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Sample records for induce mixed hematopoietic

  1. ES-cell derived hematopoietic cells induce transplantation tolerance.

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    Sabrina Bonde

    Full Text Available BACKGROUND: Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs. Up till now, however, it has been difficult to generate stable hematopoietic cells from ES cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, we derived CD45(+ HPCs from HOXB4-transduced ES cells and showed that they poorly express MHC antigens. This property allowed their long-term engraftment in sublethally irradiated recipients across MHC barriers without the need for immunosuppressive agents. Although donor cells declined in peripheral blood over 2 months, low level chimerism was maintained in the bone marrow of these mice over 100 days. More importantly, chimeric animals were protected from rejection of donor-type cardiac allografts. CONCLUSIONS: Our data show, for the first time, the efficacy of ES-derived CD45(+ HPCs to engraft in allogenic recipients without the use of immunosuppressive agents, there by protecting cardiac allografts from rejection.

  2. Ionizing radiation induces apoptosis in hematopoietic stem and progenitor cells

    International Nuclear Information System (INIS)

    Meng, A.; Zhou, D.; Geiger, H.; Zant, G.V.

    2003-01-01

    The aims of this study was to determine if ionizing radiation (IR) induces apoptosis in hematopoietic stem (HSC) and progenitor cells. Lin-cells were isolated from mouse bone marrow (BM) and pretreated with vehicle or 100 μM z-VAD 1 h prior to exposure to 4 Gy IR. The apoptotic and/or necrotic responses of these cells to IR were analyzed by measuring the annexin V and/or 7-AAD staining in HSC and progenitor populations using flow cytometry, and hematopoietic function of these cells was determined by CAFC assay. Exposure of Lin-cells to IR selectively decreased the numbers of HSC and progenitors in association with an increase in apoptosis in a time-dependent manner. Pretreatment of Lin- cells with z-VAD significantly inhibited IR-induced apoptosis and the decrease in the numbers of HSC and progenitors. However, IR alone or in combination with z-VAD did not lead to a significant increase in necrotic cell death in either HSC or progenitors. In addition, pretreatment of BM cells with z-VAD significantly attenuated IR-induced reduction in the frequencies of day-7, -28 and -35 CAFC. Exposure of HSC and progenitors to IR induces apoptosis. The induction of HSC and progenitor apoptosis contributes to IR-induced suppression of their hematopoietic function

  3. In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism.

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    Shih, Yu-Ru; Kang, Heemin; Rao, Vikram; Chiu, Yu-Jui; Kwon, Seong Keun; Varghese, Shyni

    2017-05-23

    Synthetic biomimetic matrices with osteoconductivity and osteoinductivity have been developed to regenerate bone tissues. However, whether such systems harbor donor marrow in vivo and support mixed chimerism remains unknown. We devised a strategy to engineer bone tissues with a functional bone marrow (BM) compartment in vivo by using a synthetic biomaterial with spatially differing cues. Specifically, we have developed a synthetic matrix recapitulating the dual-compartment structures by modular assembly of mineralized and nonmineralized macroporous structures. Our results show that these matrices incorporated with BM cells or BM flush transplanted into recipient mice matured into functional bone displaying the cardinal features of both skeletal and hematopoietic compartments similar to native bone tissue. The hematopoietic function of bone tissues was demonstrated by its support for a higher percentage of mixed chimerism compared with i.v. injection and donor hematopoietic cell mobilization in the circulation of nonirradiated recipients. Furthermore, hematopoietic cells sorted from the engineered bone tissues reconstituted the hematopoietic system when transplanted into lethally irradiated secondary recipients. Such engineered bone tissues could potentially be used as ectopic BM surrogates for treatment of nonmalignant BM diseases and as a tool to study hematopoiesis, donor-host cell dynamics, tumor tropism, and hematopoietic cell transplantation.

  4. Mitigation of radiation induced hematopoietic injury via regulation of Nrf-2 and increasing hematopoietic stem cells

    International Nuclear Information System (INIS)

    Patwardhan, R.S.; Sharma, Deepak; Checker, Rahul; Santosh Kumar, S.

    2014-01-01

    Therapeutic doses of ionizing radiation (IR) that can be delivered to tumors are restricted due to radiation induced damage to surrounding normal tissues thereby limiting the effectiveness of radiotherapy. Strategies to develop agents that selectively protect normal cells yielded limited success in the past. There is pressing need to develop safe, syndrome specific and effective radiation countermeasures to prevent or mitigate the harmful consequences of radiation exposure. Survival of bone marrow stem cells (HSCs) play a key role in protecting against IR induced hematopoietic injury. Many studies have shown manipulation of HSC frequency and/or survival as principal mechanism of radioprotection. It is known that, Nrf-2 plays crucial role in HSC survival and maintenance under oxidative stress conditions. In the present study, we have investigated the radioprotective ability of a flavonoid baicalein (5,6,7-trihydroxyflavone), extracted from the root of Scutellaria baicalensis Georgi, a medicinal plant traditionally used in Oriental medicine. There are numerous reports showing anti-inflammatory, anti-apoptotic, anti-oxidant, anti-cancer, anti-microbial, anti-mutagenic and neuroprotective properties of baicalein. Based on these reports, we have investigated the ability of baicalein to protect against radiation induced hematopoietic injury. Baicalein administration to mice protected against WBI induced mortality. Interestingly, the stem cell frequency increased in bone marrow cells obtained from baicalein administered mice as compared to vehicle treated mice. Baicalein treatment led to increased phospho-Nrf-2 levels in lineage negative BM-MNC. Administration of mice with Nrf-2 inhibitor prior to baicalein treatment led to significant abrogation of radioprotective ability of baicalein. This result suggests that, Nrf-2 may be playing a key role in baicalein mediated radioprotection. Here, we have shown that baicalein administration augments stem cell frequency, induces

  5. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

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    van Pel, M; van Os, R; Velders, GA; Hagoort, H; Heegaard, PMH; Lindley, IJD; Willemze, R; Fibbe, WE

    2006-01-01

    Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory

  6. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

    DEFF Research Database (Denmark)

    van Pel, M.; van Os, R.; Velders, G.A.

    2006-01-01

    Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulat...

  7. Low-dose radiation (LDR) induces hematopoietic hormesis: LDR-induced mobilization of hematopoietic progenitor cells into peripheral blood circulation.

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    Li, Wei; Wang, Guanjun; Cui, Jiuwei; Xue, Lu; Cai, Lu

    2004-11-01

    The aim of this study was to investigate the stimulating effect of low-dose radiation (LDR) on bone marrow hematopoietic progenitor cell (HPC) proliferation and peripheral blood mobilization. Mice were exposed to 25- to 100-mGy x-rays. Bone marrow and peripheral blood HPCs (BFU-E, CFU-GM, and c-kit+ cells) were measured, and GM-CSF, G-CSF, and IL-3 protein and mRNA expression were detected using ELISA, slot blot hybridization, and Northern blot methods. To functionally evaluate LDR-stimulated and -mobilized HPCs, repopulation of peripheral blood cells in lethally irradiated recipients after transplantation of LDR-treated donor HPCs was examined by WBC counts, animal survival, and colony-forming units in the recipient spleens (CFUs-S). 75-mGy x-rays induced a maximal stimulation for bone marrow HPC proliferation (CFU-GM and BFU-E formation) 48 hours postirradiation, along with a significant increase in HPC mobilization into peripheral blood 48 to 72 hours postradiation, as shown by increases in CFU-GM formation and proportion of c-kit+ cells in the peripheral mononuclear cells. 75-mGy x-rays also maximally induced increases in G-CSF and GM-CSF mRNA expression in splenocytes and levels of serum GM-CSF. To define the critical role of these hematopoietic-stimulating factors in HPC peripheral mobilization, direct administration of G-CSF at a dose of 300 microg/kg/day or 150 microg/kg/day was applied and found to significantly stimulate GM-CFU formation and increase c-kit+ cells in the peripheral mononuclear cells. More importantly, 75-mGy x-rays plus 150 microg/kg/day G-CSF (LDR/150-G-CSF) produced a similar effect to that of 300 microg/kg/day G-CSF alone. Furthermore, the capability of LDR-mobilized donor HPCs to repopulate blood cells was confirmed in lethally irradiated recipient mice by counting peripheral WBC and CFUs-S. These results suggest that LDR induces hematopoietic hormesis, as demonstrated by HPC proliferation and peripheral mobilization, providing a

  8. Angelica Sinensis Polysaccharide Prevents Hematopoietic Stem Cells Senescence in D-Galactose-Induced Aging Mouse Model

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    Xinyi Mu

    2017-01-01

    Full Text Available Age-related regression in hematopoietic stem/progenitor cells (HSC/HPCs limits replenishment of the blood and immune system and hence contributes to hematopoietic diseases and declined immunity. In this study, we employed D-gal-induced aging mouse model and observed the antiaging effects of Angelica Sinensis Polysaccharide (ASP, a major active ingredient in dong quai (Chinese Angelica Sinensis, on the Sca-1+ HSC/HPCs in vivo. ASP treatment prevents HSC/HPCs senescence with decreased AGEs levels in the serum, reduced SA-β-Gal positive cells, and promoted CFU-Mix formation in the D-gal administrated mouse. We further found that multiple mechanisms were involved: (1 ASP treatment prevented oxidative damage as total antioxidant capacity was increased and levels of reactive oxygen species (ROS, 8-OHdG, and 4-HNE were declined, (2 ASP reduced the expression of γ-H2A.X which is a DNA double strand breaks (DSBs marker and decreased the subsequent ectopic expressions of effectors in p16Ink4a-RB and p19Arf-p21Cip1/Waf senescent pathways, and (3 ASP inhibited the excessive activation of Wnt/β-catenin signaling in aged HSC/HPCs, as the expressions of β-catenin, phospho-GSK-3β, and TCF-4 were decreased, and the cyto-nuclear translocation of β-catenin was inhibited. Moreover, compared with the positive control of Vitamin E, ASP exhibited a better antiaging effect and a weaker antioxidation ability, suggesting a novel protective role of ASP in the hematopoietic system.

