominous. The identification of molecular targets with potential to drive oncogenesis remains a cornerstone for the designing of new selective cancer therapies. Crizotinib is a selective ATP-competitive inhibitor for ALK, approved for its use in lung cancer with rearrangements on ALK gene. The reported cases describe the use of crizotinib as a bridging strategy prior to allotransplantation; there are no reported prolonged survivals under monotherapy with Crizotinib. We report a case of a primary refractory ALK+ anaplastic large-cell lymphoma that sustains complete response after 3 years of crizotinib monotherapy. PMID:27441079

  11. The role of catechol-O-methyltransferase in catechol-enhanced erythroid differentiation of K562 cells.

    PubMed

    Suriguga; Li, Xiao-Fei; Li, Yang; Yu, Chun-Hong; Li, Yi-Ran; Yi, Zong-Chun

    2013-12-15

    Catechol is widely used in pharmaceutical and chemical industries. Catechol is also one of phenolic metabolites of benzene in vivo. Our previous study showed that catechol improved erythroid differentiation potency of K562 cells, which was associated with decreased DNA methylation in erythroid specific genes. Catechol is a substrate for the catechol-O-methyltransferase (COMT)-mediated methylation. In the present study, the role of COMT in catechol-enhanced erythroid differentiation of K562 cells was investigated. Benzidine staining showed that exposure to catechol enhanced hemin-induced hemoglobin accumulation and induced mRNA expression of erythroid specific genes in K562 cells. Treatment with catechol caused a time- and concentration-dependent increase in guaiacol concentration in the medium of cultured K562 cells. When COMT expression was knocked down by COMT shRNA expression in K562 cells, the production of guaiacol significantly reduced, and the sensitivity of K562 cells to cytotoxicity of catechol significantly increased. Knockdown of COMT expression by COMT shRNA expression also eliminated catechol-enhanced erythroid differentiation of K562 cells. In addition, the pre-treatment with methyl donor S-adenosyl-L-methionine or its demethylated product S-adenosyl-L-homocysteine induced a significant increase in hemin-induced Hb synthesis in K562 cells and the mRNA expression of erythroid specific genes. These findings indicated that O-methylation catalyzed by COMT acted as detoxication of catechol and involved in catechol-enhanced erythroid differentiation of K562 cells, and the production of S-adenosyl-L-homocysteine partly explained catechol-enhanced erythroid differentiation.

  12. The Effects of a Sustained, Job-Embedded Professional Development on Elementary Teachers' Math Teaching Self-Efficacy and the Resulting Effects on Their Students' Achievement

    ERIC Educational Resources Information Center

    Althauser, Krista Louise

    2010-01-01

    This study investigated the impact of a district-wide mathematics professional development program on elementary teachers' general and personal efficacy. It also explored connections among teacher efficacy and socioeconomic status with student achievement. Using a quantitative approach, a job-embedded professional development initiative…

  13. New insights into the mechanisms of mammalian erythroid chromatin condensation and enucleation.

    PubMed

    Ji, Peng

    2015-01-01

    A unique feature in mammalian erythropoiesis is the dramatic chromatin condensation followed by enucleation. This step-by-step process starts at the beginning of terminal erythropoiesis after the hematopoietic stem cells are committed to erythroid lineage. Although this phenomenon is known for decades, the mechanisms of chromatin condensation and enucleation remain elusive. Recent advances in cell and molecular biology have started to reveal the molecular pathways in the regulation of chromatin condensation, the establishment of nuclear polarity prior enucleation, and the rearrangement of actin cytoskeleton in enucleation. However, many challenging questions, especially whether and how the apoptotic mechanisms are involved in chromatin condensation and how to dissect the functions of many actin cytoskeleton proteins in cytokinesis and enucleation, remain to be answered. Here I review our current understanding of mammalian erythroid chromatin condensation and enucleation during terminal differentiation with a focus on more recent studies. I conclude with my perspective of future works in this rising topic in developmental and cell biology.

  14. Dynamic long-range chromatin interactions control Myb proto-oncogene transcription during erythroid development

    PubMed Central

    Stadhouders, Ralph; Thongjuea, Supat; Andrieu-Soler, Charlotte; Palstra, Robert-Jan; Bryne, Jan Christian; van den Heuvel, Anita; Stevens, Mary; de Boer, Ernie; Kockx, Christel; van der Sloot, Antoine; van den Hout, Mirjam; van IJcken, Wilfred; Eick, Dirk; Lenhard, Boris; Grosveld, Frank; Soler, Eric

    2012-01-01

    The key haematopoietic regulator Myb is essential for coordinating proliferation and differentiation. ChIP-Sequencing and Chromosome Conformation Capture (3C)-Sequencing were used to characterize the structural and protein-binding dynamics of the Myb locus during erythroid differentiation. In proliferating cells expressing Myb, enhancers within the Myb-Hbs1l intergenic region were shown to form an active chromatin hub (ACH) containing the Myb promoter and first intron. This first intron was found to harbour the transition site from transcription initiation to elongation, which takes place around a conserved CTCF site. Upon erythroid differentiation, Myb expression is downregulated and the ACH destabilized. We propose a model for Myb activation by distal enhancers dynamically bound by KLF1 and the GATA1/TAL1/LDB1 complex, which primarily function as a transcription elongation element through chromatin looping. PMID:22157820

  15. Dynamic long-range chromatin interactions control Myb proto-oncogene transcription during erythroid development.

    PubMed

    Stadhouders, Ralph; Thongjuea, Supat; Andrieu-Soler, Charlotte; Palstra, Robert-Jan; Bryne, Jan Christian; van den Heuvel, Anita; Stevens, Mary; de Boer, Ernie; Kockx, Christel; van der Sloot, Antoine; van den Hout, Mirjam; van Ijcken, Wilfred; Eick, Dirk; Lenhard, Boris; Grosveld, Frank; Soler, Eric

    2012-02-15

    The key haematopoietic regulator Myb is essential for coordinating proliferation and differentiation. ChIP-Sequencing and Chromosome Conformation Capture (3C)-Sequencing were used to characterize the structural and protein-binding dynamics of the Myb locus during erythroid differentiation. In proliferating cells expressing Myb, enhancers within the Myb-Hbs1l intergenic region were shown to form an active chromatin hub (ACH) containing the Myb promoter and first intron. This first intron was found to harbour the transition site from transcription initiation to elongation, which takes place around a conserved CTCF site. Upon erythroid differentiation, Myb expression is downregulated and the ACH destabilized. We propose a model for Myb activation by distal enhancers dynamically bound by KLF1 and the GATA1/TAL1/LDB1 complex, which primarily function as a transcription elongation element through chromatin looping. PMID:22157820

  16. Structural Insights into the Stability and Flexibility of Unusual Erythroid Spectrin Repeats

    SciTech Connect

    Kusunoki, H.; Macdonald, R.I.; Mondragon, A.

    2010-03-08

    Erythroid spectrin, a major component of the cytoskeletal network of the red cell which contributes to both the stability and the elasticity of the red cell membrane, is composed of two subunits, {alpha} and {beta}, each formed by 16-20 tandem repeats. The properties of the repeats and their relative arrangement are thought to be key determinants of spectrin flexibility. Here we report a 2.4 {angstrom} resolution crystal structure of human erythroid {beta}-spectrin repeats 8 and 9. This two-repeat fragment is unusual as it exhibits low stability of folding and one of its repeats lacks two tryptophans highly conserved among spectrin repeats. Two key factors responsible for the lower stability and, possibly, its flexibility, are revealed by the structure. A third novel feature of the structure is the relative orientation of the two repeats, which increases the range of possible conformations and provides new insights into atomic models of spectrin flexibility.

  17. Strategies to achieve sustainability and quality in birth defects registries: the experience of the National Registry of Congenital Anomalies of Argentina.

    PubMed

    Groisman, Boris; Bidondo, Maria Paz; Gili, Juan Antonio; Barbero, Pablo; Liascovich, Rosa

    2013-01-01

    In many low-and middle-income countries, birth defects are not considered a public health priority and are perceived by the medical community as rare, unpreventable events. In this context, a registry of birth defects should address not only the collection, analysis, and dissemination of information but also contribute to local interventions like prevention, diagnosis, and treatment. We describe the National Registry of Congenital Anomalies of Argentina (RENAC) in terms of case definition, data collection, quality assurance, and data sending, coding, analysis, and information dissemination and we present the strategies used to ensure its sustainability. We emphasize strategies for motivating the people collecting data, such as training activities, participation in research projects, returning the processed data, making useful clinical information available, giving non-monetary rewards, and linking cases to genetic services. PMID:23778694

  18. CBFβ-SMMHC creates aberrant megakaryocyte-erythroid progenitors prone to leukemia initiation in mice.

    PubMed

    Cai, Qi; Jeannet, Robin; Hua, Wei-Kai; Cook, Guerry J; Zhang, Bin; Qi, Jing; Liu, Hongjun; Li, Ling; Chen, Ching-Cheng; Marcucci, Guido; Kuo, Ya-Huei

    2016-09-15

    Acute myeloid leukemia (AML) arises through multistep clonal evolution characterized by stepwise accumulation of successive alterations affecting the homeostasis of differentiation, proliferation, self-renewal, and survival programs. The persistence and dynamic clonal evolution of leukemia-initiating cells and preleukemic stem cells during disease progression and treatment are thought to contribute to disease relapse and poor outcome. Inv(16)(p13q22) or t(16;16)(p13.1;q22), one of the most common cytogenetic abnormalities in AML, leads to expression of a fusion protein CBFβ-SMMHC (CM) known to disrupt myeloid and lymphoid differentiation. Anemia is often observed in AML but is presumed to be a secondary consequence of leukemic clonal expansion. Here, we show that CM expression induces marked deficiencies in erythroid lineage differentiation and early preleukemic expansion of a phenotypic pre-megakaryocyte/erythrocyte (Pre-Meg/E) progenitor population. Using dual-fluorescence reporter mice in lineage tracking and repopulation assays, we show that CM expression cell autonomously causes expansion of abnormal Pre-Meg/E progenitors with compromised erythroid specification and differentiation capacity. The preleukemic Pre-Meg/Es display dysregulated erythroid and megakaryocytic fate-determining factors including increased Spi-1, Gata2, and Gfi1b and reduced Zfpm1, Pf4, Vwf, and Mpl expression. Furthermore, these abnormal preleukemic Pre-Meg/Es have enhanced stress resistance and are prone to leukemia initiation upon acquiring cooperative signals. This study reveals that the leukemogenic CM fusion protein disrupts adult erythropoiesis and creates stress-resistant preleukemic Pre-Meg/E progenitors predisposed to malignant transformation. Abnormality in Meg/E or erythroid progenitors could potentially be considered an early predictive risk factor for leukemia evolution.

  19. TRAIL regulates normal erythroid maturation through an ERK-dependent pathway.

    PubMed

    Secchiero, Paola; Melloni, Elisabetta; Heikinheimo, Markku; Mannisto, Susanna; Di Pietro, Roberta; Iacone, Antonio; Zauli, Giorgio

    2004-01-15

    In order to investigate the biologic activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on human erythropoiesis, glycophorin A (GPA)+ erythroid cells were generated in serum-free liquid phase from human cord blood (CB) CD34+ progenitor cells. The surface expression of TRAIL-R1 was weakly detectable in the early-intermediate phase of erythroid differentiation (days 4-6; dim-intermediate GPA expression), whereas a clear-cut expression of TRAIL-R2 was observed through the entire course of erythroid differentiation (up to days 12-14; bright GPA expression). On the other hand, surface TRAIL-R3 and -R4 were not detected at any culture time. Besides inducing a rapid but small increase of apoptotic cell death, which was abrogated by the pan-caspase inhibitor z-VAD-fmk, the addition of recombinant TRAIL at day 6 of culture inhibited the generation of morphologically mature erythroblasts. Among the intracellular pathways investigated, TRAIL significantly stimulated the extracellular signal-regulated kinase 1/2 (ERK1/2) but not the p38/mitogen-activated protein kinase (MAPK) or the c-Jun NH2-terminal kinase (JNK) pathway. Consistently with a key role of ERK1/2 in mediating the negative effects of TRAIL on erythroid maturation, PD98059, a pharmacologic inhibitor of the ERK pathway, but not z-VAD-fmk or SB203580, a pharmacologic inhibitor of p38/MAPK, reverted the antidifferentiative effect of TRAIL on CB-derived erythroblasts. PMID:12969966

  20. CBFβ-SMMHC creates aberrant megakaryocyte-erythroid progenitors prone to leukemia initiation in mice.

    PubMed

    Cai, Qi; Jeannet, Robin; Hua, Wei-Kai; Cook, Guerry J; Zhang, Bin; Qi, Jing; Liu, Hongjun; Li, Ling; Chen, Ching-Cheng; Marcucci, Guido; Kuo, Ya-Huei

    2016-09-15

    Acute myeloid leukemia (AML) arises through multistep clonal evolution characterized by stepwise accumulation of successive alterations affecting the homeostasis of differentiation, proliferation, self-renewal, and survival programs. The persistence and dynamic clonal evolution of leukemia-initiating cells and preleukemic stem cells during disease progression and treatment are thought to contribute to disease relapse and poor outcome. Inv(16)(p13q22) or t(16;16)(p13.1;q22), one of the most common cytogenetic abnormalities in AML, leads to expression of a fusion protein CBFβ-SMMHC (CM) known to disrupt myeloid and lymphoid differentiation. Anemia is often observed in AML but is presumed to be a secondary consequence of leukemic clonal expansion. Here, we show that CM expression induces marked deficiencies in erythroid lineage differentiation and early preleukemic expansion of a phenotypic pre-megakaryocyte/erythrocyte (Pre-Meg/E) progenitor population. Using dual-fluorescence reporter mice in lineage tracking and repopulation assays, we show that CM expression cell autonomously causes expansion of abnormal Pre-Meg/E progenitors with compromised erythroid specification and differentiation capacity. The preleukemic Pre-Meg/Es display dysregulated erythroid and megakaryocytic fate-determining factors including increased Spi-1, Gata2, and Gfi1b and reduced Zfpm1, Pf4, Vwf, and Mpl expression. Furthermore, these abnormal preleukemic Pre-Meg/Es have enhanced stress resistance and are prone to leukemia initiation upon acquiring cooperative signals. This study reveals that the leukemogenic CM fusion protein disrupts adult erythropoiesis and creates stress-resistant preleukemic Pre-Meg/E progenitors predisposed to malignant transformation. Abnormality in Meg/E or erythroid progenitors could potentially be considered an early predictive risk factor for leukemia evolution. PMID:27443289

  1. RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development.

    PubMed

    Verma, Rakesh; Su, Su; McCrann, Donald J; Green, Jennifer M; Leu, Karen; Young, Peter R; Schatz, Peter J; Silva, Jeffrey C; Stokes, Matthew P; Wojchowski, Don M

    2014-08-25

    Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond known signal transduction factors, 32 new targets of EPO-modulated tyrosine phosphorylation were defined. Molecular adaptors comprised one major set including growth factor receptor-bound protein 2 (GRB2)-associated binding proteins 1-3 (GAB1-3), insulin receptor substrate 2 (IRS2), docking protein 1 (DOK1), Src homology 2 domain containing transforming protein 1 (SHC1), and sprouty homologue 1 (SPRY1) as validating targets, and SPRY2, SH2 domain containing 2A (SH2D2A), and signal transducing adaptor molecule 2 (STAM2) as novel candidate adaptors together with an ORF factor designated as regulator of human erythroid cell expansion (RHEX). RHEX is well conserved in Homo sapiens and primates but absent from mouse, rat, and lower vertebrate genomes. Among tissues and lineages, RHEX was elevated in EPCs, occurred as a plasma membrane protein, was rapidly PY-phosphorylated >20-fold upon EPO exposure, and coimmunoprecipitated with the EPOR. In UT7epo cells, knockdown of RHEX inhibited EPO-dependent growth. This was associated with extracellular signal-regulated kinase 1,2 (ERK1,2) modulation, and RHEX coupling to GRB2. In primary human EPCs, shRNA knockdown studies confirmed RHEX regulation of erythroid progenitor expansion and further revealed roles in promoting the formation of hemoglobinizing erythroblasts. RHEX therefore comprises a new EPO/EPOR target and regulator of human erythroid cell expansion that additionally acts to support late-stage erythroblast development.

  2. Late stage erythroid precursor production is impaired in mice with chronic inflammation

    PubMed Central

    Prince, Olivier D.; Langdon, Jacqueline M.; Layman, Andrew J.; Prince, Ian C.; Sabogal, Miguel; Mak, Howard H.; Berger, Alan E.; Cheadle, Chris; Chrest, Francis J.; Yu, Qilu; Andrews, Nancy C.; Xue, Qian-Li; Civin, Curt I.; Walston, Jeremy D.; Roy, Cindy N.

    2012-01-01

    Background We and others have shown previously that over-expression of hepcidin antimicrobial peptide, independently of inflammation, induces several features of anemia of inflammation and chronic disease, including hypoferremia, sequestration of iron stores and iron-restricted erythropoiesis. Because the iron-restricted erythropoiesis evident in hepcidin transgenic mice differs from the normocytic, normochromic anemia most often observed in anemia of inflammation, we tested the hypothesis that chronic inflammation may contribute additional features to anemia of inflammation which continue to impair erythropoiesis following the acute phase of inflammation in which hepcidin is active. Design and Methods We compared erythropoiesis and iron handling in mice with turpentine-induced sterile abscesses with erythropoiesis and iron handling in hepcidin transgenic mice. We compared erythrocyte indices, expression of genes in the hepcidin regulatory pathway, tissue iron distribution, expression of heme and iron transport genes in splenic macrophages, the phenotype of erythroid maturation and chloromethyl dichlorodihydrofluorescein diacetate, acetyl ester fluorescence. Results Mice with sterile abscesses exhibited an intense, acute inflammatory phase followed by a mild to moderate chronic inflammatory phase. We found that erythrocytes in mice with sterile abscesses were normocytic and normochromic in contrast to those in hepcidin transgenic mice. We also observed that although hypoferremia resolved in the late phases of inflammation, erythropoiesis remained suppressed, with evidence of inefficient maturation of erythroid precursors in the bone marrow of mice with sterile abscesses. Finally, we observed increased oxidative stress in erythroid progenitors and circulating erythrocytes of mice with sterile abscesses which was not evident in hepcidin transgenic mice. Conclusions Our results suggest that chronic inflammation inhibits late stages of erythroid production in the

  3. Histone demethylase LSD1-mediated repression of GATA-2 is critical for erythroid differentiation

    PubMed Central

    Guo, Yidi; Fu, Xueqi; Jin, Yue; Sun, Jing; Liu, Ye; Huo, Bo; Li, Xiang; Hu, Xin

    2015-01-01

    Background The transcription factor GATA-2 is predominantly expressed in hematopoietic stem and progenitor cells and counteracts the erythroid-specific transcription factor GATA-1, to modulate the proliferation and differentiation of hematopoietic cells. During hematopoietic cell differentiation, GATA-2 exhibits dynamic expression patterns, which are regulated by multiple transcription factors. Methods Stable LSD1-knockdown cell lines were established by growing murine erythroleukemia (MEL) or mouse embryonic stem cells together with virus particles, in the presence of Polybrene® at 4 μg/mL, for 24–48 hours followed by puromycin selection (1 μg/mL) for 2 weeks. Real-time polymerase chain reaction (PCR)-based quantitative chromatin immunoprecipitation (ChIP) analysis was used to test whether the TAL1 transcription factor is bound to 1S promoter in the GATA-2 locus or whether LSD1 colocalizes with TAL1 at the 1S promoter. The sequential ChIP assay was utilized to confirm the role of LSD1 in the regulation of H3K4me2 at the GATA-2 locus during erythroid differentiation. Western blot analysis was employed to detect the protein expression. The alamarBlue® assay was used to examine the proliferation of the cells, and the absorbance was monitored at optical density (OD) 570 nm and OD 600 nm. Results In this study, we showed that LSD1 regulates the expression of GATA-2 during erythroid differentiation. Knockdown of LSD1 results in increased GATA-2 expression and inhibits the differentiation of MEL and embryonic stem cells. Furthermore, we demonstrated that LSD1 binds to the 1S promoter of the GATA-2 locus and suppresses GATA-2 expression, via histone demethylation. Conclusion Our data revealed that LSD1 mediates erythroid differentiation, via epigenetic modification of the GATA-2 locus. PMID:26124638

  4. RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development.

    PubMed

    Verma, Rakesh; Su, Su; McCrann, Donald J; Green, Jennifer M; Leu, Karen; Young, Peter R; Schatz, Peter J; Silva, Jeffrey C; Stokes, Matthew P; Wojchowski, Don M

    2014-08-25

    Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond known signal transduction factors, 32 new targets of EPO-modulated tyrosine phosphorylation were defined. Molecular adaptors comprised one major set including growth factor receptor-bound protein 2 (GRB2)-associated binding proteins 1-3 (GAB1-3), insulin receptor substrate 2 (IRS2), docking protein 1 (DOK1), Src homology 2 domain containing transforming protein 1 (SHC1), and sprouty homologue 1 (SPRY1) as validating targets, and SPRY2, SH2 domain containing 2A (SH2D2A), and signal transducing adaptor molecule 2 (STAM2) as novel candidate adaptors together with an ORF factor designated as regulator of human erythroid cell expansion (RHEX). RHEX is well conserved in Homo sapiens and primates but absent from mouse, rat, and lower vertebrate genomes. Among tissues and lineages, RHEX was elevated in EPCs, occurred as a plasma membrane protein, was rapidly PY-phosphorylated >20-fold upon EPO exposure, and coimmunoprecipitated with the EPOR. In UT7epo cells, knockdown of RHEX inhibited EPO-dependent growth. This was associated with extracellular signal-regulated kinase 1,2 (ERK1,2) modulation, and RHEX coupling to GRB2. In primary human EPCs, shRNA knockdown studies confirmed RHEX regulation of erythroid progenitor expansion and further revealed roles in promoting the formation of hemoglobinizing erythroblasts. RHEX therefore comprises a new EPO/EPOR target and regulator of human erythroid cell expansion that additionally acts to support late-stage erythroblast development. PMID:25092874

  5. The Effect of Mir-451 Upregulation on Erythroid Lineage Differentiation of Murine Embryonic Stem Cells

    PubMed Central

    Obeidi, Narges; Pourfathollah, Ali Akbar; Soleimani, Masoud; Nikougoftar Zarif, Mahin; Kouhkan, Fatemeh

    2016-01-01

    Objective MicroRNAs (miRNAs) are small endogenous non-coding regulatory RNAs that control mRNAs post-transcriptionally. Several mouse stem cells miRNAs are cloned differentially regulated in different hematopoietic lineages, suggesting their possible role in hematopoietic lineage differentiation. Recent studies have shown that specific miRNAs such as Mir-451 have key roles in erythropoiesis. Materials and Methods In this experimental study, murine embryonic stem cells (mESCs) were infected with lentiviruses containing pCDH-Mir-451. Erythroid differentiation was assessed based on the expression level of transcriptional factors (Gata-1, Klf-1, Epor) and hemoglobin chains (α, β, γ , ε and ζ) genes using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and presence of erythroid surface antigens (TER-119 and CD235a) using flow cytometery. Colony-forming unit (CFU) assay was also on days 14thand 21thafter transduction. Results Mature Mir-451 expression level increased by 3.434-fold relative to the untreated mESCs on day 4 after transduction (P<0.001). Mir-451 up-regulation correlated with the induction of transcriptional factor (Gata-1, Klf-1, Epor) and hemoglobin chain (α, β, γ, ε and ζ) genes in mESCs (P<0.001) and also showed a strong correlation with presence of CD235a and Ter- 119 markers in these cells (13.084and 13.327-fold increse, respectively) (P<0.05). Moreover, mESCs treated with pCDH-Mir-451 showed a significant raise in CFU-erythroid (CFU-E) colonies (5.2-fold) compared with untreated control group (P<0.05). Conclusion Our results showed that Mir-451 up-regulation strongly induces erythroid differentiation and maturation of mESCs. Overexpression of Mir-451 may have the potential to produce artificial red blood cells (RBCs) without the presence of any stimulatory cytokines. PMID:27540521

  6. Secondary pure erythroid leukaemia in relapsed acute lymphoblastic leukaemia: lineage switch or chemotherapy effect?

    PubMed

    Gupta, Sanjeev Kumar; Kumar, Rajive; Chharchhodawala, Taher; Kumar, Lalit

    2014-05-19

    Pure erythroid leukaemia is a rare subtype of acute myeloid leukaemia (AML) and its occurrence at acute lymphoblastic leukaemia (ALL) relapse has not been reported earlier. A 39-year-old man received chemotherapy for Philadelphia-negative B cell ALL. Subsequently, he developed pure erythroid leukaemia with >80% immature erythroid precursors in bone marrow showing block positivity on periodic acid-Schiff stain, expressing CD71, CD34 but lacking CD235a. The interval between exposure to multidrug chemotherapy including cyclophosphamide and AML diagnosis was 2 years and 9 months. No cytogenetic abnormality was detected at the time of relapse. The patient died 2 weeks after starting AML chemotherapy. The relatively narrow time interval (usually 5-10 years) between chemotherapy and AML development and normal karyotype at relapse raises a possibility of lineage switch besides therapy-related AML as the likely pathogenesis. Further exploration of such cases may unravel the pathways responsible for lineage assignment in pluripotent stem cells.

  7. A novel complex, RUNX1-MYEF2, represses hematopoietic genes in erythroid cells.

    PubMed

    van Riel, Boet; Pakozdi, Tibor; Brouwer, Rutger; Monteiro, Rui; Tuladhar, Kapil; Franke, Vedran; Bryne, Jan Christian; Jorna, Ruud; Rijkers, Erik-Jan; van Ijcken, Wilfred; Andrieu-Soler, Charlotte; Demmers, Jeroen; Patient, Roger; Soler, Eric; Lenhard, Boris; Grosveld, Frank

    2012-10-01

    RUNX1 is known to be an essential transcription factor for generating hematopoietic stem cells (HSC), but much less is known about its role in the downstream process of hematopoietic differentiation. RUNX1 has been shown to be part of a large transcription factor complex, together with LDB1, GATA1, TAL1, and ETO2 (N. Meier et al., Development 133:4913-4923, 2006) in erythroid cells. We used a tagging strategy to show that RUNX1 interacts with two novel protein partners, LSD1 and MYEF2, in erythroid cells. MYEF2 is bound in undifferentiated cells and is lost upon differentiation, whereas LSD1 is bound in differentiated cells. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) and microarray expression analysis were used to show that RUNX1 binds approximately 9,000 target sites in erythroid cells and is primarily active in the undifferentiated state. Functional analysis shows that a subset of the target genes is suppressed by RUNX1 via the newly identified partner MYEF2. Knockdown of Myef2 expression in developing zebrafish results in a reduced number of HSC. PMID:22801375

  8. A Novel Complex, RUNX1-MYEF2, Represses Hematopoietic Genes in Erythroid Cells

    PubMed Central

    van Riel, Boet; Pakozdi, Tibor; Brouwer, Rutger; Monteiro, Rui; Tuladhar, Kapil; Franke, Vedran; Bryne, Jan Christian; Jorna, Ruud; Rijkers, Erik-Jan; van Ijcken, Wilfred; Andrieu-Soler, Charlotte; Demmers, Jeroen; Patient, Roger; Soler, Eric

    2012-01-01

    RUNX1 is known to be an essential transcription factor for generating hematopoietic stem cells (HSC), but much less is known about its role in the downstream process of hematopoietic differentiation. RUNX1 has been shown to be part of a large transcription factor complex, together with LDB1, GATA1, TAL1, and ETO2 (N. Meier et al., Development 133:4913–4923, 2006) in erythroid cells. We used a tagging strategy to show that RUNX1 interacts with two novel protein partners, LSD1 and MYEF2, in erythroid cells. MYEF2 is bound in undifferentiated cells and is lost upon differentiation, whereas LSD1 is bound in differentiated cells. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) and microarray expression analysis were used to show that RUNX1 binds approximately 9,000 target sites in erythroid cells and is primarily active in the undifferentiated state. Functional analysis shows that a subset of the target genes is suppressed by RUNX1 via the newly identified partner MYEF2. Knockdown of Myef2 expression in developing zebrafish results in a reduced number of HSC. PMID:22801375

  9. Thioredoxin-interacting protein regulates the differentiation of murine erythroid precursors.

    PubMed

    Gasiorek, Jadwiga J; Mikhael, Marc; Garcia-Santos, Daniel; Hui, Simon T; Ponka, Prem; Blank, Volker

    2015-05-01

    Thioredoxin-interacting protein (TXNIP) is involved in various cellular processes including redox control, metabolism, differentiation, growth, and apoptosis. With respect to hematopoiesis, TXNIP has been shown to play roles in natural killer cells, dendritic cells, and hematopoietic stem cells. Our study investigates the role of TXNIP in erythropoiesis. We observed a rapid and significant increase of TXNIP transcript and protein levels in mouse erythroleukemia cells treated with dimethyl sulfoxide or hexamethylene bisacetamide, inducers of erythroid differentiation. The upregulation of TXNIP was not abrogated by addition of the antioxidant N-acetylcysteine. The increase of TXNIP expression was confirmed in another model of erythroid differentiation, G1E-ER cells, which undergo differentiation upon activation of the GATA1 transcription factor. In addition, we showed that TXNIP levels are induced following inhibition of p38 or c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. We also observed an increase in iron uptake and a decrease in transferrin receptor protein upon TXNIP overexpression, suggesting a role in iron homeostasis. In vivo, flow cytometry analysis of cells from Txnip(-/-) mice revealed a new phenotype of impaired terminal erythropoiesis in the spleen, characterized by a partial block between basophilic and late basophilic/polychromatic erythroblasts. Based on our data, TXNIP emerges as a novel regulator of terminal erythroid differentiation.

  10. Induction of erythroid differentiation and modulation of gene expression by tiazofurin in K-562 leukemia cells.

    PubMed Central

    Olah, E; Natsumeda, Y; Ikegami, T; Kote, Z; Horanyi, M; Szelenyi, J; Paulik, E; Kremmer, T; Hollan, S R; Sugar, J

    1988-01-01

    Tiazofurin (2-beta-D-ribofuranosyl-4-thiazole-carboxamide; NSC 286193), an antitumor carbon-linked nucleoside that inhibits IMP dehydrogenase (IMP:NAD+ oxidoreductase; EC 1.1.1.205) and depletes guanylate levels, can activate the erythroid differentiation program of K-562 human leukemia cells. Tiazofurin-mediated cell differentiation is a multistep process. The inducer initiates early (less than 6 hr) metabolic changes that precede commitment to differentiation; among these early changes are decreases in IMP dehydrogenase activity and in GTP concentration, as well as alterations in the expression of certain protooncogenes (c-Ki-ras). K-562 cells do express commitment-i.e., cells exhibit differentiation without tiazofurin. Guanosine was effective in preventing the action of tiazofurin, thus providing evidence that the guanine nucleotides are critically involved in tiazofurin-initiated differentiation. Activation of transcription of the erythroid-specific gene that encodes A gamma-globin is a late (48 hr) but striking effect of tiazofurin. Down-regulation of the c-ras gene appears to be part of the complex process associated with tiazofurin-induced erythroid differentiation and relates to the perturbations of GTP metabolism. Images PMID:2901100

  11. Regulation of GATA Factor Expression Is Distinct between Erythroid and Mast Cell Lineages

    PubMed Central

    Ohmori, Shin'ya; Takai, Jun; Ishijima, Yasushi; Suzuki, Mikiko; Moriguchi, Takashi; Philipsen, Sjaak; Yamamoto, Masayuki

    2012-01-01

    The zinc finger transcription factors GATA1 and GATA2 participate in mast cell development. Although the expression of these factors is regulated in a cell lineage-specific and differentiation stage-specific manner, their regulation during mast cell development has not been clarified. Here, we show that the GATA2 mRNA level was significantly increased while GATA1 was maintained at low levels during the differentiation of mast cells derived from mouse bone marrow (BMMCs). Unlike in erythroid cells, forced expression or small interfering RNA (siRNA)-mediated knockdown of GATA1 rarely affected GATA2 expression, and vice versa, in mast cells, indicating the absence of cross-regulation between Gata1 and Gata2 genes. Chromatin immunoprecipitation assays revealed that both GATA factors bound to most of the conserved GATA sites of Gata1 and Gata2 loci in BMMCs. However, the GATA1 hematopoietic enhancer (G1HE) of the Gata1 gene, which is essential for GATA1 expression in erythroid and megakaryocytic lineages, was bound only weakly by both GATA factors in BMMCs. Furthermore, transgenic-mouse reporter assays revealed that the G1HE is not essential for reporter expression in BMMCs and peritoneal mast cells. Collectively, these results demonstrate that the expression of GATA factors in mast cells is regulated in a manner quite distinct from that in erythroid cells. PMID:22988301

  12. Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation.

    PubMed

    Alvarez-Dominguez, Juan R; Hu, Wenqian; Yuan, Bingbing; Shi, Jiahai; Park, Staphany S; Gromatzky, Austin A; van Oudenaarden, Alexander; Lodish, Harvey F

    2014-01-23

    Erythropoiesis is regulated at multiple levels to ensure the proper generation of mature red cells under multiple physiological conditions. To probe the contribution of long noncoding RNAs (lncRNAs) to this process, we examined >1 billion RNA-seq reads of polyadenylated and nonpolyadenylated RNA from differentiating mouse fetal liver red blood cells and identified 655 lncRNA genes including not only intergenic, antisense, and intronic but also pseudogene and enhancer loci. More than 100 of these genes are previously unrecognized and highly erythroid specific. By integrating genome-wide surveys of chromatin states, transcription factor occupancy, and tissue expression patterns, we identify multiple lncRNAs that are dynamically expressed during erythropoiesis, show epigenetic regulation, and are targeted by key erythroid transcription factors GATA1, TAL1, or KLF1. We focus on 12 such candidates and find that they are nuclear-localized and exhibit complex developmental expression patterns. Depleting them severely impaired erythrocyte maturation, inhibiting cell size reduction and subsequent enucleation. One of them, alncRNA-EC7, is transcribed from an enhancer and is specifically needed for activation of the neighboring gene encoding BAND 3. Our study provides an annotated catalog of erythroid lncRNAs, readily available through an online resource, and shows that diverse types of lncRNAs participate in the regulatory circuitry underlying erythropoiesis.

  13. Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation

    PubMed Central

    Alvarez-Dominguez, Juan R.; Yuan, Bingbing; Shi, Jiahai; Park, Staphany S.; Gromatzky, Austin A.; van Oudenaarden, Alexander

    2014-01-01

    Erythropoiesis is regulated at multiple levels to ensure the proper generation of mature red cells under multiple physiological conditions. To probe the contribution of long noncoding RNAs (lncRNAs) to this process, we examined >1 billion RNA-seq reads of polyadenylated and nonpolyadenylated RNA from differentiating mouse fetal liver red blood cells and identified 655 lncRNA genes including not only intergenic, antisense, and intronic but also pseudogene and enhancer loci. More than 100 of these genes are previously unrecognized and highly erythroid specific. By integrating genome-wide surveys of chromatin states, transcription factor occupancy, and tissue expression patterns, we identify multiple lncRNAs that are dynamically expressed during erythropoiesis, show epigenetic regulation, and are targeted by key erythroid transcription factors GATA1, TAL1, or KLF1. We focus on 12 such candidates and find that they are nuclear-localized and exhibit complex developmental expression patterns. Depleting them severely impaired erythrocyte maturation, inhibiting cell size reduction and subsequent enucleation. One of them, alncRNA-EC7, is transcribed from an enhancer and is specifically needed for activation of the neighboring gene encoding BAND 3. Our study provides an annotated catalog of erythroid lncRNAs, readily available through an online resource, and shows that diverse types of lncRNAs participate in the regulatory circuitry underlying erythropoiesis. PMID:24200680

  14. Control of developmentally primed erythroid genes by combinatorial co-repressor actions

    PubMed Central

    Stadhouders, Ralph; Cico, Alba; Stephen, Tharshana; Thongjuea, Supat; Kolovos, Petros; Baymaz, H. Irem; Yu, Xiao; Demmers, Jeroen; Bezstarosti, Karel; Maas, Alex; Barroca, Vilma; Kockx, Christel; Ozgur, Zeliha; van Ijcken, Wilfred; Arcangeli, Marie-Laure; Andrieu-Soler, Charlotte; Lenhard, Boris; Grosveld, Frank; Soler, Eric

    2015-01-01

    How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2–IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation. PMID:26593974

  15. Control of developmentally primed erythroid genes by combinatorial co-repressor actions.

    PubMed

    Stadhouders, Ralph; Cico, Alba; Stephen, Tharshana; Thongjuea, Supat; Kolovos, Petros; Baymaz, H Irem; Yu, Xiao; Demmers, Jeroen; Bezstarosti, Karel; Maas, Alex; Barroca, Vilma; Kockx, Christel; Ozgur, Zeliha; van Ijcken, Wilfred; Arcangeli, Marie-Laure; Andrieu-Soler, Charlotte; Lenhard, Boris; Grosveld, Frank; Soler, Eric

    2015-01-01

    How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2-IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation. PMID:26593974

  16. FOG-1 and GATA-1 act sequentially to specify definitive megakaryocytic and erythroid progenitors.

    PubMed

    Mancini, Elena; Sanjuan-Pla, Alejandra; Luciani, Luisa; Moore, Susan; Grover, Amit; Zay, Agnes; Rasmussen, Kasper D; Luc, Sidinh; Bilbao, Daniel; O'Carroll, Donal; Jacobsen, Sten Eirik; Nerlov, Claus

    2012-01-18

    The transcription factors that control lineage specification of haematopoietic stem cells (HSCs) have been well described for the myeloid and lymphoid lineages, whereas transcriptional control of erythroid (E) and megakaryocytic (Mk) fate is less understood. We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment. FOG-1-deficient HSCs and preMegEs, the latter normally bipotent for the Mk and E lineages, underwent myeloid transcriptional reprogramming, and formed myeloid, but not erythroid and megakaryocytic cells in vitro. These results identify FOG-1 and GATA-1 as required for formation of bipotent Mk/E progenitors and their E-lineage commitment, respectively, and show that FOG-1 mediates transcriptional Mk/E programming of HSCs as well as their subsequent Mk/E-lineage commitment. Finally, C/EBPs and FOG-1 exhibited transcriptional cross-regulation in early myelo-erythroid progenitors making their functional antagonism a potential mechanism for separation of the myeloid and Mk/E lineages.

  17. GATA1 and PU.1 Bind to Ribosomal Protein Genes in Erythroid Cells: Implications for Ribosomopathies

    PubMed Central

    Amanatiadou, Elsa P.; Papadopoulos, Giorgio L.; Strouboulis, John; Vizirianakis, Ioannis S.