  9. Protracted radiation-induced alterations in hematopoietic repair and recovery

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    Seed, T.M.; Fritz, T.E.

    1997-01-01

    Pathologic predisposition of beagle dogs under chronic, low daily dose (7.5 cGy day -1 ) whole-body gamma irradiation has been studied relative to molecular repair and hematopoietic competency. Molecular repair, assessed by a microscopy-based unscheduled DNA synthesis (UDS) response, was measured within proliferative and nonproliferative marrow myeloid elements of dogs with markedly different hematopoietic capacities (low capacity, aplasia-prone [AA + ] versus high capacity, myeloproliferative disease-prone [MPD + ]) under protracted radiation stress. Results indicated that protracted exposure elicited a net increase in UDS-repair capacity that was largely independent of exposure duration. This enhanced capacity resulted from the increased strength of the UDS signal together with an expanded number of positively responding cells. The combined response was strong in primitive blasts and weak in more differentiated myelocytic cells. The UDS repair response of the MPD + dogs was significantly greater than that of the AA + animals and was clearly modified relative to the controls. These results suggest that both resiliency and pathologic potential of the hematopoietic system under protracted radiation stress is, in part, associated with an augmentable DNA repair within the more primitive myeloid marrow elements. (author)

  10. Mixed chimerism following hematopoietic stem cell transplantation in pediatric thalassemia major patients: a single center experience

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    Elif Ünal İnce

    2010-03-01

    Full Text Available Objective: Stable mixed chimerism (MC may result in cure for thalassemia major patients following hematopoietic stem cell transplantation (HSCT, but rejection can occur. Twenty-eight HSCTs for thalassemia major were reviewed retrospectively to evaluate the clinical course of MC with possible risk factors and predictors of outcome, with a median follow-up of 1669 days (811-3576 days. Materials and Methods: Chimerism was detected by fluorescence in situ hybridization (FISH or multiplex polymerase chain reaction depending on the sex match between the donor and the recipient. Results: Primary rejection, stable MC and full donor chimerism was detected in 3.6%, 17.8% and 78.6% of patients, respectively. Clinically, 4/5 patients with stable MC had thalassemia trait with donor chimerism as low as 14%. One patient was started on pRBC transfusions at 2.5 years postHSCT. Conclusion: Stable MC can result in cure for thalassemia major patients. The clinical picture remains as the best guide for intervention until a more reliable predictor is available.

  11. 27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy.

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    Oguro, Hideyuki; McDonald, Jeffrey G; Zhao, Zhiyu; Umetani, Michihisa; Shaul, Philip W; Morrison, Sean J

    2017-09-01

    Extramedullary hematopoiesis (EMH) is induced during pregnancy to support rapid expansion of maternal blood volume. EMH activation requires hematopoietic stem cell (HSC) proliferation and mobilization, processes that depend upon estrogen receptor α (ERα) in HSCs. Here we show that treating mice with estradiol to model estradiol increases during pregnancy induced HSC proliferation in the bone marrow but not HSC mobilization. Treatment with the alternative ERα ligand 27-hydroxycholesterol (27HC) induced ERα-dependent HSC mobilization and EMH but not HSC division in the bone marrow. During pregnancy, 27HC levels increased in hematopoietic stem/progenitor cells as a result of CYP27A1, a cholesterol hydroxylase. Cyp27a1-deficient mice had significantly reduced 27HC levels, HSC mobilization, and EMH during pregnancy but normal bone marrow hematopoiesis and EMH in response to bleeding or G-CSF treatment. Distinct hematopoietic stresses thus induce EMH through different mechanisms. Two different ERα ligands, estradiol and 27HC, work together to promote EMH during pregnancy, revealing a collaboration of hormonal and metabolic mechanisms as well as a physiological function for 27HC in normal mice.

  12. Nicaraven attenuates radiation-induced injury in hematopoietic stem/progenitor cells in mice.

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    Miho Kawakatsu

    Full Text Available Nicaraven, a chemically synthesized hydroxyl radical-specific scavenger, has been demonstrated to protect against ischemia-reperfusion injury in various organs. We investigated whether nicaraven can attenuate radiation-induced injury in hematopoietic stem/progenitor cells, which is the conmen complication of radiotherapy and one of the major causes of death in sub-acute phase after accidental exposure to high dose radiation. C57BL/6 mice were exposed to 1 Gy γ-ray radiation daily for 5 days in succession (a total of 5 Gy, and given nicaraven or a placebo after each exposure. The mice were sacrificed 2 days after the last radiation treatment, and the protective effects and relevant mechanisms of nicaraven in hematopoietic stem/progenitor cells with radiation-induced damage were investigated by ex vivo examination. We found that post-radiation administration of nicaraven significantly increased the number, improved the colony-forming capacity, and decreased the DNA damage of hematopoietic stem/progenitor cells. The urinary levels of 8-oxo-2'-deoxyguanosine, a marker of DNA oxidation, were significantly lower in mice that were given nicaraven compared with those that received a placebo treatment, although the levels of intracellular and mitochondrial reactive oxygen species in the bone marrow cells did not differ significantly between the two groups. Interestingly, compared with the placebo treatment, the administration of nicaraven significantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α in the plasma of mice. Our data suggest that nicaraven effectively diminished the effects of radiation-induced injury in hematopoietic stem/progenitor cells, which is likely associated with the anti-oxidative and anti-inflammatory properties of this compound.

  13. Catalase inhibits ionizing radiation-induced apoptosis in hematopoietic stem and progenitor cells.

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    Xiao, Xia; Luo, Hongmei; Vanek, Kenneth N; LaRue, Amanda C; Schulte, Bradley A; Wang, Gavin Y

    2015-06-01

    Hematologic toxicity is a major cause of mortality in radiation emergency scenarios and a primary side effect concern in patients undergoing chemo-radiotherapy. Therefore, there is a critical need for the development of novel and more effective approaches to manage this side effect. Catalase is a potent antioxidant enzyme that coverts hydrogen peroxide into hydrogen and water. In this study, we evaluated the efficacy of catalase as a protectant against ionizing radiation (IR)-induced toxicity in hematopoietic stem and progenitor cells (HSPCs). The results revealed that catalase treatment markedly inhibits IR-induced apoptosis in murine hematopoietic stem cells and hematopoietic progenitor cells. Subsequent colony-forming cell and cobble-stone area-forming cell assays showed that catalase-treated HSPCs can not only survive irradiation-induced apoptosis but also have higher clonogenic capacity, compared with vehicle-treated cells. Moreover, transplantation of catalase-treated irradiated HSPCs results in high levels of multi-lineage and long-term engraftments, whereas vehicle-treated irradiated HSPCs exhibit very limited hematopoiesis reconstituting capacity. Mechanistically, catalase treatment attenuates IR-induced DNA double-strand breaks and inhibits reactive oxygen species. Unexpectedly, we found that the radioprotective effect of catalase is associated with activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway and pharmacological inhibition of STAT3 abolishes the protective activity of catalase, suggesting that catalase may protect HSPCs against IR-induced toxicity via promoting STAT3 activation. Collectively, these results demonstrate a previously unrecognized mechanism by which catalase inhibits IR-induced DNA damage and apoptosis in HSPCs.

  14. Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice

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    Pasupathi Sundaramoorthy

    2017-11-01

    Full Text Available Abstract Background Radiation exposure poses a significant threat to public health. Hematopoietic injury is one of the major manifestations of acute radiation sickness. Protection and/or mitigation of hematopoietic stem cells (HSCs from radiation injury is an important goal in the development of medical countermeasure agents (MCM. We recently identified thioredoxin (TXN as a novel molecule that has marked protective and proliferative effects on HSCs. In the current study, we investigated the effectiveness of TXN in rescuing mice from a lethal dose of total body radiation (TBI and in enhancing hematopoietic reconstitution following a lethal dose of irradiation. Methods We used in-vivo and in-vitro methods to understand the biological and molecular mechanisms of TXN on radiation mitigation. BABL/c mice were used for the survival study and a flow cytometer was used to quantify the HSC population and cell senescence. A hematology analyzer was used for the peripheral blood cell count, including white blood cells (WBCs, red blood cells (RBCs, hemoglobin, and platelets. Colony forming unit (CFU assay was used to study the colongenic function of HSCs. Hematoxylin and eosin staining was used to determine the bone marrow cellularity. Senescence-associated β-galactosidase assay was used for cell senescence. Western blot analysis was used to evaluate the DNA damage and senescence protein expression. Immunofluorescence staining was used to measure the expression of γ-H2AX foci for DNA damage. Results We found that administration of TXN 24 h following irradiation significantly mitigates BALB/c mice from TBI-induced death: 70% of TXN-treated mice survived, whereas only 25% of saline-treated mice survived. TXN administration led to enhanced recovery of peripheral blood cell counts, bone marrow cellularity, and HSC population as measured by c-Kit+Sca-1+Lin– (KSL cells, SLAM + KSL cells and CFUs. TXN treatment reduced cell senescence and radiation-induced

  15. Sodium Caseinate (CasNa) Induces Mobilization of Hematopoietic Stem Cells in a BALB/c Mouse Model.

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    Santiago-Osorio, Edelmiro; Ledesma-Martínez, Edgar; Aguiñiga-Sánchez, Itzen; Poblano-Pérez, Ignacio; Weiss-Steider, Benny; Montesinos-Montesinos, Juan José; Mora-García, María de Lourdes

    2015-09-25

    BACKGROUND Hematopoietic stem cells transplantation has high clinical potential against a wide variety of hematologic, metabolic, and autoimmune diseases and solid tumors. Clinically, hematopoietic stem cells derived from peripheral blood are currently used more than those obtained from sources such as bone marrow. However, mobilizing agents used in the clinic tend to fail in high rates, making the number of mobilized cells insufficient for transplantation. We investigated whether sodium caseinate induces functional mobilization of hematopoietic stem cells into peripheral blood of Balb/c mice. MATERIAL AND METHODS Using a mouse model, we administrated sodium caseinate or Plerixafor, a commercial mobilizing agent, and analyzed counts of hematopoietic stem cells in peripheral blood, and then cells were transplanted into lethally irradiated mice to restore hematopoiesis. All assays were performed at least twice. RESULTS We found that sodium caseinate increases the number of mononuclear cells in peripheral blood with the immunophenotype of hematopoietic stem cells (0.2 to 0.5% LSK cells), allowing them to form colonies of various cell lineages in semisolid medium (psodium caseinate as a mobilizer of hematopoietic stem cells and its potential clinical application in transplantation settings.

  16. Cytokine-Regulated GADD45G Induces Differentiation and Lineage Selection in Hematopoietic Stem Cells

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    Frederic B. Thalheimer

    2014-07-01

    Full Text Available The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.

  17. Chronic restraint-induced stress has little modifying effect on radiation hematopoietic toxicity in mice

    International Nuclear Information System (INIS)

    Wang, Bing; Tanaka, Kaoru; Katsube, Takanori; Ninomiya, Yasuharu; Vares, Guillaume; Nakajima, Tetsuo; Nenoi, Mitsuru; Liu Qiang; Morita, Akinori

    2015-01-01

    Both radiation and stresses cause detrimental effects on humans. Besides possible health effects resulting directly from radiation exposure, the nuclear plant accident is a cause of social psychological stresses. A recent study showed that chronic restraint-induced stresses (CRIS) attenuated Trp53 functions and increased carcinogenesis susceptibility of Trp53-heterozygous mice to total-body X-irradiation (TBXI), having a big impact on the academic world and a sensational effect on the public, especially the residents living in radioactively contaminated areas. It is important to investigate the possible modification effects from CRIS on radiation-induced health consequences in Trp53 wild-type (Trp53wt) animals. Prior to a carcinogenesis study, effects of TBXI on the hematopoietic system under CRIS were investigated in terms of hematological abnormality in the peripheral blood and residual damage in the bone marrow erythrocytes using a mouse restraint model. Five-week-old male Trp53wt C57BL/6J mice were restrained 6 h per day for 28 consecutive days, and TBXI (4 Gy) was given on the 8th day. Results showed that CRIS alone induced a marked decrease in the red blood cell (RBC) and the white blood cell (WBC) count, while TBXI caused significantly lower counts of RBCs, WBCs and blood platelets, and a lower concentration of hemoglobin regardless of CRIS. CRIS alone did not show any significant effect on erythrocyte proliferation and on induction of micronucleated erythrocytes, whereas TBXI markedly inhibited erythrocyte proliferation and induced a significant increase in the incidences of micronucleated erythrocytes, regardless of CRIS. These findings suggest that CRIS does not have a significant impact on radiation-induced detrimental effects on the hematopoietic system in Trp53wt mice. (author)

  18. Protein malnutrition induces bone marrow mesenchymal stem cells commitment to adipogenic differentiation leading to hematopoietic failure.

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    Cunha, Mayara Caldas Ramos; Lima, Fabiana da Silva; Vinolo, Marco Aurélio Ramirez; Hastreiter, Araceli; Curi, Rui; Borelli, Primavera; Fock, Ricardo Ambrósio

    2013-01-01

    Protein malnutrition (PM) results in pathological changes that are associated with peripheral leukopenia, bone marrow (BM) hypoplasia and alterations in the BM microenvironment leading to hematopoietic failure; however, the mechanisms involved are poorly understood. In this context, the BM mesenchymal stem cells (MSCs) are cells intimately related to the formation of the BM microenvironment, and their differentiation into adipocytes is important because adipocytes are cells that have the capability to negatively modulate hematopoiesis. Two-month-old male Balb/c mice were subjected to protein-energy malnutrition with a low-protein diet containing 2% protein, whereas control animals were fed a diet containing 12% protein. The hematopoietic parameters and the expression of CD45 and CD117 positive cells in the BM were evaluated. MSCs were isolated from BM, and their capability to produce SCF, IL-3, G-CSF and GM-CSF were analyzed. The expression of PPAR-γ and C/EBP-α as well as the expression of PPAR-γ and SREBP mRNAs were evaluated in MSCs together with their capability to differentiate into adipocytes in vitro. The malnourished animals had anemia and leukopenia as well as spleen and bone marrow hypoplasia and a reduction in the expression of CD45 and CD117 positive cells from BM. The MSCs of the malnourished mice presented an increased capability to produce SCF and reduced production of G-CSF and GM-CSF. The MSCs from the malnourished animals showed increased expression of PPAR-γ protein and PPAR-γ mRNA associated with an increased capability to differentiate into adipocytes. The alterations found in the malnourished animals allowed us to conclude that malnutrition committed MSC differentiation leading to adipocyte decision and compromised their capacity for cytokine production, contributing to an impaired hematopoietic microenvironment and inducing the bone marrow failure commonly observed in protein malnutrition states.

  19. Protein Malnutrition Induces Bone Marrow Mesenchymal Stem Cells Commitment to Adipogenic Differentiation Leading to Hematopoietic Failure

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    Cunha, Mayara Caldas Ramos; Lima, Fabiana da Silva; Vinolo, Marco Aurélio Ramirez; Hastreiter, Araceli; Curi, Rui; Borelli, Primavera; Fock, Ricardo Ambrósio

    2013-01-01

    Protein malnutrition (PM) results in pathological changes that are associated with peripheral leukopenia, bone marrow (BM) hypoplasia and alterations in the BM microenvironment leading to hematopoietic failure; however, the mechanisms involved are poorly understood. In this context, the BM mesenchymal stem cells (MSCs) are cells intimately related to the formation of the BM microenvironment, and their differentiation into adipocytes is important because adipocytes are cells that have the capability to negatively modulate hematopoiesis. Two-month-old male Balb/c mice were subjected to protein-energy malnutrition with a low-protein diet containing 2% protein, whereas control animals were fed a diet containing 12% protein. The hematopoietic parameters and the expression of CD45 and CD117 positive cells in the BM were evaluated. MSCs were isolated from BM, and their capability to produce SCF, IL-3, G-CSF and GM-CSF were analyzed. The expression of PPAR-γ and C/EBP-α as well as the expression of PPAR-γ and SREBP mRNAs were evaluated in MSCs together with their capability to differentiate into adipocytes in vitro. The malnourished animals had anemia and leukopenia as well as spleen and bone marrow hypoplasia and a reduction in the expression of CD45 and CD117 positive cells from BM. The MSCs of the malnourished mice presented an increased capability to produce SCF and reduced production of G-CSF and GM-CSF. The MSCs from the malnourished animals showed increased expression of PPAR-γ protein and PPAR-γ mRNA associated with an increased capability to differentiate into adipocytes. The alterations found in the malnourished animals allowed us to conclude that malnutrition committed MSC differentiation leading to adipocyte decision and compromised their capacity for cytokine production, contributing to an impaired hematopoietic microenvironment and inducing the bone marrow failure commonly observed in protein malnutrition states. PMID:23516566

  20. Radiation responses of hematopoietic-cells and inducing acute myeloid leukemia

    International Nuclear Information System (INIS)

    Ojima, Mitsuaki; Hirouchi, Tokuhisa

    2016-01-01

    Leukemia has consistently held the interest of researchers from the beginning of radiation carcinogenesis. One of the major reasons for this interest is the availability of several strains of mice that develop leukemia following radiation exposure after a short latency period that resemble those found in A-Bomb survivors. Previous studies have shown that rAML (Radiation-induced Acute Myeloid Leukemia) in mice show inactivation of Sfpi1 gene and a hemizygous deletion in chromosome 2. Leukemic stem cells in murine rAML have been reported to share some characteristics with common myeloid progenitor cells. In this review, we will discuss the possible mechanisms in the development of rAML stem cells, focusing on the alterations found in the leukemic stem cells and as well as the environment in which these leukemic stem cells are developed, such cytokine expression, as Well as alterations that may be found in other cells residing in the bone marrow. Hematopoietic stem cells respond to radiation exposure both as a single cell and as a part of the differentiating hematopoietic tissue for several months prior to its transformation to a rAML stem cell. It is however unclear how these 2 responses contribute to the development of the rAML stem cell. This review covers previous reports and examines the development of the rAML stem cell in detail. (author)

  1. Generating autologous hematopoietic cells from human-induced pluripotent stem cells through ectopic expression of transcription factors.

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    Hwang, Yongsung; Broxmeyer, Hal E; Lee, Man Ryul

    2017-07-01

    Hematopoietic cell transplantation (HCT) is a successful treatment modality for patients with malignant and nonmalignant disorders, usually when no other treatment option is available. The cells supporting long-term reconstitution after HCT are the hematopoietic stem cells (HSCs), which can be limited in numbers. Moreover, finding an appropriate human leukocyte antigen-matched donor can be problematic. If HSCs can be stably produced in large numbers from autologous or allogeneic cell sources, it would benefit HCT. Induced pluripotent stem cells (iPSCs) established from patients' own somatic cells can be differentiated into hematopoietic cells in vitro. This review will highlight recent methods for regulating human (h) iPSC production of HSCs and more mature blood cells. Advancements in transcription factor-mediated regulation of the developmental stages of in-vivo hematopoietic lineage commitment have begun to provide an understanding of the molecular mechanism of hematopoiesis. Such studies involve not only directed differentiation in which transcription factors, specifically expressed in hematopoietic lineage-specific cells, are overexpressed in iPSCs, but also direct conversion in which transcription factors are introduced into patient-derived somatic cells which are dedifferentiated to hematopoietic cells. As iPSCs derived from patients suffering from genetically mutated diseases would express the same mutated genetic information, CRISPR-Cas9 gene editing has been utilized to differentiate genetically corrected iPSCs into normal hematopoietic cells. IPSCs provide a model for molecular understanding of disease, and also may function as a cell population for therapy. Efficient differentiation of patient-specific iPSCs into HSCs and progenitor cells is a potential means to overcome limitations of such cells for HCT, as well as for providing in-vitro drug screening templates as tissue-on-a-chip models.