    2015-01-01

    The clear connection between ribosome biogenesis dysfunction and specific hematopoiesis-related disorders prompted us to examine the role of critical lineage-specific transcription factors in the transcriptional regulation of ribosomal protein (RP) genes during terminal erythroid differentiation. By applying EMSA and ChIP methodologies in mouse erythroleukemia cells we show that GATA1 and PU.1 bind in vitro and in vivo the proximal promoter region of the RPS19 gene which is frequently mutated in Diamond-Blackfan Anemia. Moreover, ChIPseq data analysis also demonstrates that several RP genes are enriched as potential GATA1 and PU.1 gene targets in mouse and human erythroid cells, with GATA1 binding showing an association with higher ribosomal protein gene expression levels during terminal erythroid differentiation in human and mouse. Our results suggest that RP gene expression and hence balanced ribosome biosynthesis may be specifically and selectively regulated by lineage specific transcription factors during hematopoiesis, a finding which may be clinically relevant to ribosomopathies. PMID:26447946

  18. GATA1 and PU.1 Bind to Ribosomal Protein Genes in Erythroid Cells: Implications for Ribosomopathies.

    PubMed

    Amanatiadou, Elsa P; Papadopoulos, Giorgio L; Strouboulis, John; Vizirianakis, Ioannis S

    2015-01-01

    The clear connection between ribosome biogenesis dysfunction and specific hematopoiesis-related disorders prompted us to examine the role of critical lineage-specific transcription factors in the transcriptional regulation of ribosomal protein (RP) genes during terminal erythroid differentiation. By applying EMSA and ChIP methodologies in mouse erythroleukemia cells we show that GATA1 and PU.1 bind in vitro and in vivo the proximal promoter region of the RPS19 gene which is frequently mutated in Diamond-Blackfan Anemia. Moreover, ChIPseq data analysis also demonstrates that several RP genes are enriched as potential GATA1 and PU.1 gene targets in mouse and human erythroid cells, with GATA1 binding showing an association with higher ribosomal protein gene expression levels during terminal erythroid differentiation in human and mouse. Our results suggest that RP gene expression and hence balanced ribosome biosynthesis may be specifically and selectively regulated by lineage specific transcription factors during hematopoiesis, a finding which may be clinically relevant to ribosomopathies. PMID:26447946

  19. Estrogen-induced apoptosis by inhibition of the erythroid transcription factor GATA-1.

    PubMed Central

    Blobel, G A; Orkin, S H

    1996-01-01

    Steroid hormones regulate diverse biological functions, including programmed cell death (apoptosis). Although steroid receptors have been studied extensively, relatively little is known regarding the cellular targets through which apoptosis is triggered. We show here that the ligand-activated estrogen receptor (ER) induces apoptosis in an erythroid cell line by binding to, and consequently inhibiting the activity of, GATA-1, an erythroid transcription factor essential for the survival and maturation of erythroid precursor cells. GATA-1 inhibition is reflected in the downregulation of presumptive GATA-1 target genes. Constitutive overexpression of a GATA-binding protein resistant to the effects of the ER partially rescues ER-induced apoptosis. Induction of apoptosis by a mutant ER defective in binding to the estrogen response element but active in GATA-1 inhibition suggests that ER-mediated inhibition of GATA-1 is direct and does not require estrogen response element-dependent transcriptional activation. Thus, a lineage-restricted transcription factor, such as GATA-1, constitutes one cellular target through which steroid hormones may control apoptosis. As GATA-binding proteins are evolutionarily conserved, we speculate that members of the steroid receptor family may exert some of their diverse biological functions in different cellular contexts through interference with the function of GATA-binding proteins. PMID:8657144

  20. Genetic regulatory networks programming hematopoietic stem cells and erythroid lineage specification.

    PubMed

    Swiers, Gemma; Patient, Roger; Loose, Matthew

    2006-06-15

    Erythroid cell production results from passage through cellular hierarchies dependent on differential gene expression under the control of transcription factors responsive to changing niches. We have constructed Genetic Regulatory Networks (GRNs) describing this process, based predominantly on mouse data. Regulatory network motifs identified in E. coli and yeast GRNs are found in combination in these GRNs. Feed-forward motifs with autoregulation generate forward momentum and also control its rate, which is at its lowest in hematopoietic stem cells (HSCs). The simultaneous requirement for multiple regulators in multi-input motifs (MIMs) provides tight control over expression of target genes. Combinations of MIMs, exemplified by the SCL/LMO2 complexes, which have variable content and binding sites, explain how individual regulators can have different targets in HSCs and erythroid cells and possibly also how HSCs maintain stem cell functions while expressing lineage-affiliated genes at low level, so-called multi-lineage priming. MIMs combined with cross-antagonism describe the relationship between PU.1 and GATA-1 and between two of their target genes, Fli-1 and EKLF, with victory for GATA-1 and EKLF leading to erythroid lineage specification. These GRNs are useful repositories for current regulatory information, are accessible in interactive form via the internet, enable the consequences of perturbation to be predicted, and can act as seed networks to organize the rapidly accumulating microarray data.

  1. Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes

    PubMed Central

    Sundaravel, Sriram; Duggan, Ryan; Bhagat, Tushar; Ebenezer, David L.; Liu, Hui; Yu, Yiting; Bartenstein, Matthias; Unnikrishnan, Madhu; Karmakar, Subhradip; Liu, Ting-Chun; Torregroza, Ingrid; Quenon, Thomas; Anastasi, John; McGraw, Kathy L.; Pellagatti, Andrea; Boultwood, Jacqueline; Yajnik, Vijay; Artz, Andrew; Le Beau, Michelle M.; Steidl, Ulrich; List, Alan F.; Evans, Todd; Verma, Amit; Wickrema, Amittha

    2015-01-01

    Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in −7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia. PMID:26578796

  2. Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response

    PubMed Central

    Simmons, Bryony; Saleem, Jawaad; Heath, Katherine; Cooke, Graham S.; Hill, Andrew

    2015-01-01

    Background. Achievement of a sustained virologic response (SVR) after treatment for Hepatitis C infection is associated with improved outcomes. This meta-analysis aimed to determine the impact of SVR on long-term mortality risk compared with nonresponders in a range of populations. Methods. An electronic search identified all studies assessing all-cause mortality in SVR and non-SVR patients. Eligible articles were stratified into general, cirrhotic, and populations coinfected with human immunodeficiency virus. The adjusted hazard ratio (95% confidence interval [CI]) for mortality in patients achieving SVR vs non-SVR, and pooled estimates for the 5-year mortality in each group were calculated. Results. 31 studies (n = 33 360) were identified as suitable for inclusion. Median follow-up time was 5.4 years (interquartile range, 4.9–7.5) across all studies. The adjusted hazard ratio of mortality for patients achieving SVR vs non-SVR was 0.50 (95% CI, .37–.67) in the general population, 0.26 (95% CI, .18–.74) in the cirrhotic group, and 0.21 (.10–.45) in the coinfected group. The pooled 5-year mortality rates were significantly lower for patients achieving SVR compared with non-SVR in all 3 populations. Conclusions. The results suggest that there is a significant survival benefit of achieving an SVR compared with unsuccessful treatment in a range of populations infected with hepatitis C virus. PMID:25987643

  3. The lipocalin alpha1-microglobulin protects erythroid K562 cells against oxidative damage induced by heme and reactive oxygen species.

    PubMed

    Olsson, Magnus G; Olofsson, Tor; Tapper, Hans; Akerstrom, Bo

    2008-08-01

    Alpha(1)-microglobulin is a 26 kDa plasma and tissue glycoprotein that belongs to the lipocalin protein superfamily. Recent reports show that it is a reductase and radical scavenger and that it binds heme and has heme-degrading properties. This study has investigated the protective effects of alpha(1)-microglobulin against oxidation by heme and reactive oxygen species in the human erythroid cell line, K562. The results show that alpha(1)-microglobulin prevents intracellular oxidation and up-regulation of heme oxygenase-1 induced by heme, hydrogen peroxide and Fenton reaction-generated hydroxyl radicals in the culture medium. It also reduces the cytosol of non-oxidized cells. Endogeneous expression of alpha(1)-microglobulin was up-regulated by these oxidants and silencing of the alpha(1)-microglobulin expression increased the cytosol oxidation. alpha(1)-microglobulin also inhibited cell death caused by heme and cleared cells from bound heme. Binding of heme to alpha(1)-microglobulin increased the radical reductase activity of the protein as compared to the apo-protein. Finally, alpha(1)-microglobulin was localized mainly at the cell surface both when administered exogeneously and in non-treated cells. The results suggest that alpha(1)-microglobulin is involved in the defence against oxidative cellular injury caused by haemoglobin and heme and that the protein may employ both heme-scavenging and one-electron reduction of radicals to achieve this.

  4. Simulations towards the achievement of non-inductive current ramp-up and sustainment in the National Spherical Torus Experiment Upgrade

    DOE PAGESBeta

    Poli, F. M.; Andre, R. G.; Bertelli, N.; Gerhardt, S. P.; Mueller, D.; Taylor, G.

    2015-10-30

    One of the goals of the National Spherical Torus Experiment Upgrade (NSTX-U) (Menard et al 2012 Nucl. Fusion 52 083015) is the demonstration of fully non-inductive start-up, current ramp-up and sustainment. This work discusses predictive simulations where the available heating and current drive systems are combined to maximize the non-inductive current and minimize the solenoidal contribution. Radio-frequency waves at harmonics higher than the ion cyclotron resonance (high-harmonic fast waves (HHFW)) and neutral beam injection are used to ramp the plasma current non-inductively starting from an initial Ohmic plasma. An interesting synergy is observed in the simulations between the HHFW andmore » electron cyclotron (EC) wave heating. Furthermore, time-dependent simulations indicate that, depending on the phasing of the HHFW antenna, EC wave heating can significantly increase the effectiveness of the radio-frequency power, by heating the electrons and increasing the current drive efficiency, thus relaxing the requirements on the level of HHFW power that needs to be absorbed in the core plasma to drive the same amount of fast-wave current.« less

  5. China's strategy towards environmental governance: An examination of the interaction between pedagogy and practice of environmental education in creating and achieving objectives for sustainable development

    NASA Astrophysics Data System (ADS)

    Darkhor, Patrick

    This thesis involves a case-study methodology that explores programs and initiatives undertaken in the fields of environmental education focusing on the elementary and middle school curriculum and teacher education programs in China. The major objectives of this research are (1) to study the status of environmental education in Chinese elementary and middle schools; (2) to study the commonalities in approaches to environmental education and education for sustainable development in the existing curriculum; and (3) to study the lived challenges of implementing environmental education in today's schools in China. The study will address the following question: How can elementary and middle schools integrate environmental education objectives into their existing school programs without radical curricula changes? The thesis suggests that environmental education programs can be combined naturally with a school curriculum by identifying points of overlap between existing curricula and environmental education goals to facilitate natural, unforced integration of these programs. I have investigated these programs and initiatives concomitantly with the proposals for curriculum reform developed in China. This investigation includes an in-depth examination of the impact of such programs on students, teacher education programs, school systems and local communities. Qualitative data was collected and used to describe the evolution of environmental education programs within schools in the country scrutinized in this study. Research was also conducted on the etiology, nature and potential of any program developed by Chinese school systems for the purpose of integrating environmental education within the teacher education programs and consequently within the regular classroom curriculum.

  6. Simulations towards the achievement of non-inductive current ramp-up and sustainment in the National Spherical Torus Experiment Upgrade

    SciTech Connect

    Poli, F. M.; Andre, R. G.; Bertelli, N.; Gerhardt, S. P.; Mueller, D.; Taylor, G.

    2015-10-30

    One of the goals of the National Spherical Torus Experiment Upgrade (NSTX-U) (Menard et al 2012 Nucl. Fusion 52 083015) is the demonstration of fully non-inductive start-up, current ramp-up and sustainment. This work discusses predictive simulations where the available heating and current drive systems are combined to maximize the non-inductive current and minimize the solenoidal contribution. Radio-frequency waves at harmonics higher than the ion cyclotron resonance (high-harmonic fast waves (HHFW)) and neutral beam injection are used to ramp the plasma current non-inductively starting from an initial Ohmic plasma. An interesting synergy is observed in the simulations between the HHFW and electron cyclotron (EC) wave heating. Furthermore, time-dependent simulations indicate that, depending on the phasing of the HHFW antenna, EC wave heating can significantly increase the effectiveness of the radio-frequency power, by heating the electrons and increasing the current drive efficiency, thus relaxing the requirements on the level of HHFW power that needs to be absorbed in the core plasma to drive the same amount of fast-wave current.

  7. Helper virus is not required for in vitro erythroid transformation of hematopoietic cells by Friend virus.

    PubMed

    Hankins, W D; Krantz, S B

    1980-09-01

    The Friend polycythemia virus complex (FVP), consisting of the replication-defective spleen focus-forming virus (SFFV) and a helper Friend murine leukemia virus (MuLV-F), produces erythroleukemia within 2-3 weeks in vivo. We have recently reported in vitro transformation of bone marrow cells by FVP, producing clusters of erythroid colonies (erythroid bursts) 4-6 days after infection. In contrast to uninfected bone marrow cells, FVP-treated cells proliferated and differentiated (synthesized hemoglobin) in the absence of added erythropoietin, the physiologic regulator of erythropoiesis. The relative roles of helper murine leukemia virus (MuLV) and SFFV in the in vitro erythroid transformation have now been examined. Pseudotype studies and the finding that cloned MuLV-F (free of SFFV) did not induce burst formation indicated that SFFV was essential for this in vitro effect of FVP. Because SFFV could not be obtained free of helper MuLV, we assessed the requirement of MuLV in the transformation by kinetic analyses of helper-deficient and helper-excess FVP preparations. Whereas helper-excess FVP gave single-hit kinetics both in vivo and in vitro, the helper-deficient FVP followed multiple-hit kinetics when titrated for spleen focus formation in vivo. Addition of MuLV-F to helper-deficient FVP prior to injection resulted in a marked enhancement of spleen focus formation and a conversion from multiple-hit to single-hit kinetics. In contrast, titration of this same preparation for erythroid burst transformation in vitro yielded single-hit kinetics, and the addition of helper MuLV-F had no effect. The time course of burst development was similar with or without added MuLV-F. Unlike burst transformation, SFFV production by these infected cultures followed multiple-hit kinetics. Addition of MuLV-F at the time of infection led to an enhancement of SFFV production and conversion of the titration curve from multiple-hit to single-hit. These data are consistent with the idea that

  8. PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal.

    PubMed

    Lee, Hsiang-Ying; Gao, Xiaofei; Barrasa, M Inmaculada; Li, Hu; Elmes, Russell R; Peters, Luanne L; Lodish, Harvey F

    2015-06-25

    Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid

  9. PPARα and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal

    PubMed Central

    Lee, Hsiang-Ying; Gao, Xiaofei; Barrasa, M. Inmaculada; Li, Hu; Elmes, Russell R.; Peters, Luanne L.; Lodish, Harvey F.

    2015-01-01

    Summary Many acute and chronic anemias, including hemolysis, sepsis, and genetic bone marrow failure diseases such as Diamond-Blackfan Anemia (DBA), are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production 1,2,3–5,6,7,8,9. Treatment of these anemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently we showed that glucocorticoids specifically stimulate self-renewal of the early erythroid progenitor, the burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells 10,11. Here we demonstrate that activation of the peroxisome proliferator-activated receptor alpha (PPARα) by PPARα agonists, GW7647 and fenofibrate, synergizes with glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures both of mouse fetal liver BFU-Es and of mobilized human adult CD34+ peripheral blood progenitors, the latter employing a new and effective culture system that generates normal enucleated reticulocytes. While PPARα−/− mice show no hematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPARα agonists facilitate recovery of wild-type mice, but not PPARα−/− mice, from PHZ-induced acute hemolytic anemia. We also showed that PPARα alleviates anemia in a mouse model of chronic anemia. Finally, both in control and corticosteroid-treated BFU-E cells PPARα co-occupies many chromatin sites with GR; when activated by PPARα agonists, additional PPARα is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPARα agonists in stimulating self

  10. PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal.

    PubMed

    Lee, Hsiang-Ying; Gao, Xiaofei; Barrasa, M Inmaculada; Li, Hu; Elmes, Russell R; Peters, Luanne L; Lodish, Harvey F

    2015-06-25

    Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid

  11. Downregulation of the Spi-1/PU.1 oncogene induces the expression of TRIM10/HERF1, a key factor required for terminal erythroid cell differentiation and survival.

    PubMed

    Blaybel, Rand; Théoleyre, Orianne; Douablin, Alexandre; Baklouti, Faouzi

    2008-08-01

    Sustained expression of the Spi-1/PU.1 and Fli-1 oncoproteins blocks globin gene activation in mouse erythroleukemia cells; however, only Spi-1/PU.1 expression inhibits the inclusion of exon 16 in the mature 4.1R mRNA. This splicing event is crucial for a functional 4.1R protein and, therefore, for red blood cell membrane integrity. This report demonstrates that Spi-1/PU.1 downregulation induces the activation of TRIM10/hematopoietic RING finger 1 (HERF1), a member of the tripartite motif (TRIM)/RBCC protein family needed for globin gene transcription. Additionally, we demonstrate that TRIM10/HERF1 is required for the regulated splicing of exon 16 during late erythroid differentiation. Using inducible overexpression and silencing approaches, we found that: (1) TRIM10/HERF1 knockdown inhibits hemoglobin production and exon splicing and triggers cell apoptosis in dimethylsulfoxide (DMSO)-induced cells; (2) TRIM10/HERF1 upregulation is required but is insufficient on its own to activate exon retention; (3) Fli-1 has no effect on TRIM10/HERF1 expression, whereas either DMSO-induced downregulation or shRNA-knockdown of Spi-1/PU.1 expression is sufficient to activate TRIM10/HERF1 expression; and (4) Spi-1/PU.1 knockdown triggers both the transcription and the splicing events independently of the chemical induction. Altogether, these data indicate that primary Spi-1/PU.1 downregulation acts on late erythroid differentiation through at least two pathways, one of which requires TRIM10/HERF1 upregulation and parallels the Spi-1/PU.1-induced Fli-1 shutoff regulatory cascade.

  12. ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors.

    PubMed

    Zhang, Lingbo; Prak, Lina; Rayon-Estrada, Violeta; Thiru, Prathapan; Flygare, Johan; Lim, Bing; Lodish, Harvey F

    2013-07-01

    Stem cells and progenitors in many lineages undergo self-renewing divisions, but the extracellular and intracellular proteins that regulate this process are largely unknown. Glucocorticoids stimulate red blood cell formation by promoting self-renewal of early burst-forming unit-erythroid (BFU-E) progenitors. Here we show that the RNA-binding protein ZFP36L2 is a transcriptional target of the glucocorticoid receptor (GR) in BFU-Es and is required for BFU-E self-renewal. ZFP36L2 is normally downregulated during erythroid differentiation from the BFU-E stage, but its expression is maintained by all tested GR agonists that stimulate BFU-E self-renewal, and the GR binds to several potential enhancer regions of ZFP36L2. Knockdown of ZFP36L2 in cultured BFU-E cells did not affect the rate of cell division but disrupted glucocorticoid-induced BFU-E self-renewal, and knockdown of ZFP36L2 in transplanted erythroid progenitors prevented expansion of erythroid lineage progenitors normally seen following induction of anaemia by phenylhydrazine treatment. ZFP36L2 preferentially binds to messenger RNAs that are induced or maintained at high expression levels during terminal erythroid differentiation and negatively regulates their expression levels. ZFP36L2 therefore functions as part of a molecular switch promoting BFU-E self-renewal and a subsequent increase in the total numbers of colony-forming unit-erythroid (CFU-E) progenitors and erythroid cells that are generated.

  13. Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis

    PubMed Central

    Simmons, Bryony; Saleem, Jawaad; Hill, Andrew; Riley, Richard D.; Cooke, Graham S.

    2016-01-01

    Background. Treatment for hepatitis C virus (HCV) can lead to sustained virological response (SVR) in over 90% of people. Subsequent recurrence of HCV, either from late relapse or reinfection, reverses the beneficial effects of SVR. Methods. A search identified studies analysing HCV recurrence post-SVR. The recurrence rate for each study was calculated using events/person years of follow-up (PYFU). Results were pooled using a random-effects model and used to calculate 5-year recurrence risk. Three patient groups were analysed: (1) Mono-HCV infected “low-risk” patients; (2) Mono-HCV infected “high-risk” patients (injecting drug users or prisoners); (3) human immunodeficiency virus (HIV)/HCV coinfected patients. Recurrence was defined as confirmed HCV RNA detectability post-SVR. Results. In the 43 studies of HCV mono-infected “low-risk” patients (n = 7969) the pooled recurrence rate was 1.85/1000 PYFU (95% confidence interval [CI], .71–3.35; I2 = 73%) leading to a summary 5-year recurrence risk of 0.95% (95% CI, .35%–1.69%). For the 14 studies of HCV monoinfected “high-risk” patients (n = 771) the pooled recurrence rate was 22.32/1000 PYFU (95% CI, 13.07–33.46; I2 = 27%) leading to a summary 5-year risk of 10.67% (95% CI, 6.38%–15.66%). For the 4 studies of HIV/HCV coinfected patients the pooled recurrence rate was 32.02/1000 PYFU (95% CI, .00–123.49; I2 = 96%) leading to a summary 5-year risk of 15.02% (95% CI, .00%–48.26%). The higher pooled estimates of recurrence in the high-risk and coinfected cohorts were driven by an increase in reinfection rather than late relapse. Conclusions. SVR appears durable in the majority of patients at 5 years post-treatment. The large difference in 5 year event rate by risk group is driven mainly by an increased reinfection risk. PMID:26787172

  14. Graphitic Carbon Nitride (g-C3N4)-Based Photocatalysts for Artificial Photosynthesis and Environmental Remediation: Are We a Step Closer To Achieving Sustainability?

    PubMed

    Ong, Wee-Jun; Tan, Lling-Lling; Ng, Yun Hau; Yong, Siek-Ting; Chai, Siang-Piao

    2016-06-22

    at the forefront of this research platform. It is anticipated that this review can stimulate a new research doorway to facilitate the next generation of g-C3N4-based photocatalysts with ameliorated performances by harnessing the outstanding structural, electronic, and optical properties for the development of a sustainable future without environmental detriment. PMID:27199146

  15. Is Sustainability Sustainable?

    ERIC Educational Resources Information Center

    Bonevac, Daniel

    2010-01-01

    The most important concept in current environmental thinking is "sustainability". Environmental policies, economic policies, development, resource use--all of these things, according to the consensus, ought to be sustainable. But what is sustainability? What is its ethical foundation? There is little consensus about how these questions ought to be…

  16. Role of PI3K, MAPK/ERK1/2, and p38 in implementation of the proliferative and differentiation potential of erythroid progenitors after blood loss.

    PubMed

    Dygai, A M; Zhdanov, V V; Miroshnichenko, L A; Udut, E V; Zyuz'kov, G N; Simanina, E V; Sherstoboev, E Yu; Chaikovskii, A V; Stavrova, L A; Burmina, Ya V; Khrichkova, T Yu; Reichart, D V; Goldberg, V E

    2015-02-01

    The involvement of PI3K, ERK and p38-dependent signaling system in the regulation of functional activity of erythroid precursors after blood loss (30% of circulating volume) was studied. We demonstrated the important role of PI3K and p38 in the suppression of differentiation of erythroid precursors the contribution of p38 to stimulation of mitotic activity of erythroid CFU, which maintains the growth potential of the precursors at the optimal physiological level. The classical MAPK/ERK-kinase pathway does not determine the proliferative and differentiation status of erythroid CFU. PMID:25711660

  17. Mathematical modeling reveals differential effects of erythropoietin on proliferation and lineage commitment of human hematopoietic progenitors in early erythroid culture

    PubMed Central

    Ward, Daniel; Carter, Deborah; Homer, Martin; Marucci, Lucia; Gampel, Alexandra

    2016-01-01

    Erythropoietin is essential for the production of mature erythroid cells, promoting both proliferation and survival. Whether erythropoietin and other cytokines can influence lineage commitment of hematopoietic stem and progenitor cells is of significant interest. To study lineage restriction of the common myeloid progenitor to the megakaryocyte/erythroid progenitor of peripheral blood CD34+ cells, we have shown that the cell surface protein CD36 identifies the earliest lineage restricted megakaryocyte/erythroid progenitor. Using this marker and carboxyfluorescein succinimidyl ester to track cell divisions in vitro, we have developed a mathematical model that accurately predicts population dynamics of erythroid culture. Parameters derived from the modeling of cultures without added erythropoietin indicate that the rate of lineage restriction is not affected by erythropoietin. By contrast, megakaryocyte/erythroid progenitor proliferation is sensitive to erythropoietin from the time that CD36 first appears at the cell surface. These results shed new light on the role of erythropoietin in erythropoiesis and provide a powerful tool for further study of hematopoietic progenitor lineage restriction and erythropoiesis. PMID:26589912

  18. Mutant N-RAS Induces Erythroid Lineage Dysplasia in Human CD34+ Cells

    PubMed Central

    Darley, Richard L.; Hoy, Terence G.; Baines, Paul; Padua, Rose Ann; Burnett, Alan K.

    1997-01-01

    RAS mutations arise at high frequency (20–40%) in both acute myeloid leukemia and myelodysplastic syndrome (which is considered to be a manifestation of preleukemic disease). In each case, mutations arise predominantly at the N-RAS locus. These observations suggest a fundamental role for this oncogene in leukemogenesis. However, despite its obvious significance, little is known of how this key oncogene may subvert the process of hematopoiesis in human cells. Using CD34+ progenitor cells, we have modeled the preleukemic state by infecting these cells with amphotropic retrovirus expressing mutant N-RAS together with the selectable marker gene lacZ. Expression of the lacZ gene product, β-galactosidase, allows direct identification and study of N-RAS–expressing cells by incubating infected cultures with a fluorogenic substrate for β-galactosidase, which gives rise to a fluorescent signal within the infected cells. By using multiparameter flow cytometry, we have studied the ability of CD34+ cells expressing mutant N-RAS to undergo erythroid differentiation induced by erythropoietin. By this means, we have found that erythroid progenitor cells expressing mutant N-RAS exhibit a proliferative defect resulting in an increased cell doubling time and a decrease in the proportion of cells in S + G2M phase of the cell cycle. This is linked to a slowing in the rate of differentiation as determined by comparative cell-surface marker analysis and ultimate failure of the differentiation program at the late-erythroblast stage of development. The dyserythropoiesis was also linked to an increased tendency of the RAS-expressing cells to undergo programmed cell death during their differentiation program. This erythroid lineage dysplasia recapitulates one of the most common features of myelodysplastic syndrome, and for the first time provides a causative link between mutational activation of N-RAS and the pathogenesis of preleukemia. PMID:9104820

  19. Externalization and binding of galectin-1 on cell surface of K562 cells upon erythroid differentiation.

    PubMed

    Lutomski, D; Fouillit, M; Bourin, P; Mellottée, D; Denize, N; Pontet, M; Bladier, D; Caron, M; Joubert-Caron, R

    1997-12-01

    Galectin 1 (GAL1) is a beta-galactoside-binding lectin involved in cell cycle progression. GAL1 overexpression is associated with neoplastic transformation and loss of differentiation. The gene encoding for human GAL1 resides on chromosome 22(q12; q13), and its expression is developmentally regulated. Although devoid of signal peptide GAL1 can be externalized from cells by a mechanism independent of the normal secretory process. We report here on a study of the effects of erythroid differentiation of the human leukemia cell line K562 on GAL1 protein expression. In undifferentiated K562 cells, GAL1 was expressed into the cytosol. However, the amount of GAL1 was surprisingly weaker in K562 cells than in other leukemia cell lines such as TF-1 or KG1a. Treatment of K562 cells with erythropoietin (EPO) or with aphidicolin (APH), an inhibitor for DNA polymerase alpha, induced an erythroid phenotype and led to the externalization of cytosolic GAL1 which was then bound to ligands on cell surface in a galactoside-inhibitable fashion. Our results demonstrate that acquisition of an erythroid phenotype is associated with an externalization of GAL1. The autocrine binding of GAL1 to cell surface ligands of non adherent cells such as K562 suggest that GAL1 is implicated rather in signal transduction than in cell-cell or cell-matrix interaction. Moreover, the reciprocal translocation involving chromosomes 9 and 22 t(9;22) present in K562 cells might explain the weak expression of GAL1 in K562 leukemia cells.

  20. Gamma-interferon alters globin gene expression in neonatal and adult erythroid cells

    SciTech Connect

    Miller, B.A.; Perrine, S.P.; Antognetti, G.; Perlmutter, D.H.; Emerson, S.G.; Sieff, C.; Faller, D.V.

    1987-06-01

    The effect of gamma-interferon on fetal hemoglobin synthesis by purified cord blood, fetal liver, and adult bone marrow erythroid progenitors was studied with a radioligand assay to measure hemoglobin production by BFU-E-derived erythroblasts. Coculture with recombinant gamma-interferon resulted in a significant and dose-dependent decrease in fetal hemoglobin production by neonatal and adult, but not fetal, BFU-E-derived erythroblasts. Accumulation of fetal hemoglobin by cord blood BFU-E-derived erythroblasts decreased up to 38.1% of control cultures (erythropoietin only). Synthesis of both G gamma/A gamma globin was decreased, since the G gamma/A gamma ratio was unchanged. Picograms fetal hemoglobin per cell was decreased by gamma-interferon addition, but picograms total hemoglobin was unchanged, demonstrating that a reciprocal increase in beta-globin production occurred in cultures treated with gamma-interferon. No toxic effect of gamma-interferon on colony growth was noted. The addition of gamma-interferon to cultures resulted in a decrease in the percentage of HbF produced by adult BFU-E-derived cells to 45.6% of control. Fetal hemoglobin production by cord blood, fetal liver, and adult bone marrow erythroid progenitors, was not significantly affected by the addition of recombinant GM-CSF, recombinant interleukin 1 (IL-1), recombinant IL-2, or recombinant alpha-interferon. Although fetal progenitor cells appear unable to alter their fetal hemoglobin program in response to any of the growth factors added here, the interaction of neonatal and adult erythroid progenitors with gamma-interferon results in an altered expression of globin genes.

  1. PLACENTAL GROWTH FACTOR ATTENUATES SUPPRESSION OF ERYTHROID COLONY FORMATION BY INTERFERON

    PubMed Central

    Dallalio, Gail; Means, Robert T.

    2008-01-01

    Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is associated with inflammation and with pathologic angiogenesis. PlGF is released from marrow erythroid cells and serum PlGF concentrations have been reported to distinguish sickle cell patients from healthy controls. We observed that CFU-E from homozygous sickle cell (SS) patients are less sensitive to inhibition by recombinant human (rh) γ interferon (IFN) than those from healthy controls, and the contribution of PlGF to this process was evaluated. At concentrations 10 – 1000 pg/mL, PlGF neither inhibits nor enhances CFU-E colony formation, and there were no differences between the responses of SS patients or healthy controls. rhPlGF 100 pg/mL reversed the inhibitory effects of rhγIFN on CFU-E colony formation. rhPlGF significantly attenuated rhγIFN induction of Fas ligandin an erythroid cell line (HCD57). Both HCD57 cells and CD36+ human marrow cells express Flt-1, a receptor for PlGF. Neutralizing antibody against Flt-1 partially attenuated the IFN-protective effect of rhPlGF, although this effect was not statistically significant. In conclusion, increased PlGF concentrations in the marrow of SS patients may protect erythroid progenitors from cytokine-induced inhibition of colony formation, and may be a mechanism by which erythropoiesis in sickle cell disease is preserved despite concurrent inflammation. PMID:19010294

  2. Identification and purification of human erythroid progenitor cells by monoclonal antibody to the transferrin receptor (TU 67).

    PubMed

    Herrmann, F; Griffin, J D; Sabbath, K D; Oster, W; Wernet, P; Mertelsmann, R

    1988-04-01

    Anti-TU 67 is a murine monoclonal antibody that recognizes the transferrin receptor. With respect to hematopoietic cells TU 67 is expressed by human multipotent colony-forming cells (CFU-Mix), erythroid progenitor cells (BFU-E and CFU-E) and a fraction of granulocyte/monocyte colony forming cells, but is not expressed by mature hematopoietic cells including erythrocytes, platelets, lymphocytes, and peripheral blood myeloid cells. The TU 67-positive fraction of normal bone marrow, separated by fluorescence-activated cell sorting (FACS) or immune rosettes, contained 87% of the erythroid progenitor cells. Erythroid progenitor cells were enriched up to 50-fold by using a combination of monoclonal antibodies to deplete mature hematopoietic cells, followed by positive selection of BFU-E and CFU-E by TU 67 antibody.

  3. Olive leaf components apigenin 7-glucoside and luteolin 7-glucoside direct human hematopoietic stem cell differentiation towards erythroid lineage.

    PubMed

    Samet, Imen; Villareal, Myra O; Motojima, Hideko; Han, Junkyu; Sayadi, Sami; Isoda, Hiroko

    2015-06-01

    The generation of blood cellular components from hematopoietic stem cells is important for the therapy of a broad spectrum of hematological disorders. In recent years, several lines of evidence suggested that certain nutrients, vitamins and flavonoids may have important roles in controlling the stem cell fate decision by maintaining their self-renewal or stimulating the lineage-specific differentiation. In this study, main olive leaf phytochemicals oleuropein (Olp), apigenin 7-glucoside (Api7G) and luteolin 7-glucoside (Lut7G) were investigated for their potential effects on hematopoietic stem cell differentiation using both phenotypic and molecular analysis. Oleuropein and the combination of the three compounds enhanced the differentiation of CD34+ cells into myelomonocytic cells and lymphocytes progenitors and inhibited the commitment to megakaryocytic and erythroid lineages. Treatment with Lut7G stimulated both the erythroid and the myeloid differentiation, while treatment with Api7G specifically induced the differentiation of CD34+ cells towards the erythroid lineage and inhibited the myeloid differentiation. Erythroid differentiation induced by Api7G and Lut7G treatments was confirmed by the increase in hemoglobin genes expressions (α-hemoglobin, β-hemoglobin and γ-hemoglobin) and erythroid transcription factor GATA1 expression. As revealed by microarray analysis, the mechanisms underlying the erythroid differentiation-inducing effect of Api7G on hematopoietic stem cells involves the activation of JAK/STAT signaling pathway. These findings prove the differentiation-inducing effects of olive leaf compounds on hematopoietic stem cells and highlight their potential use in the ex vivo generation of blood cells.

  4. Olive leaf components apigenin 7-glucoside and luteolin 7-glucoside direct human hematopoietic stem cell differentiation towards erythroid lineage.

    PubMed

    Samet, Imen; Villareal, Myra O; Motojima, Hideko; Han, Junkyu; Sayadi, Sami; Isoda, Hiroko

    2015-06-01

    The generation of blood cellular components from hematopoietic stem cells is important for the therapy of a broad spectrum of hematological disorders. In recent years, several lines of evidence suggested that certain nutrients, vitamins and flavonoids may have important roles in controlling the stem cell fate decision by maintaining their self-renewal or stimulating the lineage-specific differentiation. In this study, main olive leaf phytochemicals oleuropein (Olp), apigenin 7-glucoside (Api7G) and luteolin 7-glucoside (Lut7G) were investigated for their potential effects on hematopoietic stem cell differentiation using both phenotypic and molecular analysis. Oleuropein and the combination of the three compounds enhanced the differentiation of CD34+ cells into myelomonocytic cells and lymphocytes progenitors and inhibited the commitment to megakaryocytic and erythroid lineages. Treatment with Lut7G stimulated both the erythroid and the myeloid differentiation, while treatment with Api7G specifically induced the differentiation of CD34+ cells towards the erythroid lineage and inhibited the myeloid differentiation. Erythroid differentiation induced by Api7G and Lut7G treatments was confirmed by the increase in hemoglobin genes expressions (α-hemoglobin, β-hemoglobin and γ-hemoglobin) and erythroid transcription factor GATA1 expression. As revealed by microarray analysis, the mechanisms underlying the erythroid differentiation-inducing effect of Api7G on hematopoietic stem cells involves the activation of JAK/STAT signaling pathway. These findings prove the differentiation-inducing effects of olive leaf compounds on hematopoietic stem cells and highlight their potential use in the ex vivo generation of blood cells. PMID:26299581

  5. Early Initiation of Combination Antiretroviral Therapy in HIV-1–Infected Newborns Can Achieve Sustained Virologic Suppression With Low Frequency of CD4+ T Cells Carrying HIV in Peripheral Blood

    PubMed Central

    Bitnun, Ari; Samson, Lindy; Chun, Tae-Wook; Kakkar, Fatima; Brophy, Jason; Murray, Danielle; Justement, Shawn; Soudeyns, Hugo; Ostrowski, Mario; Mujib, Shariq; Harrigan, P. Richard; Kim, John; Sandstrom, Paul; Read, Stanley E.

    2014-01-01

    Background. A human immunodeficiency virus type 1 (HIV-1)–infected infant started on combination antiretroviral therapy (cART) at 30 hours of life was recently reported to have no detectable plasma viremia after discontinuing cART. The current study investigated the impact of early cART initiation on measures of HIV-1 reservoir size in HIV-1–infected children with sustained virologic suppression. Methods. Children born to HIV-1–infected mothers and started on cART within 72 hours of birth at 3 Canadian centers were assessed. HIV serology, HIV-1–specific cell-mediated immune responses, plasma viremia, cell-associated HIV-1 DNA and RNA, presence of replication-competent HIV-1, and HLA genotype were determined for HIV-1–infected children with sustained virologic suppression. Results. Of 136 cART-treated children, 12 were vertically infected (8.8%). In the 4 who achieved sustained virologic suppression, HIV serology, HIV-1–specific cell-mediated immune responses (Gag, Nef), and ultrasensitive viral load were negative. HIV-1 DNA was not detected in enriched CD4+ T cells of the 4 children (<2.6 copies/106 CD4+ T cells), whereas HIV-1 RNA was detected (19.5–130 copies/1.5 µg RNA). No virion-associated HIV-1 RNA was detected following mitogenic stimulation of peripheral blood CD4+ T cells (5.4–8.0 million CD4+ T cells) in these 4 children, but replication competent virus was detected by quantitative co-culture involving a higher number of cells in 1 of 2 children tested (0.1 infectious units/106 CD4+ T cells). Conclusions. In perinatally HIV-1–infected newborns, initiation of cART within 72 hours of birth may significantly reduce the size of the HIV-1 reservoirs. Cessation of cART may be necessary to determine whether functional HIV cure can be achieved in such children. PMID:24917662

  6. Murine tribbles homolog 2 deficiency affects erythroid progenitor development and confers macrocytic anemia on mice.

    PubMed

    Lin, Kou-Ray; Yang-Yen, Hsin-Fang; Lien, Huang-Wei; Liao, Wei-Hao; Huang, Chang-Jen; Lin, Liang-In; Li, Chung-Leung; Yen, Jeffrey Jong-Young

    2016-01-01

    Tribbles homolog 2 (Trib2) is a member of Tribbles protein pseudokinases and involves in apoptosis, autoimmunity, cancer, leukemia and erythropoiesis, however, the physiological function of Trib2 in hematopoietic system remains to be elucidated. Here, we report that Trib2 knockout (KO) mice manifest macrocytic anemia and increase of T lymphocytes. Although Trib2 deficient RBCs have similar half-life as the control RBCs, Trib2 KO mice are highly vulnerable to oxidant-induced hemolysis. Endogenous Trib2 mRNA is expressed in early hematopoietic progenitors, erythroid precursors, and lymphoid lineages, but not in mature RBCs, myeloid progenitors and granulocytes. Consistently, flow cytometric analysis and in vitro colony forming assay revealed that deletion of Trib2 mainly affected erythroid lineage development, and had no effect on either granulocyte or megakaryocyte lineages in bone marrow. Furthermore, a genetic approach using double knockout of Trib2 and C/ebpα genes in mice suggested that Trib2 promotes erythropoiesis independent of C/ebpα proteins in vivo. Finally, ectopic expression of human Trib2 in zebrafish embryos resulted in increased expression of erythropoiesis-related genes and of hemoglobin. Taking all data together, our results suggest that Trib2 positively promotes early erythrocyte differentiation and is essential for tolerance to hemolysis. PMID:27550848

  7. The genome-wide dynamics of the binding of Ldb1 complexes during erythroid differentiation.

    PubMed

    Soler, Eric; Andrieu-Soler, Charlotte; de Boer, Ernie; Bryne, Jan Christian; Thongjuea, Supat; Stadhouders, Ralph; Palstra, Robert-Jan; Stevens, Mary; Kockx, Christel; van Ijcken, Wilfred; Hou, Jun; Steinhoff, Christine; Rijkers, Erikjan; Lenhard, Boris; Grosveld, Frank

    2010-02-01

    One of the complexes formed by the hematopoietic transcription factor Gata1 is a complex with the Ldb1 (LIM domain-binding protein 1) and Tal1 proteins. It is known to be important for the development and differentiation of the erythroid cell lineage and is thought to be implicated in long-range interactions. Here, the dynamics of the composition of the complex-in particular, the binding of the negative regulators Eto2 and Mtgr1-are studied, in the context of their genome-wide targets. This shows that the complex acts almost exclusively as an activator, binding a very specific combination of sequences, with a positioning relative to transcription start site, depending on the type of the core promoter. The activation is accompanied by a net decrease in the relative binding of Eto2 and Mtgr1. A Chromosome Conformation Capture sequencing (3C-seq) assay also shows that the binding of the Ldb1 complex marks genomic interaction sites in vivo. This establishes the Ldb1 complex as a positive regulator of the final steps of erythroid differentiation that acts through the shedding of negative regulators and the active interaction between regulatory sequences. PMID:20123907

  8. Transcription of the hypersensitive site HS2 enhancer in erythroid cells.

    PubMed Central

    Tuan, D; Kong, S; Hu, K

    1992-01-01

    In the human genome, the erythroid-specific hypersensitive site HS2 enhancer regulates the transcription of the downstream beta-like globin genes 10-50 kilobases away. The mechanism of HS2 enhancer function is not known. The present study employs RNA protection assays to analyze the transcriptional status of the HS2 enhancer in transfected recombinant chloramphenicol acetyltransferase (CAT) plasmids. In erythroid K562 cells in which the HS2 enhancer is active, the HS2 sequence directs the synthesis of long enhancer transcripts that are initiated apparently from within the enhancer and elongated through the intervening DNA into the cis-linked CAT gene. In nonerythroid HL-60 cells in which the HS2 enhancer is inactive, long enhancer transcripts are not detectable. Splitting the HS2 enhancer between two tandem Ap1 sites abolishes the synthesis of a group of long enhancer transcripts and results in loss of enhancer function and transcriptional silencing of the cis-linked CAT gene. In directing the synthesis of RNA through the intervening DNA and the gene by a tracking and transcription mechanism, the HS2 enhancer may (i) open up the chromatin structure of a gene domain and (ii) deliver enhancer binding proteins to the promoter sequence where they may stimulate the transcription of the gene at the cap site. Images PMID:1454801

  9. Protein 4.1R–deficient mice are viable but have erythroid membrane skeleton abnormalities

    PubMed Central

    Shi, Zheng-Tao; Afzal, Veena; Coller, Barry; Patel, Dipti; Chasis, Joel A.; Parra, Marilyn; Lee, Gloria; Paszty, Chris; Stevens, Mary; Walensky, Loren; Peters, Luanne L.; Mohandas, Narla; Rubin, Edward; Conboy, John G.