  2. Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients.

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    Phondeechareon, Tanapol; Wattanapanitch, Methichit; U-Pratya, Yaowalak; Damkham, Chanapa; Klincumhom, Nuttha; Lorthongpanich, Chanchao; Kheolamai, Pakpoom; Laowtammathron, Chuti; Issaragrisil, Surapol

    2016-10-01

    Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients.

  3. Protective effects of E838 on hematopoietic damage induced by radiaton

    International Nuclear Information System (INIS)

    Wang, Yueying; Liu, Qiang; Li, Deguan; Meng, Aimin; Wu, Hongying; Lu, Lu; Wang, Yong; Wang, Ruqin; Zhang, Liangan

    2008-01-01

    Full text: Purpose E838 was a new Ethinyl estradiol derivative with radioprotective property which could significantly elevate the irradiated mice survival rate of 30d. E838 also showed prevention and therapeutical effect in the leucopenia caused by radio-chemotherapy, but exhibit little estrogenic-like effects. In this study, we examined the protective effects of E838 on DNA damage and hematopoietic injury induced by irradiation in IRM-2 mice. Methods: IRM-2 mice were randomized into six groups: control, E838 5 mg/kg, E838 7.5 mg/kg, E838 10 mg/kg, ethinyl estradiol and nilestriol. After intraperitoneal injection 3 consecutive days, mice were exposed 1 Gy whole body γ-irradiation. Then the peripheral blood lymphocyte was collected to observe DNA double-strand breaks by neutral single cell gel electrophoresis (SCGE). Comet images were analyzed by CASP software. Two indexes were choiced, i.e. amount of DNA in the comet tail (tDNA %), Olive Tail Moment (OTM ). In the another experiment, treatment regimen same to the above experiment but the mice were exposed to 7.5 Gy whole body γ-irradiation. Bone marrow nucleated cell (BMC) per femur and endogenous spleen colony (CFU-S) were determined to evaluate the hematopoietic function at 9 days after irradiation. Results: tDNA % in different dose E838 (5, 7.5, 10 mg/kg) treated mice were decreased 67.6 %, 82.7 %, 74.9 % compared to the radiation control, respectively(P<0.001). The tDNA % reduction in 7.5mg/kg group were greater than those in ethinyl' estradiol (66.7 %) and nilestriol (66.7 %) treated mice significantly(P<0.01). OTM in E838 (5, 7.5, 10 mg/kg) treated irradiated mice were decreased 88.1 %, 95.3 %, 92.5 %(P<0.01), the OTM reduction in 5, 7.5mg/kg group were greater than those in ethinyl estradiol (86.3 %) and nilestriol(87.5 %) treated irradiated mice (P<0.01). BMC and CFU-S in E838 treated irradiated mice were 40 %∼60% higher than those in irradiated control mice (P<0.05∼0.01). Conclusion: The results

  4. Novel pathways to erythropoiesis induced by dimerization of intracellular C-Mpl in human hematopoietic progenitors.

    Science.gov (United States)

    Parekh, Chintan; Sahaghian, Arineh; Kim, William; Scholes, Jessica; Ge, Shundi; Zhu, Yuhua; Asgharzadeh, Shahab; Hollis, Roger; Kohn, Donald; Ji, Lingyun; Malvar, Jemily; Wang, Xiaoyan; Crooks, Gay

    2012-04-01

    The cytokine thrombopoietin (Tpo) plays a critical role in hematopoiesis by binding to the extracellular domain and inducing homodimerization of the intracellular signaling domain of its receptor, c-Mpl. Mpl homodimerization can also be accomplished by binding of a synthetic ligand to a constitutively expressed fusion protein F36VMpl consisting of a ligand binding domain (F36V) and the intracellular signaling domain of Mpl. Unexpectedly, in contrast to Tpo stimulation, robust erythropoiesis is induced after dimerization of F36VMpl in human CD34+ progenitor cells. The goal of this study was to define the hematopoietic progenitor stages at which dimerization of intracellular Mpl induces erythropoiesis and the downstream molecular events that mediate this unanticipated effect. Dimerization (in the absence of erythropoietin and other cytokines) in human common myeloid progenitors and megakaryocytic erythroid progenitors caused a significant increase in CD34+ cells (p Mpl in human myeloerythroid progenitors induces progenitor expansion and erythropoiesis through molecular mechanisms that are not shared by Tpo stimulation of endogenous Mpl. Copyright © 2012 AlphaMed Press.

  5. Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells.

    Directory of Open Access Journals (Sweden)

    Tuoen Liu

    Full Text Available Myelodysplastic syndromes (MDS are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q compared to non-del(5q MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q-associated MDS.

  6. Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88

    Directory of Open Access Journals (Sweden)

    Huajia Zhang

    2016-06-01

    Full Text Available Toll-like receptor 4 (TLR4 plays a central role in host responses to bacterial infection, but the precise mechanism(s by which its downstream signaling components coordinate the bone marrow response to sepsis is poorly understood. Using mice deficient in TLR4 downstream adapters MYD88 or TRIF, we demonstrate that both cell-autonomous and non-cell-autonomous MYD88 activation are major causes of myelosuppression during sepsis, while having a modest impact on hematopoietic stem cell (HSC functions. In contrast, cell-intrinsic TRIF activation severely compromises HSC self-renewal without directly affecting myeloid cells. Lipopolysaccharide-induced activation of MYD88 or TRIF contributes to cell-cycle activation of HSC and induces rapid and permanent changes in transcriptional programs, as indicated by persistent downregulation of Spi1 and CebpA expression after transplantation. Thus, distinct mechanisms downstream of TLR4 signaling mediate myelosuppression and HSC exhaustion during sepsis through unique effects of MyD88 and TRIF.

  7. The study on the preparation of rhIL-6 and its effects on recovery of mice from radiation-induced hematopoietic aplasia

    International Nuclear Information System (INIS)

    Yang Jicheng; Zhang Yun; Sheng Weihua

    1997-08-01

    The E coil highly expressing rhIL-6 constructed by our department was fermented and rhIL-6 products were extracted and purified. The specific activity of the purified rhIL-6 products reached 4.83 x 10 8 IU/mg. The rhIL-6 products were used to treat BALB/c mice injured by 60 Co irradiation for six days (2 μg/big/each). The results showed that the bleeding time, coagulation time and prothrombin time of the rhIL-6 treatment group were significantly shorter than those of the control group (P<0.01), the platelet count and WBC increased by 130% and 165% in the treatment group as compared with the control, the numbers of CFU-Mix cultured in vitro and CFU-s in spleen were significantly higher than those in the control group (P<0.01). These results suggest that rhIL-6 exerts beneficial effects on the recovery of mice from radiation-induced injuries of hematopoietic stem/progenitor cells, and thus helps recovery from radiation injury of bone marrow and hematopoietic function. (17 refs., 4 figs., 5 tabs.)

  8. Patient housing barriers to hematopoietic cell transplantation: results from a mixed-methods study of transplant center social workers.

    Science.gov (United States)

    Preussler, Jaime M; Mau, Lih-Wen; Majhail, Navneet S; Bevans, Margaret; Clancy, Emilie; Messner, Carolyn; Parran, Leslie; Pederson, Kate A; Ferguson, Stacy Stickney; Walters, Kent; Murphy, Elizabeth A; Denzen, Ellen M

    2016-03-01

    Hematopoietic cell transplantation (HCT) is performed in select centers in the United States (U.S.), and patients are often required to temporarily relocate to receive care. The purpose of this study was to identify housing barriers impacting access to HCT and potential solutions. A mixed-methods primary study of HCT social workers was conducted to learn about patient housing challenges and solutions in place that help address those barriers. Three telephone focus groups were conducted with adult and pediatric transplant social workers (n = 15). Focus group results informed the design of a national survey. The online survey was e-mailed to a primary social worker contact at 133 adult and pediatric transplant centers in the U.S. Transplant centers were classified based on the patient population cared for by the social worker. The survey response rate was 49%. Among adult programs (n = 45), 93% of centers had patients that had to relocate closer to the transplant center to proceed with HCT. The most common type of housing option offered was discounted hotel rates. Among pediatric programs (n = 20), 90% of centers had patients that had to relocate closer to the transplant center to proceed with HCT. Ronald McDonald House was the most common option available. This study is the first to explore housing challenges faced by patients undergoing HCT in the U.S. from the perspective of social workers and to highlight solutions that centers use. Transplant centers will benefit from this knowledge by learning about options for addressing housing barriers for their patients.