    1999-01-01

    A diverse family of protein 4.1R isoforms is encoded by a complex gene on human chromosome 1. Although the prototypical 80-kDa 4.1R in mature erythrocytes is a key component of the erythroid membrane skeleton that regulates erythrocyte morphology and mechanical stability, little is known about 4.1R function in nucleated cells. Using gene knockout technology, we have generated mice with complete deficiency of all 4.1R protein isoforms. These 4.1R-null mice were viable, with moderate hemolytic anemia but no gross abnormalities. Erythrocytes from these mice exhibited abnormal morphology, lowered membrane stability, and reduced expression of other skeletal proteins including spectrin and ankyrin, suggesting that loss of 4.1R compromises membrane skeleton assembly in erythroid progenitors. Platelet morphology and function were essentially normal, indicating that 4.1R deficiency may have less impact on other hematopoietic lineages. Nonerythroid 4.1R expression patterns, viewed using histochemical staining for lacZ reporter activity incorporated into the targeted gene, revealed focal expression in specific neurons in the brain and in select cells of other major organs, challenging the view that 4.1R expression is widespread among nonerythroid cells. The 4.1R knockout mice represent a valuable animal model for exploring 4.1R function in nonerythroid cells and for determining pathophysiological sequelae to 4.1R deficiency. PMID:9927493

  10. During EPO or anemia challenge, erythroid progenitor cells transit through a selectively expandable proerythroblast pool.

    PubMed

    Dev, Arvind; Fang, Jing; Sathyanarayana, Pradeep; Pradeep, Anamika; Emerson, Christine; Wojchowski, Don M

    2010-12-01

    Investigations of bone marrow (BM) erythroblast development are important for clinical concerns but are hindered by progenitor cell and tissue availability. We therefore sought to more specifically define dynamics, and key regulators, of the formation of developing BM erythroid cell cohorts. A unique Kit(-)CD71(high)Ter119(-) "stage E2" proerythroblast pool first is described, which (unlike its Kit(+) "stage E1" progenitors, or maturing Ter119(+) "stage E3" progeny) proved to selectively expand ∼ 7-fold on erythropoietin challenge. During short-term BM transplantation, stage E2 proerythroblasts additionally proved to be a predominantly expanded progenitor pool within spleen. This E1→E2→E3 erythroid series reproducibly formed ex vivo, enabling further characterizations. Expansion, in part, involved E1 cell hyperproliferation together with rapid E2 conversion plus E2 stage restricted BCL2 expression. Possible erythropoietin/erythropoietin receptor proerythroblast stage specific events were further investigated in mice expressing minimal erythropoietin receptor alleles. For a hypomorphic erythropoietin receptor-HM allele, major defects in erythroblast development occurred selectively at stage E2. In addition, stage E2 cells proved to interact productively with primary BM stromal cells in ways that enhanced both survival and late-stage development. Overall, findings reveal a novel transitional proerythroblast compartment that deploys unique expansion devices.

  11. Murine tribbles homolog 2 deficiency affects erythroid progenitor development and confers macrocytic anemia on mice

    PubMed Central

    Lin, Kou-Ray; Yang-Yen, Hsin-Fang; Lien, Huang-Wei; Liao, Wei-Hao; Huang, Chang-Jen; Lin, Liang-In; Li, Chung-Leung; Yen, Jeffrey Jong-Young

    2016-01-01

    Tribbles homolog 2 (Trib2) is a member of Tribbles protein pseudokinases and involves in apoptosis, autoimmunity, cancer, leukemia and erythropoiesis, however, the physiological function of Trib2 in hematopoietic system remains to be elucidated. Here, we report that Trib2 knockout (KO) mice manifest macrocytic anemia and increase of T lymphocytes. Although Trib2 deficient RBCs have similar half-life as the control RBCs, Trib2 KO mice are highly vulnerable to oxidant-induced hemolysis. Endogenous Trib2 mRNA is expressed in early hematopoietic progenitors, erythroid precursors, and lymphoid lineages, but not in mature RBCs, myeloid progenitors and granulocytes. Consistently, flow cytometric analysis and in vitro colony forming assay revealed that deletion of Trib2 mainly affected erythroid lineage development, and had no effect on either granulocyte or megakaryocyte lineages in bone marrow. Furthermore, a genetic approach using double knockout of Trib2 and C/ebpα genes in mice suggested that Trib2 promotes erythropoiesis independent of C/ebpα proteins in vivo. Finally, ectopic expression of human Trib2 in zebrafish embryos resulted in increased expression of erythropoiesis-related genes and of hemoglobin. Taking all data together, our results suggest that Trib2 positively promotes early erythrocyte differentiation and is essential for tolerance to hemolysis. PMID:27550848

  12. Transcription of the hypersensitive site HS2 enhancer in erythroid cells

    SciTech Connect

    Tuan, D.; Suming Kong; Hu, K. )

    1992-12-01

    In the human genome, the erythroid-specific hypersensitive site HS2 enhancer regulates the transcription of the downstream [beta]-like globin genes 10-50 kilobases away. The mechanism of HS2 enhancer function is not known. The present study employs RNA protection assays to analyze the transcriptional status of the HS2 enhancer in transfected recombinant chloramphenicol acetyltransferase (CAT) plasmids. In erythroid K562 cells in which the HS2 enhancer is active, the HS2 sequence directs the synthesis of long enhancer transcripts that are initiated apparently from within the enhancer and elongated through the intervening DNA into the cis-linked CAT gene. In nonerythroid HL-60 cells in which the HS2 enhancer is inactive, long enhancer transcripts are not detectable. Splitting the HS2 enhancer between two tandem Ap1 sites abolishes the synthesis of a group of long enhancer transcripts and results in loss of enhancer function and transcriptional silencing of the cis-linked CAT gene. In directing the synthesis of RNA through the intervening DNA and the gene by a tracking and transcription mechanism, the HS2 enhancer may (i) open up the chromatin structure of a gene domain and (ii) deliver enhancer binding proteins to the promoter sequence where they may stimulate the transcription of the gene at the cap site. 42 refs., 4 figs., 1 tab.

  13. Structural and functional characterization of an atypical activation domain in erythroid Kruppel-like factor (EKLF).

    PubMed

    Mas, Caroline; Lussier-Price, Mathieu; Soni, Shefali; Morse, Thomas; Arseneault, Geneviève; Di Lello, Paola; Lafrance-Vanasse, Julien; Bieker, James J; Omichinski, James G

    2011-06-28

    Erythroid Krüppel-like factor (EKLF) plays an important role in erythroid development by stimulating β-globin gene expression. We have examined the details by which the minimal transactivation domain (TAD) of EKLF (EKLFTAD) interacts with several transcriptional regulatory factors. We report that EKLFTAD displays homology to the p53TAD and, like the p53TAD, can be divided into two functional subdomains (EKLFTAD1 and EKLFTAD2). Based on sequence analysis, we found that EKLFTAD2 is conserved in KLF2, KLF4, KLF5, and KLF15. In addition, we demonstrate that EKLFTAD2 binds the amino-terminal PH domain of the Tfb1/p62 subunit of TFIIH (Tfb1PH/p62PH) and four domains of CREB-binding protein/p300. The solution structure of the EKLFTAD2/Tfb1PH complex indicates that EKLFTAD2 binds Tfb1PH in an extended conformation, which is in contrast to the α-helical conformation seen for p53TAD2 in complex with Tfb1PH. These studies provide detailed mechanistic information into EKLFTAD functions as well as insights into potential interactions of the TADs of other KLF proteins. In addition, they suggest that not only have acidic TADs evolved so that they bind using different conformations on a common target, but that transitioning from a disordered to a more ordered state is not a requirement for their ability to bind multiple partners. PMID:21670263

  14. Interleukin 3 promotes erythroid burst formation in serum-free cultures without detectable erythropoietin

    SciTech Connect

    Goodman, J.W.; Hall, E.A.; Miller, K.L.; Shinpock, S.G.

    1985-05-01

    Erythroid burst-forming units (BFU-E) from mouse bone marrow were grown for 7 days in agar or serum-free methylcellulose cultures in the presence or absence of erythropoietin (Ep) and/or interleukin 3 (IL-3). It was found that IL-3, even in the absence of serum and detectable Ep, was able to stimulate the full development of many erythroid bursts. This IL-3 effect was cell-dose dependent and did not appear to correlate with Ep dose. Spontaneous bursts and those stimulated by Ep only were rare and when seen were very small relative to those produced by IL-3 or IL-3 plus Ep. When addition of IL-3 or Ep to 7-day cultures was delayed, IL-3 but not Ep was shown to maintain BFU-E. No evidence was found by radioimmunoassay that Ep was produced or released in 7-day, serum-free cultures of bone marrow nor was Ep activity detected in culture media except those to which it had been added deliberately.

  15. Sustainable development.

    PubMed

    Dudani, A T

    1996-01-01

    Many attempts have been made over the last decade to define sustainable development (SD). However, it is much easier to describe one's expectations of SD. The discussion over SD grew in the wake of the Brundlandt Commission report, Our Common Future (OCF), which describes SD as a process of change in which resources, the direction of investment, orientation of technological development, and institutional change all enhance the potential to meet human needs today and in the future. The OCF stresses the interrelationship between SD and economic development such that nothing can be at the expense of environmental destruction. Close cooperation is needed at the domestic and international political, social, and economic levels and spheres in order to achieve long-term SD. The author discusses the state of affairs in the US and sustainable agriculture and SD.

  16. Achieving Sustainable Construction in Affordable Housing

    SciTech Connect

    Barcik, M.K.; Creech, D.B.; Ternes, M.P.

    1998-12-07

    An energy-efficient design and construction checklist and information sheets on energy-efficient design and construction are two products being developed. These products will help affordable housing providers take the first steps toward a whole-house approach to the design and implementation of energy-efficient construction practices. The checklist presents simple and clear guidance on energy improvements that can be readily addressed now by most affordable housing providers. The information sheets complement the checklist by providing installation instructions and material specifications that are accompanied by detailed graphics. The information sheets also identify benefits of recommended energy-efficiency measures and procedures including cost savings and impacts on health and comfort. This paper presents details on the checklist and information sheets and discusses their use in two affordable housing projects.

  17. Achieving Sustainability in Learning and Teaching Initiatives

    ERIC Educational Resources Information Center

    Brew, Angela; Cahir, Jayde

    2014-01-01

    Universities have a long history of change in learning and teaching to suit various government initiatives and institutional priorities. Academic developers now are frequently required to address strategic learning and teaching priorities. This paper asks how, in such a context, academic developers can ensure that work they do in relation to one…

  18. VLA-5-mediated Adhesion to Fibronectin Accelerates Hemin-stimulated Erythroid Differentiation of K562 Cells through Induction of VLA-4 Expression*

    PubMed Central

    Tanaka, Rika; Owaki, Toshiyuki; Kamiya, Sadahiro; Matsunaga, Takuya; Shimoda, Kazuya; Kodama, Hiroaki; Hayashi, Ryo; Abe, Takashi; Harada, Yosei P.; Shimonaka, Motoyuki; Yajima, Hirofumi; Terada, Hiroshi; Fukai, Fumio

    2009-01-01

    Fibronectin plays important roles in erythropoiesis through the fibronectin receptors VLA-4 and VLA-5. However, the substantial role of these fibronectin receptors and their functional assignment in erythroid differentiation are not yet fully understood. Here, we investigated the effects of cell adhesion to fibronectin on erythroid differentiation using K562 human erythroid progenitor cells. Erythroid differentiation could be induced in K562 cells in suspension by stimulating with hemin. This hemin-stimulated erythroid differentiation was highly accelerated when cells were induced to adhere to fibronectin by treatment with TNIIIA2, a peptide derived from tenascin-C, which has recently been found to induce β1-integrin activation. Another integrin activator, Mn2+, also accelerated hemin-stimulated erythroid differentiation. Adhesive interaction with fibronectin via VLA-4 as well as VLA-5 was responsible for acceleration of the hemin-stimulated erythroid differentiation in response to TNIIIA2, although K562 cells should have been lacking in VLA-4. Adhesion to fibronectin forced by TNIIIA2 causally induced VLA-4 expression in K562 cells, and this was blocked by the RGD peptide, an antagonist for VLA-5. The resulting adhesive interaction with fibronectin via VLA-4 strongly enhanced the hemin-stimulated activation of p38 mitogen-activated protein kinase, which was shown to serve as a signaling molecule crucial for erythroid differentiation. Suppression of VLA-4 expression by RNA interference abrogated acceleration of hemin-stimulated erythroid differentiation in response to TNIIIA2. Thus, VLA-4 and VLA-5 may contribute to erythropoiesis at different stages of erythroid differentiation. PMID:19460753

  19. Binding of HMG 17 to mononucleosomes of the avian beta-globin gene cluster in erythroid and non-erythroid cells.

    PubMed Central

    Brotherton, T W; Reneker, J; Ginder, G D

    1990-01-01

    The binding of HMG 17 to stripped core mononucleosomes containing DNA from the avian beta-globin gene cluster was examined to determine whether binding in vitro in this developmentally-regulated gene domain was associated with transcriptional activity or DNaseI-sensitivity in intact nuclei. Mononucleosomes were prepared from primitive and definitive stage embryonic red blood cells of chick embryos, adult reticulocytes, adult reticulocytes in which embryonic rho-globin transcription was induced, and adult thymus cells. Preferential binding by HMG 17 to mononucleosomes containing the beta-globin gene cluster was confined to erythroid-derived mononucleosomes that contain the embryonic rho-globin gene, the adult beta-globin gene, and DNA sequences located between these two genes, but not to those that contain the embryonic epsilon-globin gene. Comparison of these results to the known patterns of transcription and DNaseI-sensitivity within the beta-globin gene cluster shows that HMG 17 binding, although tissue-specific, does not correlate directly with either DNaseI-sensitivity or active gene transcription, but is dependent on other factors present in core mononucleosomes from this active gene domain. Images PMID:1692412

  20. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8/S100A9

    PubMed Central

    Schneider, Rebekka K.; Schenone, Monica; Ferreira, Monica Ventura; Kramann, Rafael; Joyce, Cailin E.; Hartigan, Christina; Beier, Fabian; Brümmendorf, Tim H.; Gehrming, Ulrich; Platzbecker, Uwe; Büsche, Guntram; Knüchel, Ruth; Chen, Michelle C.; Waters, Christopher S.; Chen, Edwin; Chu, Lisa P.; Novina, Carl D.; Lindsley, R. Coleman; Carr, Steven A.; Ebert, Benjamin L.

    2016-01-01

    Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100a8/S100a9 proteins in purified erythroblasts. S100a8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100a8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS. PMID:26878232

  1. Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation.

    PubMed

    Rimmelé, Pauline; Kosmider, Olivier; Mayeux, Patrick; Moreau-Gachelin, Françoise; Guillouf, Christel

    2007-04-01

    Overexpression of the transcription factor Spi-1/PU.1 in mice leads to acute erythroleukemia characterized by a differentiation block at the proerythroblastic stage. In this study, we made use of a new cellular system allowing us to reach graded expression of Spi-1 in preleukemic cells to dissect mechanisms of Spi-1/ PU-1 in erythroleukemogenesis. This system is based on conditional production of 1 or 2 spi-1-interfering RNAs stably inserted into spi-1 transgenic proerythroblasts. We show that Spi-1 knock-down was sufficient to reinstate the erythroid differentiation program. This differentiation process was associated with an exit from the cell cycle. Evidence is provided that in the presence of erythropoietin (Epo), Spi-1 displays an antiapoptotic role that is independent of its function in blocking erythroid differentiation. Apoptosis inhibited by Spi-1 did not involve activation of the Fas/FasL signaling pathway nor a failure to activate Epo receptor (EpoR). Furthermore, we found that reducing the Spi-1 level yields to ERK dephosphorylation and increased phosphorylation of AKT and STAT5, suggesting that Spi-1 may affect major signaling pathways downstream of the EpoR in erythroid cells. These findings reveal 2 distinct roles for Spi-1 during erythroleukemogenesis: Spi-1 blocks the erythroid differentiation program and acts to impair apoptotic death in cooperation with an Epo signaling.

  2. Erythroid cell growth and differentiation in vitro in the simulated microgravity environment of the NASA rotating wall vessel bioreactor

    NASA Technical Reports Server (NTRS)

    Sytkowski, A. J.; Davis, K. L.

    2001-01-01

    Prolonged exposure of humans and experimental animals to the altered gravitational conditions of space flight has adverse effects on the lymphoid and erythroid hematopoietic systems. Although some information is available regarding the cellular and molecular changes in lymphocytes exposed to microgravity, little is known about the erythroid cellular changes that may underlie the reduction in erythropoiesis and resultant anemia. We now report a reduction in erythroid growth and a profound inhibition of erythropoietin (Epo)-induced differentiation in a ground-based simulated microgravity model system. Rauscher murine erythroleukemia cells were grown either in tissue culture vessels at 1 x g or in the simulated microgravity environment of the NASA-designed rotating wall vessel (RWV) bioreactor. Logarithmic growth was observed under both conditions; however, the doubling time in simulated microgravity was only one-half of that seen at 1 x g. No difference in apoptosis was detected. Induction with Epo at the initiation of the culture resulted in differentiation of approximately 25% of the cells at 1 x g, consistent with our previous observations. In contrast, induction with Epo at the initiation of simulated microgravity resulted in only one-half of this degree of differentiation. Significantly, the growth of cells in simulated microgravity for 24 h prior to Epo induction inhibited the differentiation almost completely. The results suggest that the NASA RWV bioreactor may serve as a suitable ground-based microgravity simulator to model the cellular and molecular changes in erythroid cells observed in true microgravity.

  3. Control of erythroid cell production via caspase-mediated cleavage of transcription factor SCL/Tal-1.

    PubMed

    Zeuner, A; Eramo, A; Testa, U; Felli, N; Pelosi, E; Mariani, G; Srinivasula, S M; Alnemri, E S; Condorelli, G; Peschle, C; De Maria, R

    2003-08-01

    SCL/Tal-1 is a helix-loop-helix (HLH) transcription factor required for blood cell development, whose abnormal expression is responsible for induction of T-cell acute lymphoblastic leukemia. We show here that SCL/Tal-1 is a key target of caspases in developing erythroblasts. SCL/Tal-1 degradation occurred rapidly after caspase activation and preceded the cleavage of the major erythroid transcription factor GATA-1. Expression of a caspase-resistant SCL/Tal-1 in erythroid progenitors was able to prevent amplification of caspase activation, GATA-1 degradation and impaired erythropoiesis induced by growth factor deprivation or death receptor triggering. The potent proerythropoietic activity of uncleavable SCL/Tal-1 was clearly evident in the absence of erythropoietin, a condition that did not allow survival of normal erythroid cells or expansion of erythroblasts expressing caspase-resistant GATA-1. In the absence of erythropoietin, cells expressing caspase-resistant SCL/Tal-1 maintain high levels of Bcl-X(L), which inhibits amplification of the caspase cascade and mediates protection from apoptosis. Thus, SCL/TAL-1 is a survival factor for erythroid cells, whereas caspase-mediated cleavage of SCL/Tal-1 results in amplification of caspase activation, GATA-1 degradation and impaired erythropoiesis.

  4. How Schools Sustain Success

    ERIC Educational Resources Information Center

    Chrisman, Valerie

    2005-01-01

    A growing number of the US schools, under the microscope of increased accountability, are identified as underperforming on the basis of low-test scores. Yet sustained increases in student achievement are problematic for underperforming schools.

  5. CTCF and CohesinSA-1 Mark Active Promoters and Boundaries of Repressive Chromatin Domains in Primary Human Erythroid Cells

    PubMed Central

    Steiner, Laurie A.; Schulz, Vincent; Makismova, Yelena; Lezon-Geyda, Kimberly; Gallagher, Patrick G.

    2016-01-01

    Background CTCF and cohesinSA-1 are regulatory proteins involved in a number of critical cellular processes including transcription, maintenance of chromatin domain architecture, and insulator function. To assess changes in the CTCF and cohesinSA-1 interactomes during erythropoiesis, chromatin immunoprecipitation coupled with high throughput sequencing and mRNA transcriptome analyses via RNA-seq were performed in primary human hematopoietic stem and progenitor cells (HSPC) and primary human erythroid cells from single donors. Results Sites of CTCF and cohesinSA-1 co-occupancy were enriched in gene promoters in HSPC and erythroid cells compared to single CTCF or cohesin sites. Cell type-specific CTCF sites in erythroid cells were linked to highly expressed genes, with the opposite pattern observed in HSPCs. Chromatin domains were identified by ChIP-seq with antibodies against trimethylated lysine 27 histone H3, a modification associated with repressive chromatin. Repressive chromatin domains increased in both number and size during hematopoiesis, with many more repressive domains in erythroid cells than HSPCs. CTCF and cohesinSA-1 marked the boundaries of these repressive chromatin domains in a cell-type specific manner. Conclusion These genome wide data, changes in sites of protein occupancy, chromatin architecture, and related gene expression, support the hypothesis that CTCF and cohesinSA-1 have multiple roles in the regulation of gene expression during erythropoiesis including transcriptional regulation at gene promoters and maintenance of chromatin architecture. These data from primary human erythroid cells provide a resource for studies of normal and perturbed erythropoiesis. PMID:27219007

  6. The effect of high intensity microwave exposure on enucleation of murine erythroid cells in vitro.

    PubMed

    Sciandra, J J; Repasky, E; Subjeck, J R; Johnson, R J

    1982-03-01

    We have examined the effects of microwave vs sham exposure on the enucleation phase of murine erythroid cells in vitro. While enucleation occurs rapidly in vivo, it occurs somewhat slower in vitro and can be quantitated in terms of rate. Exposure to 915 MHz electromagnetic radiation is found to significantly reduce the rate of enucleation (P less than 0.001). Exposure is carried out in a TE10 mode energized water-filled temperature-controlled waveguide. It is hypothesized that the effects of the exposure are on cytoplasmic or plasma membrane-associated structures since the nucleus at this stage of maturation is completely condensed and inactive. This assay is of direct interest in itself as well as providing a tool for the investigation of biological response to microwave exposure.

  7. Iron overload impairs proliferation of erythroid progenitors cells (BFU-E) from patients with myelodysplastic syndromes.

    PubMed

    Hartmann, Julia; Braulke, Friederike; Sinzig, Ursula; Wulf, Gerald; Maas, Jens Holger; Konietschke, Frank; Haase, Detlef

    2013-03-01

    In patients with myelodysplastic syndromes (MDS) iron overload caused by long-term red blood cell transfusions is an important factor for comorbidity especially in low-risk MDS. In this report we present the results of a comparative study based on colony formation assays of hematopoietic cells in MDS patients with and without iron overload. We demonstrate that iron overload suppresses the proliferation of erythroid progenitors cells (BFU-E), while the myeloid compartment (CFU-GM) was not found to be affected. Even patients with slightly elevated ferritin values show an impaired proliferation capacity in comparison to patients with normal ferritin levels. Furthermore, we show that this negative impact is reversible by sufficient iron chelation therapy.

  8. Critical role of the matricellular protein SPARC in mediating erythroid progenitor cell development in zebrafish.

    PubMed

    Ceinos, Rosa M; Torres-Nuñez, Eva; Chamorro, Ruben; Novoa, Beatriz; Figueras, Antonio; Ruane, Neil M; Rotllant, Josep

    2013-01-01

    Sparc (osteonectin) is a multifunctional matricellular glycoprotein expressed by many differentiated cells. Members of this family mediate cell-matrix interactions rather than acting as structural components of the extracellular matrix (ECM); therefore, they can influence many remodelling events, including haematopoiesis. We have investigated the role of sparc in embryonic haematopoiesis using a morpholino antisense oligonucleotide-based knockdown approach. Knockdown of sparc function resulted in specific erythroid progenitor cell differentiation defects that were highlighted by changes in gene expression and morphology, which could be rescued by injection of sparc mRNA. Furthermore, a comparison of blood phenotypes of sparc and fgfs knockdowns with similar defects and the sparc rescue of the fgf21 blood phenotype places sparc downstream of fgf21 in the genetic network regulating haematopoiesis in zebrafish. These results establish a role for an ECM protein (Sparc) as an important regulator of embryonic haematopoiesis during early development in zebrafish.

  9. The exon-intron organization of the human erythroid [beta]-spectrin gene

    SciTech Connect

    Amin, K.M.; Forget, B.G. ); Scarpa, A.L.; Curtis, P.J. ); Winkelmann, J.C. )

    1993-10-01

    The human erythrocyte [beta]-spectrin gene DNA has been cloned from overlapping human genomic phage and cosmid recombinants. The entire erythroid [beta]-spectrin mRNA is encoded by 32 exons that range in size from 49 to 871 bases. The exon/intron junctions have been identified and the exons mapped. There is no correlation between intron positions and the repeat units of 106 amino acids within domain II of the [beta]-spectrin gene. The scatter of the introns over the 17 repeats argues against the 106-amino-acid unit representing a minigene that underwent repeated duplication resulting in the present [beta]-spectrin gene. In fact, the two largest exons, exon 14 (871 bp) and 16 (757 bp), extend over 4 and 3 repeat units of 106 amino acids, respectively, while repeat [beta]10 is encoded by 4 exons. No single position of an intron in the [beta]-spectrin gene is conserved between any of the 17 [beta]-spectrin and 22 [alpha]-spectrin repeat units. The nucleotide sequences of the exon/intron boundaries conform to the consensus splice site sequences except for exon 20, whose 5[prime] donor splice-site sequence begins with GC. The [beta]-spectrin isoform present in the human brain, the skeletal muscle, and the cardiac muscle is an alternatively spliced product of the erythroid [beta]-spectrin gene. This splice site is located within the coding sequences of exon 32 and its utilization in nonerythroid tissues leads to the use of 4 additional downstream exons with a size range of 44 to 530 bp. 55 refs., 3 figs., 3 tabs.

  10. Multiple physical stresses induce γ-globin gene expression and fetal hemoglobin production in erythroid cells.

    PubMed

    Schaeffer, Emily K; West, Rachel J; Conine, Sarah J; Lowrey, Christopher H

    2014-04-01

    Increased fetal hemoglobin (HbF) expression is beneficial for β-hemoglobinopathy patients; however, current inducing agents do not possess the ideal combination of efficacy, safety and ease of use. Better understanding the mechanisms involved in γ-globin gene induction is critical for designing improved therapies, as no complete mechanism for any inducing agent has been identified. Given the cytotoxic nature of most known inducing drugs, we hypothesized that γ-globin is a cell stress response gene, and that induction occurs via activation of cell stress signaling pathways. We tested this hypothesis by investigating the ability of physical stresses including heat-shock (HS), UV- and X-irradiation and osmotic shock to increase γ-globin gene expression in erythroid cells. Experiments in K562 and KU812 cells showed that each of these stresses increased steady-state γ-globin mRNA levels, but only after 3-5days of treatments. HS and UV also increased γ-globin mRNA and HbF levels in differentiating primary human erythroid cells. Mechanistic studies showed that HS affects γ-globin mRNA at multiple levels, including nascent transcription and transcript stability, and that induction is dependent on neither the master regulator of the canonical HS response, HSF1, nor p38 MAPK. Inhibitor panel testing identified PI3K inhibitor LY294002 as a novel inducing agent and revealed potential roles for NFκB and VEGFR/PDGFR/Raf kinases in HS-mediated γ-globin gene induction. These findings suggest that cell stress signaling pathways play an important role in γ-globin gene induction and may provide novel targets for the pharmacologic induction of fetal hemoglobin.

  11. Parvovirus B19 Replication and Expression in Differentiating Erythroid Progenitor Cells

    PubMed Central

    Bua, Gloria; Manaresi, Elisabetta; Bonvicini, Francesca; Gallinella, Giorgio

    2016-01-01

    The pathogenic Parvovirus B19 (B19V) is characterized by a strict adaptation to erythroid progenitor cells (EPCs), a heterogeneous population of differentiating cells with diverse phenotypic and functional properties. In our work, we studied the dynamics of B19V infection in EPCs in dependence on the cell differentiation stage, in terms of distribution of infected cells, synthesis of viral nucleic acids and production of infectious virus. EPCs at early differentiation stage led to an abortive infection, without viral genome replication and a very low transcriptional activity. EPCs at later stages were permissive, with highest levels of viral replicative activity at day 9 (+3.0 Log from 2 to 48 hpi) and lower levels at day 18 (+1.5 Log from 2 to 48 hpi). B19V DNA increment was in accordance with the percentage of cells positive to flow-FISH assay (41.4% at day 9, 1.1% at day 18). Quantitation of total RNA indicated a close association of genome replication and transcription with viral RNA accumulation within infected cells related to viral DNA increase during the course of infection. Analysis of the different classes of mRNAs revealed two distinct pattern of genome expression profile with a fine regulation in the frequency utilization of RNA processing signals: an early phase, when cleavage at the proximal site leading to a higher relative production of mRNA for NS protein, and a late phase, when cleavage at the distal site was more frequent leading to higher relative abundance of mRNA for VP and 11 kDA proteins. Infectious virus was released from cells at day 6–15, but not at day 18. Our results, providing a detailed description of B19V replication and expression profile in differentiating EPCs, highlight the very tight adaptation of B19V to a specific cellular target defined both by its erythroid lineage and its differentiation stage. PMID:26845771

  12. Lifetime achievement

    NASA Astrophysics Data System (ADS)

    Carlowicz, Michael

    The American Association for the Advancement of Science (AAAS) is accepting nominations for the 1996 Philip Hauge Abelson Prize. The prize is awarded annually to either a public servant who has made sustained contributions to the advancement of science or to scientists who have distinguished themselves for both the quality of their work and their leadership in the scientific community.

  13. Recombinant erythroid Kruppel-like factor fused to GATA1 up-regulates delta- and gamma-globin expression in erythroid cells.

    PubMed

    Zhu, Jianqiong; Chin, Kyung; Aerbajinai, Wulin; Trainor, Cecelia; Gao, Peter; Rodgers, Griffin P

    2011-03-17

    The β-hemoglobinopathies sickle cell disease and β-thalassemia are among the most common human genetic disorders worldwide. Hemoglobin A2 (HbA2, α₂δ₂) and fetal hemoglobin (HbF, α₂γ₂) both inhibit the polymerization of hemoglobin S, which results in erythrocyte sickling. Expression of erythroid Kruppel-like factor (EKLF) and GATA1 is critical for transitioning hemoglobin from HbF to hemoglobin A (HbA, α₂β₂) and HbA2. The lower levels of δ-globin expression compared with β-globin expression seen in adulthood are likely due to the absence of an EKLF-binding motif in the δ-globin proximal promoter. In an effort to up-regulate δ-globin to increase HbA2 expression, we created a series of EKLF-GATA1 fusion constructs composed of the transactivation domain of EKLF and the DNA-binding domain of GATA1, and then tested their effects on hemoglobin expression. EKLF-GATA1 fusion proteins activated δ-, γ-, and β-globin promoters in K562 cells, and significantly up-regulated δ- and γ-globin RNA transcript and protein expression in K562 and/or CD34(+) cells. The binding of EKLF-GATA1 fusion proteins at the GATA1 consensus site in the δ-globin promoter was confirmed by chromatin immunoprecipitation assay. Our studies demonstrate that EKLF-GATA1 fusion proteins can enhance δ-globin expression through interaction with the δ-globin promoter, and may represent a new genetic therapeutic approach to β-hemoglobinopathies.

  14. Decision Guidance for Sustainable Manufacturing

    ERIC Educational Resources Information Center

    Shao, Guodong

    2013-01-01

    Sustainable manufacturing has significant impacts on a company's business performance and competitiveness in today's world. A growing number of manufacturing industries are initiating efforts to address sustainability issues; however, to achieve a higher level of sustainability, manufacturers need methodologies for formally describing, analyzing,…

  15. Increase of microRNA-210, Decrease of Raptor Gene Expression and Alteration of Mammalian Target of Rapamycin Regulated Proteins following Mithramycin Treatment of Human Erythroid Cells

    PubMed Central

    Bianchi, Nicoletta; Finotti, Alessia; Ferracin, Manuela; Lampronti, Ilaria; Zuccato, Cristina; Breveglieri, Giulia; Brognara, Eleonora; Fabbri, Enrica; Borgatti, Monica; Negrini, Massimo; Gambari, Roberto

    2015-01-01

    Expression and regulation of microRNAs is an emerging issue in erythroid differentiation and globin gene expression in hemoglobin disorders. In the first part of this study microarray analysis was performed both in mithramycin-induced K562 cells and erythroid precursors from healthy subjects or β-thalassemia patients producing low or high levels of fetal hemoglobin. We demonstrated that: (a) microRNA-210 expression is higher in erythroid precursors from β-thalassemia patients with high production of fetal hemoglobin; (b) microRNA-210 increases as a consequence of mithramycin treatment of K562 cells and human erythroid progenitors both from healthy and β-thalassemia subjects; (c) this increase is associated with erythroid induction and elevated expression of γ-globin genes; (d) an anti-microRNA against microRNA-210 interferes with the mithramycin-induced changes of gene expression. In the second part of the study we have obtained convergent evidences suggesting raptor mRNA as a putative target of microRNA-210. Indeed, microRNA-210 binding sites of its 3’-UTR region were involved in expression and are targets of microRNA-210-mediated modulation in a luciferase reporter assays. Furthermore, (i) raptor mRNA and protein are down-regulated upon mithramycin-induction both in K562 cells and erythroid progenitors from healthy and β-thalassemia subjects. In addition, (ii) administration of anti-microRNA-210 to K562 cells decreased endogenous microRNA-210 and increased raptor mRNA and protein expression. Finally, (iii) treatment of K562 cells with premicroRNA-210 led to a decrease of raptor mRNA and protein. In conclusion, microRNA-210 and raptor are involved in mithramycin-mediated erythroid differentiation of K562 cells and participate to the fine-tuning and control of γ-globin gene expression in erythroid precursor cells. PMID:25849663

  16. Evaluation of hematopoietic cells and myeloid/erythroid ratio in the bone marrow of the pheasant (Phasianus colchicus).

    PubMed

    Tadjalli, Mina; Nazifi, Saeed; Haghjoo, Rahil

    2013-01-01

    In order to study the normal hematopoiesis, cellular components and myeloid/erythroid (M/E) ratio in the bone marrow of the pheasant (Phasianus colchicus), bone marrow samples were collected from the proximal tibiotarsus bone of 16 clinically healthy adult pheasant. The bone marrow smears were stained using the Giemsa stain. The results indicated that the development and formation of blood cells in the bone marrow of pheasant were similar to other birds, whereas the morphology of the cells was similar to chickens, ducks, quail, and black-head gull. The mean M/E ratio was 1.24, the mean erythroid percentage was 42.24, the mean myeloid percentage was 52.62, and the mean percentage of all other cells percentage was 5.38. There was no significant difference in any of the cellular composition between male and female.

  17. The DEK Oncoprotein Is a Critical Component of the EKLF/KLF1 Enhancer in Erythroid Cells

    PubMed Central

    Lohmann, Felix; Dangeti, Mohan; Soni, Shefali; Chen, Xiaoyong; Planutis, Antanas; Baron, Margaret H.; Choi, Kyunghee

    2015-01-01

    Understanding how transcriptional regulators are themselves controlled is important in attaining a complete picture of the intracellular effects that follow signaling cascades during early development and cell-restricted differentiation. We have addressed this issue by focusing on the regulation of EKLF/KLF1, a zinc finger transcription factor that plays a necessary role in the global regulation of erythroid gene expression. Using biochemical affinity purification, we have identified the DEK oncoprotein as a critical factor that interacts with an essential upstream enhancer element of the EKLF promoter and exerts a positive effect on EKLF levels. This element also binds a core set of erythroid transcription factors, suggesting that DEK is part of a tissue-restricted enhanceosome that contains BMP4-dependent and -independent components. Together with local enrichment of properly coded histones and an open chromatin domain, optimal transcriptional activation of the EKLF locus can be established. PMID:26303528

  18. Gaucher Disease-Induced Pluripotent Stem Cells Display Decreased Erythroid Potential and Aberrant Myelopoiesis

    PubMed Central

    Sgambato, Judi A.; Park, Tea Soon; Miller, Diana; Panicker, Leelamma M.; Sidransky, Ellen; Lun, Yu; Awad, Ola; Bentzen, Søren M.; Zambidis, Elias T.

    2015-01-01

    Gaucher disease (GD) is the most common lysosomal storage disease resulting from mutations in the lysosomal enzyme glucocerebrosidase (GCase). The hematopoietic abnormalities in GD include the presence of characteristic Gaucher macrophages that infiltrate patient tissues and cytopenias. At present, it is not clear whether these cytopenias are secondary to the pathological activity of Gaucher cells or a direct effect of GCase deficiency on hematopoietic development. To address this question, we differentiated induced pluripotent stem cells (iPSCs) derived from patients with types 1, 2, and 3 GD to CD34+/CD45+/CD43+/CD143+ hematopoietic progenitor cells (HPCs) and examined their developmental potential. The formation of GD-HPCs was unaffected. However, these progenitors demonstrated a skewed lineage commitment, with increased myeloid differentiation and decreased erythroid differentiation and maturation. Interestingly, myeloid colony-formation assays revealed that GD-HPCs, but not control-HPCs, gave rise to adherent, macrophage-like cells, another indication of abnormal myelopoiesis. The extent of these hematologic abnormalities correlated with the severity of the GCase mutations. All the phenotypic abnormalities of GD-HPCs observed were reversed by incubation with recombinant GCase, indicating that these developmental defects were caused by the mutated GCase. Our results show that GCase deficiency directly impairs hematopoietic development. Additionally, our results suggest that aberrant myelopoiesis might contribute to the pathological properties of Gaucher macrophages, which are central to GD manifestations. The hematopoietic developmental defects we observed reflect hematologic abnormalities in patients with GD, demonstrating the utility of GD-iPSCs for modeling this disease. Significance This study showed that hematopoietic progenitors from patients with Gaucher disease (GD) have intrinsic developmental abnormalities that reflect characteristic clinical

  19. Function of caspases in regulating apoptosis caused by erythropoietin deprivation in erythroid progenitors.

    PubMed

    Gregoli, P A; Bondurant, M C

    1999-02-01

    Erythropoietin (EP) is required by late stage erythroid progenitor cells to prevent apoptosis. In a previous study (Gregoli and Bondurant, 1997, Blood 90:630-640), it was shown that rapid proteolytic conversion of procaspase 3 to the fully activated enzyme occurred when erythroblasts were deprived of EP for as little as 2 h. In the present study, protein and mRNA analyses of erythroblasts indicated the presence of the proenzyme precursors of caspases 1, 2, 3, 5, 6, 7, 8, and 9. The effects of various caspase inhibitors on caspase 3 processing and on apoptosis were examined. These inhibitors were benzyloxycarbonyl (z-) and fluoromethyl-ketone (FMK) derivatives of peptides that serve as substrates for selected caspases. z-VAD-FMK, t-butoxycarbonyl-aspartate-FMK (Boc-D-FMK), and z-IETD-FMK blocked the initial cleavage of procaspase 3, while z-DEVD-FMK, z-VEID-FMK, and z-VDVAD-FMK did not block the initial cleavage but had some effect on blocking apoptosis. The peptide inhibitor z-FA-FMK, which inhibits cathepsins B and L but is not known to inhibit caspases, altered caspase 3 processing to a final 19 kDa large subunit that appeared to retain enzymatic activity. The action of z-FA-FMK in preventing the usual conversion to a 1 7 kDa subunit suggests the possibility that a noncaspase protease may be involved in caspase 3 processing. Studies with the peptide inhibitors and EP were done to determine the short- and long-term effectiveness of the caspase inhibitors in protecting EP-deprived cells from apoptosis. Although several of the inhibitors were effective, z-IETD-FMK was studied most extensively because of its specificity for enzymes which cleave procaspase 3 at aspartate 175 (IETD175). Large percentages of EP-deprived erythroblasts treated with z-IETD-FMK appeared morphologically normal and negative by a DNA strand breakage (TUNEL) assay at 24 h (75%) compared to EP-deprived controls (10%) which were not treated with inhibitor. However, inhibitor-treated erythroid

  20. Inactivation of Rb and E2f8 Synergizes To Trigger Stressed DNA Replication during Erythroid Terminal Differentiation

    PubMed Central

    Ghazaryan, Seda; Sy, Chandler; Hu, Tinghui; An, Xiuli; Mohandas, Narla; Fu, Haiqing; Aladjem, Mirit I.; Chang, Victor T.; Opavsky, Rene

    2014-01-01

    Rb is critical for promoting cell cycle exit in cells undergoing terminal differentiation. Here we show that during erythroid terminal differentiation, Rb plays a previously unappreciated and unorthodox role in promoting DNA replication and cell cycle progression. Specifically, inactivation of Rb in erythroid cells led to stressed DNA replication, increased DNA damage, and impaired cell cycle progression, culminating in defective terminal differentiation and anemia. Importantly, all of these defects associated with Rb loss were exacerbated by the concomitant inactivation of E2f8. Gene expression profiling and chromatin immunoprecipitation (ChIP) revealed that Rb and E2F8 cosuppressed a large array of E2F target genes that are critical for DNA replication and cell cycle progression. Remarkably, inactivation of E2f2 rescued the erythropoietic defects resulting from Rb and E2f8 deficiencies. Interestingly, real-time quantitative PCR (qPCR) on E2F2 ChIPs indicated that inactivation of Rb and E2f8 synergizes to increase E2F2 binding to its target gene promoters. Taken together, we propose that Rb and E2F8 collaborate to promote DNA replication and erythroid terminal differentiation by preventing E2F2-mediated aberrant transcriptional activation through the ability of Rb to bind and sequester E2F2 and the ability of E2F8 to compete with E2F2 for E2f-binding sites on target gene promoters. PMID:24865965

  1. Glucocorticoids improve erythroid progenitor maintenance and dampen Trp53 response in a mouse model of Diamond-Blackfan anaemia.

    PubMed

    Sjögren, Sara E; Siva, Kavitha; Soneji, Shamit; George, Amee J; Winkler, Marcus; Jaako, Pekka; Wlodarski, Marcin; Karlsson, Stefan; Hannan, Ross D; Flygare, Johan

    2015-11-01

    Diamond-Blackfan anaemia (DBA) is a rare congenital disease causing severe anaemia and progressive bone marrow failure. The majority of patients carry mutations in ribosomal proteins, which leads to depletion of erythroid progenitors in the bone marrow. As many as 40% of all DBA patients receive glucocorticoids to alleviate their anaemia. However, despite their use in DBA treatment for more than half a century, the therapeutic mechanisms of glucocorticoids remain largely unknown. Therefore we sought to study disease specific effects of glucocorticoid treatment using a ribosomal protein s19 (Rps19) deficient mouse model of DBA. This study determines for the first time that a mouse model of DBA can respond to glucocorticoid treatment, similar to DBA patients. Our results demonstrate that glucocorticoid treatment reduces apoptosis, rescues erythroid progenitor depletion and premature differentiation of erythroid cells. Furthermore, glucocorticoids prevent Trp53 activation in Rps19-deficient cells- in a disease-specific manner. Dissecting the therapeutic mechanisms behind glucocorticoid treatment of DBA provides indispensible insight into DBA pathogenesis. Identifying mechanisms important for DBA treatment also enables development of more disease-specific treatments of DBA. PMID:26305041

  2. Glucocorticoids improve erythroid progenitor maintenance and dampen Trp53 response in a mouse model of Diamond-Blackfan anaemia.

    PubMed

    Sjögren, Sara E; Siva, Kavitha; Soneji, Shamit; George, Amee J; Winkler, Marcus; Jaako, Pekka; Wlodarski, Marcin; Karlsson, Stefan; Hannan, Ross D; Flygare, Johan

    2015-11-01

    Diamond-Blackfan anaemia (DBA) is a rare congenital disease causing severe anaemia and progressive bone marrow failure. The majority of patients carry mutations in ribosomal proteins, which leads to depletion of erythroid progenitors in the bone marrow. As many as 40% of all DBA patients receive glucocorticoids to alleviate their anaemia. However, despite their use in DBA treatment for more than half a century, the therapeutic mechanisms of glucocorticoids remain largely unknown. Therefore we sought to study disease specific effects of glucocorticoid treatment using a ribosomal protein s19 (Rps19) deficient mouse model of DBA. This study determines for the first time that a mouse model of DBA can respond to glucocorticoid treatment, similar to DBA patients. Our results demonstrate that glucocorticoid treatment reduces apoptosis, rescues erythroid progenitor depletion and premature differentiation of erythroid cells. Furthermore, glucocorticoids prevent Trp53 activation in Rps19-deficient cells- in a disease-specific manner. Dissecting the therapeutic mechanisms behind glucocorticoid treatment of DBA provides indispensible insight into DBA pathogenesis. Identifying mechanisms important for DBA treatment also enables development of more disease-specific treatments of DBA.

  3. The glucocorticoid receptor is a key regulator of the decision between self-renewal and differentiation in erythroid progenitors.

    PubMed Central

    Wessely, O; Deiner, E M; Beug, H; von Lindern, M

    1997-01-01

    During development and in regenerating tissues such as the bone marrow, progenitor cells constantly need to make decisions between proliferation and differentiation. We have used a model system, normal erythroid progenitors of the chicken, to determine the molecular players involved in making this decision. The molecules identified comprised receptor tyrosine kinases (c-Kit and c-ErbB) and members of the nuclear hormone receptor superfamily (thyroid hormone receptor and estrogen receptor). Here we identify the glucocorticoid receptor (GR) as a key regulator of erythroid progenitor self-renewal (i.e. continuous proliferation in the absence of differentiation). In media lacking a GR ligand or containing a GR antagonist, erythroid progenitors failed to self-renew, even if c-Kit, c-ErbB and the estrogen receptor were activated simultaneously. To induce self-renewal, the GR required the continuous presence of an activated receptor tyrosine kinase and had to cooperate with the estrogen receptor for full activity. Mutant analysis showed that DNA binding and a functional AF-2 transactivation domain are required for proliferation stimulation and differentiation arrest. c-myb was identified as a potential target gene of the GR in erythroblasts. It could be demonstrated that delta c-Myb, an activated c-Myb protein, can functionally replace the GR. PMID:9029148

  4. Nuclear factor, erythroid 2-like 2-associated molecular signature predicts lung cancer survival

    PubMed Central

    Qian, Zhongqing; Zhou, Tong; Gurguis, Christopher I.; Xu, Xiaoyan; Wen, Qing; Lv, Jingzhu; Fang, Fang; Hecker, Louise; Cress, Anne E.; Natarajan, Viswanathan; Jacobson, Jeffrey R.; Zhang, Donna D.; Garcia, Joe G. N.; Wang, Ting

    2015-01-01

    Nuclear factor, erythroid 2-like 2 (NFE2L2), a transcription factor also known as NF-E2-related factor 2 (Nrf2), is a key cytoprotective gene that regulates critical antioxidant and stress-responsive genes. Nrf2 has been demonstrated to be a promising therapeutic target and useful biomarker in malignant disease. We hypothesized that NFE2L2-mediated gene expression would reflect cancer severity and progression. We conducted a meta-analysis of microarray data for 240 NFE2L2-mediated genes that were enriched in tumor tissues. We then developed a risk scoring system based on NFE2L2 gene expression profiling and designated 50 tumor-associated genes as the NFE2L2-associated molecular signature (NAMS). We tested the relationship between this gene expression signature and both recurrence-free survival and overall survival in lung cancer patients. We find that NAMS predicts clinical outcome in the training cohort and in 12 out of 20 validation cohorts. Cox proportional hazard regressions indicate that NAMS is a robust prognostic gene signature, independent of other clinical and pathological factors including patient age, gender, smoking, gene alteration, MYC level, and cancer stage. NAMS is an excellent predictor of recurrence-free survival and overall survival in human lung cancer. This gene signature represents a promising prognostic biomarker in human lung cancer. PMID:26596768

  5. Erythropoietin, a novel versatile player regulating energy metabolism beyond the erythroid system.

    PubMed

    Wang, Li; Di, Lijun; Noguchi, Constance Tom

    2014-01-01

    Erythropoietin (EPO), the required cytokine for promoting the proliferation and differentiation of erythroid cells to stimulate erythropoiesis, has been reported to act as a pleiotropic cytokine beyond hematopoietic system. The various activities of EPO are determined by the widespread distribution of its cell surface EPO receptor (EpoR) in multiple tissues including endothelial, neural, myoblasts, adipocytes and other cell types. EPO activity has been linked to angiogenesis, neuroprotection, cardioprotection, stress protection, anti-inflammation and especially the energy metabolism regulation that is recently revealed. The investigations of EPO activity in animals and the expression analysis of EpoR provide more insights on the potential of EPO in regulating energy metabolism and homeostasis. The findings of crosstalk between EPO and some important energy sensors and the regulation of EPO in the cellular respiration and mitochondrial function further provide molecular mechanisms for EPO activity in metabolic activity regulation. In this review, we will summarize the roles of EPO in energy metabolism regulation and the activity of EPO in tissues that are tightly associated with energy metabolism. We will also discuss the effects of EPO in regulating oxidative metabolism and mitochondrial function, the interactions between EPO and important energy regulation factors, and the protective role of EPO from stresses that are related to metabolism, providing a brief overview of previously less appreciated EPO biological function in energy metabolism and homeostasis. PMID:25170305

  6. Nuclear factor erythroid 2-related factor gene variants and susceptibility of arsenic-related skin lesions.

    PubMed

    Cordova, E J; Valenzuela, O L; Sánchez-Peña, L C; Escamilla-Guerrero, G; Hernández-Zavala, A; Orozco, L; Del Razo, L M

    2014-06-01

    Inorganic arsenic (iAs) is an important pollutant associated with various chronic-degenerative diseases. The cytoprotective protein nuclear factor erythroid 2-related factor (NRF2) has been proposed as an important responsive mechanism against iAs exposure. The aim of this study was to determine whether the risk of skin lesions in people exposed to iAs-contaminated water could be modified by the presence of single nucleotide polymorphisms in the NRF2 coding gene. We studied 117 individuals with long-term iAs exposure and 120 nonexposed individuals. Total As was determined in water, meanwhile iAs and its metabolites were measured in urine. The iAs-induced skin lesion status was evaluated by expert dermatologists. We sequenced the promoter region of NRF2 in a sample of 120 healthy donors. We found four polymorphisms previously reported and one novel polymorphism in the 5' regulatory region of the NRF2. In this study, we did not find allelic and genotype association of NRF2 polymorphisms with iAs-related skin lesion. However, the analysis of haplotypes composed by -653GA, and -617CA NRF2 single nucleotide polymorphisms showed a significant association with protection against skin lesions in the low-As exposure group. This is the first report studying the association between NRF2 polymorphisms and susceptibility of As-related skin lesions. Increasing the sample size will allow us to confirm this data. PMID:24107458

  7. Iron as the Key Modulator of Hepcidin Expression in Erythroid Antibody-Mediated Hypoplasia

    PubMed Central

    Fernandes, J. C.; Garrido, P.; Ribeiro, S.; Rocha-Pereira, P.; Bronze-da-Rocha, E.; Belo, L.; Costa, E.; Reis, F.; Santos-Silva, A.

    2014-01-01

    Erythroid hypoplasia (EH) is a rare complication associated with recombinant human erythropoietin (rHuEPO) therapies, due to development of anti-rHuEPO antibodies; however, the underlying mechanisms remain poorly clarified. Our aim was to manage a rat model of antibody-mediated EH induced by rHuEPO and study the impact on iron metabolism and erythropoiesis. Wistar rats treated during 9 weeks with a high rHuEPO dose (200 IU) developed EH, as shown by anemia, reduced erythroblasts, reticulocytopenia, and plasmatic anti-rHuEPO antibodies. Serum iron was increased and associated with mRNA overexpression of hepatic hepcidin and other iron regulatory mediators and downregulation of matriptase-2; overexpression of divalent metal transporter 1 and ferroportin was observed in duodenum and liver. Decreased EPO expression was observed in kidney and liver, while EPO receptor was overexpressed in liver. Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function. Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia. This leads to a serum iron increase, which seems to stimulate hepcidin expression despite no evidence of inflammation, thus suggesting iron as the key modulator of hepcidin synthesis. These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy. PMID:25580431

  8. Acute megakaryoblastic leukemia, unlike acute erythroid leukemia, predicts an unfavorable outcome after allogeneic HSCT.

    PubMed

    Ishiyama, Ken; Yamaguchi, Takuhiro; Eto, Tetsuya; Ohashi, Kazuteru; Uchida, Naoyuki; Kanamori, Heiwa; Fukuda, Takahiro; Miyamura, Koichi; Inoue, Yoshiko; Taguchi, Jun; Mori, Takehiko; Iwato, Koji; Morishima, Yasuo; Nagamura-Inoue, Tokiko; Atsuta, Yoshiko; Sakamaki, Hisashi; Takami, Akiyoshi

    2016-08-01

    Acute erythroid leukemia (FAB-M6) and acute megakaryoblastic leukemia (FAB-M7) exhibit closely related properties in cells regarding morphology and the gene expression profile. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the mainstay of the treatment for both subtypes of leukemia due to their refractoriness to chemotherapy and high rates of relapse, it remains unclear whether allo-HSCT is curative in such cases due to their scarcity. We retrospectively examined the impact of allo-HSCT in 382 patients with M6 and 108 patients with M7 using nationwide HSCT data and found the overall survival (OS) and relapse rates of the M6 patients to be significantly better than those of the M7 patients after adjusting for confounding factors and statistically comparable with those of the patients with M0/M1/M2/M4/M5 disease. Consequently, the factors of age, gender, performance status, karyotype, disease status at HSCT and development of graft-vs.-host disease predicted the OS for the M6 patients, while the performance status and disease status at HSCT were predictive of the OS for the M7 patients. These findings substantiate the importance of distinguishing between M6 and M7 in the HSCT setting and suggest that unknown mechanisms influence the HSCT outcomes of these closely related subtypes of leukemia. PMID:27244257

  9. Nuclear factor erythroid 2-related factor gene variants and susceptibility of arsenic-related skin lesions.

    PubMed

    Cordova, E J; Valenzuela, O L; Sánchez-Peña, L C; Escamilla-Guerrero, G; Hernández-Zavala, A; Orozco, L; Del Razo, L M

    2014-06-01

    Inorganic arsenic (iAs) is an important pollutant associated with various chronic-degenerative diseases. The cytoprotective protein nuclear factor erythroid 2-related factor (NRF2) has been proposed as an important responsive mechanism against iAs exposure. The aim of this study was to determine whether the risk of skin lesions in people exposed to iAs-contaminated water could be modified by the presence of single nucleotide polymorphisms in the NRF2 coding gene. We studied 117 individuals with long-term iAs exposure and 120 nonexposed individuals. Total As was determined in water, meanwhile iAs and its metabolites were measured in urine. The iAs-induced skin lesion status was evaluated by expert dermatologists. We sequenced the promoter region of NRF2 in a sample of 120 healthy donors. We found four polymorphisms previously reported and one novel polymorphism in the 5' regulatory region of the NRF2. In this study, we did not find allelic and genotype association of NRF2 polymorphisms with iAs-related skin lesion. However, the analysis of haplotypes composed by -653GA, and -617CA NRF2 single nucleotide polymorphisms showed a significant association with protection against skin lesions in the low-As exposure group. This is the first report studying the association between NRF2 polymorphisms and susceptibility of As-related skin lesions. Increasing the sample size will allow us to confirm this data.

  10. FOXP1 Expression in Normal and Neoplastic Erythroid and Myeloid Cells.

    PubMed

    Lovrić, Eva; Pavlov, Katarina Horvat; Korać, Petra; Dominis, Mara

    2015-09-01

    FOXP1 protein was firstly analyzed in normal tissues, and afterwards in different tumor tissues, mainly carcinoma and lymphoma. In B-cell malignancies, its role was well explored; its expression was shown to be connected with disease prognosis in certain B-non Hodgkin lymphomas. In this study, 16 bone marrow trephine samples from patients with no hematopoietic malignancies and 10 samples from peripheral blood of healthy individuals were immunostained with anti-FOXP1 antibody. Positive cells in bone marrows were not only lymphocytes, but also cells that are immunohistochemically positive for glycophorin C or myeloperoxidase. Peripheral blood samples showed no other positive cells, but small round lymphocytes. Additionally 60 samples from patients with myeloid lineage neoplasms were analyzed. 25 samples from patients with myelodysplastic syndrome (MDS) and 35 patients with myeloproliferative disease (MPD) were double immunostained with anti-FOXP1/anti-glycophorin C and anti-FOXP1/anti-myeloperoxidase antibodies. FOXP1 was found to be expressed in 22 cases of MDS and in none of MPD cases. Its expression in MDS was observed mostly in myeloperoxidase positive cells in contrast to gylcophorin C positive cells. Only two cases revealed both myeloperoxidase positive cells and gylcophorin C positive cells expressing FOXP1 transcription factor. Our results show that FOXP1 is present in normal cells of erythroid and myeloid linages and thus suggest its possible role in development of all hematopoetic cells as well as possible involvement in neoplasm development of myeloid disorders. PMID:26898077

  11. An erythroid chaperone that facilitates folding of α-globin subunits for hemoglobin synthesis

    PubMed Central

    Yu, Xiang; Kong, Yi; Dore, Louis C.; Abdulmalik, Osheiza; Katein, Anne M.; Zhou, Suiping; Choi, John K.; Gell, David; Mackay, Joel P.; Gow, Andrew J.; Weiss, Mitchell J.

    2007-01-01

    Erythrocyte precursors produce abundant α- and β-globin proteins, which assemble with each other to form hemoglobin A (HbA), the major blood oxygen carrier. αHb-stabilizing protein (AHSP) binds free α subunits reversibly to maintain their structure and limit their ability to generate reactive oxygen species. Accordingly, loss of AHSP aggravates the toxicity of excessive free α-globin caused by β-globin gene disruption in mice. Surprisingly, we found that AHSP also has important functions when free α-globin is limited. Thus, compound mutants lacking both Ahsp and 1 of 4 α-globin genes (genotype Ahsp–/–α-globin*α/αα) exhibited more severe anemia and Hb instability than mice with either mutation alone. In vitro, recombinant AHSP promoted folding of newly translated α-globin, enhanced its refolding after denaturation, and facilitated its incorporation into HbA. Moreover, in erythroid precursors, newly formed free α-globin was destabilized by loss of AHSP. Therefore, in addition to its previously defined role in detoxification of excess α-globin, AHSP also acts as a molecular chaperone to stabilize nascent α-globin for HbA assembly. Our findings illustrate what we believe to be a novel adaptive mechanism by which a specialized cell coordinates high-level production of a multisubunit protein and protects against various synthetic imbalances. PMID:17607360

  12. Perturbation of nucleosome structure by the erythroid transcription factor GATA-1.

    PubMed

    Boyes, J; Omichinski, J; Clark, D; Pikaart, M; Felsenfeld, G

    1998-06-12

    The ability of transcription factors to gain access to their sites in chromatin requires the disruption or displacement of nucleosomes covering the promoter, signalled by the generation of a nuclease hypersensitive site. We characterise here the alterations in nucleosome structure caused by binding of the erythroid factor GATA-1 to a nucleosome carrying GATA-1 sites. DNase I and micrococcal nuclease probes show that GATA-1 binding causes extensive, cooperative breakage of the histone/DNA contacts to generate a complex very similar to that formed by the factor with free DNA. The only region which differs is confined to about 50 bp surrounding the nucleosome dyad axis which appears to be the domain of residual contact between the DNA and histone octamer. Despite considerable breakage of the histone/DNA contacts, the complex is completely stable in solution, and disruption of the nucleosome is entirely reversible: it is regenerated quantitatively upon removal of the transcription factor. Moreover, the histone 2A/2B component of the octamer does not exchange to external competitor. We suggest that formation of this complex may be a step in the generation of a fully hypersensitive site in vivo over regulatory elements containing GATA family binding sites. PMID:9641976

  13. Therapeutic Effects of Erythroid Differentiation Regulator 1 on Imiquimod-Induced Psoriasis-Like Skin Inflammation

    PubMed Central

    Kim, Kyung Eun; Houh, Younkyung; Park, Hyun Jeong; Cho, Daeho

    2016-01-01

    Psoriasis is a common skin disease accompanied by chronic inflammation. In previous studies, erythroid differentiation regulator 1 (ERDR1) was shown to have a negative correlation with proinflammatory cytokine IL-18. However, the role of ERDR1 in the inflammatory skin disease psoriasis has not been evaluated. In this study, to investigate the role of ERDR1 in psoriasis, recombinant ERDR1 was injected intraperitoneally into a psoriasis mouse model. Recombinant ERDR1 (rERDR1) significantly alleviated the symptoms of psoriasis-like skin inflammation and reduced the mRNA of various psoriasis-related markers, including keratin 14, S100A8, and Th17-related cytokines IL-17 and IL-22, suggesting that rERDR1 exerts therapeutic effects on psoriasis via the regulation of Th17 functions. Additionally, the expression of CCL20, a well-known Th17 attracting chemokine, was determined. CCL20 expression significantly decreased in the rERDR1-injected group compared with the vehicle (PBS)-injected group. CCR6 expression in the psoriatic lesional skin was also decreased by rERDR1 administration, implying the inhibition of CCR6-expressing Th17 cell chemotaxis via the downregulation of CCL20. Taken together, this study provides the first evidence that ERDR1 may be a potential therapeutic target for psoriasis. PMID:26901187

  14. Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor γ Essential for Resistance to Crescentic GN.

    PubMed

    Henique, Carole; Bollee, Guillaume; Lenoir, Olivia; Dhaun, Neeraj; Camus, Marine; Chipont, Anna; Flosseau, Kathleen; Mandet, Chantal; Yamamoto, Masayuki; Karras, Alexandre; Thervet, Eric; Bruneval, Patrick; Nochy, Dominique; Mesnard, Laurent; Tharaux, Pierre-Louis

    2016-01-01

    Necrotizing and crescentic rapidly progressive GN (RPGN) is a life-threatening syndrome characterized by a rapid loss of renal function. Evidence suggests that podocyte expression of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) may prevent podocyte injury, but the function of glomerular PPARγ in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARγ abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARγ in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Pparγ gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARγ gain-of-function approach achieved by systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN in mice with podocyte-specific Pparγ gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)-deficient mice, loss of podocyte PPARγ was observed at baseline. NRF2 deficiency markedly aggravated the course of RPGN, an effect that was partially prevented by TZD administration. Furthermore, delayed administration of TZD, initiated after the onset of RPGN, still alleviated the severity of experimental RPGN. These findings establish a requirement for the NRF2-PPARγ cascade in podocytes, and we suggest that these transcription factors have a role in augmenting the tolerance of glomeruli to severe immune-complex mediated injury. The NRF2-PPARγ pathway may be a therapeutic target for RPGN. PMID:25999406

  15. Sustainability Frontiers

    ERIC Educational Resources Information Center

    Selby, David

    2010-01-01

    This article introduces Sustainability Frontiers, a newly formed, international, not-for-profit alliance of sustainability and global educators dedicated to challenging and laying bare the assumptions, exposing the blind spots, and transgressing the boundaries of mainstream understandings of sustainability-related education. Among the orthodoxies…

  16. Measuring Energy Sustainability

    SciTech Connect

    Greene, David L

    2009-01-01

    For the purpose of measurement, energy sustainability is defined as ensuring that future generations have energy resources that enable them to achieve a level of well-being at least as good as that of the current generation. It is recognized that there are valid, more comprehensive understandings of sustainability and that energy sustainability as defined here is only meaningful when placed in a broader context. Still, measuring energy sustainability is important to society because the rates of consumption of some fossil resources are now substantial in relation to measures of ultimate resources, and because conflicts between fossil energy use and environmental sustainability are intensifying. Starting from the definition, an equation for energy sustainability is derived that reconciles renewable fl ows and nonrenewable stocks, includes the transformation of energy into energy services, incorporates technological change and, at least notionally, allows for changes in the relationship between energy services and societal well-being. Energy sustainability must be measured retrospectively as well as prospectively, and methods for doing each are discussed. Connections to the sustainability of other resources are also critical. The framework presented is merely a starting point; much remains to be done to make it operational.

  17. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection

    PubMed Central

    Elahi, Shokrollah; Ertelt, James M.; Kinder, Jeremy M.; Jiang, Tony T.; Zhang, Xuzhe; Xin, Lijun; Chaturvedi, Vandana; Strong, Beverly S.; Qualls, Joseph E.; Steinbrecher, Kris A.; Kalfa, Theodosia A.; Shaaban, Aimen F.; Way, Sing Sing

    2014-01-01

    Newborn infants are highly susceptible to infection. This defect in host defence has generally been ascribed to the immaturity of neonatal immune cells; however, the degree of hyporesponsiveness is highly variable and depends on the stimulation conditions1–7. These discordant responses illustrate the need for a more unified explanation for why immunity is compromised in neonates. Here we show that physiologically enriched CD71+ erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after co-culture with neonatal splenocytes. Neonatal CD71+ cells express the enzyme arginase-2, and arginase activity is essential for the immunosuppressive properties of these cells because molecular inhibition of this enzyme or supplementation with l-arginine overrides immunosuppression. In addition, the ablation of CD71+ cells in neonatal mice, or the decline in number of these cells as postnatal development progresses parallels the loss of suppression, and restored resistance to the perinatal pathogens Listeria monocytogenes and Escherichia coli8,9. However, CD71+ cell-mediated susceptibility to infection is counterbalanced by CD71+ cell-mediated protection against aberrant immune cell activation in the intestine, where colonization with commensal microorganisms occurs swiftly after parturition10,11.Conversely, circumventing such colonization by using antimicrobials or gnotobiotic germ-free mice overrides these protective benefits. Thus, CD71+ cells quench the excessive inflammation induced by abrupt colonization with commensal microorganisms after parturition. This finding challenges the idea that the susceptibility of neonates to infection reflects immune-cell-intrinsic defects and instead highlights processes that are developmentally more essential and inadvertently mitigate innate immune protection. We anticipate that

  18. Expression of nuclear factor, erythroid 2-like 2-mediated genes differentiates tuberculosis.

    PubMed

    Qian, Zhongqing; Lv, Jingzhu; Kelly, Gabriel T; Wang, Hongtao; Zhang, Xiaojie; Gu, Wanjun; Yin, Xiaofeng; Wang, Ting; Zhou, Tong

    2016-07-01

    During infection and host defense, nuclear factor, erythroid 2-like 2 (Nrf2) dependent signaling is an efficient antioxidant defensive mechanism used by host cells to control the destructive effects of reactive oxygen species. This allows for effective defense responses against microbes while minimizing oxidative injury to the host cell itself. As a central regulator of antioxidant genes, Nrf2 has gained great attention in its pivotal role in infection, especially in tuberculosis (TB), the top infectious disease killer worldwide. To elucidate the genes potentially regulated by Nrf2 in TB, we conducted a meta-analysis on published gene expression datasets. Firstly, we compared the global gene expression profiles between control and Nrf2-deficient human cells. The differentially expressed genes were deemed as "Nrf2-mediated genes". Next, the whole blood gene expression pattern of TB patients was compared with that of healthy controls, pneumonia patients, and lung cancer patients. We found that the genes deregulated in TB significantly overlap with the Nrf2-mediated genes. Based on the intersection of Nrf2-mediated and TB-regulated genes, we identified an Nrf2-mediated 17-gene signature, which reflects a cluster of gene ontology terms highly related to TB physiology. We demonstrated that the 17-gene signature can be used to distinguish TB patients from healthy controls and patients with latent TB infection, pneumonia, or lung cancer. Also, the Nrf2-mediated gene signature can be used as an indicator of the anti-TB therapeutic response. More importantly, we confirmed that the predictive power of the Nrf2-mediated 17-gene signature is significantly better than the random gene sets selected from the human transcriptome. Also, the 17-gene signature performs even better than the random gene signatures selected from TB-associated genes. Our study confirms the central role of Nrf2 in TB pathogenesis and provides a novel and useful diagnostic method to differentiate TB

  19. Recombinant erythroid differentiation regulator 1 inhibits both inflammation and angiogenesis in a mouse model of rosacea.

    PubMed

    Kim, Miri; Kim, Kyung-Eun; Jung, Haw Young; Jo, Hyunmu; Jeong, Seo-Won; Lee, Jahyung; Kim, Chang Han; Kim, Heejong; Cho, Daeho; Park, Hyun Jeong

    2015-09-01

    The erythroid differentiation regulator 1 (Erdr1), which is a novel and highly conserved factor, was recently reported to be negatively regulated by IL-18 and to play a crucial role as an antimetastatic factor. IL-18 is a proinflammatory cytokine that functions as an angiogenic mediator in inflammation. Rosacea is a chronic inflammatory skin disorder that is characterized by abnormal inflammation and vascular hyperactivity of the facial skin. To determine whether Erdr1 contributes to the regulation of the chronic inflammatory process in the development of rosacea, an immunohistochemical analysis was performed in healthy donors and patients with rosacea. In this study, we showed that Erdr1 was downregulated, whereas IL-18 was upregulated, in patients with rosacea, which led us to question the role of Erdr1 in this disorder. Moreover, a rosacea-like BALB/c mouse model was used to determine the role of Erdr1 in rosacea in vivo. LL-37 injection induced typical rosacea features, including erythema, telangiectasia and inflammation. Treatment with recombinant Erdr1 (rErdr1) resulted in a significant reduction of erythema, inflammatory cell infiltration (including CD4(+) and CD8(+) T cells), and microvessel density with vascular endothelial growth factor (VEGF). Taken together, our findings suggest that rErdr1 may be involved in attenuating the inflammation and angiogenesis associated with the pathogenesis of rosacea. Thus, these results provide new insight into the mechanism involved in this condition and indicate that rErdr1 could be a potential target for therapeutic intervention of rosacea.

  20. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection

    NASA Astrophysics Data System (ADS)

    Elahi, Shokrollah; Ertelt, James M.; Kinder, Jeremy M.; Jiang, Tony T.; Zhang, Xuzhe; Xin, Lijun; Chaturvedi, Vandana; Strong, Beverly S.; Qualls, Joseph E.; Steinbrecher, Kris A.; Kalfa, Theodosia A.; Shaaban, Aimen F.; Way, Sing Sing

    2013-12-01

    Newborn infants are highly susceptible to infection. This defect in host defence has generally been ascribed to the immaturity of neonatal immune cells; however, the degree of hyporesponsiveness is highly variable and depends on the stimulation conditions. These discordant responses illustrate the need for a more unified explanation for why immunity is compromised in neonates. Here we show that physiologically enriched CD71+ erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after co-culture with neonatal splenocytes. Neonatal CD71+ cells express the enzyme arginase-2, and arginase activity is essential for the immunosuppressive properties of these cells because molecular inhibition of this enzyme or supplementation with L-arginine overrides immunosuppression. In addition, the ablation of CD71+ cells in neonatal mice, or the decline in number of these cells as postnatal development progresses parallels the loss of suppression, and restored resistance to the perinatal pathogens Listeria monocytogenes and Escherichia coli. However, CD71+ cell-mediated susceptibility to infection is counterbalanced by CD71+ cell-mediated protection against aberrant immune cell activation in the intestine, where colonization with commensal microorganisms occurs swiftly after parturition. Conversely, circumventing such colonization by using antimicrobials or gnotobiotic germ-free mice overrides these protective benefits. Thus, CD71+ cells quench the excessive inflammation induced by abrupt colonization with commensal microorganisms after parturition. This finding challenges the idea that the susceptibility of neonates to infection reflects immune-cell-intrinsic defects and instead highlights processes that are developmentally more essential and inadvertently mitigate innate immune protection. We anticipate that these

  1. Erythroid Krüppel-like factor (EKLF) is active in primitive and definitive erythroid cells and is required for the function of 5'HS3 of the beta-globin locus control region.

    PubMed

    Tewari, R; Gillemans, N; Wijgerde, M; Nuez, B; von Lindern, M; Grosveld, F; Philipsen, S

    1998-04-15

    Disruption of the gene for transcription factor EKLF (erythroid Krüppel-like factor) results in fatal anaemia caused by severely reduced expression of the adult beta-globin gene, while other erythroid-specific genes, including the embryonic epsilon- and fetal gamma-globin genes, are expressed normally. Thus, EKLF is thought to be a stage-specific factor acting through the CACC box in the beta-gene promoter, even though it is already present in embryonic red cells. Here, we show that a beta-globin gene linked directly to the locus control region (LCR) is expressed at embryonic stages, and that this is only modestly reduced in EKLF-/- embryos. Thus, embryonic beta-globin expression is not intrinsically dependent on EKLF. To investigate whether EKLF functions in the locus control region, we analysed the expression of LCR-driven lacZ reporters. This shows that EKLF is not required for reporter activation by the complete LCR. However, embryonic expression of reporters driven by 5'HS3 of the LCR requires EKLF. This suggests that EKLF interacts directly with the CACC motifs in 5'HS3 and demonstrates that EKLF is also a transcriptional activator in embryonic erythropoiesis. Finally, we show that overexpression of EKLF results in an earlier switch from gamma- to beta-globin expression. Adult mice with the EKLF transgene have reduced platelet counts, suggesting that EKLF levels affect the balance between the megakaryocytic and erythroid lineages. Interestingly, the EKLF transgene rescues the lethal phenotype of EKLF null mice, setting the stage for future studies aimed at the analysis of the EKLF protein and its role in beta-globin gene activation.

  2. Expression of oncogenic K-ras from its endogenous promoter leads to a partial block of erythroid differentiation and hyperactivation of cytokine-dependent signaling pathways.

    PubMed

    Zhang, Jing; Liu, Yangang; Beard, Caroline; Tuveson, David A; Jaenisch, Rudolf; Jacks, Tyler E; Lodish, Harvey F

    2007-06-15

    When overexpressed in primary erythroid progenitors, oncogenic Ras leads to the constitutive activation of its downstream signaling pathways, severe block of terminal erythroid differentiation, and cytokine-independent growth of primary erythroid progenitors. However, whether high-level expression of oncogenic Ras is required for these phenotypes is unknown. To address this issue, we expressed oncogenic K-ras (K-ras(G12D)) from its endogenous promoter using a tetracycline-inducible system. We show that endogenous K-ras(G12D) leads to a partial block of terminal erythroid differentiation in vivo. In contrast to results obtained when oncogenic Ras was overexpressed from retroviral vectors, endogenous levels of K-ras(G12D) fail to constitutively activate but rather hyperactivate cytokine-dependent signaling pathways, including Stat5, Akt, and p44/42 MAPK, in primary erythroid progenitors. This explains previous observations that hematopoietic progenitors expressing endogenous K-ras(G12D) display hypersensitivity to cytokine stimulation in various colony assays. Our results support efforts to modulate Ras signaling for treating hematopoietic malignancies.

  3. Aberrant splicing of genes involved in haemoglobin synthesis and impaired terminal erythroid maturation in SF3B1 mutated refractory anaemia with ring sideroblasts.

    PubMed

    Conte, Simona; Katayama, Shintaro; Vesterlund, Liselotte; Karimi, Mohsen; Dimitriou, Marios; Jansson, Monika; Mortera-Blanco, Teresa; Unneberg, Per; Papaemmanuil, Elli; Sander, Birgitta; Skoog, Tiina; Campbell, Peter; Walfridsson, Julian; Kere, Juha; Hellström-Lindberg, Eva

    2015-11-01

    Refractory anaemia with ring sideroblasts (RARS) is distinguished by hyperplastic inefficient erythropoiesis, aberrant mitochondrial ferritin accumulation and anaemia. Heterozygous mutations in the spliceosome gene SF3B1 are found in a majority of RARS cases. To explore the link between SF3B1 mutations and anaemia, we studied mutated RARS CD34(+) marrow cells with regard to transcriptome sequencing, splice patterns and mutational allele burden during erythroid differentiation. Transcriptome profiling during early erythroid differentiation revealed a marked up-regulation of genes involved in haemoglobin synthesis and in the oxidative phosphorylation process, and down-regulation of mitochondrial ABC transporters compared to normal bone marrow. Moreover, mis-splicing of genes involved in transcription regulation, particularly haemoglobin synthesis, was confirmed, indicating a compromised haemoglobinization during RARS erythropoiesis. In order to define the phase during which erythroid maturation of SF3B1 mutated cells is most affected, we assessed allele burden during erythroid differentiation in vitro and in vivo and found that SF3B1 mutated erythroblasts showed stable expansion until late erythroblast stage but that terminal maturation to reticulocytes was significantly reduced. In conclusion, SF3B1 mutated RARS progenitors display impaired splicing with potential downstream consequences for genes of key importance for haemoglobin synthesis and terminal erythroid differentiation.

  4. Sustainability Research Under EPA/NRMRL

    EPA Science Inventory

    Sustainability means different things to different people, but most can agree that maintaining and supporting critical ecosystems over the long term is important for environmental and human health. Achieving sustainability involves a broad view of environmental stewardship. When ...