  9. Immune Reconstitution Kinetics following Intentionally Induced Mixed Chimerism by Nonmyeloablative Transplantation.

    Directory of Open Access Journals (Sweden)

    Nayoun Kim

    Full Text Available Establishing mixed chimerism is a promising approach for inducing donor-specific transplant tolerance. The establishment and maintenance of mixed chimerism may enable long-term engraftment of organ transplants while minimizing the use of immunosuppressants. Several protocols for inducing mixed chimerism have been reported; however, the exact mechanism underlying the development of immune tolerance remains to be elucidated. Therefore, understanding the kinetics of engraftment during early post-transplant period may provide insight into establishing long-term mixed chimerism and permanent transplant tolerance. In this study, we intentionally induced allogeneic mixed chimerism using a nonmyeloablative regimen by host natural killer (NK cell depletion and T cell-depleted bone marrow (BM grafts in a major histocompatibility complex (MHC-mismatched murine model and analyzed the kinetics of donor (C57BL/6 and recipient (BALB/c engraftment in the weeks following transplantation. Donor BM cells were well engrafted and stabilized without graft-versus-host disease (GVHD as early as one week post-bone marrow transplantation (BMT. Donor-derived thymic T cells were reconstituted four weeks after BMT; however, the emergence of newly developed T cells was more obvious at the periphery as early as two weeks after BMT. Also, the emergence and changes in ratio of recipient- and donor-derived NKT cells and antigen presenting cells (APCs including dendritic cells (DCs and B cells were noted after BMT. Here, we report a longitudinal analysis of the development of donor- and recipient-originated hematopoietic cells in various lymphatic tissues of intentionally induced mixed chimerism mouse model during early post-transplant period. Through the understanding of immune reconstitution at early time points after nonmyeloablative BMT, we suggest guidelines on intentionally inducing durable mixed chimerism.

  10. Phenotypic and Functional Changes Induced in Hematopoietic Stem/Progenitor Cells After Gamma-Ray Radiation Exposure

    Energy Technology Data Exchange (ETDEWEB)

    Simonnet, A.J.; Nehme, J.; Leboulch, Ph.; Tronik-Le Roux, D. [Institute of Emerging Diseases and Innovative Therapies, Functional Bioengineering Laboratory, Commissariat a l' Energie Atomique (CEA), Evry (France); Simonnet, A.J.; Nehme, J.; Leboulch, Ph.; Tronik-Le Roux, D. [Institut National de la Sante et de la Recherche Medicale (INSERM) U733 (Unite Mixte de Recherche) - UMR INSERM CEA Paris XI (France); Vaigot, P. [Institute of Cellular and Molecular Radiation Biology, Department of Genetic Instability, Recombination and Repair, Commissariat a l' Energie Atomique, Fontenay-aux-Roses (France); Vaigot, P. [UMR 217, UMR-CEA-Centre National de la Recherche Scientifique (France); Barroca, V. [Laboratory of Gametogenesis, Apoptosis, Genotoxicity, Institute of Cellular and Molecular Radiation Biology, Commissariat a l' Energie Atomique, Fontenay-aux-Roses (France); Barroca, V. [Institut National de la Sante et de la Recherche Medicale U566 - UMR INSERM-CEA-PARIS VII (France); Leboulch, Ph. [Genetics Division, Brigham and Women' s Hospital and Harvard Medical School, Boston, Massachusetts (US)

    2009-07-01

    Ionizing radiation (IR) exposure causes rapid and acute bone marrow (BM) suppression that is reversible for nonlethal doses. Evidence is accumulating that IR can also provoke long-lasting residual hematopoietic injury. To better understand these effects, we analyzed phenotypic and functional changes in the stem/progenitor compartment of irradiated mice over a 10-week period. We found that hematopoietic stem cells (HSCs) identified by their repopulating ability continued to segregate within the Hoechst dye excluding 'side population (SP)' early after IR exposure. However, transient phenotypic changes were observed within this cell population: Sca-1 (S) and c-Kit (K) expression levels were increased and severely reduced, respectively, with a concurrent increase in the proportion of SPSK cells positive for established indicators of the presence of HSCs: CD150 and CD105. Ten weeks after IR exposure, expression of Sca-1 and c-Kit at the SP cell surface returned to control levels, and BM cellularity of irradiated mice was restored. However, the c-Kit{sup +}Sca-1{sup +}Lin{sup -/low} (KSL) stem/progenitor compartment displayed major phenotypic modifications, including an increase and a severe decrease in the frequencies of CD150{sup +}Flk2{sup -} and CD150{sup -}Flk2{sup +} cells, respectively. CD150{sup +} KSL cells also showed impaired reconstituting ability, an increased tendency to apoptosis, and accrued DNA damage. Finally, 15 weeks after exposure, irradiated mice, but not age matched controls, allowed engraftment and significant hematopoietic contribution from transplanted con-genic HSCs without additional host conditioning. These results provide novel insight in our understanding of immediate and delayed IR-induced hematopoietic injury and highlight similarities between HSCs of young irradiated and old mice. (authors)

  11. Phenotypic and Functional Changes Induced in Hematopoietic Stem/Progenitor Cells After Gamma-Ray Radiation Exposure

    International Nuclear Information System (INIS)

    Simonnet, A.J.; Nehme, J.; Leboulch, Ph.; Tronik-Le Roux, D.; Simonnet, A.J.; Nehme, J.; Leboulch, Ph.; Tronik-Le Roux, D.; Vaigot, P.; Vaigot, P.; Barroca, V.; Barroca, V.; Leboulch, Ph.

    2009-01-01

    Ionizing radiation (IR) exposure causes rapid and acute bone marrow (BM) suppression that is reversible for nonlethal doses. Evidence is accumulating that IR can also provoke long-lasting residual hematopoietic injury. To better understand these effects, we analyzed phenotypic and functional changes in the stem/progenitor compartment of irradiated mice over a 10-week period. We found that hematopoietic stem cells (HSCs) identified by their repopulating ability continued to segregate within the Hoechst dye excluding 'side population (SP)' early after IR exposure. However, transient phenotypic changes were observed within this cell population: Sca-1 (S) and c-Kit (K) expression levels were increased and severely reduced, respectively, with a concurrent increase in the proportion of SPSK cells positive for established indicators of the presence of HSCs: CD150 and CD105. Ten weeks after IR exposure, expression of Sca-1 and c-Kit at the SP cell surface returned to control levels, and BM cellularity of irradiated mice was restored. However, the c-Kit + Sca-1 + Lin -/low (KSL) stem/progenitor compartment displayed major phenotypic modifications, including an increase and a severe decrease in the frequencies of CD150 + Flk2 - and CD150 - Flk2 + cells, respectively. CD150 + KSL cells also showed impaired reconstituting ability, an increased tendency to apoptosis, and accrued DNA damage. Finally, 15 weeks after exposure, irradiated mice, but not age matched controls, allowed engraftment and significant hematopoietic contribution from transplanted con-genic HSCs without additional host conditioning. These results provide novel insight in our understanding of immediate and delayed IR-induced hematopoietic injury and highlight similarities between HSCs of young irradiated and old mice. (authors)

  12. Induced isospin mixing in direct nuclear reactions

    International Nuclear Information System (INIS)

    Lenske, H.

    1979-07-01

    The effect of charge-dependent interactions on nuclear reactions is investigated. First, a survey is given on the most important results concerning the charge dependence of the nucleon-nucleon interaction. The isospin symmetry and invariance principles are discussed. Violations of the isospin symmetry occuring in direct nuclear reactions are analysed using the soupled channel theory, the folding model and microscopic descriptions. Finally, induced isospin mixing in isospin-forbidden direct reactions is considered using the example of the inelastic scattering of deuterons on 12 C. (KBE)

  13. Defect-induced mix experiment for NIF

    Directory of Open Access Journals (Sweden)

    Schmitt M.J.

    2013-11-01

    Full Text Available The Defect Induced Mix Experiment (DIME-II will measure the implosion and mix characteristics of CH capsules filled with 5 atmospheres of DT by incorporating mid-Z dopant layers of Ge and Ga. This polar direct drive (PDD experiment also will demonstrate the filling of a CH capsule at target chamber center using a fill tube. Diagnostics for these experiments include areal x-ray backlighting to obtain early time images of the implosion trajectory and a multiple-monochromatic imager (MMI to collect spectrally-resolved images of the capsule dopant line emission near bangtime. The inclusion of two (or more thin dopant layers at separate depths within the capsule shell facilitates spatial correlation of mix between the layers and the hot gas core on a single shot. The dopant layers are typically 2 μm thick and contain dopant concentrations of 1.5%. Three dimensional Hydra simulations have been performed to assess the effects of PDD asymmetry on capsule performance.

  14. Assessment of benzene-induced hematotoxicity using a human-like hematopoietic lineage in NOD/Shi-scid/IL-2Rγnull mice.

    Directory of Open Access Journals (Sweden)

    Masayuki Takahashi

    Full Text Available Despite recent advancements, it is still difficult to evaluate in vivo responses to toxicants in humans. Development of a system that can mimic the in vivo responses of human cells will enable more accurate health risk assessments. A surrogate human hematopoietic lineage can be established in NOD/Shi-scid/IL-2Rγ(null (NOG mice by transplanting human hematopoietic stem/progenitor cells (Hu-NOG mice. Here, we first evaluated the toxic response of human-like hematopoietic lineage in NOG mice to a representative toxic agent, benzene. Flow cytometric analysis showed that benzene caused a significant decrease in the number of human hematopoietic stem/progenitor cells in the bone marrow and the number of human leukocytes in the peripheral blood and hematopoietic organs. Next, we established chimeric mice by transplanting C57BL/6 mouse-derived bone marrow cells into NOG mice (Mo-NOG mice. A comparison of the degree of benzene-induced hematotoxicity in donor-derived hematopoietic lineage cells within Mo-NOG mice indicated that the toxic response of Hu-NOG mice reflected interspecies differences in susceptibilities to benzene. Responses to the toxic effects of benzene were greater in lymphoid cells than in myeloid cells in Mo-NOG and Hu-NOG mice. These findings suggested that Hu-NOG mice may be a powerful in vivo tool for assessing hematotoxicity in humans, while accounting for interspecies differences.

  15. Heat transfer characteristics of induced mixed convection

    International Nuclear Information System (INIS)

    Weiss, Y.; Lahav, C.; Szanto, M.; Shai, I.