  5. Sequential induction of heme pathway enzymes during erythroid differentiation of mouse Friend leukemia virus-infected cells

    PubMed Central

    1976-01-01

    The process of erythroid differentiation in mouse Friend leukemia virus transformed cells (T3-C1-2) was examined by following changes in several enzyme activities of the heme biosynthetic pathway and in heme concentration while the cells were undergoing erythroid differentiation after treatment with dimethylsulfoxide. Untreated cells on the one hand, have a limited capacity for spontaneous differentiation. On the other hand, dimethylsulfoxide(DMSO)-treated cells showed an increase in the activities of delta-aminolevulinic acid (ALA) synthetase, ALA dehydratase, uroporphyrinogen-I synthetase, ferrochelatase, and heme concentration by days 1, 1.5, 2, and 4, respectively. The increase of the heme pathway enzymes and heme concentration followed the order of these enzymes or products as they are arranged in the heme biosynthetic pathway. These changes induced by DMSO were effectively inhibited by treatment with actinomycin D, suggesting that continued RNA synthesis is required for the differentiation process. 5-bromo-2'-deoxyuridine (BrdU) (10(-5) M) inhibited the DMSO-induced changes of the heme pathway enzymes. BrdU was most effective when it was present during the first 2 days of cell culture. It gradually lost its inhibitory effect when added after the 3rd day or later. The BrdU-mediated inhibition was completely overcome by the addition of thymidine (7 x 10(-5) M), but not by uridine (7 x 10(-5) M). All these data suggest that a sequential induction of the heme pathway enzyme takes place during erythroid differentiation of Friend leukemia cells, and that the sequential induction of the enzymes may be due to a sequential activation of genes coding for these enzyme activities. PMID:1249519

  6. Sustainability and Higher Education

    ERIC Educational Resources Information Center

    Hales, David

    2008-01-01

    People face four fundamental dilemmas, which are essentially moral choices: (1) alleviating poverty; (2) removing the gap between rich and poor; (3) controlling the use of violence for political ends; and (4) changing the patterns of production and consumption and achieving the transition to sustainability. The world in which future generations…

  7. UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development

    PubMed Central

    Cai, Yafei; Pi, Wenhu; Sivaprakasam, Satish; Zhu, Xiaobin; Zhang, Mingsheng; Chen, Jijun; Makala, Levi; Lu, Chunwan; Wu, Jianchu; Teng, Yong; Pace, Betty; Tuan, Dorothy; Singh, Nagendra; Li, Honglin

    2015-01-01

    The Ufm1 conjugation system is an ubiquitin-like modification system that consists of Ufm1, Uba5 (E1), Ufc1 (E2), and less defined E3 ligase(s) and targets. The biological importance of this system is highlighted by its essential role in embryogenesis and erythroid development, but the underlying mechanism is poorly understood. UFBP1 (Ufm1 binding protein 1, also known as DDRGK1, Dashurin and C20orf116) is a putative Ufm1 target, yet its exact physiological function and impact of its ufmylation remain largely undefined. In this study, we report that UFBP1 is indispensable for embryonic development and hematopoiesis. While germ-line deletion of UFBP1 caused defective erythroid development and embryonic lethality, somatic ablation of UFBP1 impaired adult hematopoiesis, resulting in pancytopenia and animal death. At the cellular level, UFBP1 deficiency led to elevated ER (endoplasmic reticulum) stress and activation of unfolded protein response (UPR), and consequently cell death of hematopoietic stem/progenitor cells. In addition, loss of UFBP1 suppressed expression of erythroid transcription factors GATA-1 and KLF1 and blocked erythroid differentiation from CFU-Es (colony forming unit-erythroid) to proerythroblasts. Interestingly, depletion of Uba5, a Ufm1 E1 enzyme, also caused elevation of ER stress and under-expression of erythroid transcription factors in erythroleukemia K562 cells. By contrast, knockdown of ASC1, a newly identified Ufm1 target that functions as a transcriptional co-activator of hormone receptors, led to down-regulation of erythroid transcription factors, but did not elevate basal ER stress. Furthermore, we found that ASC1 was associated with the promoters of GATA-1 and Klf1 in a UFBP1-dependent manner. Taken together, our findings suggest that UFBP1, along with ASC1 and other ufmylation components, play pleiotropic roles in regulation of hematopoietic cell survival and differentiation via modulating ER homeostasis and erythroid lineage

  8. UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development.

    PubMed

    Cai, Yafei; Pi, Wenhu; Sivaprakasam, Satish; Zhu, Xiaobin; Zhang, Mingsheng; Chen, Jijun; Makala, Levi; Lu, Chunwan; Wu, Jianchu; Teng, Yong; Pace, Betty; Tuan, Dorothy; Singh, Nagendra; Li, Honglin

    2015-11-01

    The Ufm1 conjugation system is an ubiquitin-like modification system that consists of Ufm1, Uba5 (E1), Ufc1 (E2), and less defined E3 ligase(s) and targets. The biological importance of this system is highlighted by its essential role in embryogenesis and erythroid development, but the underlying mechanism is poorly understood. UFBP1 (Ufm1 binding protein 1, also known as DDRGK1, Dashurin and C20orf116) is a putative Ufm1 target, yet its exact physiological function and impact of its ufmylation remain largely undefined. In this study, we report that UFBP1 is indispensable for embryonic development and hematopoiesis. While germ-line deletion of UFBP1 caused defective erythroid development and embryonic lethality, somatic ablation of UFBP1 impaired adult hematopoiesis, resulting in pancytopenia and animal death. At the cellular level, UFBP1 deficiency led to elevated ER (endoplasmic reticulum) stress and activation of unfolded protein response (UPR), and consequently cell death of hematopoietic stem/progenitor cells. In addition, loss of UFBP1 suppressed expression of erythroid transcription factors GATA-1 and KLF1 and blocked erythroid differentiation from CFU-Es (colony forming unit-erythroid) to proerythroblasts. Interestingly, depletion of Uba5, a Ufm1 E1 enzyme, also caused elevation of ER stress and under-expression of erythroid transcription factors in erythroleukemia K562 cells. By contrast, knockdown of ASC1, a newly identified Ufm1 target that functions as a transcriptional co-activator of hormone receptors, led to down-regulation of erythroid transcription factors, but did not elevate basal ER stress. Furthermore, we found that ASC1 was associated with the promoters of GATA-1 and Klf1 in a UFBP1-dependent manner. Taken together, our findings suggest that UFBP1, along with ASC1 and other ufmylation components, play pleiotropic roles in regulation of hematopoietic cell survival and differentiation via modulating ER homeostasis and erythroid lineage

  9. LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.

    PubMed

    Maeda, Takahiro; Ito, Keisuke; Merghoub, Taha; Poliseno, Laura; Hobbs, Robin M; Wang, Guocan; Dong, Lin; Maeda, Manami; Dore, Louis C; Zelent, Arthur; Luzzatto, Lucio; Teruya-Feldstein, Julie; Weiss, Mitchell J; Pandolfi, Pier Paolo

    2009-10-01

    GATA-1-dependent transcription is essential for erythroid differentiation and maturation. Suppression of programmed cell death is also thought to be critical for this process; however, the link between these two features of erythropoiesis has remained elusive. Here, we show that the POZ-Krüppel family transcription factor, LRF (also known as Zbtb7a/Pokemon), is a direct target of GATA1 and plays an essential antiapoptotic role during terminal erythroid differentiation. We find that loss of Lrf leads to lethal anemia in embryos, due to increased apoptosis of late-stage erythroblasts. This programmed cell death is Arf and p53 independent and is instead mediated by upregulation of the proapoptotic factor Bim. We identify Lrf as a direct repressor of Bim transcription. In strong support of this mechanism, genetic Bim loss delays the lethality of Lrf-deficient embryos and rescues their anemia phenotype. Thus, our data define a key transcriptional cascade for effective erythropoiesis, whereby GATA-1 suppresses BIM-mediated apoptosis via LRF. PMID:19853566

  10. Evolving insights into the synergy between erythropoietin and thrombopoietin and the bipotent erythroid/megakaryocytic progenitor cell.

    PubMed

    Papayannopoulou, Thalia; Kaushansky, Kenneth

    2016-08-01

    Although the synergy between erythropoietin and thrombopoietin has previously been pointed out, the clonal demonstration of a human bipotent erythroid/megakaryocytic progenitor (MEP) was first published in Experimental Hematology (Papayannopoulou T, Brice M, Farrer D, Kaushansky K. Exp Hematol. 1996;24:660-669) and later in the same year in Blood (Debili N, Coulombel L, Croisille L, et al. Blood. 1996;88:1284-1296). This demonstration, and the fact that both bipotent and monopotent erythroid or megakaryocytic progenitors co-express markers of both lineages and respond to both lineage-specific transcription factors, has provided a background for the extensive use of MEP assessment by fluorescence-activated cell sorting in many subsequent studies. Beyond this, the demonstration of shared regulatory elements and the presence of single mutations affecting both lineages have inspired further studies to decipher how the shift in transcription factor networks occurs from one lineage to the other. Furthermore, in addition to shared effects, erythropoietin and thrombopoietin have additional independent effects. Most notable for thrombopoietin is its effect on hematopoietic stem cells illustrated by in vitro and in vivo approaches. PMID:26773569

  11. LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.

    PubMed

    Maeda, Takahiro; Ito, Keisuke; Merghoub, Taha; Poliseno, Laura; Hobbs, Robin M; Wang, Guocan; Dong, Lin; Maeda, Manami; Dore, Louis C; Zelent, Arthur; Luzzatto, Lucio; Teruya-Feldstein, Julie; Weiss, Mitchell J; Pandolfi, Pier Paolo

    2009-10-01

    GATA-1-dependent transcription is essential for erythroid differentiation and maturation. Suppression of programmed cell death is also thought to be critical for this process; however, the link between these two features of erythropoiesis has remained elusive. Here, we show that the POZ-Krüppel family transcription factor, LRF (also known as Zbtb7a/Pokemon), is a direct target of GATA1 and plays an essential antiapoptotic role during terminal erythroid differentiation. We find that loss of Lrf leads to lethal anemia in embryos, due to increased apoptosis of late-stage erythroblasts. This programmed cell death is Arf and p53 independent and is instead mediated by upregulation of the proapoptotic factor Bim. We identify Lrf as a direct repressor of Bim transcription. In strong support of this mechanism, genetic Bim loss delays the lethality of Lrf-deficient embryos and rescues their anemia phenotype. Thus, our data define a key transcriptional cascade for effective erythropoiesis, whereby GATA-1 suppresses BIM-mediated apoptosis via LRF.

  12. Immunophenotypic Profiling of Erythroid Progenitor-Derived Extracellular Vesicles in Diamond-Blackfan Anaemia: A New Diagnostic Strategy.

    PubMed

    Macrì, Serena; Pavesi, Elisa; Crescitelli, Rossella; Aspesi, Anna; Vizziello, Claudia; Botto, Carlotta; Corti, Paola; Quarello, Paola; Notari, Patrizia; Ramenghi, Ugo; Ellis, Steven Robert; Dianzani, Irma

    2015-01-01

    Diamond-Blackfan Anaemia (DBA) is a rare inherited anaemia caused by heterozygous mutations in one of 13 ribosomal protein genes. Erythroid progenitors (BFU-E and CFU-E) in bone marrow (BM) show a proapoptotic phenotype. Suspicion of DBA is reached after exclusion of other forms of BM failure syndromes. To improve DBA diagnosis, which is confirmed by mutation analysis, we tested a new approach based on the study of extracellular vesicles (EVs) isolated from plasma by differential centrifugations and analysed by flow cytometry. We chose CD34, CD71 and CD235a markers to study erythroid EVs. We characterised the EVs immunophentoypic profiles of 13 DBA patients, 22 healthy controls and 16 patients with other haematological diseases. Among the three EVs clusters we found, only the CD34+/CD71low population showed statistically significant differences between DBA patients and controls (p< 0.05). The absence of this cluster is in agreement with the low levels of BFU-E found in DBA patients. The assessment of ROC curves demonstrated the potential diagnostic value of this population. We suggest that this assay may be useful to improve DBA diagnosis as a quicker and less invasive alternative to BM BFU-E culture analysis. PMID:26394034

  13. Erythroid pyrimidine 5'-nucleotidase: cloning, developmental expression, and regulation by cAMP and in vivo hypoxia.

    PubMed

    Mass, Markus; Simo, Erika; Dragon, Stefanie

    2003-12-01

    A characteristic process of terminal erythroid differentiation is the degradation of ribosomal RNA into mononucleotides. The pyrimidine mononucleotides can be dephosphorylated by pyrimidine 5'-nucleotidase (P5N-I). In humans, a lack of this enzyme causes hemolytic anemia with ribosomal structures and trinucleotides retained in the red blood cells (RBCs). Although the protein/nucleotide sequence of P5N-I is known in mammals, the onset and regulation of P5N-I during erythroid maturation is unknown. However, in circulating chicken embryonic RBCs, the enzyme is induced together with carbonic anhydrase (CAII) and 2,3-bisphosphoglycerate (2,3-BPG) by norepinephrine (NE) and adenosine, which are released by the embryo under hypoxic conditions. Here, we present the chicken P5N-I sequence and the gene expression of P5N-I during RBC maturation; the profile of gene expression follows the enzyme activity with a rise between days 13 and 16 of embryonic development. The p5n-I expression is induced (1) in definitive but not primitive RBCs by stimulation of beta-adrenergic/adenosine receptors, and (2) in definitive RBCs by hypoxic incubation of the chicken embryo. Since embryonic RBCs increase their hemoglobin-oxygen affinity by degradation of nucleotides such as uridine triphosphate (UTP) and cytidine triphosphate (CTP), the induction of p5n-I expression can be seen as an adaptive response to hypoxia.

  14. Immunophenotypic Profiling of Erythroid Progenitor-Derived Extracellular Vesicles in Diamond-Blackfan Anaemia: A New Diagnostic Strategy.

    PubMed

    Macrì, Serena; Pavesi, Elisa; Crescitelli, Rossella; Aspesi, Anna; Vizziello, Claudia; Botto, Carlotta; Corti, Paola; Quarello, Paola; Notari, Patrizia; Ramenghi, Ugo; Ellis, Steven Robert; Dianzani, Irma

    2015-01-01

    Diamond-Blackfan Anaemia (DBA) is a rare inherited anaemia caused by heterozygous mutations in one of 13 ribosomal protein genes. Erythroid progenitors (BFU-E and CFU-E) in bone marrow (BM) show a proapoptotic phenotype. Suspicion of DBA is reached after exclusion of other forms of BM failure syndromes. To improve DBA diagnosis, which is confirmed by mutation analysis, we tested a new approach based on the study of extracellular vesicles (EVs) isolated from plasma by differential centrifugations and analysed by flow cytometry. We chose CD34, CD71 and CD235a markers to study erythroid EVs. We characterised the EVs immunophentoypic profiles of 13 DBA patients, 22 healthy controls and 16 patients with other haematological diseases. Among the three EVs clusters we found, only the CD34+/CD71low population showed statistically significant differences between DBA patients and controls (p< 0.05). The absence of this cluster is in agreement with the low levels of BFU-E found in DBA patients. The assessment of ROC curves demonstrated the potential diagnostic value of this population. We suggest that this assay may be useful to improve DBA diagnosis as a quicker and less invasive alternative to BM BFU-E culture analysis.

  15. Erythroid-Specific Expression of β-globin from Sleeping Beauty-Transduced Human Hematopoietic Progenitor Cells

    PubMed Central

    Sjeklocha, Lucas M.; Park, Chang-Won; Wong, Phillip Y-P; Roney, Mark J.; Belcher, John D.; Kaufman, Dan S.; Vercellotti, Gregory M.; Hebbel, Robert P.; Steer, Clifford J.

    2011-01-01

    Gene therapy for sickle cell disease will require efficient delivery of a tightly regulated and stably expressed gene product to provide an effective therapy. In this study we utilized the non-viral Sleeping Beauty (SB) transposon system using the SB100X hyperactive transposase to transduce human cord blood CD34+ cells with DsRed and a hybrid IHK–β-globin transgene. IHK transduced cells were successfully differentiated into multiple lineages which all showed transgene integration. The mature erythroid cells had an increased β-globin to γ-globin ratio from 0.66±0.08 to 1.05±0.12 (p = 0.05), indicating expression of β-globin from the integrated SB transgene. IHK–β-globin mRNA was found in non-erythroid cell types, similar to native β-globin mRNA that was also expressed at low levels. Additional studies in the hematopoietic K562 cell line confirmed the ability of cHS4 insulator elements to protect DsRed and IHK–β-globin transgenes from silencing in long-term culture studies. Insulated transgenes had statistically significant improvement in the maintenance of long term expression, while preserving transgene regulation. These results support the use of Sleeping Beauty vectors in carrying an insulated IHK–β-globin transgene for gene therapy of sickle cell disease. PMID:22216176

  16. Erythroid-specific expression of β-globin from Sleeping Beauty-transduced human hematopoietic progenitor cells.

    PubMed

    Sjeklocha, Lucas M; Park, Chang-Won; Wong, Phillip Y-P; Roney, Mark J; Belcher, John D; Kaufman, Dan S; Vercellotti, Gregory M; Hebbel, Robert P; Steer, Clifford J

    2011-01-01

    Gene therapy for sickle cell disease will require efficient delivery of a tightly regulated and stably expressed gene product to provide an effective therapy. In this study we utilized the non-viral Sleeping Beauty (SB) transposon system using the SB100X hyperactive transposase to transduce human cord blood CD34(+) cells with DsRed and a hybrid IHK-β-globin transgene. IHK transduced cells were successfully differentiated into multiple lineages which all showed transgene integration. The mature erythroid cells had an increased β-globin to γ-globin ratio from 0.66±0.08 to 1.05±0.12 (p=0.05), indicating expression of β-globin from the integrated SB transgene. IHK-β-globin mRNA was found in non-erythroid cell types, similar to native β-globin mRNA that was also expressed at low levels. Additional studies in the hematopoietic K562 cell line confirmed the ability of cHS4 insulator elements to protect DsRed and IHK-β-globin transgenes from silencing in long-term culture studies. Insulated transgenes had statistically significant improvement in the maintenance of long term expression, while preserving transgene regulation. These results support the use of Sleeping Beauty vectors in carrying an insulated IHK-β-globin transgene for gene therapy of sickle cell disease.

  17. Immunophenotypic Profiling of Erythroid Progenitor-Derived Extracellular Vesicles in Diamond-Blackfan Anaemia: A New Diagnostic Strategy

    PubMed Central

    Macrì, Serena; Aspesi, Anna; Vizziello, Claudia; Botto, Carlotta; Corti, Paola; Quarello, Paola; Notari, Patrizia; Ramenghi, Ugo; Ellis, Steven Robert; Dianzani, Irma

    2015-01-01

    Diamond-Blackfan Anaemia (DBA) is a rare inherited anaemia caused by heterozygous mutations in one of 13 ribosomal protein genes. Erythroid progenitors (BFU-E and CFU-E) in bone marrow (BM) show a proapoptotic phenotype. Suspicion of DBA is reached after exclusion of other forms of BM failure syndromes. To improve DBA diagnosis, which is confirmed by mutation analysis, we tested a new approach based on the study of extracellular vesicles (EVs) isolated from plasma by differential centrifugations and analysed by flow cytometry. We chose CD34, CD71 and CD235a markers to study erythroid EVs. We characterised the EVs immunophentoypic profiles of 13 DBA patients, 22 healthy controls and 16 patients with other haematological diseases. Among the three EVs clusters we found, only the CD34+/CD71low population showed statistically significant differences between DBA patients and controls (p< 0.05). The absence of this cluster is in agreement with the low levels of BFU-E found in DBA patients. The assessment of ROC curves demonstrated the potential diagnostic value of this population. We suggest that this assay may be useful to improve DBA diagnosis as a quicker and less invasive alternative to BM BFU-E culture analysis. PMID:26394034

  18. Structural and functional characterization of an atypical activation domain in erythroid Krüppel-like factor (EKLF)

    PubMed Central

    Mas, Caroline; Lussier-Price, Mathieu; Soni, Shefali; Morse, Thomas; Arseneault, Geneviève; Di Lello, Paola; Lafrance-Vanasse, Julien; Bieker, James J.; Omichinski, James G.

    2011-01-01

    Erythroid Krüppel-like factor (EKLF) plays an important role in erythroid development by stimulating β-globin gene expression. We have examined the details by which the minimal transactivation domain (TAD) of EKLF (EKLFTAD) interacts with several transcriptional regulatory factors. We report that EKLFTAD displays homology to the p53TAD and, like the p53TAD, can be divided into two functional subdomains (EKLFTAD1 and EKLFTAD2). Based on sequence analysis, we found that EKLFTAD2 is conserved in KLF2, KLF4, KLF5, and KLF15. In addition, we demonstrate that EKLFTAD2 binds the amino-terminal PH domain of the Tfb1/p62 subunit of TFIIH (Tfb1PH/p62PH) and four domains of CREB-binding protein/p300. The solution structure of the EKLFTAD2/Tfb1PH complex indicates that EKLFTAD2 binds Tfb1PH in an extended conformation, which is in contrast to the α-helical conformation seen for p53TAD2 in complex with Tfb1PH. These studies provide detailed mechanistic information into EKLFTAD functions as well as insights into potential interactions of the TADs of other KLF proteins. In addition, they suggest that not only have acidic TADs evolved so that they bind using different conformations on a common target, but that transitioning from a disordered to a more ordered state is not a requirement for their ability to bind multiple partners. PMID:21670263

  19. Sustainable Learning

    ERIC Educational Resources Information Center

    Cadwell, Louise; Dillon, Robert

    2011-01-01

    Green schools have moved into a new era that focuses on building a culture of sustainability in every aspect of learning in schools. In the early stages of sustainability education, the focus was on recycling and turning off the lights. Now, students and adults together are moving into the areas of advocacy and action that are based on a deep…

  20. Sustainability 101

    ERIC Educational Resources Information Center

    Shi, David

    2008-01-01

    Sustainability is one of the leading issues of this time. Climate change is real, and widespread commitment and creativity are needed to combat its negative effects. Higher education is the seedbed of the sustainability movement. Much climate research and environmental science takes place on college and university campuses, which are, by their…

  1. Sustainable Biofuels Development Center

    SciTech Connect

    Reardon, Kenneth F.

    2015-03-01

    The mission of the Sustainable Bioenergy Development Center (SBDC) is to enhance the capability of America’s bioenergy industry to produce transportation fuels and chemical feedstocks on a large scale, with significant energy yields, at competitive cost, through sustainable production techniques. Research within the SBDC is organized in five areas: (1) Development of Sustainable Crops and Agricultural Strategies, (2) Improvement of Biomass Processing Technologies, (3) Biofuel Characterization and Engine Adaptation, (4) Production of Byproducts for Sustainable Biorefining, and (5) Sustainability Assessment, including evaluation of the ecosystem/climate change implication of center research and evaluation of the policy implications of widespread production and utilization of bioenergy. The overall goal of this project is to develop new sustainable bioenergy-related technologies. To achieve that goal, three specific activities were supported with DOE funds: bioenergy-related research initiation projects, bioenergy research and education via support of undergraduate and graduate students, and Research Support Activities (equipment purchases, travel to attend bioenergy conferences, and seminars). Numerous research findings in diverse fields related to bioenergy were produced from these activities and are summarized in this report.

  2. Sustainability Base Construction Update

    NASA Technical Reports Server (NTRS)

    Mewhinney, Michael

    2012-01-01

    Construction of the new Sustainability Base Collaborative support facility, expected to become the highest performing building in the federal government continues at NASA's Ames Research Center, Moffet Field, Calif. The new building is designed to achieve a platinum rating under the leadership in Energy and Environment Design (LEED) new construction standards for environmentally sustainable construction developed by the U. S. Green Building Council, Washington, D. C. When completed by the end of 2011, the $20.6 million building will feature near zero net energy consumption, use 90 percent less potable water than conventionally build buildings of equivalent size, and will result in reduced building maintenance costs.

  3. RUNX1B Expression Is Highly Heterogeneous and Distinguishes Megakaryocytic and Erythroid Lineage Fate in Adult Mouse Hematopoiesis

    PubMed Central

    Draper, Julia E.; Sroczynska, Patrycja; Tsoulaki, Olga; Leong, Hui Sun; Fadlullah, Muhammad Z. H.; Miller, Crispin; Kouskoff, Valerie; Lacaud, Georges

    2016-01-01

    The Core Binding Factor (CBF) protein RUNX1 is a master regulator of definitive hematopoiesis, crucial for hematopoietic stem cell (HSC) emergence during ontogeny. RUNX1 also plays vital roles in adult mice, in regulating the correct specification of numerous blood lineages. Akin to the other mammalian Runx genes, Runx1 has two promoters P1 (distal) and P2 (proximal) which generate distinct protein isoforms. The activities and specific relevance of these two promoters in adult hematopoiesis remain to be fully elucidated. Utilizing a dual reporter mouse model we demonstrate that the distal P1 promoter is broadly active in adult hematopoietic stem and progenitor cell (HSPC) populations. By contrast the activity of the proximal P2 promoter is more restricted and its upregulation, in both the immature Lineage- Sca1high cKithigh (LSK) and bipotential Pre-Megakaryocytic/Erythroid Progenitor (PreMegE) populations, coincides with a loss of erythroid (Ery) specification. Accordingly the PreMegE population can be prospectively separated into “pro-erythroid” and “pro-megakaryocyte” populations based on Runx1 P2 activity. Comparative gene expression analyses between Runx1 P2+ and P2- populations indicated that levels of CD34 expression could substitute for P2 activity to distinguish these two cell populations in wild type (WT) bone marrow (BM). Prospective isolation of these two populations will enable the further investigation of molecular mechanisms involved in megakaryocytic/erythroid (Mk/Ery) cell fate decisions. Having characterized the extensive activity of P1, we utilized a P1-GFP homozygous mouse model to analyze the impact of the complete absence of Runx1 P1 expression in adult mice and observed strong defects in the T cell lineage. Finally, we investigated how the leukemic fusion protein AML1-ETO9a might influence Runx1 promoter usage. Short-term AML1-ETO9a induction in BM resulted in preferential P2 upregulation, suggesting its expression may be important to

  4. Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells

    PubMed Central

    Salopiata, Florian; Depner, Sofia; Wäsch, Marvin; Böhm, Martin E.; Mücke, Oliver; Plass, Christoph; Lehmann, Wolf D.; Kreutz, Clemens; Timmer, Jens; Klingmüller, Ursula

    2016-01-01

    Lung cancer, with its most prevalent form non-small-cell lung carcinoma (NSCLC), is one of the leading causes of cancer-related deaths worldwide, and is commonly treated with chemotherapeutic drugs such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO). However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells. Here, we verified that the NSCLC cell line H838 expresses functional erythropoietin receptors (EPOR) and that treatment with EPO reduces cisplatin-induced apoptosis. To pinpoint differences in EPO-induced survival signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid) and H838 cells, we combined mathematical modeling with a method for feature selection, the L1 regularization. Utilizing an example model and simulated data, we demonstrated that this approach enables the accurate identification and quantification of cell type-specific parameters. We applied our strategy to quantitative time-resolved data of EPO-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative real-time PCR (qRT-PCR) in CFU-E and H838 cells as well as H838 cells overexpressing human EPOR (H838-HA-hEPOR). The established parsimonious mathematical model was able to simultaneously describe the data sets of CFU-E, H838 and H838-HA-hEPOR cells. Seven cell type-specific parameters were identified that included for example parameters for nuclear translocation of STAT5 and target gene induction. Cell type-specific differences in target gene induction were experimentally validated by qRT-PCR experiments. The systematic identification of pathway differences and sensitivities of EPOR signaling in CFU-E and H838 cells revealed potential targets for intervention to selectively inhibit EPO-induced signaling in the tumor cells but leave the responses in erythroid

  5. Generation of a High Number of Healthy Erythroid Cells from Gene-Edited Pyruvate Kinase Deficiency Patient-Specific Induced Pluripotent Stem Cells

    PubMed Central

    Garate, Zita; Quintana-Bustamante, Oscar; Crane, Ana M.; Olivier, Emmanuel; Poirot, Laurent; Galetto, Roman; Kosinski, Penelope; Hill, Collin; Kung, Charles; Agirre, Xabi; Orman, Israel; Cerrato, Laura; Alberquilla, Omaira; Rodriguez-Fornes, Fatima; Fusaki, Noemi; Garcia-Sanchez, Felix; Maia, Tabita M.; Ribeiro, Maria L.; Sevilla, Julian; Prosper, Felipe; Jin, Shengfang; Mountford, Joanne; Guenechea, Guillermo; Gouble, Agnes; Bueren, Juan A.; Davis, Brian R.; Segovia, Jose C.

    2015-01-01

    Summary Pyruvate kinase deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs) from peripheral blood mononuclear cells (PB-MNCs) of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR). Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses. PMID:26549847

  6. Generation of a High Number of Healthy Erythroid Cells from Gene-Edited Pyruvate Kinase Deficiency Patient-Specific Induced Pluripotent Stem Cells.

    PubMed

    Garate, Zita; Quintana-Bustamante, Oscar; Crane, Ana M; Olivier, Emmanuel; Poirot, Laurent; Galetto, Roman; Kosinski, Penelope; Hill, Collin; Kung, Charles; Agirre, Xabi; Orman, Israel; Cerrato, Laura; Alberquilla, Omaira; Rodriguez-Fornes, Fatima; Fusaki, Noemi; Garcia-Sanchez, Felix; Maia, Tabita M; Ribeiro, Maria L; Sevilla, Julian; Prosper, Felipe; Jin, Shengfang; Mountford, Joanne; Guenechea, Guillermo; Gouble, Agnes; Bueren, Juan A; Davis, Brian R; Segovia, Jose C

    2015-12-01

    Pyruvate kinase deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs) from peripheral blood mononuclear cells (PB-MNCs) of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR). Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses.

  7. Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression.

    PubMed

    Chlon, Timothy M; McNulty, Maureen; Goldenson, Benjamin; Rosinski, Alexander; Crispino, John D

    2015-05-01

    GATA1 is a master transcriptional regulator of the differentiation of several related myeloid blood cell types, including erythrocytes and megakaryocytes. Germ-line mutations that cause loss of full length GATA1, but allow for expression of the short isoform (GATA1s), are associated with defective erythropoiesis in a subset of patients with Diamond Blackfan Anemia. Despite extensive studies of GATA1s in megakaryopoiesis, the mechanism by which GATA1s fails to support normal erythropoiesis is not understood. In this study, we used global gene expression and chromatin occupancy analysis to compare the transcriptional activity of GATA1s to GATA1. We discovered that compared to GATA1, GATA1s is less able to activate the erythroid gene expression program and terminal differentiation in cells with dual erythroid-megakaryocytic differentiation potential. Moreover, we found that GATA1s bound to many of its erythroid-specific target genes less efficiently than full length GATA1. These results suggest that the impaired ability of GATA1s to promote erythropoiesis in DBA may be caused by failure to occupy erythroid-specific gene regulatory elements. PMID:25682601

  8. Generation of a High Number of Healthy Erythroid Cells from Gene-Edited Pyruvate Kinase Deficiency Patient-Specific Induced Pluripotent Stem Cells.

    PubMed

    Garate, Zita; Quintana-Bustamante, Oscar; Crane, Ana M; Olivier, Emmanuel; Poirot, Laurent; Galetto, Roman; Kosinski, Penelope; Hill, Collin; Kung, Charles; Agirre, Xabi; Orman, Israel; Cerrato, Laura; Alberquilla, Omaira; Rodriguez-Fornes, Fatima; Fusaki, Noemi; Garcia-Sanchez, Felix; Maia, Tabita M; Ribeiro, Maria L; Sevilla, Julian; Prosper, Felipe; Jin, Shengfang; Mountford, Joanne; Guenechea, Guillermo; Gouble, Agnes; Bueren, Juan A; Davis, Brian R; Segovia, Jose C

    2015-12-01

    Pyruvate kinase deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs) from peripheral blood mononuclear cells (PB-MNCs) of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR). Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses. PMID:26549847

  9. Sustainable Development.

    ERIC Educational Resources Information Center

    Auerbach, Raymond

    1994-01-01

    Discusses South African national development priorities, sustainable development, and the future of agriculture and presents three scenarios of possible national action: production for sale and export, household food security, and conservation of natural resources. (MKR)

  10. Sustainable markets for sustainable energy

    SciTech Connect

    Millan, J.; Smyser, C.

    1997-12-01

    The author discusses how the Inter-American Development Bank (IDB) is involved in sustainable energy development. It presently has 50 loans and grants for non conventional renewable energy projects and ten grants for efficiency programs for $600 and $17 million respectively, representing 100 MW of power. The IDB is concerned with how to create a sustainable market for sustainable energy projects. The IDB is trying to work with government, private sector, NGOs, trading allies, credit sources, and regulators to find proper roles for such projects. He discusses how the IDB is working to expand its vision and objectives in renewable energy projects in Central and South America.

  11. Moving Toward Universal Health Coverage (UHC) to Achieve Inclusive and Sustainable Health Development: Three Essential Strategies Drawn From Asian Experience Comment on "Improving the World's Health Through the Post-2015 Development Agenda: Perspectives from Rwanda".

    PubMed

    Xu, Ye; Huang, Cheng; Colón-Ramos, Uriyoán

    2015-01-01

    Binagwaho and colleagues' perspective piece provided a timely reflection on the experience of Rwanda in achieving the Millennium Development Goals (MDGs) and a proposal of 5 principles to carry forward in post-2015 health development. This commentary echoes their viewpoints and offers three lessons for health policy reforms consistent with these principles beyond 2015. Specifically, we argue that universal health coverage (UHC) is an integrated solution to advance the global health development agenda, and the three essential strategies drawn from Asian countries' health reforms toward UHC are: (1) Public financing support and sequencing health insurance expansion by first extending health insurance to the extremely poor, vulnerable, and marginalized population are critical for achieving UHC; (2) Improved quality of delivered care ensures supply-side readiness and effective coverage; (3) Strategic purchasing and results-based financing creates incentives and accountability for positive changes. These strategies were discussed and illustrated with experience from China and other Asian economies. PMID:26673477

  12. Moving Toward Universal Health Coverage (UHC) to Achieve Inclusive and Sustainable Health Development: Three Essential Strategies Drawn From Asian Experience Comment on "Improving the World's Health Through the Post-2015 Development Agenda: Perspectives from Rwanda".

    PubMed

    Xu, Ye; Huang, Cheng; Colón-Ramos, Uriyoán

    2015-01-01

    Binagwaho and colleagues' perspective piece provided a timely reflection on the experience of Rwanda in achieving the Millennium Development Goals (MDGs) and a proposal of 5 principles to carry forward in post-2015 health development. This commentary echoes their viewpoints and offers three lessons for health policy reforms consistent with these principles beyond 2015. Specifically, we argue that universal health coverage (UHC) is an integrated solution to advance the global health development agenda, and the three essential strategies drawn from Asian countries' health reforms toward UHC are: (1) Public financing support and sequencing health insurance expansion by first extending health insurance to the extremely poor, vulnerable, and marginalized population are critical for achieving UHC; (2) Improved quality of delivered care ensures supply-side readiness and effective coverage; (3) Strategic purchasing and results-based financing creates incentives and accountability for positive changes. These strategies were discussed and illustrated with experience from China and other Asian economies.

  13. Defects of protein production in erythroid cells revealed in a zebrafish Diamond-Blackfan anemia model for mutation in RPS19.

    PubMed

    Zhang, Y; Ear, J; Yang, Z; Morimoto, K; Zhang, B; Lin, S

    2014-01-01

    Diamond-Blackfan anemia (DBA) is a rare congenital red cell aplasia that classically presents during early infancy in DBA patients. Approximately, 25% of patients carry a mutation in the ribosomal protein (RP) S19 gene; mutations in RPS24, RPS17, RPL35A, RPL11, and RPL5 have been reported. How ribosome protein deficiency causes defects specifically to red blood cells in DBA has not been well elucidated. To genetically model the predominant ribosome defect in DBA, we generated an rps19 null mutant through the use of TALEN-mediated gene targeting in zebrafish. Molecular characterization of this mutant line demonstrated that rps19 deficiency reproduced the erythroid defects of DBA, including a lack of mature red blood cells and p53 activation. Notably, we found that rps19 mutants' production of globin proteins was significantly inhibited; however, globin transcript level was either increased or unaffected in rps19 mutant embryos. This dissociation of RNA/protein levels of globin genes was confirmed in another zebrafish DBA model with defects in rpl11. Using transgenic zebrafish with specific expression of mCherry in erythroid cells, we showed that protein production in erythroid cells was decreased when either rps19 or rpl11 was mutated. L-Leucine treatment alleviated the defects of protein production in erythroid cells and partially rescued the anemic phenotype in both rps19 and rpl11 mutants. Analysis of this model suggests that the decreased protein production in erythroid cells likely contributes to the blood-specific phenotype of DBA. Furthermore, the newly generated rps19 zebrafish mutant should serve as a useful animal model to study DBA. Our in vivo findings may provide clues for the future therapy strategy for DBA.

  14. Effects of nucleoside analog incorporation on DNA binding to the DNA binding domain of the GATA-1 erythroid transcription factor.

    PubMed

    Foti, M; Omichinski, J G; Stahl, S; Maloney, D; West, J; Schweitzer, B I

    1999-02-01

    We investigate here the effects of the incorporation of the nucleoside analogs araC (1-beta-D-arabinofuranosylcytosine) and ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl] guanine) into the DNA binding recognition sequence for the GATA-1 erythroid transcription factor. A 10-fold decrease in binding affinity was observed for the ganciclovir-substituted DNA complex in comparison to an unmodified DNA of the same sequence composition. AraC substitution did not result in any changes in binding affinity. 1H-15N HSQC and NOESY NMR experiments revealed a number of chemical shift changes in both DNA and protein in the ganciclovir-modified DNA-protein complex when compared to the unmodified DNA-protein complex. These changes in chemical shift and binding affinity suggest a change in the binding mode of the complex when ganciclovir is incorporated into the GATA DNA binding site.

  15. Effects of nucleoside analog incorporation on DNA binding to the DNA binding domain of the GATA-1 erythroid transcription factor.

    PubMed

    Foti, M; Omichinski, J G; Stahl, S; Maloney, D; West, J; Schweitzer, B I

    1999-02-01

    We investigate here the effects of the incorporation of the nucleoside analogs araC (1-beta-D-arabinofuranosylcytosine) and ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl] guanine) into the DNA binding recognition sequence for the GATA-1 erythroid transcription factor. A 10-fold decrease in binding affinity was observed for the ganciclovir-substituted DNA complex in comparison to an unmodified DNA of the same sequence composition. AraC substitution did not result in any changes in binding affinity. 1H-15N HSQC and NOESY NMR experiments revealed a number of chemical shift changes in both DNA and protein in the ganciclovir-modified DNA-protein complex when compared to the unmodified DNA-protein complex. These changes in chemical shift and binding affinity suggest a change in the binding mode of the complex when ganciclovir is incorporated into the GATA DNA binding site. PMID:10037146

  16. The small 11kDa nonstructural protein of human parvovirus B19 plays a key role in inducing apoptosis during B19 virus infection of primary erythroid progenitor cells

    PubMed Central

    Chen, Aaron Yun; Zhang, Elizabeth Yan; Guan, Wuxiang; Cheng, Fang; Kleiboeker, Steve; Yankee, Thomas M.

    2010-01-01

    Human parvovirus B19 (B19V) infection shows a strong erythroid tropism and drastically destroys erythroid progenitor cells, thus leading to most of the disease outcomes associated with B19V infection. In this study, we systematically examined the 3 B19V nonstructural proteins, 7.5kDa, 11kDa, and NS1, for their function in inducing apoptosis in transfection of primary ex vivo–expanded erythroid progenitor cells, in comparison with apoptosis induced during B19V infection. Our results show that 11kDa is a more significant inducer of apoptosis than NS1, whereas 7.5kDa does not induce apoptosis. Furthermore, we determined that caspase-10, an initiator caspase in death receptor signaling, is the most active caspase in apoptotic erythroid progenitors induced by 11kDa and NS1 as well as during B19V infection. More importantly, cytoplasm-localized 11kDa is expressed at least 100 times more than nucleus-localized NS1 at the protein level in primary erythroid progenitor cells infected with B19V; and inhibition of 11kDa expression using antisense oligos targeting specifically to the 11kDa-encoding mRNAs reduces apoptosis significantly during B19V infection of erythroid progenitor cells. Taken together, these results demonstrate that the 11kDa protein contributes to erythroid progenitor cell death during B19V infection. PMID:19861680

  17. Complete genomic organization of the human erythroid p55 gene (MPP1), a membrane-associated guanylate kinase homologue

    SciTech Connect

    Kim, A.C.; Metzenberg, A.B.; Sahr, K.E.

    1996-01-15

    Human p55 is an abundantly palmitoylated phosphoprotein of the erythroid membrane. It is the prototype of a newly discovered family of membrane-associated proteins termed MAGUKs (membrane-associated guanylate kinase homologues). The MAGUKs interact with the cytoskeleton and regulate cell proliferation, signaling pathways, and intercellular junctions. Here, we report the complete intron-exon map of the human erythroid p55 gene (HGMW-approved symbol MPP1). The structure of the p55 gene was determined from cosmid clones isolated from a cosmid library specific for the human X chromosome. There is a single copy of the p55 gene, composed of 12 exons and spanning approximately 28 kb in the q28 region of the human X chromosome. The exon sizes range from 69 (exon 5) to 203 bp (intron 2) to {approximately}14 kb (intron 1). The intron-exon boundaries conform to the donor/acceptor consensus sequence, GT-AG, for splice junctions. Several of the exon boundaries correspond to the boundaries of functional domains in the p55 protein. These domains include a SH3 motif and a region that binds to cytoskeletal protein 4.1. In addition, a comparison of the genomic and the primary structures of p55 reveals a highly conserved phosphotyrosine domain located between the protein 4.1 binding domain and the guanylate kinase domain. Finally, promoter activity measurements of the region immediately upstream of the p55 gene, which contains several cis-elements commonly found in housekeeping genes, suggest that a CpG island may be associated with the p55 gene expression in vivo. 42 refs., 5 figs., 1 tab.

  18. Human Erythroid 5-Aminolevulinate Synthase Mutations Associated with X-Linked Protoporphyria Disrupt Conformational Equilibrium and Enhance Product Release†

    PubMed Central

    Fratz, Erica J.; Clayton, Jerome; Hunter, Gregory A.; Ducamp, Sarah; Breydo, Leonid; Uversky, Vladimir N.; Deybach, Jean-Charles; Gouya, Laurent; Puy, Hervé; Ferreira, Gloria C.