    1996-01-01

    In the present work we focus our attention on the opposed Induced Mixed Convection case, i.e. the flow field structure in a vertical cylinder, closed at its bottom, opens at the top, and being heated circumferentially. The paper reports an experimental study of this complex heat transfer process. For a better understanding of the flow field and the related heat transfer process, two different experimental systems were built. The first was a flow visualization system, with water as the working fluid, while the second system enabled quantitative measurements of the temperature field in air. All the experiments were performed in the turbulent flow regime. In order to learn about all possible flow regimes, the visualization tests were conducted in three different length-to-diameter ratios (1/d=1,5,10). Quantitative measurements of the cylindrical wall temperature, as well as the radial and axial temperature profiles in the flow field, were taken in the air system. Based on the visualization observation and the measured wall temperature profile, it was found that the OIMC can be characterized by three main regimes: a mixing regime at the top, a central turbulent core and a boundary layer type of flow adjacent to the heated wall. (authors)

  16. Nitrogen-containing bisphosphonate induces a newly discovered hematopoietic structure in the omentum of an anemic mouse model by stimulating G-CSF production.

    Science.gov (United States)

    Otsuka, Hirotada; Yagi, Hideki; Endo, Yasuo; Soeta, Satoshi; Nonaka, Naoko; Nakamura, Masanori

    2017-02-01

    We previously reported that the injection of nitrogen-containing bisphosphonate (NBP) induced the site of erythropoiesis to shift from the bone marrow (BM) to the spleen. Our previous study established a severely anemic mouse model that was treated with a combination of NBP with phenylhydrazine (PHZ), which induced newly discovered hematopoietic organs in the omentum. No reports have shown that new hematopoietic organs form under any condition. We characterized the structures and factors related to the formation of these new organs. Splenectomized mice were treated with NBP to inhibit erythropoiesis in the BM and then injected with PHZ to induce hemolytic anemia. The mice showed severe anemia and wine-colored structures appeared in the omentum. Some hematopoietic cells, including megakaryocytes, and well-developed sinuses were observed in these structures. Numerous TER119-positive erythroblasts were located with cells positive for PCNA, a cell proliferation marker. C-kit-positive cells were detected and mRNAs related to hematopoiesis were expressed in these structures. Moreover, TER119-positive erythroblasts emerged and formed clusters and hematopoiesis-related factors were detected in the omentum of mice treated with NBP and PHZ. The levels of G-CSF in the serum and hematopoietic progenitor cells (HPCs) in the peripheral blood were increased upon treatment with both NBP and PHZ. These results suggest that the induced hematopoietic structures act as the sites of erythropoiesis and that NBP-induced G-CSF production causes HPC mobilization, homing and colonization in the omentum because they constitutively express some factors, including SDF-1; thus, the newly discovered hematopoietic structure in this study might be formed.

  17. Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells

    International Nuclear Information System (INIS)

    Goto, Aya; Mouri, Akihiro; Nagai, Tomoko; Yoshimi, Akira; Ukigai, Mako; Tsubai, Tomomi; Hida, Hirotake; Ozaki, Norio; Noda, Yukihiro

    2016-01-01

    Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100 μM) and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H 4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H 4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H 4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H 4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation. - Highlights: • HL-60

  18. Involvement of the histamine H{sub 4} receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells

    Energy Technology Data Exchange (ETDEWEB)

    Goto, Aya; Mouri, Akihiro; Nagai, Tomoko; Yoshimi, Akira; Ukigai, Mako; Tsubai, Tomomi; Hida, Hirotake [Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503 (Japan); Ozaki, Norio [Department of Psychiatry, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Noda, Yukihiro, E-mail: ynoda@meijo-u.ac.jp [Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503 (Japan)

    2016-09-01

    Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100 μM) and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H{sub 4} receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H{sub 4} receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H{sub 4} receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H{sub 4} receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation

  19. Oxymetholone Therapy of Fanconi Anemia Suppresses Osteopontin Transcription and Induces Hematopoietic Stem Cell Cycling

    Directory of Open Access Journals (Sweden)

    Qing-Shuo Zhang

    2015-01-01

    Full Text Available Androgens are widely used for treating Fanconi anemia (FA and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2−/− mice were used to assess the therapeutic efficacy of oxymetholone (OXM and its mechanism of action. Eighteen-month-old Fancd2−/− mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug’s action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure.

  20. Intermittency and Topology of Shock Induced Mixing

    Science.gov (United States)

    Tellez, Jackson; Redondo, Jose M.; Ben Mahjoub, Otman; Malik, Nadeem; Vila, Teresa

    2016-04-01

    The advance of a Rayleigh-Taylor front is described in Linden & Redondo (1991),[1-3] and may be shown to follow a quadratic law in time where the width of the growing region of instability depends on the local mixing efficiency of the different density fluids that accelerate against each other g is the acceleration and A is the Atwood number defined as the diference of densities divided by their sum. This results show the independence of the large amplitude structures on the initial conditions the width of the mixing region depends also on the intermittency of the turbulence. Then dimensional analysis may also depend on the relevant reduced acceleration driven time and the molecular reactive time akin to Damkholer number and the fractal structure of the contact zone [2,4]. Detailed experiments and simulations on RT and RM shock induced fronts analized with respect to structure functions are able to determine which mechanisms are most effective in local mixing which increase the effective fractal dimension, as well as the effect of higher order geometrical parameters, such as the structure functions, in non-homogeneous fluids (Mahjoub et al 1998)[5]. The structure of a Mixing blob shows a relatively sharp head with most of the mixing taking place at the sides due to what seems to be shear instability very similar to the Kelvin-Helmholtz instabilities, but with sideways accelerations. The formation of the blobs and spikes with their secondary instabilities produces a turbulent cascade, evident just after about 1 non-dimensional time unit, from a virtual time origin that takes into account the linear growth phase, as can be seen by the growth of the fractal dimension for different volume fractions. Two-dimensional cuts of the 3D flow also show that vortex flows have closed or spiral streamlines around their core. Examples of such flows can be also seen in the laboratory, for example at the interface of atwo-layer stratified fluid in a tank in which case streamlines

  1. Therapeutic effects of combined cytokines on hematopoietic injuries induced by 4.5 Gy γ-rays irradiation in beagles

    International Nuclear Information System (INIS)

    Zhao Jianzhi; Li Ming; Xing Shuang; Hu Zhiqing; Xiong Guolin; Xie Ling; Ou Hongling; Huang Haixiao; Zhao Zhenhu; Wang Ning; Wang Jinxiang; Miao Jingcheng; Zhu Nankang; Zhang Xueguang; Cong Yuwen; Zhang Ri; Luo Qingliang

    2010-01-01

    Objective: To observe the therapeutic effects of combined cytokines on hematopoietic injuries induced by 4.5 Gy 60 Co γ-rays irradiation in beagles, and to provide experimental evidences for the clinical treatment of extremely severe myeloid acute radiation sickness (ARS). Methods: 16 beagles were given 4.5 Gy 60 Co γ-rays total body irradiation, and then randomly assigned into irradiation control group, supportive care group and cytokines group. In addition to supportive care, recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human interleukin-11 (rhIL-11) and recombinant human interleukin-2 (rhIL-2) were administered subcutaneouly to dogs in cytokines group. Peripheral blood hemogram was examined once every two days. Bone marrow and peripheral blood were collected to proceed colony cultivation 4 d pre-irradiation and 1 and 45 d post-irradiation. Conventional histopathological sections sternum were prepared to observe the histomorphology changes. Results: After irradiation, the population of all kinds of cells in peripheral blood declined sharply. WBC nadir was elevated (1.04 x 10 9 /L, but 0.28 x 10 9 /L and 0.68 x 10 9 /L for the irradiation control group and the supportive care group separately), the duration of thrombocytopenia was shortened (24 days, but 33 days for the supportive care group) and red blood cell counts were maintained in the range of normal values after cytokines treatment in combination. The colony forming efficiency of haemopoietic stem cells (HSCs) in bone marrow and peripheral blood decreased obviously 1 d post irradiation, but recovered to the level of that before irradiation 45 d post irradiation after supportive care and cytokines treatment. Hematopoietic cells disappeared in bone marrow of animals in irradiation control group, but hematopoietic functions were recovered after cytokines were administrated. Conclusions: RhG-CSF, rhIL-11 and rhIL-2 used in combination could elevate WBC nadir, accelerate the

  2. Nitric oxide-induced murine hematopoietic stem cell fate involves multiple signaling proteins, gene expression, and redox modulation.

    Science.gov (United States)

    Nogueira-Pedro, Amanda; Dias, Carolina C; Regina, Helena; Segreto, C; Addios, Priscilla C; Lungato, Lisandro; D'Almeida, Vania; Barros, Carlos C; Higa, Elisa M S; Buri, Marcus V; Ferreira, Alice T; Paredes-Gamero, Edgar Julian

    2014-11-01

    There are a growing number of reports showing the influence of redox modulation in cellular signaling. Although the regulation of hematopoiesis by reactive oxygen species (ROS) and reactive nitrogen species (RNS) has been described, their direct participation in the differentiation of hematopoietic stem cells (HSCs) remains unclear. In this work, the direct role of nitric oxide (NO(•)), a RNS, in the modulation of hematopoiesis was investigated using two sources of NO(•) , one produced by endothelial cells stimulated with carbachol in vitro and another using the NO(•)-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) in vivo. Two main NO(•) effects were observed: proliferation of HSCs-especially of the short-term HSCs-and its commitment and terminal differentiation to the myeloid lineage. NO(•)-induced proliferation was characterized by the increase in the number of cycling HSCs and hematopoietic progenitor cells positive to BrdU and Ki-67, upregulation of Notch-1, Cx43, PECAM-1, CaR, ERK1/2, Akt, p38, PKC, and c-Myc. NO(•)-induced HSCs differentiation was characterized by the increase in granulocytic-macrophage progenitors, granulocyte-macrophage colony forming units, mature myeloid cells, upregulation of PU.1, and C/EBPα genes concomitantly to the downregulation of GATA-3 and Ikz-3 genes, activation of Stat5 and downregulation of the other analyzed proteins mentioned above. Also, redox status modulation differed between proliferation and differentiation responses, which is likely associated with the transition of the proliferative to differentiation status. Our findings provide evidence of the role of NO(•) in inducing HSCs proliferation and myeloid differentiation involving multiple signaling. © 2014 AlphaMed Press.

  3. Mitigating the Effects of Xuebijing Injection on Hematopoietic Cell Injury Induced by Total Body Irradiation with γ rays by Decreasing Reactive Oxygen Species Levels

    Directory of Open Access Journals (Sweden)

    Deguan Li

    2014-06-01

    Full Text Available Hematopoietic injury is the most common side effect of radiotherapy. However, the methods available for the mitigating of radiation injury remain limited. Xuebijing injection (XBJ is a traditional Chinese medicine used to treat sepsis in the clinic. In this study, we investigated the effects of XBJ on the survival rate in mice with hematopoietic injury induced by γ ray ionizing radiation (IR. Mice were intraperitoneally injected with XBJ daily for seven days after total body irradiation (TBI. Our results showed that XBJ (0.4 mL/kg significantly increased 30-day survival rates in mice exposed to 7.5 Gy TBI. This effect may be attributable to improved preservation of white blood cells (WBCs and hematopoietic cells, given that bone marrow (BM cells from XBJ-treated mice produced more granulocyte-macrophage colony forming units (CFU-GM than that in the 2 Gy/TBI group. XBJ also decreased the levels of reactive oxygen species (ROS by increasing glutathione (GSH and superoxide dismutase (SOD levels in serum and attenuated the increased BM cell apoptosis caused by 2 Gy/TBI. In conclusion, these findings suggest that XBJ enhances the survival rate of irradiated mice and attenuates the effects of radiation on hematopoietic injury by decreasing ROS production in BM cells, indicating that XBJ may be a promising therapeutic candidate for reducing hematopoietic radiation injury.

  4. Limited transplantation of antigen-expressing hematopoietic stem cells induces long-lasting cytotoxic T cell responses.

    Directory of Open Access Journals (Sweden)

    Warren L Denning

    2011-02-01

    Full Text Available Harnessing the ability of cytotoxic T lymphocytes (CTLs to recognize and eradicate tumor or pathogen-infected cells is a critical goal of modern immune-based therapies. Although multiple immunization strategies efficiently induce high levels of antigen-specific CTLs, the initial increase is typically followed by a rapid contraction phase resulting in a sharp decline in the frequency of functional CTLs. We describe a novel approach to immunotherapy based on a transplantation of low numbers of antigen-expressing hematopoietic stem cells (HSCs following nonmyeloablative or partially myeloablative conditioning. Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model. Recipient animals display high levels of antigen-specific CTLs four months following transplantation in contrast to dendritic cell-immunized animals in which the response typically declines at 4-6 weeks post-immunization. Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting. Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo. In conclusion, the data presented here supports potential application of immunization by limited transplantation of antigen-expressing HSCs for the prevention and treatment of cancer and therapeutic immunization of chronic infectious diseases such as HIV-1/AIDS.

  5. Radioresistant canine hematopoietic cells

    International Nuclear Information System (INIS)

    Kawakami, T.G.; Shimizu, J.; Rosenblatt, L.S.; Goldman, M.

    1987-01-01

    Survival of dogs that are continuously exposed to a moderate dose-rate of gamma radiation (10 cGy/day) is dependent on the age of the dog at the time of exposure. Most dogs exposed postpartum to gamma radiation suffered from suppressed hematopoiesis and died of aplasia. On the other hand, none of the in utero-exposed dogs suffered from suppressed hematopoiesis and most became long-term survivors, tolerating 10-fold greater total dose, but dying of myeloproliferative disease (MPD). Using acute gamma irradiation of hematopoietic cells and colony forming unit cell assay (CFU), they observed that a canine hematopoietic cell line established from a myeloid leukemic dog that was a long-term survivor of continuous irradiation was approximately 4-fold more radioresistant than a hematopoietic cell line established from a dog with nonradiation-induced myeloid leukemia or hematopoietic cells from normal canine bone marrow. In utero dogs that are long-term survivors of continuous irradiation have radioresistant hematopoietic cells, and radioresistance that is a constitutive property of the cells

  6. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

    Energy Technology Data Exchange (ETDEWEB)

    Ali, Haytham [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Galal, Omima [Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Abdelrahim, Eman [Department of Medical Histology, Qena Faculty of Medicine, South Valley University (Egypt); Ono, Yusuke [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Mostafa, Emtethal [Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Li, Tao-Sheng, E-mail: litaoshe@nagasaki-u.ac.jp [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)

    2014-09-26

    Highlights: • Nicaraven mitigated the radiation-induced reduction of c-kit{sup +} stem cells. • Nicaraven enhanced the function of hematopoietic stem/progenitor cells. • Complex mechanisms involved in the protection of nicaraven to radiation injury. - Abstract: Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5 Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30 min before exposure to 50 mGy γ-ray daily for 30 days in sequences (cumulative dose of 1.5 Gy). Mice were victimized 24 h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit{sup +} stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60–90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit{sup +} stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms.

  7. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

    International Nuclear Information System (INIS)

    Ali, Haytham; Galal, Omima; Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan; Abdelrahim, Eman; Ono, Yusuke; Mostafa, Emtethal; Li, Tao-Sheng

    2014-01-01

    Highlights: • Nicaraven mitigated the radiation-induced reduction of c-kit + stem cells. • Nicaraven enhanced the function of hematopoietic stem/progenitor cells. • Complex mechanisms involved in the protection of nicaraven to radiation injury. - Abstract: Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5 Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30 min before exposure to 50 mGy γ-ray daily for 30 days in sequences (cumulative dose of 1.5 Gy). Mice were victimized 24 h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit + stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60–90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit + stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms

  8. Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells.

    Science.gov (United States)

    Ruud, Johan; Wilhelms, Daniel Björk; Nilsson, Anna; Eskilsson, Anna; Tang, Yan-Juan; Ströhle, Peter; Caesar, Robert; Schwaninger, Markus; Wunderlich, Thomas; Bäckhed, Fredrik; Engblom, David; Blomqvist, Anders

    2013-05-01

    Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

  9. H4 histamine receptors mediate cell cycle arrest in growth factor-induced murine and human hematopoietic progenitor cells.

    Directory of Open Access Journals (Sweden)

    Anne-France Petit-Bertron

    Full Text Available The most recently characterized H4 histamine receptor (H4R is expressed preferentially in the bone marrow, raising the question of its role during hematopoiesis. Here we show that both murine and human progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid colony formation. H4R activation prevents the induction of cell cycle genes through a cAMP/PKA-dependent pathway that is not associated with apoptosis. It is mediated specifically through H4R signaling since gene silencing or treatment with selective antagonists restores normal cell cycle progression. The arrest of growth factor-induced G1/S transition protects murine and human progenitor cells from the toxicity of the cell cycle-dependent anticancer drug Ara-C in vitro and reduces aplasia in a murine model of chemotherapy. This first evidence for functional H4R expression in hematopoietic progenitors opens new therapeutic perspectives for alleviating hematotoxic side effects of antineoplastic drugs.

  10. Improved hematopoietic differentiation efficiency of gene-corrected beta-thalassemia induced pluripotent stem cells by CRISPR/Cas9 system.

    Science.gov (United States)

    Song, Bing; Fan, Yong; He, Wenyin; Zhu, Detu; Niu, Xiaohua; Wang, Ding; Ou, Zhanhui; Luo, Min; Sun, Xiaofang

    2015-05-01

    The generation of beta-thalassemia (β-Thal) patient-specific induced pluripotent stem cells (iPSCs), subsequent homologous recombination-based gene correction of disease-causing mutations/deletions in the β-globin gene (HBB), and their derived hematopoietic stem cell (HSC) transplantation offers an ideal therapeutic solution for treating this disease. However, the hematopoietic differentiation efficiency of gene-corrected β-Thal iPSCs has not been well evaluated in the previous studies. In this study, we used the latest gene-editing tool, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9), to correct β-Thal iPSCs; gene-corrected cells exhibit normal karyotypes and full pluripotency as human embryonic stem cells (hESCs) showed no off-targeting effects. Then, we evaluated the differentiation efficiency of the gene-corrected β-Thal iPSCs. We found that during hematopoietic differentiation, gene-corrected β-Thal iPSCs showed an increased embryoid body ratio and various hematopoietic progenitor cell percentages. More importantly, the gene-corrected β-Thal iPSC lines restored HBB expression and reduced reactive oxygen species production compared with the uncorrected group. Our study suggested that hematopoietic differentiation efficiency of β-Thal iPSCs was greatly improved once corrected by the CRISPR/Cas9 system, and the information gained from our study would greatly promote the clinical application of β-Thal iPSC-derived HSCs in transplantation.

  11. Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

    Science.gov (United States)

    Aisa, Yoshinobu; Mori, Takehiko; Kudo, Masumi; Yashima, Tomoko; Kondo, Sakiko; Yokoyama, Akihiro; Ikeda, Yasuo; Okamoto, Shinichiro

    2005-04-01

    The purpose of this study was to evaluate the efficacy of oral cryotherapy to prevent high-dose melphalan-induced stomatitis. Eighteen consecutive recipients of allogeneic hematopoietic stem cell transplant conditioned with high-dose melphalan (140 mg/m2) in combination with fludarabine alone or with fludarabine and additional chemotherapy or radiation were enrolled. The severity of stomatitis was graded according to the National Cancer Institute Common Toxicity Criteria. Patients were kept on oral cryotherapy using ice chips and ice-cold water shortly before, during, and for additional 90 min after completion of melphalan administration. Only two of 18 patients (11.1%) developed grade 2 or 3 stomatitis while six of seven patients in the historical control developed it (85.7%; P=0.001). These results suggested that oral cryotherapy could effectively prevent stomatitis caused by high-dose melphalan, and we recommend that it should be incorporated into the conditioning regimen with high-dose melphalan.