    2015-01-01

    Regulation of 5-aminolevulinate synthase (ALAS) is at the origin of balanced heme production in mammals. Mutations in the C-terminal region of human erythroid-specific ALAS (hALAS2) are associated with X-linked protoporphyria (XLPP), a disease characterized by extreme photosensitivity, with elevated blood concentrations of free protoporphyrin IX and zinc protoporphyrin. To investigate the molecular basis for this disease, recombinant hALAS2 and variants of the enzyme harboring the gain-of-function XLPP mutations were constructed, purified, and analyzed kinetically, spectroscopically and thermodynamically. Enhanced activities of the XLPP variants resulted from accelerations in the rate at which the product 5-aminolevulinate (ALA) was released from the enzyme. Circular dichroism spectroscopy revealed that the XLPP mutations altered the microenvironment of the pyridoxal 5’-phosphate cofactor, which underwent further and specific alterations upon succinyl-CoA binding. Transient kinetic analyses of the variant-catalyzed reactions and protein fluorescence quenching upon ALA binding to the XLPP variants demonstrated that the protein conformational transition step associated with product release was predominantly affected. Of relevance, XLPP could also be modeled in cell culture. We propose that 1) the XLPP mutations destabilize the succinyl-CoA-induced hALAS2 closed conformation and thus accelerate ALA release, 2) the extended C-terminus of wild-type mammalian ALAS2 provides a regulatory role that allows for allosteric modulation of activity, thereby controlling the rate of erythroid heme biosynthesis, and 3) this control is disrupted in XLPP, resulting in porphyrin accumulation. PMID:26300302

  19. The SOD1 transgene expressed in erythroid cells alleviates fatal phenotype in congenic NZB/NZW-F1 mice.

    PubMed

    Otsuki, Noriyuki; Konno, Tasuku; Kurahashi, Toshihiro; Suzuki, Saori; Lee, Jaeyong; Okada, Futoshi; Iuchi, Yoshihito; Homma, Takujiro; Fujii, Junichi

    2016-07-01

    Oxidative stress due to a superoxide dismutase 1 (SOD1) deficiency causes anemia and autoimmune responses, which are phenotypically similar to autoimmune hemolytic anemia (AIHA) and systemic lupus erythematosus (SLE) in C57BL/6 mice and aggravates AIHA pathogenesis in New Zealand black (NZB) mice. We report herein on an evaluation of the role of reactive oxygen species (ROS) in a model mouse with inherited SLE, that is, F1 mice of the NZB × New Zealand white (NZW) strain. The ROS levels within red blood cells (RBCs) of the F1 mice were similar to the NZW mice but lower compared to the NZB mice throughout adult period. Regarding SLE pathogenesis, we examined the effects of an SOD1 deficiency or the overexpression of human SOD1 in erythroid cells by establishing corresponding congenic F1 mice. A SOD1 deficiency caused an elevation in ROS production, methemoglobin content, and hyperoxidation of peroxiredoxin in RBC of the F1 mice, which were all consistent with elevated oxidative stress. However, while the overexpression of human SOD1 in erythroid cells extended the life span of the congenic F1 mice, the SOD1 deficiency had no effect on life span compared to wild-type F1 mice. It is generally recognized that NZW mice possess a larval defect in the immune system and that NZB mice trigger an autoimmune reaction in the F1 mice. Our results suggest that the oxidative insult originated from the NZB mouse background has a functional role in triggering an aberrant immune reaction, leading to fatal responses in F1 mice. PMID:27080108

  20. Reprogramming of human peripheral blood monocytes to erythroid lineage by blocking of the PU-1 gene expression.

    PubMed

    Nouri, Masoumeh; Deezagi, Abdolkhalegh; Ebrahimi, Marzieh

    2016-03-01

    In hematopoietic system development, PU.1 and GATA-1 as lineage-specific transcription factors (TF) are expressed in common myeloid progenitors. The cross antagonism between them ascertains gene expression programs of monocytic and erythroid cells, respectively. This concept in transdifferentiation approaches has not been well considered yet, especially in intralineage conversion systems. To demonstrate whether PU.1 suppression induces monocyte lineage conversion into red blood cells, a combination of three PU.1-specific siRNAs was implemented to knock down PU.1 gene expression and generate the balance in favor of GATA-1 expression to induce erythroid differentiation. For this purpose, monocytes were isolated from human peripheral blood and transfected by PU.1 siRNAs. In transfected monocytes, the rate of PU.1 expression in mRNA level was significantly decreased until 0.38 ± 0.118 when compared to untreated monocytes at 72 h (p value ≤0.05) which resulted in significant overexpression of GATA1 of 16.1 ± 0.343-fold compared to the untreated group (p value ≤0.01). Subsequently, overexpression of hemoglobin (α 13.26 ± 1.34-fold; p value≤0.0001) and β-globin (37.55 ± 16.56-fold; p value≤0.0001) was observed when compared to control groups. The results of western immunoblotting confirm those findings too. While, reduced expression of monocyte, CD14 gene, was observed in qRT-PCR and flow cytometry results. Our results suggest that manipulating the ratio of the two TFs in bifurcation differentiation pathways via applying siRNA technology can possibly change the cells' fate as a safe way for therapeutics application.

  1. Annual Sustainability Report FY 2014. Incorporates NREL Site Sustainability Plan

    SciTech Connect

    Rukavina, Frank

    2015-07-01

    NREL's Sustainability Program is responsible for upholding all executive orders, federal regulations, U.S. Department of Energy (DOE) orders, and goals related to sustainable and resilient facility operations. But NREL continues to expand sustainable practices above and beyond the laboratory's regulations and requirements to ensure that the laboratory fulfills its mission into the future, leaves the smallest possible legacy footprint, and models sustainable operations and behaviors on national, regional, and local levels. The report, per the GRI reporting format, elaborates on multi-year goals relative to executive orders, achievements, and challenges; and success stories provide specific examples. A section called 'Sustaining NREL's Future Through Integration' provides insight into how NREL is successfully expanding the adoption of renewable energy technologies through integration.

  2. Achieving Energy Efficiency Through Real-Time Feedback

    SciTech Connect

    Nesse, Ronald J.

    2011-09-01

    Through the careful implementation of simple behavior change measures, opportunities exist to achieve strategic gains, including greater operational efficiencies, energy cost savings, greater tenant health and ensuing productivity and an improved brand value through sustainability messaging and achievement.

  3. cAMP and in vivo hypoxia induce tob, ifr1, and fos expression in erythroid cells of the chick embryo.

    PubMed

    Dragon, Stefanie; Offenhäuser, Nina; Baumann, Rosemarie

    2002-04-01

    During avian embryonic development, terminal erythroid differentiation occurs in the circulation. Some of the key events, such as the induction of erythroid 2,3-bisphosphoglycerate (2,3-BPG), carbonic anhydrase (CAII), and pyrimidine 5'-nucleotidase (P5N) synthesis are oxygen dependent (Baumann R, Haller EA, Schöning U, and Weber M, Dev Biol 116: 548-551, 1986; Dragon S and Baumann R, Am J Physiol Regulatory Integrative Comp Physiol 280: R870-R878, 2001; Dragon S, Carey C, Martin K, and Baumann R, J Exp Biol 202: 2787-2795, 1999; Dragon S, Glombitza S, Götz R, and Baumann R, Am J Physiol Regulatory Integrative Comp Physiol 271: R982-R989, 1996; Dragon S, Hille R, Götz R, and Baumann R, Blood 91: 3052-3058, 1998; Million D, Zillner P, and Baumann R, Am J Physiol Regulatory Integrative Comp Physiol 261: R1188-R1196, 1991) in an indirect way: hypoxia stimulates the release of norepinephrine (NE)/adenosine into the circulation (Dragon et al., J Exp Biol 202: 2787-2795, 1999; Dragon et al., Am J Physiol Regulatory Integrative Comp Physiol 271: R982-R989, 1996). This leads via erythroid beta-adrenergic/adenosine A(2) receptor activation to a cAMP signal inducing several proteins in a transcription-dependent manner (Dragon et al., Am J Physiol Regulatory Integrative Comp Physiol 271: R982-R989, 1996; Dragon et al., Blood 91: 3052-3058, 1998; Glombitza S, Dragon S, Berghammer M, Pannermayr M, and Baumann R, Am J Physiol Regulatory Integrative Comp Physiol 271: R973-R981, 1996). To understand how the cAMP-dependent processes are initiated, we screened an erythroid cDNA library for cAMP-regulated genes. We detected three genes that were strongly upregulated (>5-fold) by cAMP in definitive and primitive red blood cells. They are homologous to the mammalian Tob, Ifr1, and Fos proteins. In addition, the genes are induced in the intact embryo during short-term hypoxia. Because the genes are regulators of proliferation and differentiation in other cell types, we suggest that c

  4. Action of antithymocyte globulin on normal human erythroid progenitor cell proliferation in vitro: erythropoietic growth-enhancing factors are released from marrow accessory cells.

    PubMed

    Mangan, K F; D'Alessandro, L; Mullaney, M T

    1986-04-01

    Studies were undertaken to determine the mechanism of action of a horse antithymocyte globulin preparation (ATGAM) (HATG) and its control preparation of horse gamma globulin (HIgG) on the proliferation of normal human marrow and blood erythroid progenitor cells (CFU-E, BFU-E) in vitro. In preincubation studies with marrow mononuclear cells and complement, HATG did not significantly augment CFU-E or BFU-E growth greater than that expected because of removal of marrow T cells by this agent. However, direct addition of HATG but not HIgG to marrow cultures significantly stimulated CFU-E and BFU-E up to two to four times that of media or HIgG controls (P less than 0.05). The peak effect was observed at 10 to 100 micrograms/ml HATG; HATG was toxic at 1000 micrograms/ml. By contrast, the OKT3 monoclonal antibody was less stimulatory than HATG. The in vitro erythropoietic stimulatory effect of HATG was dependent on the presence of accessory cells because removal of T cells or monocytes (less than 2% to 5%) or adsorptions of HATG with T cells or monocytes reduced its stimulatory effect, highly purified BFU-E nearly devoid of accessory cells required irradiated accessory cells for demonstration of the HATG stimulatory effect, and an erythroid burst-promoting activity was released from T cells or unseparated mononuclear cells in the presence of HATG but not HIgG. The HATG enhancing effect was optimal in the first 96 hours of cultures in the presence of erythropoietin, and was reproducible with three separate lots of HATG. Up to 16% of HATG-stimulated erythroid colonies expressed nonerythroid lineage cells. Iron 59 incorporation into heme of CFU-E- or BFU-E-derived colonies was augmented equally by HATG or HIgG at 10 micrograms/ml. Erythropoietin dose-response curves and studies with antierythropoietin sera suggested that HATG also increased the sensitivity of erythroid progenitor cells to very low concentrations of erythropoietin. We conclude that HATG but not HIgG control

  5. Exergy sustainability.

    SciTech Connect

    Robinett, Rush D. III; Wilson, David Gerald; Reed, Alfred W.

    2006-05-01

    Exergy is the elixir of life. Exergy is that portion of energy available to do work. Elixir is defined as a substance held capable of prolonging life indefinitely, which implies sustainability of life. In terms of mathematics and engineering, exergy sustainability is defined as the continuous compensation of irreversible entropy production in an open system with an impedance and capacity-matched persistent exergy source. Irreversible and nonequilibrium thermodynamic concepts are combined with self-organizing systems theories as well as nonlinear control and stability analyses to explain this definition. In particular, this paper provides a missing link in the analysis of self-organizing systems: a tie between irreversible thermodynamics and Hamiltonian systems. As a result of this work, the concept of ''on the edge of chaos'' is formulated as a set of necessary and sufficient conditions for stability and performance of sustainable systems. This interplay between exergy rate and irreversible entropy production rate can be described as Yin and Yang control: the dialectic synthesis of opposing power flows. In addition, exergy is shown to be a fundamental driver and necessary input for sustainable systems, since exergy input in the form of power is a single point of failure for self-organizing, adaptable systems.

  6. The road to sustainability

    SciTech Connect

    Sarrao, John L; Crabtree, George

    2009-01-01

    Sustainability is the hottest topic in energy research today, but what does it actually mean? George Crabtree and John Sarrao describe what makes a technology sustainable, and outline the materials-science challenges standing between us and clean, long-lasting energy. Although most people agree that more-sustainable energy technologies are desirable, they often find it harder to agree on exactly how sustainable these technologies need to be, and even precisely what is meant by sustainability. To clarify the debate, we suggest three criteria for sustainability, each of which captures a different feature of the problem. While we do not have the lUxury of achieving full sustainability for all of our next-generation energy technologies, we can use these definitions to select our strategic sustainability targets and track our progress toward achieving them. As will become clear, the most sustainable energy technologies require the most challenging fundamental science breakthroughs. The first criterion for sustainability is 'lasts a long time'. This quality has been a feature of many energy sources we have used historically, including wood in ancient times and oil throughout most of the 20th century. The definition of 'long time' is, of course, relative: the world's demand for energy long ago outpaced the ability of wood to supply it, and the production of oil is likely to peak sometime within the next few decades. Substantial reductions in the rate of oil consumption through higher-efficiency processes can significantly impact on how long non-renewable resources last. In applying the 'long time' criterion, we need to distinguish between energy sources that are effectively limitless and those that are finite but, for the moment, adequate. The second criterion for sustainability is 'does no harm'. Burning fossil fuels releases pollutants such as sulphur and mercury that endanger human health, as well as greenhouse gases like carbon dioxide that threaten climate stability

  7. Y-12 Site Sustainability Plan

    SciTech Connect

    Spencer, Charles G

    2012-12-01

    The accomplishments to date and the long-range planning of the Y-12 Energy Management and Sustainability and Stewardship programs support the U.S. Department of Energy (DOE) and the National Nuclear Security Administration (NNSA) vision for a commitment to energy effi ciency and sustainability and to achievement of the Guiding Principles. Specifi cally, the Y-12 vision is to support the Environment, Safety and Health Policy and the DOE Strategic Sustainability Performance Plan, while promoting overall sustainability and reduction of greenhouse gas emissions. The mission of the Y-12 Energy Management program is to incorporate energy-effi cient technologies site-wide and to position Y-12 to meet NNSA energy requirement needs through 2025 and beyond. The plan addresses greenhouse gases, buildings, fleet management, water use, pollution prevention, waste reduction, sustainable acquisition, electronic stewardship and data centers, site innovation and government-wide support.

  8. GIS-mapping of environmental assessment of the territories in the region of intense activity for the oil and gas complex for achievement the goals of the Sustainable Development (on the example of Russia)

    NASA Astrophysics Data System (ADS)

    Yermolaev, Oleg

    2014-05-01

    The uniform system of complex scientific-reference ecological-geographical should act as a base for the maintenance of the Sustainable Development (SD) concept in the territories of the Russian Federation subjects or certain regions. In this case, the assessment of the ecological situation in the regions can be solved by the conjugation of the two interrelated system - the mapping and the geoinformational. The report discusses the methodological aspects of the Atlas-mapping for the purposes of SD in the regions of Russia. The Republic of Tatarstan viewed as a model territory where a large-scale oil-gas complex "Tatneft" PLC works. The company functions for more than 60 years. Oil fields occupy an area of more than 38 000 km2; placed in its territory about 40 000 oil wells, more than 55 000 km of pipelines; more than 3 billion tons of oil was extracted. Methods for to the structure and requirements for the Atlas's content were outlined. The approaches to mapping of "an ecological dominant" of SD conceptually substantiated following the pattern of a large region of Russia. Several trends of thematically mapping were suggested to be distinguished in the Atlas's structure: • The background history of oil-fields mine working; • The nature preservation technologies while oil extracting; • The assessment of natural conditions of a humans vital activity; • Unfavorable and dangerous natural processes and phenomena; • The anthropogenic effect and environmental surroundings change; • The social-economical processes and phenomena. • The medical-ecological and geochemical processes and phenomena; Within these groups the other numerous groups can distinguished. The maps of unfavorable and dangerous processes and phenomena subdivided in accordance with the types of processes - of endogenous and exogenous origin. Among the maps of the anthropogenic effects on the natural surroundings one can differentiate the maps of the influence on different nature's spheres

  9. Teaching Sustainability/Teaching Sustainably

    ERIC Educational Resources Information Center

    Bartels, Kirsten Allen, Ed.; Parker, Kelly A., Ed.

    2011-01-01

    Over the coming decades, every academic discipline will have to respond to the paradigm of more sustainable life practices because students will be living in a world challenged by competition for resources and climate change, and will demand that every academic discipline demonstrate substantial and corresponding relevance. This book takes as its…

  10. Sustainable NREL

    ScienceCinema

    None

    2016-07-12

    The National Renewable Energy Laboratory prides itself on not only advancing the renewable energy, but "walking the talk" when it comes to sustainable practices. "When you look at our laboratories, you will see energy efficiency in action, but you'll also see renewable energy. We walk the walk and we talk the talk. We believe in it and we want to live it also."

  11. Sustainable NREL

    SciTech Connect

    2011-01-01

    The National Renewable Energy Laboratory prides itself on not only advancing the renewable energy, but "walking the talk" when it comes to sustainable practices. "When you look at our laboratories, you will see energy efficiency in action, but you'll also see renewable energy. We walk the walk and we talk the talk. We believe in it and we want to live it also."

  12. Graded Achievement, Tested Achievement, and Validity

    ERIC Educational Resources Information Center

    Brookhart, Susan M.

    2015-01-01

    Twenty-eight studies of grades, over a century, were reviewed using the argument-based approach to validity suggested by Kane as a theoretical framework. The review draws conclusions about the meaning of graded achievement, its relation to tested achievement, and changes in the construct of graded achievement over time. "Graded…

  13. Y-12 Site Sustainability Plan

    SciTech Connect

    Sherry, T D; Kohlhorst, D P; Little, S K

    2011-12-01

    The accomplishments to date and the long-range planning of the Y-12 Energy Management and Sustainability and Stewardship programs support the DOE and the National Nuclear Security Administration (NNSA) vision for a commitment to energy efficiency and sustainability and to achievement of the Guiding Principles. Specifically, the Y-12 vision is to support the Environment, Safety and Health Policy and the DOE Strategic Sustainability Performance Plan (SSPP) while promoting overall sustainability and reduction of greenhouse gas (GHG) emissions. Table ES.2 gives a comprehensive overview of Y-12's performance status and planned actions. B&W Y-12's Energy Management mission is to incorporate renewable energy and energy efficient technologies site-wide and to position Y-12 to meet NNSA energy requirement needs through 2025 and beyond. During FY 2011, the site formed a sustainability team (Fig. ES.1). The sustainability team provides a coordinated approach to meeting the various sustainability requirements and serves as a forum for increased communication and consistent implementation of sustainability activities at Y-12. The sustainability team serves as an information exchange mechanism to promote general awareness of sustainability information, while providing a system to document progress and to identify resources. These resources are necessary to implement activities that support the overall goals of sustainability, including reducing the use of resources and conserving energy. Additionally, the team's objectives include: (1) Foster a Y-12-wide philosophy to conserve resources; (2) Reduce the impacts of production operations in a cost-effective manner; (3) Increase materials recycling; (4) Use a minimum amount of energy and fuel; (5) Create a minimum of waste and pollution in achieving Y-12-strategic objectives; (6) Develop and implement techniques, technologies, process modifications, and programs that support sustainable acquisition; (7) Minimize the impacts to

  14. Genetic manipulation of RPS5 gene expression modulates the initiation of commitment of MEL cells to erythroid maturation: Implications in understanding ribosomopathies.

    PubMed

    Vizirianakis, Ioannis S; Papachristou, Eleni T; Andreadis, Panagiotis; Zopounidou, Elena; Matragkou, Christina N; Tsiftsoglou, Asterios S

    2015-07-01

    Impairment of ribosome biogenesis contributes to the molecular pathophysiology of ribosomopathies by deregulating cell-lineage specific proliferation, differentiation and apoptosis decisions of haematopoietic progenitor cells. Here, using pro-erythroblast-like murine erythroleukemia (MEL) cells, a model system of erythroid maturation, we aimed to investigate whether genetic manipulation of RPS5 expression affects the capacity of cells to grow and differentiate in culture. Parental MEL cells stably transfected with full length RPS5 cDNA in sense (MEL-C14 culture) or antisense (MEL-antisenseRPS5 culture) orientation, as well as MEL cells transiently transfected with siRNAs specific for RPS5 gene silencing (MEL-RPS5siRNA culture) were assessed for their ability to fully execute their erythroid maturation program in culture. The data obtained thus far indicate that: a) MEL-antisenseRPS5 exhibit a pronounced delay in the initiation of differentiation, as well as an impairment of commitment, since the continuous presence of the inducer in culture is required for the cells to fully execute their erythroid maturation program. b) RNAi-mediating silencing of RPS5 gene expression resulted in the inability of MEL cells to differentiate; however, when these cells were allowed to recapitulate normal RPS5 gene expression levels they regained their differentiation capacity by accumulating high proportion of erythroid mature cells. c) Interestingly the latter, is accompanied by morphological changes of cells and an impairment of their proliferation and apoptosis potential. Such data for the first time correlate the RPS5 gene expression levels with the differentiation capacity of MEL cells in vitro, a fact that might also have implications in understanding ribosomopathies. PMID:25998414

  15. Hydrogen Sulfide Levels and Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) Activity Are Attenuated in the Setting of Critical Limb Ischemia (CLI)

    PubMed Central

    Islam, Kazi N; Polhemus, David J; Donnarumma, Erminia; Brewster, Luke P; Lefer, David J

    2015-01-01

    Background Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are endogenous enzymatic sources of hydrogen sulfide (H2S). Functions of H2S are mediated by several targets including ion channels and signaling proteins. Nuclear factor-erythroid 2-related factor 2 is responsible for the expression of antioxidant response element–regulated genes and is known to be upregulated by H2S. We examined the levels of H2S, H2S-producing enzymes, and nuclear factor-erythroid 2-related factor 2 activation status in skeletal muscle obtained from critical limb ischemia (CLI) patients. Methods and Results Gastrocnemius tissues were attained postamputation from human CLI and healthy control patients. We found mRNA and protein levels of cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase were significantly decreased in skeletal muscle of CLI patients as compared to control. H2S and sulfane sulfur levels were significantly decreased in skeletal muscle of CLI patients. We also observed significant reductions in nuclear factor-erythroid 2-related factor 2 activation as well as antioxidant proteins, such as Cu, Zn-superoxide dismutase, catalase, and glutathione peroxidase in skeletal muscle of CLI patients. Biomarkers of oxidative stress, such as malondialdehyde and protein carbonyl formation, were significantly increased in skeletal muscle of CLI patients as compared to healthy controls. Conclusions The data demonstrate that H2S bioavailability and nuclear factor-erythroid 2-related factor 2 activation are both attenuated in CLI tissues concomitant with significantly increased oxidative stress. Reductions in the activity of H2S-producing enzymes may contribute to the pathogenesis of CLI. PMID:25977470

  16. Primary hematopoietic cells from DBA patients with mutations in RPL11 and RPS19 genes exhibit distinct erythroid phenotype in vitro.

    PubMed

    Moniz, H; Gastou, M; Leblanc, T; Hurtaud, C; Crétien, A; Lécluse, Y; Raslova, H; Larghero, J; Croisille, L; Faubladier, M; Bluteau, O; Lordier, L; Tchernia, G; Vainchenker, W; Mohandas, N; Da Costa, L

    2012-01-01

    Diamond-Blackfan anemia (DBA) is caused by aberrant ribosomal biogenesis due to ribosomal protein (RP) gene mutations. To develop mechanistic understanding of DBA pathogenesis, we studied CD34⁺ cells from peripheral blood of DBA patients carrying RPL11 and RPS19 ribosomal gene mutations and determined their ability to undergo erythroid differentiation in vitro. RPS19 mutations induced a decrease in proliferation of progenitor cells, but the terminal erythroid differentiation was normal with little or no apoptosis. This phenotype was related to a G₀/G₁ cell cycle arrest associated with activation of the p53 pathway. In marked contrast, RPL11 mutations led to a dramatic decrease in progenitor cell proliferation and a delayed erythroid differentiation with a marked increase in apoptosis and G₀/G₁ cell cycle arrest with activation of p53. Infection of cord blood CD34⁺ cells with specific short hairpin (sh) RNAs against RPS19 or RPL11 recapitulated the two distinct phenotypes in concordance with findings from primary cells. In both cases, the phenotype has been reverted by shRNA p53 knockdown. These results show that p53 pathway activation has an important role in pathogenesis of DBA and can be independent of the RPL11 pathway. These findings shed new insights into the pathogenesis of DBA. PMID:22833095

  17. Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia.

    PubMed

    Jaako, P; Debnath, S; Olsson, K; Zhang, Y; Flygare, J; Lindström, M S; Bryder, D; Karlsson, S

    2015-11-01

    Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesis in DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanisms of p53 activation and its relevance for the erythroid defect remain elusive. Previous studies have indicated that activation of p53 is caused by the inhibition of mouse double minute 2 (Mdm2), the main negative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whether this mechanism solely mediates the p53-dependent component found in DBA. To approach this question, we crossed our mouse model for RPS19-deficient DBA with Mdm2(C305F) knock-in mice that have a disrupted 5S RNP-Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2(C305F) reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo. Unexpectedly, disruption of the 5S RNP-Mdm2 interaction also led to selective defect in erythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53 homeostasis mediated by the 5S RNP-Mdm2 interaction. Finally, we provide evidence indicating that physiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of the hematopoietic system in a cell-autonomous manner over time.

  18. Beta-globin active chromatin Hub formation in differentiating erythroid cells and in p45 NF-E2 knock-out mice.

    PubMed

    Kooren, Jurgen; Palstra, Robert-Jan; Klous, Petra; Splinter, Erik; von Lindern, Marieke; Grosveld, Frank; de Laat, Wouter

    2007-06-01

    Expression of the beta-globin genes proceeds from basal to exceptionally high levels during erythroid differentiation in vivo. High expression is dependent on the locus control region (LCR) and coincides with more frequent LCR-gene contacts. These contacts are established in the context of an active chromatin hub (ACH), a spatial chromatin configuration in which the LCR, together with other regulatory sequences, loops toward the active beta-globin-like genes. Here, we used recently established I/11 cells as a model system that faithfully recapitulates the in vivo erythroid differentiation program to study the molecular events that accompany and underlie ACH formation. Upon I/11 cell induction, histone modifications changed, the ACH was formed, and the beta-globin-like genes were transcribed at rates similar to those observed in vivo. The establishment of frequent LCR-gene contacts coincided with a more efficient loading of polymerase onto the beta-globin promoter. Binding of the transcription factors GATA-1 and EKLF to the locus, although previously shown to be required, was not sufficient for ACH formation. Moreover, we used knock-out mice to show that the erythroid transcription factor p45 NF-E2, which has been implicated in beta-globin gene regulation, is dispensable for beta-globin ACH formation.

  19. Transcription factors Fli1 and EKLF in the differentiation of megakaryocytic and erythroid progenitor in 5q- syndrome and in Diamond-Blackfan anemia.

    PubMed

    Neuwirtova, Radana; Fuchs, Ota; Holicka, Monika; Vostry, Martin; Kostecka, Arnost; Hajkova, Hana; Jonasova, Anna; Cermak, Jaroslav; Cmejla, Radek; Pospisilova, Dagmar; Belickova, Monika; Siskova, Magda; Hochova, Ivana; Vondrakova, Jana; Sponerova, Dana; Kadlckova, Eva; Novakova, Ludmila; Brezinova, Jana; Michalova, Kyra

    2013-01-01

    Friend leukemia virus integration 1 (Fli1) and erythroid Krüppel-like factor (EKLF) participate under experimental conditions in the differentiation of megakaryocytic and erythroid progenitor in cooperation with other transcription factors, cytokines, cytokine receptors, and microRNAs. Defective erythropoiesis with refractory anemia and effective megakaryopoiesis with normal or increased platelet count is typical for 5q- syndrome. We decided to evaluate the roles of EKLF and Fli1 in the pathogenesis of this syndrome and of another ribosomopathy, Diamond-Blackfan anemia (DBA). Fli1 and EKLF mRNA levels were examined in mononuclear blood and bone marrow cells from patients with 5q- syndrome, low-risk MDS patients with normal chromosome 5, DBA patients, and healthy controls. In 5q- syndrome, high Fli1 mRNA levels in the blood and bone marrow mononuclear cells were found. In DBA, Fli1 expression did not differ from the controls. EKLF mRNA level was significantly decreased in the blood and bone marrow of 5q- syndrome and in all DBA patients. We propose that the elevated Fli1 in 5q- syndrome protects megakaryocytic cells from ribosomal stress contrary to erythroid cells and contributes to effective though dysplastic megakaryopoiesis.

  20. Haem-regulated eIF2α kinase is necessary for adaptive gene expression in erythroid precursors under the stress of iron deficiency

    PubMed Central

    Liu, Sijin; Bhattacharya, Sanchita; Han, Anping; Suragani, Rajasekhar N. V. S.; Zhao, Wanting; Fry, Rebecca C.; Chen, Jane-Jane

    2016-01-01

    Summary Haem-regulated eIF2α kinase (HRI) is essential for the regulation of globin gene translation and the survival of erythroid precursors in iron/haem deficiency. This study found that that in iron deficiency, fetal definitive erythropoiesis is inhibited at the basophilic erythroblast stage with increased proliferation and elevated apoptosis. This hallmark of ineffective erythropoiesis is more severe in HRI deficiency. Microarray gene profiling analysis showed that HRI was required for adaptive gene expression in erythroid precursors during chronic iron deficiency. The number of genes with expression affected more than twofold increased, from 213 in iron deficiency and 73 in HRI deficiency, to 3135 in combined iron and HRI deficiencies. Many of these genes are regulated by Gata1 and Fog1. We demonstrate for the first time that Gata1 expression in developing erythroid precursors is decreased in iron deficiency, and is decreased further in combined iron and HRI deficiencies. Additionally, Fog1 expression is decreased in combined deficiencies, but not in iron or HRI deficiency alone. Our results indicate that HRI confers adaptive gene expression in developing erythroblasts during iron deficiency through maintaining Gata1/Fog1 expression. PMID:18665838

  1. Transcriptional activation of human adult alpha-globin genes by hypersensitive site-40 enhancer: function of nuclear factor-binding motifs occupied in erythroid cells.

    PubMed Central

    Rombel, I; Hu, K Y; Zhang, Q; Papayannopoulou, T; Stamatoyannopoulos, G; Shen, C K

    1995-01-01

    The developmental stage- and erythroid lineage-specific activation of the human embryonic zeta- and fetal/adult alpha-globin genes is controlled by an upstream regulatory element [hypersensitive site (HS)-40] with locus control region properties, a process mediated by multiple nuclear factor-DNA complexes. In vitro DNase I protection experiments of the two G+C-rich, adult alpha-globin promoters have revealed a number of binding sites for nuclear factors that are common to HeLa and K-562 extracts. However, genomic footprinting analysis has demonstrated that only a subset of these sites, clustered between -130 and +1, is occupied in an erythroid tissue-specific manner. The function of these in vivo-occupied motifs of the alpha-globin promoters, as well as those previously mapped in the HS-40 region, is assayed by site-directed mutagenesis and transient expression in embryonic/fetal erythroid K-562 cells. These studies, together with our expression data on the human embryonic zeta-globin promoter, provide a comprehensive view of the functional roles of individual nuclear factor-DNA complexes in the final stages of transcriptional activation of the human alpha-like globin promoters by the HS-40 element. Images Fig. 2 Fig. 3 Fig. 5 Fig. 6 PMID:7604012

  2. Primary hematopoietic cells from DBA patients with mutations in RPL11 and RPS19 genes exhibit distinct erythroid phenotype in vitro

    PubMed Central

    Moniz, H; Gastou, M; Leblanc, T; Hurtaud, C; Crétien, A; Lécluse, Y; Raslova, H; Larghero, J; Croisille, L; Faubladier, M; Bluteau, O; Lordier, L; Tchernia, G; Vainchenker, W; Mohandas, N; Da Costa, L

    2012-01-01

    Diamond-Blackfan anemia (DBA) is caused by aberrant ribosomal biogenesis due to ribosomal protein (RP) gene mutations. To develop mechanistic understanding of DBA pathogenesis, we studied CD34+ cells from peripheral blood of DBA patients carrying RPL11 and RPS19 ribosomal gene mutations and determined their ability to undergo erythroid differentiation in vitro. RPS19 mutations induced a decrease in proliferation of progenitor cells, but the terminal erythroid differentiation was normal with little or no apoptosis. This phenotype was related to a G0/G1 cell cycle arrest associated with activation of the p53 pathway. In marked contrast, RPL11 mutations led to a dramatic decrease in progenitor cell proliferation and a delayed erythroid differentiation with a marked increase in apoptosis and G0/G1 cell cycle arrest with activation of p53. Infection of cord blood CD34+ cells with specific short hairpin (sh) RNAs against RPS19 or RPL11 recapitulated the two distinct phenotypes in concordance with findings from primary cells. In both cases, the phenotype has been reverted by shRNA p53 knockdown. These results show that p53 pathway activation has an important role in pathogenesis of DBA and can be independent of the RPL11 pathway. These findings shed new insights into the pathogenesis of DBA. PMID:22833095

  3. Why Sustainable Practices Matter.

    PubMed

    Rich, Jeff

    2016-01-01

    Sustainable thinking provides an opportunity to create new value to the mission of health care, rather than settling for less. Success stories and case studies exist, which if replicated can have an enormous positive effect. The future holds promise. Many health care organizations are signing up with efforts such as the Healthier Hospitals initiative, a program of the Practice Greenhealth membership organization for sustainable health care, to set new standards and learn more about methods to reduce the environmental footprint and negative health effects from the delivery of care to their communities. Providing safe and affordable care to patients and their families must remain paramount in the decisions that are made, but good environmental stewardship can be achieved. Setting organizational goals holds the key to finding the optimal balance. PMID:27333682

  4. Why Sustainable Practices Matter.

    PubMed

    Rich, Jeff

    2016-01-01

    Sustainable thinking provides an opportunity to create new value to the mission of health care, rather than settling for less. Success stories and case studies exist, which if replicated can have an enormous positive effect. The future holds promise. Many health care organizations are signing up with efforts such as the Healthier Hospitals initiative, a program of the Practice Greenhealth membership organization for sustainable health care, to set new standards and learn more about methods to reduce the environmental footprint and negative health effects from the delivery of care to their communities. Providing safe and affordable care to patients and their families must remain paramount in the decisions that are made, but good environmental stewardship can be achieved. Setting organizational goals holds the key to finding the optimal balance.

  5. Radioprotection of mice with interleukin-1: Relationship to the number of erythroid and granulocyte-macrophage colony-forming cells

    SciTech Connect

    Schwartz, G.N.; Patchen, M.L.; Neta, R.; MacVittie, T.J.

    1990-01-01

    This report presents the results of an investigation of changes in the number of erythroid and granulocyte-macrophage colony forming cells (GM-CFC) that had occurred in tissues of normal B6D2F1 mice 20 h after administration of a radioprotective dose (150 ng) of human recombinant interleukin-1 (rIL-1). Neutrophilia in the peripheral blood and changes in the tissue distribution of GM-CFC demonstrated that cells were mobilized from the bone marrow in response to rIL-1 injection. For example, 20 h after rIL-1 injection marrow GM-CFC numbers were 80% of the numbers in bone marrow from saline-injected mice. Associated with this decrease there was a twofold increase in the number of peripheral blood and splenic GM-CFC. Also, as determined by hydroxyurea injection, there was an increase in the number of GM-CFC in S phase of the cell cycle in the spleen, but not in the bone marrow. Data in this report suggest that when compared to the spleen, stimulation of granulopoiesis after rIL-1 injection is delayed in the bone marrow.

  6. Resveratrol: Antioxidant activity and induction of fetal hemoglobin in erythroid cells from normal donors and β-thalassemia patients.

    PubMed

    Fibach, Eitan; Prus, Eugenia; Bianchi, Nicoletta; Zuccato, Cristina; Breveglieri, Giulia; Salvatori, Francesca; Finotti, Alessia; Lipucci di Paola, Michele; Brognara, Eleonora; Lampronti, Ilaria; Borgatti, Monica; Gambari, Roberto

    2012-06-01

    Thalassemia and sickle-cell anemia (SCA) present a major public health problem in countries where the number of carriers and affected individuals is high. As a result of the abnormalities in hemoglobin production, cells of thalassemia and SCA patients exhibit oxidative stress, which ultimately is responsible for the chronic anemia observed. Therefore, identification of compounds exhibiting both antioxidant and hemoglobin-inducing activities is highly needed. Our results demonstrate resveratrol to be such a compound. This was shown both in the human K562 cell line, as well as in erythroid precursors derived from normal donors and β-thalassemia patients. Resveratrol was shown to exhibit antioxidant activity and to stimulate the expression of the γ-globin genes and the accumulation of fetal hemoglobin (HbF). To the best of our knowledge, this is the first report pointing to such a double effect of resveratrol. Since this natural product is already marketed as an antioxidant, future investigations should concentrate on demonstrating its potential to augment HbF production in experimental animal models (e.g., thalassemia and SCA mice) as well as in patients. We believe that the potential of clinical use of resveratrol as an antioxidant and HbF stimulator may offer a simple and inexpensive treatment to patients.

  7. The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

    SciTech Connect

    Uziel, Orit; Kanfer, Gil; Beery, Einat; Yelin, Dana; Shepshelovich, Daniel; Bakhanashvili, Mary; Nordenberg, Jardena; Lahav, Meir

    2014-07-18

    Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway.

  8. Effect of fetal hemoglobin-stimulating medicines on the interaction of DNA and protein of important erythroid regulatory elements.

    PubMed

    Ji, Xin-Jun; Liu, De-pei; Xu, Dong-Dong; Li, Lei; Liang, Chih-chuan

    2003-08-01

    Beta-Thalassemia is the most common single gene disorder in the world, which is caused by the imbalance between alpha-globin chain and beta-globin chain synthesis. Several medicines, such as 5-azacytidine, hydroxyurea, cytarabine, vinblatine, butyrate, and myleran, have been shown to be able to reactivate gamma-globin chain synthesis during the adult stage, and some of them (5-azacytidine, hydroxyurea, myleran, and butyrate) have been used clinically to treat thalassemia and sickle cell disease. Much research efforts are focusing on the determination of the underlying mechanisms of medicine action. In this experiment, as an effort to probe the underlying mechanism of medicine action, we used ligation-mediated polymerase chain reaction and in vivo footprinting methods to study the DNA-protein interaction at critical erythroid regulatory elements after hydroxyurea or myleran administration to mice. Our results showed that the patterns of in vivo footprints at both the hypersensitive site 2 of the locus control region and the beta-globin gene promoter were changed after medicine treatment. We proposed based on these results that the medicines' administration might result in a change in the interaction between trans-acting factors and cis-acting elements at these regions. These changes might influence the assembly of the transcription complex and, lastly, influence the expression of the beta-globin gene.

  9. Structure of the Membrane Proximal Oxioreductase Domain of Human Steap3, the Dominant Ferrireductase of the Erythroid Transferrin Cycle

    SciTech Connect

    Sendamarai, A.K.; Ohgami, R.S.; Fleming, M.D.; Lawrence, C.M.

    2009-05-27

    The daily production of 200 billion erythrocytes requires 20 mg of iron, accounting for nearly 80% of the iron demand in humans. Thus, erythroid precursor cells possess an efficient mechanism for iron uptake in which iron loaded transferrin (Tf) binds to the transferrin receptor (TfR) at the cell surface. The Tf:TfR complex then enters the endosome via receptor-mediated endocytosis. Upon endosomal acidification, iron is released from Tf, reduced to Fe{sup 2+} by Steap3, and transported across the endosomal membrane by divalent metal iron transporter 1. Steap3, the major ferrireductase in erythrocyte endosomes, is a member of a unique family of reductases. Steap3 is comprised of an N-terminal cytosolic oxidoreductase domain and a C-terminal heme-containing transmembrane domain. Cytosolic NADPH and a flavin are predicted cofactors, but the NADPH/flavin binding domain differs significantly from those in other eukaryotic reductases. Instead, Steap3 shows remarkable, although limited homology to FNO, an archaeal oxidoreductase. We have determined the crystal structure of the human Steap3 oxidoreductase domain in the absence and presence of NADPH. The structure reveals an FNO-like domain with an unexpected dimer interface and substrate binding sites that are well positioned to direct electron transfer from the cytosol to a heme moiety predicted to be fixed within the transmembrane domain. Here, we discuss possible gating mechanisms for electron transfer across the endosomal membrane.

  10. Human and Murine Hematopoietic Stem Cell Aging Is Associated with Functional Impairments and Intrinsic Megakaryocytic/Erythroid Bias

    PubMed Central

    Rundberg Nilsson, Alexandra; Soneji, Shamit; Adolfsson, Sofia; Bryder, David; Pronk, Cornelis Jan

    2016-01-01

    Aging within the human hematopoietic system associates with various deficiencies and disease states, including anemia, myeloid neoplasms and reduced adaptive immune responses. Similar phenotypes are observed in mice and have been linked to alterations arising at the hematopoietic stem cell (HSC) level. Such an association is, however, less established in human hematopoiesis and prompted us here to detail characteristics of the most primitive human hematopoietic compartments throughout ontogeny. In addition, we also attempted to interrogate similarities between aging human and murine hematopoiesis. Coupled to the transition from human cord blood (CB) to young and aged bone marrow (BM), we observed a gradual increase in frequency of candidate HSCs. This was accompanied by functional impairments, including decreased lymphoid output and reduced proliferative potential. Downstream of human HSCs, we observed decreasing levels of common lymphoid progenitors (CLPs), and increasing frequencies of megakaryocyte/erythrocyte progenitors (MEPs) with age, which could be linked to changes in lineage-affiliated gene expression patterns in aged human HSCs. These findings were paralleled in mice. Therefore, our data support the notion that age-related changes also in human hematopoiesis involve the HSC pool, with a prominent skewing towards the megakaryocytic/erythroid lineages, and suggests conserved mechanisms underlying aging of the blood cell system. PMID:27368054

  11. Structural characterization of a noncovalent complex between ubiquitin and the transactivation domain of the erythroid-specific factor EKLF.

    PubMed

    Raiola, Luca; Lussier-Price, Mathieu; Gagnon, David; Lafrance-Vanasse, Julien; Mascle, Xavier; Arseneault, Genevieve; Legault, Pascale; Archambault, Jacques; Omichinski, James G

    2013-11-01

    Like other acidic transactivation domains (TAD), the minimal TAD from the erythroid-specific transcription factor EKLF (EKLFTAD) has been shown to contribute both to its transcriptional activity as well as to its ubiquitin(UBI)-mediated degradation. In this article, we examine the activation-degradation role of the acidic TAD of EKLF and demonstrate that the first 40 residues (EKLFTAD1) within this region form a noncovalent interaction with UBI. Nuclear magnetic resonance (NMR) structural studies of an EKLFTAD1-UBI complex show that EKLFTAD1 adopts a 14-residue α helix that forms the recognition interface with UBI in a similar manner as the UBI-interacting helix of Rabex5. We also identify a similar interaction between UBI and the activation-degradation region of SREBP1a, but not with the activation-degradation regions of p53, GAL4, and VP16. These results suggest that select activation-degradation regions like the ones found in EKLF and SREBP1a function in part through their ability to form noncovalent interactions with UBI. PMID:24139988

  12. Neuroprotective effects of salidroside on focal cerebral ischemia/reperfusion injury involve the nuclear erythroid 2-related factor 2 pathway

    PubMed Central

    Han, Jing; Xiao, Qing; Lin, Yan-hua; Zheng, Zhen-zhu; He, Zhao-dong; Hu, Juan; Chen, Li-dian

    2015-01-01

    Salidroside, the main active ingredient extracted from Rhodiola crenulata, has been shown to be neuroprotective in ischemic cerebral injury, but the underlying mechanism for this neuroprotection is poorly understood. In the current study, the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was investigated in a rat model of middle cerebral artery occlusion. Salidroside (30 mg/kg) reduced infarct size, improved neurological function and histological changes, increased activity of superoxide dismutase and glutathione-S-transferase, and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion. Furthermore, salidroside apparently increased Nrf2 and heme oxygenase-1 expression. These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved. The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke. PMID:26889188

  13. Reactive Oxygen Species and Nuclear Factor Erythroid 2-Related Factor 2 Activation in Diabetic Nephropathy: A Hidden Target

    PubMed Central

    Abdo, Shaaban; Zhang, Shao-Ling; Chan, John S.D.

    2015-01-01

    Hyperglycemia, oxidative stress and renin-angiotensin system (RAS) dysfunction have been implicated in diabetic nephropathy (DN) progression, but the underlying molecular mechanisms are far from being fully understood. In addition to the systemic RAS, the existence of a local intrarenal RAS in renal proximal tubular cells has been recognized. Angiotensinogen is the sole precursor of all angiotensins (Ang). Intrarenal reactive oxygen species (ROS) generation, Ang II level and RAS gene expression are up-regulated in diabetes, indicating that intrarenal ROS and RAS activation play an important role in DN. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is one of the major protective processes that occurs in response to intracellular oxidative stress. Nrf2 stimulates an array of antioxidant enzymes that convert excessive ROS to less reactive or less damaging forms. Recent studies have, however, revealed that Nrf2 activation might have other undesirable effects in diabetic animals and in diabetic patients with chronic kidney disease. This mini-review summarizes current knowledge of the relationship between ROS, Nrf2 and intra renal RAS activation in DN progression as well as possible novel target(s) for DN treatment. PMID:26213634

  14. Sustaining automobility

    SciTech Connect

    Pasek, J.E.; Schneider, R.W.; Sciance, F.S.

    1996-12-31

    This year marks the 100th anniversary of the automobile in America. This paper discusses the history of the automobile, its value to personal transportation, and the challenges faced in making the automobile energy efficient and environmentally compatible. Also included are some thoughts on how personal mobility can be sustained into the future. Understanding the history of transportation innovation and the reasons for the huge success of the automobile can help point the way to the successful innovations that will improve mankind`s mobility in the future and at the same time continue to make it cleaner, safer, and more energy efficient.

  15. Dynamics of α-globin locus chromatin structure and gene expression during erythroid differentiation of human CD34+ cells in culture

    PubMed Central

    Mahajan, Milind C; Karmakar, Subhradip; Krause, Diane; Weissman, Sherman M

    2009-01-01

    Objective The aim of the present study has been to establish serum free culture conditions for the ex vivo expansion and differentiation of human CD34+ cells into erythroid lineage and to study the chromatin structure, gene expression and transcription factor recruitment at the α–globin locus in the developing erythron. Methods A basal IMDM cell culture medium with 1% bovine serum albumin as a serum replacement and a combination of cytokines and growth factors was used for the expansion and differentiation of the CD34+ cells. Expression patterns of the alpha and beta like genes at various stages of erythropoiesis was studied by Reverse transcriptase (RT)-qPCR analysis, profile of key erythroid transcription factors was investigated by western blotting, and the chromatin structure and transcription factor recruitment at the alpha globin locus was investigated by ChIP-qPCR analysis. Results Human CD34+ cells in the serum free medium undergo near synchronous erythroid differentiation to yield large amount of cells at different differentiation stages. We observe distinct patterns of the histone modifications and transcription factor binding at the α-globin locus during erythroid differentiation of CD34+ cells. NF-E2 was present at upstream activator sites even before addition of erythropoietin (Epo), while bound GATA-1 was only detectable after Epo treatment. After seven days of erythropoietin treatment, H3K4Me2 modification uniformly increases throughout the α–globin locus. Acetylation at H3K9 and binding of Pol II, NF-E2 and GATA-1 were restricted to certain HS sites of the enhancer and theta gene, and were conspicuously low at the α-like globin promoters. Rearrangement of the insulator binding factor CTCF took place at and around the α-globin locus as CD34+ cells differentiated into erythroid pathway. Conclusion Our results indicate that remodeling of the upstream elements may be the primary event in activation of α–globin gene expression. Activation of

  16. Farming with Grass: Achieving Sustainable Mixed Agricultural Landscapes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Agriculture in grassland environments is facing multiple stresses from shifting demographics, declining and fragmented agricultural landscapes, declining environmental quality, variable and changing climate, volatile and increasing energy costs, marginal economic returns, and globalization. Grassla...

  17. Successful systems sustaining change.

    PubMed

    Bullas, Sheila; Bryant, John

    2007-01-01

    Much has been published on the success and particularly the failure of IT projects; still failures are commonplace. This prospective study focused from the outset on assessing risk of failure and addressing critical success factors. The aim was to apply existing methods in a challenging acute care hospital where success demanded rapid achievement of sustainable improvements in clinical and administrative processes. The implementations were part of the English National Programme for IT. The desired outcomes required the integration of accepted tools and techniques to provide a pragmatic approach to systems implementation: Lean, Six Sigma, PRINCE2 and Benefits Management. The outcome and further insights into success and failure of IT projects in healthcare are described. In particular lessons are identified related to the business need for the project and the successful achievement of the required benefits and business change.

  18. Materials for Sustainable Energy

    NASA Astrophysics Data System (ADS)

    Crabtree, George

    2009-03-01

    The global dependence on fossil fuels for energy is among the greatest challenges facing our economic, social and political future. The uncertainty in the cost and supply of oil threatens the global economy and energy security, the pollution of fossil combustion threatens human health, and the emission of greenhouse gases threatens global climate. Meeting the demand for double the current global energy use in the next 50 years without damaging our economy, security, environment or climate requires finding alternative sources of energy that are clean, abundant, accessible and sustainable. The transition to greater sustainability involves tapping unused energy flows such as sunlight and wind, producing electricity without carbon emissions from clean coal and high efficiency nuclear power plants, and using energy more efficiently in solid-state lighting, fuel cells and transportation based on plug-in hybrid and electric cars. Achieving these goals requires creating materials of increasing complexity and functionality to control the transformation of energy between light, electrons and chemical bonds. Challenges and opportunities for developing the complex materials and controlling the chemical changes that enable greater sustainability will be presented.

  19. Day one sustainability

    NASA Astrophysics Data System (ADS)

    Orr, John; Ibell, Timothy; Evernden, Mark; Darby, Antony

    2015-05-01

    Emissions reductions targets for the UK set out in the Climate Change Act for the period to 2050 will only be achieved with significant changes to the built environment, which is currently estimated to account for 50% of the UK's carbon emissions. The socio-technological nature of Civil Engineering means that this field is uniquely placed to lead the UK through such adaptations. This paper discusses the importance of interdisciplinary teaching to produce multi-faceted team approaches to sustainable design solutions. Methods for measuring success in education are often not fit for purpose, producing good students but poor engineers. Real-world failures to apply sustainable design present a serious, difficult to detect, and ultimately economically negative situation. Techniques to replace summative examinations are presented and discussed, with the aim of enhancing core technical skills alongside those required for sustainable design. Finally, the role of our future engineers in policy-making is discussed. In addition to carbon, the provision of water and food will heavily influence the work of civil engineers in the coming decades. Leadership from civil engineers with the technical knowledge and social awareness to tackle these issues will be required. This provides both opportunities and challenges for engineering education in the UK.

  20. Sustainable water management practices and remote sensing.

    EPA Science Inventory

    The United States Environmental Protection Agency’s charge to protect human health and the environment requires a long-term commitment to creating sustainable solutions to environmental problems. The most direct way to ensure that management practices are achieving sustainability...

  1. Applying a Model of Sustainability on Campus.

    ERIC Educational Resources Information Center

    Waite, Phillip S.

    2003-01-01

    Examines the natural resource planning theory of Walter Firey as a conceptual base for planning efforts aimed at achieving sustainable policies and practices on university and college campuses. Explains that sustainable policies and practices are those that, according to Firey's theory, are simultaneously ecologically possible, economically…

  2. Professional Development Leading to Sustained Change

    ERIC Educational Resources Information Center

    Stickney, Catherine Alaimo

    2012-01-01

    Determining effective change that leads to sustainable improved student achievement remains an elusive goal for most educational communities. This research addresses the question of what factors of professional development promote sustained change within a school organization. The survey questions focus on the formation of professional learning…

  3. Online PBL: A Route to Sustainability Education?

    ERIC Educational Resources Information Center

    Tomkinson, Bland; Hutt, Ian

    2012-01-01

    Purpose: The purpose of this paper is to investigate online problem-based learning (PBL) as a route to achieving sustainability education using sponsored projects. Design/methodology/approach: The Royal Academy of Engineering sponsored project at Manchester; to foster education in sustainability through inter-disciplinary problem-based approaches,…

  4. Our Vision for a Sustainable Wales

    ERIC Educational Resources Information Center

    Davidson, Jane

    2010-01-01

    The Welsh Assembly Government is committed to putting sustainable development at the heart of all it does. In May 2009, the Assembly launched its latest scheme, "One Wales: One Planet," which sets out a clear definition of sustainable development as enhancing the economic, social and environmental wellbeing of people and communities, achieving a…

  5. Sustainability Science Needs Sustainable Data!

    NASA Astrophysics Data System (ADS)

    Downs, R. R.; Chen, R. S.

    2013-12-01

    Sustainability science (SS) is an 'emerging field of research dealing with the interactions between natural and social systems, and with how those interactions affect the challenge of sustainability: meeting the needs of present and future generations while substantially reducing poverty and conserving the planet's life support systems' (Kates, 2011; Clark, 2007). Bettencourt & Kaur (2011) identified more than 20,000 scientific papers published on SS topics since the 1980s with more than 35,000 distinct authors. They estimated that the field is currently growing exponentially, with the number of authors doubling approximately every 8 years. These scholars are undoubtedly using and generating a vast quantity and variety of data and information for both SS research and applications. Unfortunately we know little about what data the SS community is actually using, and whether or not the data that SS scholars generate are being preserved for future use. Moreover, since much SS research is conducted by cross-disciplinary, multi-institutional teams, often scattered around the world, there could well be increased risks of data loss, reduced data quality, inadequate documentation, and poor long-term access and usability. Capabilities and processes therefore need to be established today to support continual, reliable, and efficient preservation of and access to SS data in the future, especially so that they can be reused in conjunction with future data and for new studies not conceived in the original data collection activities. Today's long-term data stewardship challenges include establishing sustainable data governance to facilitate continuing management, selecting data to ensure that limited resources are focused on high priority SS data holdings, securing sufficient rights to allow unforeseen uses, and preparing data to enable use by future communities whose specific research and information needs are not yet known. Adopting sustainable models for archival

  6. Crystal Structure of the Nonerythroid [alpha]-Spectrin Tetramerization Site Reveals Differences between Erythroid and Nonerythroid Spectrin Tetramer Formation

    SciTech Connect

    Mehboob, Shahila; Song, Yuanli; Witek, Marta; Long, Fei; Santarsiero, Bernard D.; Johnson, Michael E.; Fung, Leslie W.-M.

    2010-06-21

    We have solved the crystal structure of a segment of nonerythroid {alpha}-spectrin ({alpha}II) consisting of the first 147 residues to a resolution of 2.3 {angstrom}. We find that the structure of this segment is generally similar to a corresponding segment from erythroid {alpha}-spectrin ({alpha}I) but exhibits unique differences with functional significance. Specific features include the following: (i) an irregular and frayed first helix (Helix C{prime}); (ii) a helical conformation in the junction region connecting Helix C{prime} with the first structural domain (D1); (iii) a long A1B1 loop in D1; and (iv) specific inter-helix hydrogen bonds/salt bridges that stabilize D1. Our findings suggest that the hydrogen bond networks contribute to structural domain stability, and thus rigidity, in {alpha}II, and the lack of such hydrogen bond networks in {alpha}I leads to flexibility in {alpha}I. We have previously shown the junction region connecting Helix C{prime} to D1 to be unstructured in {alpha}I (Park, S., Caffrey, M. S., Johnson, M. E., and Fung, L. W. (2003) J. Biol. Chem. 278, 21837-21844) and now find it to be helical in {alpha}II, an important difference for {alpha}-spectrin association with {beta}-spectrin in forming tetramers. Homology modeling and molecular dynamics simulation studies of the structure of the tetramerization site, a triple helical bundle of partial domain helices, show that mutations in {alpha}-spectrin will affect Helix C{prime} structural flexibility and/or the junction region conformation and may alter the equilibrium between spectrin dimers and tetramers in cells. Mutations leading to reduced levels of functional tetramers in cells may potentially lead to abnormal neuronal functions.

  7. Asn-150 of Murine Erythroid 5-Aminolevulinate Synthase Modulates the Catalytic Balance between the Rates of the Reversible Reaction.

    PubMed

    Stojanovski, Bosko M; Ferreira, Gloria C

    2015-12-25

    5-Aminolevulinate synthase (ALAS) catalyzes the first step in mammalian heme biosynthesis, the pyridoxal 5'-phosphate (PLP)-dependent and reversible reaction between glycine and succinyl-CoA to generate CoA, CO2, and 5-aminolevulinate (ALA). Apart from coordinating the positioning of succinyl-CoA, Rhodobacter capsulatus ALAS Asn-85 has a proposed role in regulating the opening of an active site channel. Here, we constructed a library of murine erythroid ALAS variants with substitutions at the position occupied by the analogous bacterial asparagine, screened for ALAS function, and characterized the catalytic properties of the N150H and N150F variants. Quinonoid intermediate formation occurred with a significantly reduced rate for either the N150H- or N150F-catalyzed condensation of glycine with succinyl-CoA during a single turnover. The introduced mutations caused modifications in the ALAS active site such that the resulting variants tipped the balance between the forward- and reverse-catalyzed reactions. Although wild-type ALAS catalyzes the conversion of ALA into the quinonoid intermediate at a rate 6.3-fold slower than the formation of the same quinonoid intermediate from glycine and succinyl-CoA, the N150F variant catalyzes the forward reaction at a mere 1.2-fold faster rate than that of the reverse reaction, and the N150H variant reverses the rate values with a 1.7-fold faster rate for the reverse reaction than that for the forward reaction. We conclude that the evolutionary selection of Asn-150 was significant for optimizing the forward enzymatic reaction at the expense of the reverse, thus ensuring that ALA is predominantly available for heme biosynthesis.

  8. V-erbA generates ribosomes devoid of RPL11 and regulates translational activity in avian erythroid progenitors.

    PubMed

    Nguyen-Lefebvre, A T; Leprun, G; Morin, V; Viñuelas, J; Couté, Y; Madjar, J-J; Gandrillon, O; Gonin-Giraud, S

    2014-03-20

    The v-erbA oncogene transforms chicken erythrocytic progenitors (T2EC) by blocking their differentiation and freezing them in a state of self-renewal. Transcriptomes of T2EC, expressing either v-erbA or a non-transforming form of v-erbA (S61G), were compared using serial analysis of gene expression and some, but not all, mRNA-encoding ribosomal proteins were seen to be affected by v-erbA. These results suggest that this oncogene could modulate the composition of ribosomes. In the present study, we demonstrate, using two-dimensional difference in gel electrophoresis, that v-erbA-expressing cells have a lower amount of RPL11 associated with the ribosomes. The presence of ribosomes devoid of RPL11 in v-erbA-expressing cells was further confirmed by immunoprecipitation. In order to assess the possible impact of these specialized ribosomes on the translational activity, we analyzed proteomes of either v-erbA or S61G-expressing cells using 2D/mass spectrometry, and identified nine proteins present in differing amounts within these cells. Among these proteins, we focused on HSP70 because of its involvement in erythroid differentiation. Our results indicate that, in v-erbA-expressing cells, hsp70 is not only transcribed but also translated more efficiently, as shown by polyribosome fractionation experiments. We demonstrate here, for the first time, the existence of ribosomes with different protein components, notably ribosomes devoid of RPL11, and a regulation of mRNA translation depending on v-erbA oncogene expression.

  9. Biochemical measurements on single erythroid progenitor cells shed light on the combinatorial regulation of red blood cell production.

    PubMed

    Wang, Weijia; Akbarian, Vahe; Audet, Julie

    2013-02-01

    Adult bone marrow (BM) erythrocyte colony-forming units (CFU-Es) are important cellular targets for the treatment of anemia and also for the manufacture of red blood cells (RBCs) ex vivo. We obtained quantitative biochemical measurements from single and small numbers of CFU-Es by isolating and analyzing c-Kit(+)CD71(high)Ter119(-) cells from adult mouse BM and this allowed us to identify two mechanisms that can be manipulated to increase RBC production. As expected, maximum RBC output was obtained when CFU-Es were stimulated with a combination of Stem Cell Factor (SCF) and Erythropoietin (EPO) mainly because SCF supports a transient CFU-E expansion and EPO promotes the survival and terminal differentiation of erythroid progenitors. However, we found that one of the main factors limiting the output in RBCs was that EPO induces a downregulation of c-Kit expression which limits the transient expansion of CFU-Es. In the presence of SCF, the EPO-mediated downregulation of c-Kit on CFU-Es is delayed but still significant. Moreover, treatment of CFU-Es with 1-Naphthyl PP1 could partially inhibit the downregulation of c-Kit induced by EPO, suggesting that this process is dependent on a Src family kinase, v-Src and/or c-Fyn. We also found that CFU-E survival and proliferation was dependent on the level of time-integrated extracellular-regulated kinase (ERK) activation in these cells, all of which could be significantly increased when SCF and EPO were combined with mouse fetal liver-derived factors. Taken together, these results suggest two novel molecular strategies to increase RBC production and regeneration. PMID:23168618

  10. The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma.

    PubMed

    Li, Bingzong; Fu, Jinxiang; Chen, Ping; Ge, Xueping; Li, Yali; Kuiatse, Isere; Wang, Hua; Wang, Huihan; Zhang, Xingding; Orlowski, Robert Z

    2015-12-11

    Resistance to the proteasome inhibitor bortezomib is an emerging clinical problem whose mechanisms have not been fully elucidated. We considered the possibility that this could be associated with enhanced proteasome activity in part through the action of the proteasome maturation protein (POMP). Bortezomib-resistant myeloma models were used to examine the correlation between POMP expression and bortezomib sensitivity. POMP expression was then modulated using genetic and pharmacologic approaches to determine the effects on proteasome inhibitor sensitivity in cell lines and in vivo models. Resistant cell lines were found to overexpress POMP, and while its suppression in cell lines enhanced bortezomib sensitivity, POMP overexpression in drug-naive cells conferred resistance. Overexpression of POMP was associated with increased levels of nuclear factor (erythroid-derived 2)-like (NRF2), and NRF2 was found to bind to and activate the POMP promoter. Knockdown of NRF2 in bortezomib-resistant cells reduced POMP levels and proteasome activity, whereas its overexpression in drug-naive cells increased POMP and proteasome activity. The NRF2 inhibitor all-trans-retinoic acid reduced cellular NRF2 levels and increased the anti-proliferative and pro-apoptotic activities of bortezomib in resistant cells, while decreasing proteasome capacity. Finally, the combination of all-trans-retinoic acid with bortezomib showed enhanced activity against primary patient samples and in a murine model of bortezomib-resistant myeloma. Taken together, these studies validate a role for the NRF2/POMP axis in bortezomib resistance and identify NRF2 and POMP as potentially attractive targets for chemosensitization to this proteasome inhibitor.

  11. Sustainable Scientists

    SciTech Connect

    Mills, Evan

    2008-12-31

    Scientists are front and center in quantifying and solving environmental problems. Yet, as a spate of recent news articles in scientific journals point out, much can be done to enhance sustainability within the scientific enterprise itself, particularly by trimming the energy use associated with research facilities and the equipment therein (i,ii,iii, iv). Sponsors of research unwittingly spend on the order of $10 billion each year on energy in the U.S. alone, and the underlying inefficiencies drain funds from the research enterprise while causing 80 MT CO2-equivalent greenhouse-gas emissions (see Box). These are significant sums considering the opportunity costs in terms of the amount of additional research that could be funded and emissions that could be reduced if the underlying energy was used more efficiently. By following commercially proven best practices in facility design and operation, scientists--and the sponsors of science--can cost-effectively halve these costs, while doing their part to put society on alow-carbon diet.

  12. Human parvovirus B19 causes cell cycle arrest of human erythroid progenitors via deregulation of the E2F family of transcription factors

    PubMed Central

    Wan, Zhihong; Zhi, Ning; Wong, Susan; Keyvanfar, Keyvan; Liu, Delong; Raghavachari, Nalini; Munson, Peter J.; Su, Su; Malide, Daniela; Kajigaya, Sachiko; Young, Neal S.

    2010-01-01

    Human parvovirus B19 (B19V) is the only human pathogenic parvovirus. It causes a wide spectrum of human diseases, including fifth disease (erythema infectiosum) in children and pure red cell aplasia in immunocompromised patients. B19V is highly erythrotropic and preferentially replicates in erythroid progenitor cells (EPCs). Current understanding of how B19V interacts with cellular factors to regulate disease progression is limited, due to a lack of permissive cell lines and animal models. Here, we employed a recently developed primary human CD36+ EPC culture system that is highly permissive for B19V infection to identify cellular factors that lead to cell cycle arrest after B19V infection. We found that B19V exploited the E2F family of transcription factors by downregulating activating E2Fs (E2F1 to E2F3a) and upregulating repressive E2Fs (E2F4 to E2F8) in the primary CD36+ EPCs. B19V nonstructural protein 1 (NS1) was a key viral factor responsible for altering E2F1–E2F5 expression, but not E2F6–E2F8 expression. Interaction between NS1 and E2F4 or E2F5 enhanced the nuclear import of these repressive E2Fs and induced stable G2 arrest. NS1-induced G2 arrest was independent of p53 activation and increased viral replication. Downstream E2F4/E2F5 targets, which are potentially involved in the progression from G2 into M phase and erythroid differentiation, were identified by microarray analysis. These findings provide new insight into the molecular pathogenesis of B19V in highly permissive erythroid progenitors. PMID:20890043

  13. Candidate ligand for the c-kit transmembrane kinase receptor: KL, a fibroblast derived growth factor stimulates mast cells and erythroid progenitors.

    PubMed Central

    Nocka, K; Buck, J; Levi, E; Besmer, P

    1990-01-01

    The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor for an unidentified ligand and is allelic with the murine white-spotting locus (W). W mutations affect melanogenesis, gametogenesis and hematopoiesis during development and in adult life. Cellular targets of W mutations in hematopoiesis include distinct cell populations in the erythroid and mast cell lineages as well as stem cells. In the absence of interleukin-3 (IL-3) mast cells derived from normal mice but not from W mutant mice can be maintained by co-culture with 3T3 fibroblasts. Based on the defective proliferative response of W mast cells in the 3T3 fibroblast co-culture system it had been proposed that fibroblasts produce the c-kit ligand. We have used a mast cell proliferation assay to purify a 30 kd protein, designated KL, from conditioned medium of Balb/3T3 fibroblasts to apparent homogeneity. KL stimulates the proliferation of normal bone marrow derived mast cells but not mast cells from W mice, although both normal and mutant mast cells respond similarly to IL-3. Connective tissue-type mast cells derived from the peritoneal cavity of normal mice were found to express a high level of c-kit protein on their surface and to proliferate in response to KL. The effect of KL on erythroid progenitor cells was investigated as well. In combination with erythropoietin, KL was found to stimulate early erythroid progenitors (BFU-E) from fetal liver and spleen cells but not from bone marrow cells of adult mice and from fetal liver cells of W/W mice.(ABSTRACT TRUNCATED AT 250 WORDS) Images Fig. 1. Fig. 3. Fig. 5. Fig. 7. PMID:1698611

  14. Antisense myb inhibition of purified erythroid progenitors in development and differentiation is linked to cycling activity and expression of DNA polymerase alpha

    SciTech Connect

    Valtieri, M.; Venturelli, D.; Care, A.; Fossati, C.; Pelosi, E.; Labbaye, C.; Mattia, G.; Gewirtz, A.M.; Calabretta, B.; Peschle, C. )

    1991-03-15

    These studies aimed to determine the expression and functional role of c-myb in erythroid progenitors with different cycling activities. In the first series of experiments the erythroid burst-forming unit (BFU-E) and colony-forming unit (CFU-E) populations from adult peripheral blood (PB), bone marrow (BM), and embryonic-fetal liver (FL) were treated with either c-myb antisense oligomers or 3H-thymidine (3H-TdR). A direct correlation was always observed between the inhibitory effect of anti-myb oligomers and the level of cycling activity. Thus, the inhibitory effect of antisense c-myb on the number of BFU-E colonies was 28.3% +/- 15.8% in PB, 53.4% +/- 9.3% in BM, and 68.2% +/- 24.5% in FL. Both adult and embryonic CFU-E were markedly inhibited. Using purified PB progenitors, we observed a similar pattern, although with slightly lower inhibitory effects. In the 3H-TdR suicide assay the killing index of BFU-E was 8.9% +/- 4.2% in PB, 29.4% +/- 6.5% in BM, and 40.1% +/- 9.6% in FL. The values for adult and embryonic CFU-E were 55.7% +/- 7.9% and 60.98% +/- 6.6%, respectively. We then investigated the kinetics of c-myb mRNA level during the erythroid differentiation of purified adult PB and FL BFU-E, as evaluated in liquid-phase culture by reverse transcription-polymerase chain reaction. Adult erythroid precursors showed a gradual increase of c-myb mRNA from day 4 through day 8 of culture and a sharp decrease at later times, whereas the expression of c-myb mRNA and protein in differentiation embryonic precursors peaked 2 days earlier. In both cases, c-myb mRNA level peaked at the CFU-E stage of differentiation. Finally, highly purified adult PB BFU-E were stimulated into cycling by a 3-day treatment with interleukin-3 in liquid phase: both the sensitivity to c-myb antisense oligomers and the 3H-TdR suicide index showed a gradual, strictly parallel increase.

  15. ABO alleles are linked with haplotypes of an erythroid cell-specific regulatory element in intron 1 with a few exceptions attributable to genetic recombination.

    PubMed

    Nakajima, T; Sano, R; Takahashi, Y; Watanabe, K; Kubo, R; Kobayashi, M; Takahashi, K; Takeshita, H; Kominato, Y

    2016-01-01

    Recent investigation of transcriptional regulation of the ABO genes has identified a candidate erythroid cell-specific regulatory element, named the +5·8-kb site, in the first intron of ABO. Six haplotypes of the site have been reported previously. The present genetic population study demonstrated that each haplotype was mostly linked with specific ABO alleles with a few exceptions, possibly as a result of hybrid formation between common ABO alleles. Thus, investigation of these haplotypes could provide a clue to further elucidation of ABO alleles.

  16. Sustainable NREL - Site Sustainability Plan FY 2015

    SciTech Connect

    None, None

    2015-01-01

    NREL's Site Sustainability Plan FY 2015 reports on sustainability plans for the lab for the year 2015 based on Executive Order Goals and provides the status on planned actions cited in the FY 2014 report.

  17. Sustainable Campus: Engaging the Community in Sustainability

    ERIC Educational Resources Information Center

    Too, Linda; Bajracharya, Bhishna

    2015-01-01

    Purpose: The purpose of this paper is to identify the major factors necessary for engaging university campus community in sustainability. While general awareness in sustainability issues has improved in recent years through mass media coverage, this knowledge is not always translated into actual sustainable practice. Studies have indicated that…

  18. Comparing Science Achievement Constructs: Targeted and Achieved

    ERIC Educational Resources Information Center

    Ferrara, Steve; Duncan, Teresa

    2011-01-01

    This article illustrates how test specifications based solely on academic content standards, without attention to other cognitive skills and item response demands, can fall short of their targeted constructs. First, the authors inductively describe the science achievement construct represented by a statewide sixth-grade science proficiency test.…

  19. Mobility and Reading Achievement.

    ERIC Educational Resources Information Center

    Waters, Theresa Z.

    A study examined the effect of geographic mobility on elementary school students' achievement. Although such mobility, which requires students to make multiple moves among schools, can have a negative impact on academic achievement, the hypothesis for the study was that it was not a determining factor in reading achievement test scores. Subjects…

  20. University Presidents' Conceptualizations of Sustainability in Higher Education

    ERIC Educational Resources Information Center

    Wright, Tarah

    2010-01-01

    Purpose: The purpose of this paper is to examine how a cohort of university presidents and vice-presidents in Canadian universities conceptualize sustainable development, sustainable universities, the role universities play in achieving a sustainable future, key issues facing the university, and the barriers to implementing sustainability…

  1. An Understanding of Sustainability and Education for Sustainable Development among German Student Teachers and Trainee Teachers of Chemistry

    ERIC Educational Resources Information Center

    Burmeister, Mareike; Eilks, Ingo

    2013-01-01

    Sustainable development is a central concern of today's politics across the world. Different political agendas have been developed to promote sustainability and make it a political goal worldwide. As stated in Agenda 21, the political debate seems to agree that education has to play a key role in achieving sustainability. But practices…

  2. Education for Sustainability-Challenges and Opportunities: The Case of RCEs (Regional Centres of Expertise in Education for Sustainable Development)

    ERIC Educational Resources Information Center

    Wade, Ros

    2016-01-01

    This article will focus on the challenges of leadership and management of a key initiative of the 20052014 UN Decade of Education for Sustainable Development (DESD), namely the Regional Centres of Expertise in Education for Sustainability (RCEs). It will argue that in order to achieve sustainability, there is a need to move away from outdated…

  3. Infection of the erythroid cell line, KU812Ep6 with human parvovirus B19 and its application to titration of B19 infectivity.

    PubMed

    Miyagawa, E; Yoshida, T; Takahashi, H; Yamaguchi, K; Nagano, T; Kiriyama, Y; Okochi, K; Sato, H

    1999-12-01

    A human parvovirus B19 (B19) infectivity assay was developed using the erythroid cell line, KU812Ep6. KU812Ep6 was cloned for high efficiency infection with B19 in vitro, in the presence of erythropoietin by a limiting dilution method from the parent cell line, KU812. B19 was effectively propagated in KU812Ep6 and was detected for B19 antigens, VP1 and VP2. The titers of B19 positive sera measured with KU812Ep6 cells were in the range of 10(6) to 10(8) TCID50 ml. This KU812Ep6 infectivity assay had a 10(3)-10(4.5) higher sensitivity than the colony forming unit-erythroid (CFU-e) injury assay. It was calculated that one TCID50 needed 10(3) B19 genome copies, judging from the infectivity assay and semi-quantitative PCR. The KU812Ep6 infectivity assay was also used to determine infectivity of B19 in vitro, and to evaluate inactivation, as well as clearance of the virus. The inactivation of B19 by heating was carried out and infectivity declined from 10(4) TCID50 ml to < 10 TCID50 ml (lower limit of detection) at 60 degrees C for 3 h or at 70 degrees C for 30 min, but only decreased to 10(2.5) TCID50 ml at 50 degrees C for 8 h.

  4. In utero and in vitro effects of benzene and its metabolites on erythroid differentiation and the role of reactive oxygen species

    SciTech Connect

    Badham, Helen J.; Winn, Louise M.

    2010-05-01

    Benzene is a ubiquitous occupational and environmental toxicant. Exposures to benzene both prenatally and during adulthood are associated with the development of disorders such as aplastic anemia and leukemia. Mechanisms of benzene toxicity are unknown; however, generation of reactive oxygen species (ROS) by benzene metabolites may play a role. Little is known regarding the effects of benzene metabolites on erythropoiesis. Therefore, to determine the effects of in utero exposure to benzene on the growth and differentiation of fetal erythroid progenitor cells (CFU-E), pregnant CD-1 mice were exposed to benzene and CFU-E numbers were assessed in fetal liver (hematopoietic) tissue. In addition, to determine the effect of benzene metabolite-induced ROS generation on erythropoiesis, HD3 chicken erythroblast cells were exposed to benzene, phenol, or hydroquinone followed by stimulation of erythrocyte differentiation. Our results show that in utero exposure to benzene caused significant alterations in female offspring CFU-E numbers. In addition, exposure to hydroquinone, but not benzene or phenol, significantly reduced the percentage of differentiated HD3 cells, which was associated with an increase in ROS. Pretreatment of HD3 cells with polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) prevented hydroquinone-induced inhibition of erythropoiesis, supporting the hypothesis that ROS generation is involved in the development of benzene erythrotoxicity. In conclusion, this study provided evidence that ROS generated as a result of benzene metabolism may significantly alter erythroid differentiation, potentially leading to the development of Blood Disorders.

  5. Control of erythroid differentiation: asynchronous expression of the anion transporter and the peripheral components of the membrane skeleton in AEV- and S13-transformed cells

    PubMed Central

    1986-01-01

    Chicken erythroblasts transformed with avian erythroblastosis virus or S13 virus provide suitable model systems with which to analyze the maturation of immature erythroblasts into erythrocytes. The transformed cells are blocked in differentiation at around the colony-forming unit- erythroid stage of development but can be induced to differentiate in vitro. Analysis of the expression and assembly of components of the membrane skeleton indicates that these cells simultaneously synthesize alpha-spectrin, beta-spectrin, ankyrin, and protein 4.1 at levels that are comparable to those of mature erythroblasts. However, they do not express any detectable amounts of anion transporter. The peripheral membrane skeleton components assemble transiently and are subsequently rapidly catabolized, resulting in 20-40-fold lower steady-state levels than are found in maturing erythrocytes. Upon spontaneous or chemically induced terminal differentiation of these cells expression of the anion transporter is initiated with a concommitant increase in the steady- state levels of the peripheral membrane-skeletal components. These results suggest that during erythropoiesis, expression of the peripheral components of the membrane skeleton is initiated earlier than that of the anion transporter. Furthermore, they point a key role for the anion transporter in conferring long-term stability to the assembled erythroid membrane skeleton during terminal differentiation. PMID:2946700

  6. Thalidomide is more efficient than sodium butyrate in enhancing GATA-1 and EKLF gene expression in erythroid progenitors derived from HSCs with β-globin gene mutation

    PubMed Central

    Jalali Far, Mohammad Ali; Dehghani Fard, Ali; Hajizamani, Saiedeh; Mossahebi-Mohammadi, Majid; Yaghooti, Hamid; Saki, Najmaldin

    2016-01-01

    Background: Efficient induction of fetal hemoglobin (HbF) is considered as an effective therapeutic approach in beta thalassemia. HbF inducer agents can induce the expression of γ-globin gene and produce high levels of HbF via different epigenetic and molecular mechanisms. Thalidomide and sodium butyrate are known as HbF inducer drugs. Material and methods: CD133+ stem cells were isolated from umbilical cord blood of a newborn with minor β-thalassemia in order to evaluate the effects of these two drugs on the in vitro expression of GATA-1 and EKLF genes as erythroid transcription factors. CD133+ stem cells were expanded and differentiated into erythroid lineage and then treated with thalidomide and sodium butyrate and finally analyzed by quantitative real-time PCR. Statistical analysis was performed using student’s t-test by SPSS software. Results: Thalidomide and sodium butyrate increased GATA-1 and EKLF gene expression, compared to the non-treated control (P<0.05). Conclusion: Thalidomide was more efficient than sodium butyrate in augmenting expression of GATA-1 and EKLF genes. It seems that GATA-1 and EKLF have crucial roles in the efficient induction of HbF by thalidomide. PMID:27047649

  7. Transcriptional Activity of Erythroid Kruppel-like Factor (EKLF/KLF1) Modulated by PIAS3 (Protein Inhibitor of Activated STAT3)*

    PubMed Central

    Siatecka, Miroslawa; Soni, Shefali; Planutis, Antanas; Bieker, James J.

    2015-01-01

    Erythroid Kruppel-like factor (EKLF or KLF1) is a transcription factor crucial for red cell development that is directly involved in regulation of a large number of erythroid genes. EKLF serves mostly as an activator of expression of these genes; however, it can act also as a repressor. Here, we present evidence that EKLF interacts with proteins from the PIAS (protein inhibitor of activated STAT) family that convey repressive activity to EKLF in the absence of sumoylation. Our studies identify PIAS3 as a transcriptional corepressor of EKLF for at least a subset of its target genes during erythropoiesis (e.g. β-globin, α-hemoglobin stabilizing protein). We demonstrate an interaction between EKLF and PIAS proteins confirmed by in vivo coimmunoprecipitation assays with both exogenous and endogenous proteins. We identified an LXXLL signature motif located near the N terminus of PIAS proteins that, although not involved in the EKLF-PIAS3 interaction, is required for the transrepression activity. Knockdown of endogenous PIAS3 accelerates differentiation of both murine erythroleukemia cells, as well as fetal liver cells, whereas an increase in PIAS3 levels inhibits this increase. Using chromatin immunoprecipitation assays, we show that PIAS3 preferentially occupies the β-globin promoter in undifferentiated murine erythroleukemia cells. Together these results demonstrate that an interaction between EKLF and PIAS3 provides a novel mode of regulation of EKLF activity in the absence of sumolylation and furthermore shows an important involvement of PIAS proteins in erythropoiesis. PMID:25713074

  8. Parvovirus B19 Infection of Human Primary Erythroid Progenitor Cells Triggers ATR-Chk1 Signaling, Which Promotes B19 Virus Replication ▿

    PubMed Central

    Luo, Yong; Lou, Sai; Deng, Xuefeng; Liu, Zhengwen; Li, Yi; Kleiboeker, Steve; Qiu, Jianming

    2011-01-01

    Human parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells of the human bone marrow. Although the mechanism by which the B19V genome replicates in these cells has not been studied in great detail, accumulating evidence has implicated involvement of the cellular DNA damage machinery in this process. Here, we report that, in ex vivo-expanded human erythroid progenitor cells, B19V infection induces a broad range of DNA damage responses by triggering phosphorylation of all the upstream kinases of each of three repair pathways: ATM (ataxia-telangiectasi mutated), ATR (ATM and Rad3 related), and DNA-PKcs (DNA-dependent protein kinase catalytic subunit). We found that phosphorylated ATM, ATR, and DNA-PKcs, and also their downstream substrates and components (Chk2, Chk1, and Ku70/Ku80 complex, respectively), localized within the B19V replication center. Notably, inhibition of kinase phosphorylation (through treatment with either kinase-specific inhibitors or kinase-specific shRNAs) revealed requirements for signaling of ATR and DNA-PKcs, but not ATM, in virus replication. Inhibition of the ATR substrate Chk1 led to similar levels of decreased virus replication, indicating that signaling via the ATR-Chk1 pathway is critical to B19V replication. Notably, the cell cycle arrest characteristic of B19V infection was not rescued by interference with the activity of any of the three repair pathway kinases. PMID:21680529

  9. Cis-vaccenic acid induces differentiation and up-regulates gamma globin synthesis in K562, JK1 and transgenic mice erythroid progenitor stem cells.

    PubMed

    Aimola, Idowu A; Inuwa, Hajiya M; Nok, Andrew J; Mamman, Aisha I; Bieker, James J

    2016-04-01

    Gamma globin induction remains a promising pharmacological therapeutic treatment mode for sickle cell anemia and beta thalassemia, however Hydroxyurea remains the only FDA approved drug which works via this mechanism. In this regard, we assayed the γ-globin inducing capacity of Cis-vaccenic acid (CVA). CVA induced differentiation of K562, JK1 and transgenic mice primary bone marrow hematopoietic progenitor stem cells. CVA also significantly up-regulated γ-globin gene expression in JK-1 and transgenic mice bone marrow erythroid progenitor stem cells (TMbmEPSCs) but not K562 cells without altering cell viability. Increased γ-globin expression was accompanied by KLF1 suppression in CVA induced JK-1 cells. Erythropoietin induced differentiation of JK-1 cells 24h before CVA induction did not significantly alter CVA induced differentiation and γ-globin expression in JK-1 cells. Inhibition of JK-1 and Transgenic mice bone marrow erythroid progenitor stem cells Fatty acid elongase 5 (Elovl5) and Δ(9) desaturase suppressed the γ-globin inductive effects of CVA. CVA treatment failed to rescue γ-globin expression in Elovl5 and Δ(9)-desaturase inhibited cells 48 h post inhibition in JK-1 cells. The data suggests that CVA directly modulates differentiation of JK-1 and TMbmEPSCs, and indirectly modulates γ-globin gene expression in these cells. Our findings provide important clues for further evaluations of CVA as a potential fetal hemoglobin therapeutic inducer. PMID:26879870

  10. Youth Action Council on Sustainable Innovation (YACSI) Report: Making Innovation Sustainable Among Youth in Canada.

    ERIC Educational Resources Information Center

    2002

    A study surveyed 241 high-achieving youth aged 15-25 regarding how innovation can be made sustainable among youth in Canada. Results were insightful and pointed to actionable steps for the Youth Action Council for Sustainable Innovation and the federal government. Findings indicated the following: youth can be more innovative if they have the…

  11. Is Sustainable Remediation Now a Self-Sustaining Process? an International Progress Report

    NASA Astrophysics Data System (ADS)

    Smith, J. W. N.

    2014-12-01

    Sustainable remediation - the consideration of environmental, social and economic factors associated with soil and groundwater risk-management options, to help select the best overall solution - has been a rapidly evolving topic in recent years. The first published reference[1] to 'sustainable remediation' was in the title of a 1999 conference paper by Kearney et al., (1999), but activity really accelerated in the middle-late 2000's, with establishment of a number of collaborative sustainable remediation groups and fora, and increased publication rates in the peer reviewed literature (Fig 1). Figure 1. Journal paper publications with search term 'sustainable remediation' (SCOPUS survey, 17 July 2014) This presentation will review the international progress of sustainable remediation concept development and application in regulatory and corporate decision-making processes. It will look back at what has already been achieved, provide an update on the latest initiatives and developments, and look forward to what the future of sustainable remediation might look like. Specifically it will describe: Sustainable remediation frameworks: synergies and international collaboration; Latest guidance and tools developed by the various sustainable remediation organisations (SuRFs), including the SuRF-UK Best Management Practices and Tier 1 Briefcase; Best practice standard development by ASTM and ISO; Regulatory acceptance of sustainable remediation, including incorporation into legislation, and the NICOLE - Common Forum Joint statement on 'risk-informed and sustainable remediation' in Europe; Examples of corporate adoption of sustainable remediation principles. The presentation will conclude with a look forward to a vision of sustainable remediation in 2020.

  12. Sox7-sustained expression alters the balance between proliferation and differentiation of hematopoietic progenitors at the onset of blood specification.

    PubMed

    Gandillet, Arnaud; Serrano, Alicia G; Pearson, Stella; Lie-A-Ling, Michael; Lacaud, Georges; Kouskoff, Valerie

    2009-11-26

    The molecular mechanisms that regulate the balance between proliferation and differentiation of precursors at the onset of hematopoiesis specification are poorly understood. By using a global gene expression profiling approach during the course of embryonic stem cell differentiation, we identified Sox7 as a potential candidate gene involved in the regulation of blood lineage formation from the mesoderm germ layer. In the present study, we show that Sox7 is transiently expressed in mesodermal precursors as they undergo specification to the hematopoietic program. Sox7 knockdown in vitro significantly decreases the formation of both primitive erythroid and definitive hematopoietic progenitors as well as endothelial progenitors. In contrast, Sox7-sustained expression in the earliest committed hematopoietic precursors promotes the maintenance of their multipotent and self-renewing status. Removal of this differentiation block driven by Sox7-enforced expression leads to the efficient differentiation of hematopoietic progenitors to all erythroid and myeloid lineages. This study identifies Sox7 as a novel and important player in the molecular regulation of the first committed blood precursors. Furthermore, our data demonstrate that the mere sustained expression of Sox7 is sufficient to completely alter the balance between proliferation and differentiation at the onset of hematopoiesis.

  13. Sustainability and the health care manager: part I.

    PubMed

    Ramirez, Bernardo; Oetjen, Reid M; Malvey, Donna

    2011-01-01

    Given the current operating climate, organizations are coming under pressure to develop and implement sustainability programs and projects, yet few managers truly understand what is meant by sustainability and its implications for managing organizations. This article examines the concept of sustainability and provides a broader definition of the term than going "green." Using a puzzle metaphor, the authors outline and explain the different components of sustainability and provide a checklist for achieving sustainability goals. In addition, resources such as guides and tools are reviewed and offered to assist managers in gaining more insight into the challenges and complexity of sustainability.

  14. Sustaining Writing Theory

    ERIC Educational Resources Information Center

    Patrick, Amy M.

    2010-01-01

    This article examines ways in which the fundamentals of both writing studies and sustainability studies overlap and complement each other, ultimately moving toward a theory of writing that not only is sustainable, but that also sustains writing practice across a variety of areas. For example, in order to be sustainable, both writing and…

  15. 2010 Campus Sustainability Review

    ERIC Educational Resources Information Center

    Association for the Advancement of Sustainability in Higher Education, 2011

    2011-01-01

    With this review of campus sustainability efforts in 2010, the editors aim to give readers--those who are often immersed in the day-to-day particulars of sustainability efforts--the same chance to take a step back and take a broader look at where they stand with sustainability in higher education. This inaugural 2010 Campus Sustainability Review…

  16. SUSTAINABILITY AND COMPLEX SYSTEMS

    EPA Science Inventory

    The important question in sustainability is not whether the world is sustainable, but whether a humanly acceptable regime of the world is sustainable. World commission on environment and development defines sustainability as ‘development that meets the needs of the present withou...

  17. Designing sustainable acute hospitals.

    PubMed

    Cory, Alistair

    2008-01-01

    The need to provide sustainable hospitals lies in the fact that we have an obligation to act responsibly towards good stewardship of our environment and the world's precious resources, ensuring a healthy future for coming generations. As such, a sustainable hospital must sit squarely in a sustainable society, and the global and local context should be considered when designing a sustainable health facility.

  18. Organizing for Sustainability

    ERIC Educational Resources Information Center

    Brown, William M.; Hamburger, Michael W.

    2012-01-01

    A successful campus sustainability effort catalyzes broad engagement of the campus community and integration of sustainability principles into the academic and operational components of campus life. Although many universities have embraced sustainability as a new core value, others have been more sluggish in adopting sustainability principles to…

  19. Focus on sustainability.

    PubMed

    Thompson, R J; Godiksen, L; Hansen, G; Gustafson, D J; Brinkerhoff, D W; Ingle, M D; Rounds, T; Wing, H

    1990-01-01

    In recent years, sustainability has become one of the most critical concepts in international development and is having a dramatic impact on the way development is conceptualized and carried out. The US Agency for International Development (USAID) is incorporating this concept into its programs and projects. Factors encouraging sustainability of projects and programs include host government policies that support or constrain program objectives, national and/or local commitment to project goals, managerial leadership that helps shape improved policies, collaboration at all staff levels in program management, financial resources that cover program operational costs, appropriate program technology, integration of the program with the social and cultural setting of the country, community involvement in the program, sound environmental management, technical assistance oriented to transferring skills and increasing institutional capacity, perception by the host country that the project is "effective," training provided by the project to transfer skill needed for capacity-building, integration of the program into existing institutional framework, and external political, economic and environmental factors. Impediments to sustainability are often inherent in the donor agency's programming process. This includes the implicit assumption that program objectives can be accomplished in a relatively short time frame, when in fact capacity-building requires a lengthy commitment. USAID professionals are pressured to show near-term results which emphasize outputs rather than purpose and goal-level accomplishments achievable only after extensive effort. The emphasis on obligating money and on the project paper as a sales document leads project designers to talk with a great deal more certainty about project results than is warranted by the complex development situation. Uncertainty and flexibility should be designed into projects so activities and objects can change as more

  20. General Achievement Trends: Oklahoma

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  1. General Achievement Trends: Georgia

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  2. General Achievement Trends: Nebraska

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  3. General Achievement Trends: Arkansas

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  4. General Achievement Trends: Maryland

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  5. General Achievement Trends: Maine

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  6. General Achievement Trends: Iowa

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  7. General Achievement Trends: Texas

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  8. General Achievement Trends: Hawaii

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  9. General Achievement Trends: Kansas

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  10. General Achievement Trends: Florida

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  11. General Achievement Trends: Massachusetts

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  12. General Achievement Trends: Tennessee

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  13. General Achievement Trends: Alabama

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  14. General Achievement Trends: Virginia

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  15. General Achievement Trends: Michigan

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  16. General Achievement Trends: Colorado

    ERIC Educational Resources Information Center

    Center on Education Policy, 2009

    2009-01-01

    This general achievement trends profile includes information that the Center on Education Policy (CEP) and the Human Resources Research Organization (HumRRO) obtained from states from fall 2008 through April 2009. Included herein are: (1) Bullet points summarizing key findings about achievement trends in that state at three performance…

  17. Inverting the Achievement Pyramid

    ERIC Educational Resources Information Center

    White-Hood, Marian; Shindel, Melissa

    2006-01-01

    Attempting to invert the pyramid to improve student achievement and increase all students' chances for success is not a new endeavor. For decades, educators have strategized, formed think tanks, and developed school improvement teams to find better ways to improve the achievement of all students. Currently, the No Child Left Behind Act (NCLB) is…

  18. Achievement Test Program.

    ERIC Educational Resources Information Center

    Ohio State Dept. of Education, Columbus. Trade and Industrial Education Service.

    The Ohio Trade and Industrial Education Achievement Test battery is comprised of seven basic achievement tests: Machine Trades, Automotive Mechanics, Basic Electricity, Basic Electronics, Mechanical Drafting, Printing, and Sheet Metal. The tests were developed by subject matter committees and specialists in testing and research. The Ohio Trade and…

  19. School Effects on Achievement.

    ERIC Educational Resources Information Center

    Nichols, Robert C.

    The New York State Education Department conducts a Pupil Evaluation Program (PEP) in which each year all third, sixth, and ninth grade students in the state are given a series of achievement tests in reading and mathematics. The data accumulated by the department includes achievement test scores, teacher characteristics, building and curriculum…

  20. Heritability of Creative Achievement

    ERIC Educational Resources Information Center

    Piffer, Davide; Hur, Yoon-Mi

    2014-01-01

    Although creative achievement is a subject of much attention to lay people, the origin of individual differences in creative accomplishments remain poorly understood. This study examined genetic and environmental influences on creative achievement in an adult sample of 338 twins (mean age = 26.3 years; SD = 6.6 years). Twins completed the Creative…

  1. Confronting the Achievement Gap

    ERIC Educational Resources Information Center

    Gardner, David

    2007-01-01

    This article talks about the large achievement gap between children of color and their white peers. The reasons for the achievement gap are varied. First, many urban minorities come from a background of poverty. One of the detrimental effects of growing up in poverty is receiving inadequate nourishment at a time when bodies and brains are rapidly…

  2. Achieving Public Schools

    ERIC Educational Resources Information Center

    Abowitz, Kathleen Knight

    2011-01-01

    Public schools are functionally provided through structural arrangements such as government funding, but public schools are achieved in substance, in part, through local governance. In this essay, Kathleen Knight Abowitz explains the bifocal nature of achieving public schools; that is, that schools are both subject to the unitary Public compact of…

  3. Achieving permanency for LGBTQ youth.

    PubMed

    Jacobs, Jill; Freundlich, Madelyn

    2006-01-01

    This article brings together two significant efforts in the child welfare field: achieving permanence for youth in out-of-home care and meeting the needs of lesbian, gay, bisexual, transgender and questioning (LGBTQ) youth. During the past several years, a national movement has taken place to assure all children and youth have a permanent family connection before leaving the child welfare system; however, LGBTQ youth are not routinely included in the permanency discussions. At the same time, efforts in addressing the needs of LGBTQ youth have increased, but permanency is rarely mentioned as a need. This article offers models of permanence and practices to facilitate permanence with LGBTQ youth and their families. It also offers a youth-driven, individualized process, using youth development principles to achieve relational, physical, and legal permanence. Reunification efforts are discussed, including services, supports, and education required for youth to return to their family of origin. For those who cannot return home, other family resources are explored. The article also discusses cultural issues as they affect permanence for LGBTQ youth, and, finally, addresses the need for ongoing support services to sustain and support permanency.

  4. Health and sustainability.

    PubMed

    Kjӕrgård, Bente; Land, Birgit; Bransholm Pedersen, Kirsten

    2014-09-01

    In the present article, we explore how sustainable development strategies and health promotion strategies can be bridged. The concept of the 'duality of structure' is taken as our starting point for understanding the linkages between health promotion and sustainable development, and for uncovering the structural properties or conditions which either enable or constrain sustainable public health initiatives. We argue that strategies towards health promotion are not sufficiently integrated with strategies for sustainable development, and thus political strategies aimed at solving health problems or sustainability problems may cause new, undesired and unforeseen environmental or health problems. First, we explore how the relation between health and sustainability is articulated in international policy documents. Next, we develop a model for understanding the relation between health promotion and sustainability. Third, we use examples from agriculture and food production to illustrate that health and sustainability are mutually enabling and constraining. We conclude that while the renewed focus on food security and food inequalities has brought the health and sustainability dimensions of the food system onto the political agenda, the conceptualization of duality between health and sustainability could be a new platform for a critical and theoretical stance towards the market-oriented food system strategy. Thinking along the lines of duality means that the integration of health promotion strategies and sustainable development strategies cannot be based on an approach to integration in which either health or sustainability is given precedence over the other. From a duality perspective, integration means conceiving sustainability from a health perspective and health from a sustainability perspective.

  5. Activity at work, innovation and sustainable development.

    PubMed

    Béguin, P; Duarte, F; Lima, F; Pueyo, V

    2012-01-01

    The aim of this paper is to present and discuss a French-Brazilian project (CAPES-COFECUB) centered on the relations between sustainable development, innovation and changes in work activities that accompany these innovations for sustainable development. Sustainable development calls for an integrated approach of three dimensions: social equity, economic viability and environmental sustainability. In order to achieve this integration, considerable innovations efforts are required. However, the work, understood as a productive act, is deeply lacking in the current researches. Starting from the idea that work is a "fundamental need" the goal of this project is to propose innovative methods that can be used for designing production systems from the perspective of sustainable development. PMID:22316705

  6. Sustaining Rural Communities through Sustainable Agriculture.

    ERIC Educational Resources Information Center

    Ikerd, John

    A 5-year collaborative project between Missouri, Michigan State, and Nebraska Universities to provide new opportunities for rural community self-development through sustainable agriculture had mixed results. This happened because community members did not understand the principles of sustainability, and because the extension education system was…

  7. The Road to Sustainability. Sustainability Workbook

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2002

    2002-01-01

    Sustainability seems generally thought to mean raising money. But money is only part of the equation. Money cannot be raised without a quality program, a quality program demonstrates results, effective results are based on sound management practices, etc. Sustainability therefore, is many things that in combination make something capable of…

  8. Modeling Tourism Sustainable Development

    NASA Astrophysics Data System (ADS)

    Shcherbina, O. A.; Shembeleva, E. A.

    The basic approaches to decision making and modeling tourism sustainable development are reviewed. Dynamics of a sustainable development is considered in the Forrester's system dynamics. Multidimensionality of tourism sustainable development and multicriteria issues of sustainable development are analyzed. Decision Support Systems (DSS) and Spatial Decision Support Systems (SDSS) as an effective technique in examining and visualizing impacts of policies, sustainable tourism development strategies within an integrated and dynamic framework are discussed. Main modules that may be utilized for integrated modeling sustainable tourism development are proposed.

  9. An Urban Middle School Case Study of Mathematics Achievement

    ERIC Educational Resources Information Center

    Paul, Cynthia S.; Vaidya, Sheila R.

    2014-01-01

    What does it take to change a school's mathematics achievement profile from low to one that is proficient and advanced? Is this transformed achievement profile sustainable? Such is the story presented here, in this three-phase case study of a K-8 urban charter school's mathematics program. The first phase discusses the school's…

  10. Did Tanzania Achieve the Second Millennium Development Goal? Statistical Analysis

    ERIC Educational Resources Information Center

    Magoti, Edwin

    2016-01-01

    Development Goal "Achieve universal primary education", the challenges faced, along with the way forward towards achieving the fourth Sustainable Development Goal "Ensure inclusive and equitable quality education and promote lifelong learning opportunities for all". Statistics show that Tanzania has made very promising steps…

  11. Student Achievement and Motivation

    ERIC Educational Resources Information Center

    Flammer, Gordon H.; Mecham, Robert C.

    1974-01-01

    Compares the lecture and self-paced methods of instruction on the basis of student motivation and achieveme nt, comparing motivating and demotivating factors in each, and their potential for motivation and achievement. (Authors/JR)

  12. Growth of erythroid burst-forming units (BFU-E) in cultures of canine bone marrow and peripheral blood cells: effect of serum from irradiated dogs

    SciTech Connect

    Kreja, L.; Baltschukat, K.; Nothdurft, W.

    1988-08-01

    Erythroid burst-forming units (BFU-E) from canine bone marrow and peripheral blood could be grown in methylcellulose in the presence of an appropriate batch of fetal calf serum (FCS), transferrin, and erythropoietin (Epo). However, improved colony formation (size and number of bursts) was obtained when serum from total body irradiated dogs was present in the culture. This serum, obtained from dogs at day 9 after total body irradiation with a dose of 3.9 Gy, reduced markedly the Epo requirement of BFU-E. Furthermore, it allowed the omission of FCS from the culture medium if cholesterol and bovine serum albumin (BSA) were used as FCS substitutes. BFU-E concentrations were found to be rather different in the peripheral blood and in bone marrow samples from different sites (i.e., iliac crest, sternum, and humerus) of normal beagles. The studies further show that canine bone marrow BFU-E can be cryopreserved in liquid nitrogen.

  13. Sustaining Cyberinfrastructure Interoperabililty

    NASA Astrophysics Data System (ADS)

    Moore, R. W.; Rajasekar, A.

    2015-12-01

    The National Science Foundation has initiated multiple cyberinfrastructure projects through the DataNet Parters, Data Infrastructure Building Blocks, Big Data Hubs, EarthCube, and XSEDE programs. Each project builds a component of cyberinfrastructure, such as collaboration environments, repositories, archives, union catalogs, or data manipulation services. The DataNet Federation Consortium (DFC) (datafed.org) has explored the types of interoperability mechanisms that are needed to build research collaboration environments that span the multiple NSF projects. Based on collaborations with each group, three basic mechanisms have proven to be sufficient: 1) Strong Federation: Tightly coupled federations in which shared name spaces are used for users and files along with communications based on well-defined protocols and API interfaces. Trust relationships based on policies play a major role in this federation. 2) Soft Federation: Loosly coupled federation where one system invokes remote services offered by another using service level communications. No name spaces are shared in such a federation. This type of federation is useful when well-defined services are available remotely on the internet. 3) Asynchronous Federation: Weakly coupled federation in which no direct interaction occurs between the systems. This level of federation is very extensible and flexible. Long-term sustainability can be achieved when the interoperability mechanisms enable interaction between old and new technologies - with the interactions being flexible or rigid depending upon the strength of trust needed between the systems. Sustaining cyberinfrastructure interoperability becomes feasible when the mechanisms enable the capture of the knowledge needed for interaction, without requiring changes to either sets of infrastructure. The DFC project has implemented all three types of federation to link services and systems based on the needs of the users.

  14. Exploring the Ambiguity: What Faculty Leaders Really Think of Sustainability in Higher Education

    ERIC Educational Resources Information Center

    Wright, Tarah; Horst, Naomi

    2013-01-01

    Purpose: The purpose of this paper is to examine how a cohort of university faculty leaders in Canadian universities conceptualize sustainable development, sustainable universities, the role universities play in achieving a sustainable future, key issues facing the university, and the barriers to implementing sustainability initiatives on campus.…

  15. Erythroid progenitor cells (CFU-E*) from Friend virus-infected mice undergo VVFe suicide in vitro in the absence of added erythropoietin

    SciTech Connect

    Del Rizzo, D.F.; Axelrad, A.A.

    1985-11-01

    The authors have investigated the effect of VVFe on the survival in suspension of erythropoietin (epo)-independent erythroid progenitor cells (CFU-E*) induced by Friend polycythemia virus (FV). Spleen cells from C3Hf/Bi mice previously infected with FV were exposed to carrier-free VVFe, and the survival of CFU-E* as a function of time in liquid medium was determined from the number of erythroid colonies that developed from these cells seeded in plasma cultures without added epo. The results showed that spleen CFU-E* were highly vulnerable to VVFe. Marrow CFU-E* behaved in a similar manner. The VVFe responsible for their suicide had been presented to the progenitor cells only during the 4-h period of incubation, after which they were washed and plated in excess nonradioactive iron. They therefore conclude that CFU-E* themselves, and not only their progeny, are capable of actively incorporating iron. Under the same conditions in the absence of added epo, the effect of VVFe on the survival of normal spleen or marrow CFU-E could not be assessed because two few normal CFU-E survived the incubation period. Normal bone marrow cells incubated in complete medium containing epo retained their capacity for erythrocytic colony formation, and CFU-E could then be shown to be vulnerable to VVFe. Thus, either the iron-incorporating system of normal CFU-E was inducible by epo, or else epo permitted survival of the CFU-E so that the activity of a constitutive iron-incorporating system could be recognized.

  16. Recombinant adeno-associated virus (rAAV)-mediated expression of a human gamma-globin gene in human progenitor-derived erythroid cells.

    PubMed

    Miller, J L; Donahue, R E; Sellers, S E; Samulski, R J; Young, N S; Nienhuis, A W

    1994-10-11

    Effective gene therapy for the severe hemoglobin (Hb) disorders, sickle-cell anemia and thalassemia, will require an efficient method to transfer, integrate, and express a globin gene in primary erythroid cells. To evaluate recombinant adeno-associated virus (rAAV) for this purpose, we constructed a rAAV vector encoding a human gamma-globin gene (pJM24/vHS432A gamma). Its 4725-nucleotide genome consists of two 180-bp AAV inverted terminal repeats flanking the core elements of hypersensitive sites 2, 3, and 4 from the locus control region of the beta-globin gene cluster, linked to a mutationally marked A gamma-globin gene (A gamma) containing native promoter and RNA processing signals. CD34+ human hematopoietic cells were exposed to rAAV particles at a multiplicity of infection of 500-1000 and cultured in semisolid medium containing several cytokines. A reverse transcriptase polymerase chain reaction assay distinguished mRNA signals derived from transduced and endogenous human gamma-globin genes. Twenty to 40% of human erythroid burst-forming unit-derived colonies expressed the rAAV-transduced A gamma-globin gene at levels 4-71% that of the endogenous gamma-globin genes. The HbF content of pooled control colonies was 26%, whereas HbF was 40% of the total in pooled colonies derived from rAAV transduced progenitors. These data establish that rAAV containing elements from the locus control region linked to a gamma-globin gene are capable of transferring and expressing that gene in primary human hematopoietic cells resulting in a substantial increase in HbF content.

  17. Recombinant adeno-associated virus (rAAV)-mediated expression of a human gamma-globin gene in human progenitor-derived erythroid cells.

    PubMed Central

    Miller, J L; Donahue, R E; Sellers, S E; Samulski, R J; Young, N S; Nienhuis, A W

    1994-01-01

    Effective gene therapy for the severe hemoglobin (Hb) disorders, sickle-cell anemia and thalassemia, will require an efficient method to transfer, integrate, and express a globin gene in primary erythroid cells. To evaluate recombinant adeno-associated virus (rAAV) for this purpose, we constructed a rAAV vector encoding a human gamma-globin gene (pJM24/vHS432A gamma). Its 4725-nucleotide genome consists of two 180-bp AAV inverted terminal repeats flanking the core elements of hypersensitive sites 2, 3, and 4 from the locus control region of the beta-globin gene cluster, linked to a mutationally marked A gamma-globin gene (A gamma) containing native promoter and RNA processing signals. CD34+ human hematopoietic cells were exposed to rAAV particles at a multiplicity of infection of 500-1000 and cultured in semisolid medium containing several cytokines. A reverse transcriptase polymerase chain reaction assay distinguished mRNA signals derived from transduced and endogenous human gamma-globin genes. Twenty to 40% of human erythroid burst-forming unit-derived colonies expressed the rAAV-transduced A gamma-globin gene at levels 4-71% that of the endogenous gamma-globin genes. The HbF content of pooled control colonies was 26%, whereas HbF was 40% of the total in pooled colonies derived from rAAV transduced progenitors. These data establish that rAAV containing elements from the locus control region linked to a gamma-globin gene are capable of transferring and expressing that gene in primary human hematopoietic cells resulting in a substantial increase in HbF content. Images PMID:7524085

  18. FORUM: Is Ecotourism Sustainable?

    PubMed

    Wall

    1997-07-01

    / It is legitimate to ask whether and in what form tourism might contribute to sustainable development. This is not the same as sustainable tourism which, as a single-sector approach to development, may overlook important linkages with other sectors. If tourism is to contribute to sustainable development, then it must be economically viable, ecologically sensitive and culturally appropriate. Ecotourism is often advocated as being a sustainable form of tourism but imprecision in terminology clouds basic issues and there are strong economic, ecological, and cultural reasons for believing that, even in its purest forms, ecotourism is likely to present substantial challenges to destination areas, particularly if it competes for scarce resources and displaces existing uses and users. Sustainable tourism and ecotourism are not synonyms, many forms of ecotourism may not be sustainable, and if ecotourism is to contribute to sustainable development, then careful planning and management will be required.KEY WORDS: Ecotourism; Sustainable development; Development; Tourism PMID:9175538

  19. Sustainability Indicators and Metrics

    EPA Science Inventory

    Sustainability is about preserving human existence. Indicators and metrics are absolutely necessary to provide at least a semi-quantitative assessment of progress towards or away from sustainability. Otherwise, it becomes impossible to objectively assess whether progress is bei...

  20. FORUM: Is Ecotourism Sustainable?

    PubMed

    Wall

    1997-07-01

    / It is legitimate to ask whether and in what form tourism might contribute to sustainable development. This is not the same as sustainable tourism which, as a single-sector approach to development, may overlook important linkages with other sectors. If tourism is to contribute to sustainable development, then it must be economically viable, ecologically sensitive and culturally appropriate. Ecotourism is often advocated as being a sustainable form of tourism but imprecision in terminology clouds basic issues and there are strong economic, ecological, and cultural reasons for believing that, even in its purest forms, ecotourism is likely to present substantial challenges to destination areas, particularly if it competes for scarce resources and displaces existing uses and users. Sustainable tourism and ecotourism are not synonyms, many forms of ecotourism may not be sustainable, and if ecotourism is to contribute to sustainable development, then careful planning and management will be required.KEY WORDS: Ecotourism; Sustainable development; Development; Tourism

  1. Urban climate, weather and sustainability

    NASA Astrophysics Data System (ADS)

    Mills, Gerald

    As concentrated areas of human activities, urban areas and urbanization are key drivers of global environmental change and pose a challenge to the achievement of sustainability. One of the key goals of sustainable development is to separate increases in non-renewable resource use (particularly fossil fuels) from economic growth. This is to be accomplished by modifying individual practices, encouraging technological innovation and redesigning systems of production and consumption. Settlements represent a scale at which significant advances on each of these can be made and where there is an existing management structure. However, urban areas currently consume a disproportionate share of the Earth's resources and urbanization has modified local climate and weather significantly, usually to the detriment of urban dwellers. There is now a lengthy history of urban climate study that links existing settlement form to climatic consequences yet, there is little evidence that climate information is incorporated into urban designs or that the climatic impact of different plans is considered. Consequently, opportunities for planning sustainable urban forms that are suitable to local climates and promote energy conservation and healthy atmospheres are not taken and much effort is later expended in `fixing' problems that emerge. This paper will outline the links between urban climate and sustainability, identify gaps in our urban climate knowledge and discuss the opportunities and barriers to the application of this knowledge to urban design and planning.

  2. Social sustainability and collaborative learning.

    PubMed

    Källström, Helena Nordström; Ljung, Magnus

    2005-06-01

    The social dimension is central to sustainable development of agri-food systems. If farmers are not satisfied with their situation or motivated to continue farming, many of today's environmental goals will be impossible to achieve. Between 1997 and 2003, several case studies were carried out on social sustainability, the importance of recognition in the farming system, and the potential role of increased collaboration between actors. The main hypothesis was that improved recognition is a basis for sustainable social conditions. Our findings show that many farmers today perceive an impoverished social situation. They believe they lack control over decisions, which hinders their ability to continue farming. Public images and political decisions show a lack of respect for farmers' skills and knowledge. However, increased collaboration among actors is believed to be one important way forward, creating stronger relationships and networks, as well as a stronger identity for farmers. Our findings emphasize the need for authorities and other organizations to support farmers and to facilitate collaborative learning and decision-making processes for socioecological sustainability.

  3. Transferring Education for Sustainability

    ERIC Educational Resources Information Center

    Gafoor, Kunnathodi Abdul; Umer Farooque, T. K.

    2013-01-01

    Sustainability stands for sustaining the past, meeting needs of the present without compromising the ability to meet future needs. It should meet the individual and social needs, present and future needs local and global needs. A sustainable education that meets this requirements surely be a transferable education; an education that transfers from…

  4. Sustainable Learning Organizations

    ERIC Educational Resources Information Center

    Velazquez, Luis E.; Esquer, Javier; Munguia, Nora E.; Moure-Eraso, Rafael

    2011-01-01

    Purpose: The purpose of this paper is to debate how companies may better become a sustainable learning organization by offering the most used and insightful concepts of sustainability. Design/methodology/approach: Through literature review, learning organization and sustainability perspectives are explored and compared. Findings: Learning…

  5. Custodial Operations: Green & Sustainable

    ERIC Educational Resources Information Center

    Campbell, J. Kirk

    2008-01-01

    Custodial Operations can have a significant impact on institutional green and sustainable goals if given the proper support and challenge. This article describes the green and sustainable custodial operations in place at Carleton College in Northfield, Minnesota. The article reviews the college's sustainable efforts on biodegradables, packaging,…

  6. Sustainability Statement and Policy

    ERIC Educational Resources Information Center

    Journal of Education for Sustainable Development, 2009

    2009-01-01

    This article presents nine resources that focus on environmental education and sustainability. These include: (1) "Sustainability Statement and Policy," Dalhousie University, Nova Scotia, Canada, 2009, which is available at http://office.sustainability.dal.ca/Governance; (2) "Climate Literacy: The Essential Principles of Climate Sciences,"…

  7. Measuring Educational Sustainability

    ERIC Educational Resources Information Center

    Selvanathan, Rani G.

    2013-01-01

    There are many definitions that are attributable to the meaning of sustainability. Sustainability can be viewed as long-lasting, effective result of a project, venture, action, or investment without consuming additional future resources. Because of the wide nature of its applicability, a universal measure of sustainability is hard to come by. This…

  8. Sustainability of physical activity promoting environments and influences on sustainability following a structural intervention in residential children's homes.

    PubMed

    Dominick, Gregory M; Tudose, Alina; Pohlig, Ryan T; Saunders, Ruth P

    2016-04-01

    Research examining sustainability of health promotion programs within organizational settings is limited. The Environmental Interventions in Residential Children's Homes (ENRICH) was a structural intervention that trained Wellness Teams (WTs) within residential children's homes (RCH) to target environmental changes that promote physical activity (PA) among residential youth. This study examines the sustainability of PA promoting environments and influences on sustainability within RCHs. A sustainability survey was administered to 14 RCHs 2 years after receiving ENRICH. Variables included sustainability of PA promoting environments, Organizational Influences, perceived organizational and individual benefits, and implementation of PA and general (i.e. Global) wellness activities. Activities reported as sustained and barriers were used descriptively to inform sustainability. Path analyses explained the relationship between sustainability influences and sustainability of PA promoting environments. Sustainability was found in 8 of 14 (57%) RCHs. Sustained activities reflected greater Global versus PA implementation. Global implementation mediated the relationship between Organizational Influences and sustainability, which may have been more easily achieved since Global activities were most likely controlled by WTs and did not require extensive organizational support from RCH administrators. Results highlight the importance of defining and assessing different implementation types when measuring sustainability and influences on sustainability within RCHs organizations.

  9. Performance sustaining intracortical neural prostheses

    NASA Astrophysics Data System (ADS)

    Nuyujukian, Paul; Kao, Jonathan C.; Fan, Joline M.; Stavisky, Sergey D.; Ryu, Stephen I.; Shenoy, Krishna V.

    2014-12-01

    Objective. Neural prostheses, or brain-machine interfaces, aim to restore efficient communication and movement ability to those suffering from paralysis. A major challenge these systems face is robust performance, particularly with aging signal sources. The aim in this study was to develop a neural prosthesis that could sustain high performance in spite of signal instability while still minimizing retraining time. Approach. We trained two rhesus macaques implanted with intracortical microelectrode arrays 1-4 years prior to this study to acquire targets with a neurally-controlled cursor. We measured their performance via achieved bitrate (bits per second, bps). This task was repeated over contiguous days to evaluate the sustained performance across time. Main results. We found that in the monkey with a younger (i.e., two year old) implant and better signal quality, a fixed decoder could sustain performance for a month at a rate of 4 bps, the highest achieved communication rate reported to date. This fixed decoder was evaluated across 22 months and experienced a performance decline at a rate of 0.24 bps yr-1. In the monkey with the older (i.e., 3.5 year old) implant and poorer signal quality, a fixed decoder could not sustain performance for more than a few days. Nevertheless, performance in this monkey was maintained for two weeks without requiring additional online retraining time by utilizing prior days’ experimental data. Upon analysis of the changes in channel tuning, we found that this stability appeared partially attributable to the cancelling-out of neural tuning fluctuations when projected to two-dimensional cursor movements. Significance. The findings in this study (1) document the highest-performing communication neural prosthesis in monkeys, (2) confirm and extend prior reports of the stability of fixed decoders, and (3) demonstrate a protocol for system stability under conditions where fixed decoders would otherwise fail. These improvements to decoder

  10. Iowa Women of Achievement.

    ERIC Educational Resources Information Center

    Ohrn, Deborah Gore, Ed.

    1993-01-01

    This issue of the Goldfinch highlights some of Iowa's 20th century women of achievement. These women have devoted their lives to working for human rights, education, equality, and individual rights. They come from the worlds of politics, art, music, education, sports, business, entertainment, and social work. They represent Native Americans,…

  11. Achieving Peace through Education.

    ERIC Educational Resources Information Center

    Clarken, Rodney H.

    While it is generally agreed that peace is desirable, there are barriers to achieving a peaceful world. These barriers are classified into three major areas: (1) an erroneous view of human nature; (2) injustice; and (3) fear of world unity. In a discussion of these barriers, it is noted that although the consciousness and conscience of the world…

  12. Increasing Male Academic Achievement

    ERIC Educational Resources Information Center

    Jackson, Barbara Talbert

    2008-01-01

    The No Child Left Behind legislation has brought greater attention to the academic performance of American youth. Its emphasis on student achievement requires a closer analysis of assessment data by school districts. To address the findings, educators must seek strategies to remedy failing results. In a mid-Atlantic district of the Unites States,…

  13. Leadership Issues: Raising Achievement.

    ERIC Educational Resources Information Center

    Horsfall, Chris, Ed.

    This document contains five papers examining the meaning and operation of leadership as a variable affecting student achievement in further education colleges in the United Kingdom. "Introduction" (Chris Horsfall) discusses school effectiveness studies' findings regarding the relationship between leadership and effective schools, distinguishes…

  14. Achievements or Disasters?

    ERIC Educational Resources Information Center

    Goodwin, MacArthur

    2000-01-01

    Focuses on policy issues that have affected arts education in the twentieth century, such as: interest in discipline-based arts education, influence of national arts associations, and national standards and coordinated assessment. States that whether the policy decisions are viewed as achievements or disasters are for future determination. (CMK)

  15. Achieving True Consensus.

    ERIC Educational Resources Information Center

    Napier, Rod; Sanaghan, Patrick

    2002-01-01

    Uses the example of Vermont's Middlebury College to explore the challenges and possibilities of achieving consensus about institutional change. Discusses why, unlike in this example, consensus usually fails, and presents four demands of an effective consensus process. Includes a list of "test" questions on successful collaboration. (EV)

  16. School Students' Science Achievement

    ERIC Educational Resources Information Center

    Shymansky, James; Wang, Tzu-Ling; Annetta, Leonard; Everett, Susan; Yore, Larry D.

    2013-01-01

    This paper is a report of the impact of an externally funded, multiyear systemic reform project on students' science achievement on a modified version of the Third International Mathematics and Science Study (TIMSS) test in 33 small, rural school districts in two Midwest states. The systemic reform effort utilized a cascading leadership strategy…

  17. Essays on Educational Achievement

    ERIC Educational Resources Information Center

    Ampaabeng, Samuel Kofi

    2013-01-01

    This dissertation examines the determinants of student outcomes--achievement, attainment, occupational choices and earnings--in three different contexts. The first two chapters focus on Ghana while the final chapter focuses on the US state of Massachusetts. In the first chapter, I exploit the incidence of famine and malnutrition that resulted to…

  18. Assessing Handwriting Achievement.

    ERIC Educational Resources Information Center

    Ediger, Marlow

    Teachers in the school setting need to emphasize quality handwriting across the curriculum. Quality handwriting means that the written content is easy to read in either manuscript or cursive form. Handwriting achievement can be assessed, but not compared to the precision of assessing basic addition, subtraction, multiplication, and division facts.…

  19. Intelligence and Educational Achievement

    ERIC Educational Resources Information Center

    Deary, Ian J.; Strand, Steve; Smith, Pauline; Fernandes, Cres

    2007-01-01

    This 5-year prospective longitudinal study of 70,000+ English children examined the association between psychometric intelligence at age 11 years and educational achievement in national examinations in 25 academic subjects at age 16. The correlation between a latent intelligence trait (Spearman's "g"from CAT2E) and a latent trait of educational…

  20. Explorations in achievement motivation

    NASA Technical Reports Server (NTRS)

    Helmreich, Robert L.

    1982-01-01

    Recent research on the nature of achievement motivation is reviewed. A three-factor model of intrinsic motives is presented and related to various criteria of performance, job satisfaction and leisure activities. The relationships between intrinsic and extrinsic motives are discussed. Needed areas for future research are described.