  12. Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells

    NARCIS (Netherlands)

    T.B. van Dijk (Thamar); M. Parren-Van Amelsvoort (Martine); H. Mano; M.M. von Lindern (Marieke); B. Löwenberg (Bob); E. van den Akker (Emile)

    2000-01-01

    textabstractStem cell factor (SCF) has an important role in the proliferation, differentiation, survival, and migration of hematopoietic cells. SCF exerts its effects by binding to cKit, a receptor with intrinsic tyrosine kinase activity. Activation of

  13. The application of hematopoietic growth factors in drug-induced agranulocytosis: a review of 70 cases

    NARCIS (Netherlands)

    Sprikkelman, A.; de Wolf, J. T.; Vellenga, E.

    1994-01-01

    Since 1989, granulocyte-macrophage and granulocyte colony-stimulating factors (GM-CSF, G-CSF) have been increasingly applied in the treatment of drug-induced agranulocytosis. In order to evaluate the effectiveness of GM-CSF and G-CSF in the treatment of drug-induced agranulocytosis, we have studied

  14. Mixing induced reactive transport in fractured crystalline rocks

    International Nuclear Information System (INIS)

    Martinez-Landa, Lurdes; Carrera, Jesus; Dentz, Marco; Fernàndez-Garcia, Daniel; Nardí, Albert; Saaltink, Maarten W.

    2012-01-01

    In this paper the solute retention properties of crystalline fractured rocks due to mixing-induced geochemical reactions are studied. While fractured media exhibit paths of fast flow and transport and thus short residence times for conservative solutes, at the same time they promote mixing and dilution due to strong heterogeneity, which leads to sharp concentration contrasts. Enhanced mixing and dilution have a double effect that favors crystalline fractured media as a possible host medium for nuclear waste disposal. Firstly, peak radionuclide concentrations are attenuated and, secondly, mixing-induced precipitation reactions are enhanced significantly, which leads to radionuclide immobilization. An integrated framework is presented for the effective modeling of these flow, transport and reaction phenomena, and the interaction between them. In a simple case study, the enhanced dilution and precipitation potential of fractured crystalline rocks are systematically studied and quantified and contrasted it to retention and attenuation in an equivalent homogeneous formation.

  15. Boiling induced mixed convection in cooling loops

    International Nuclear Information System (INIS)

    Knebel, J.U.; Janssens-Maenhout, G.; Mueller, U.

    2000-01-01

    This article describes the SUCO program performed at the Forschungszentrum Karlsruhe. The SUCO program is a three-step series of scaled model experiments investigating the possibility of a sump cooling concept for future light water reactors. In case of a core melt accident, the sump cooling concept realises a decay heat removal system that is based on passive safety features within the containment. The article gives, first, results of the experiments in the 1:20 linearly scaled SUCOS-2D test facility. The experimental results are scaled-up to the conditions in the prototype, allowing a statement with regard to the feasibility of the sump cooling concept. Second, the real height SUCOT test facility with a volume and power scale of 1:356 that is aimed at investigating the mixed single-phase and two-phase natural circulation flow in the reactor sump, together with first measurement results, are discussed. Finally, a numerical approach to model the subcooled nucleate boiling phenomena in the test facility SUCOT is presented. Physical models describing interfacial mass, momentum and-heat transfer are developed and implemented in the commercial software package CFX4.1. The models are validated for an isothermal air-water bubbly flow experiment and a subcooled boiling experiment in vertical annular water flow. (author)

  16. Mixing-induced quantum non-Markovianity and information flow

    Science.gov (United States)

    Breuer, Heinz-Peter; Amato, Giulio; Vacchini, Bassano

    2018-04-01

    Mixing dynamical maps describing open quantum systems can lead from Markovian to non-Markovian processes. Being surprising and counter-intuitive, this result has been used as argument against characterization of non-Markovianity in terms of information exchange. Here, we demonstrate that, quite the contrary, mixing can be understood in a natural way which is fully consistent with existing theories of memory effects. In particular, we show how mixing-induced non-Markovianity can be interpreted in terms of the distinguishability of quantum states, system-environment correlations and the information flow between system and environment.

  17. Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment

    Directory of Open Access Journals (Sweden)

    Jean-Paul Vernot

    2017-02-01

    Full Text Available An understanding of the cell interactions occurring in the leukemic microenvironment and their functional consequences for the different cell players has therapeutic relevance. By co-culturing mesenchymal stem cells (MSC with the REH acute lymphocytic leukemia (ALL cell line, we have established an in vitro leukemic niche for the functional evaluation of hematopoietic stem/progenitor cells (HSPC, CD34+ cells. We showed that the normal homeostatic control exerted by the MSC over the HSPC is considerably lost in this leukemic microenvironment: HSPC increased their proliferation rate and adhesion to MSC. The adhesion molecules CD54 and CD44 were consequently upregulated in HSPC from the leukemic niche. Consequently, with this adhesive phenotype, HSPC showed less Stromal derived factor-1 (SDF-1-directed migration. Interestingly, multipotency was severely affected with an important reduction in the absolute count and the percentage of primitive progenitor colonies. It was possible to simulate most of these HSPC alterations by incubation of MSC with a REH-conditioned medium, suggesting that REH soluble factors and their effect on MSC are important for the observed changes. Of note, these HSPC alterations were reproduced when primary leukemic cells from an ALL type B (ALL-B patient were used to set up the leukemic niche. These results suggest that a general response is induced in the leukemic niche to the detriment of HSPC function and in favor of leukemic cell support. This in vitro leukemic niche could be a valuable tool for the understanding of the molecular events responsible for HSPC functional failure and a useful scenario for therapeutic evaluation.

  18. Clustered DNA damages induced in human hematopoietic cells by low doses of ionizing radiation

    Science.gov (United States)

    Sutherland, Betsy M.; Bennett, Paula V.; Cintron-Torres, Nela; Hada, Megumi; Trunk, John; Monteleone, Denise; Sutherland, John C.; Laval, Jacques; Stanislaus, Marisha; Gewirtz, Alan

    2002-01-01

    Ionizing radiation induces clusters of DNA damages--oxidized bases, abasic sites and strand breaks--on opposing strands within a few helical turns. Such damages have been postulated to be difficult to repair, as are double strand breaks (one type of cluster). We have shown that low doses of low and high linear energy transfer (LET) radiation induce such damage clusters in human cells. In human cells, DSB are about 30% of the total of complex damages, and the levels of DSBs and oxidized pyrimidine clusters are similar. The dose responses for cluster induction in cells can be described by a linear relationship, implying that even low doses of ionizing radiation can produce clustered damages. Studies are in progress to determine whether clusters can be produced by mechanisms other than ionizing radiation, as well as the levels of various cluster types formed by low and high LET radiation.

  19. Pre-administration of safe exogenous substance minimizes radiation induced bone-marrow aplsia which may otherwise lead to hematopoietic disaster

    International Nuclear Information System (INIS)

    Gupta, Manju Lata; Verma, Savita; Ranjan, Rajiv

    2014-01-01

    Radiation induces injuries to biological system primarily by producing free radicals and also by directly interacting with cellular entities. In irradiated animals hematopoietic system gets severely affected leading to inactive microenvironment, damaged blood vessels and non functional endothelial cells of the marrow. Vascular damage inhibits the efficacy of stem cells to proliferate and differentiate. Release of pro-inflammatory cytokines and activation of fibroblast further contribute to the development of radiation-induced fibrosis. Various findings have revealed the occurrence of radiation induced aplasia and vascular damage cause large number of RBCs occupying the space and intrusion of fibrotic cells in the marrow of irradiated mice. Administration of effective radioprotective agents prior to irradiation has been amply reported for significant decline in the grade of vascular damage and inclusion of marrow fibrous tissues in these animals. In addition the formulations have also shown the presence stem cell population which is efficient to proliferate, differentiate and ultimately enrich bone marrow cellularity within 25-40 days depending on type of radiation and its dose and dose rate. Protection to bone marrow is multi-factorial phenomenon out of which inhibition of radiation induced free radical generation has been recognized as the key factor but essentially not the lone one. Protection to colony forming ability of bone marrow is also critically important which occurs mainly due to DNA protection and up-regulation of repair pathways. Preservation of microenvironment for providing stem cells to remain functional is lately reported as equally prominent factor. Our studies on a combination of two compounds of natural origin, administered to lethally irradiated animals have shown recovery in stem/precursor cells of all hematopoietic lineages. Major entities related to hematopoietic system were found nearly 90% recovered within 30 days. Current talk is focused

  20. Mixed chemical-induced oxidative stress in occupational exposure ...

    African Journals Online (AJOL)

    Mixed chemical-induced oxidative stress in occupational exposure in Nigerians. JI Anetor, SA Yaqub, GO Anetor, AC Nsonwu, FAA Adeniyi, S Fukushima. Abstract. Exposure to single chemicals and associated disorders in occupational environments has received significant attention. Understanding these events holds ...

  1. Umbelliferone suppresses radiation induced DNA damage and apoptosis in hematopoietic cells of mice

    International Nuclear Information System (INIS)

    Jayakumar, S.; Bhilwade, H.N.; Chaubey, R.C.

    2012-01-01

    Radiotherapy is one of the major modes of treatment for different types of cancers. But the success of radiotherapy is limited by injury to the normal cells. Protection of the normal cells from radiation damage by radioprotectors can increase therapeutic efficiency. These radioprotectors can also be used during nuclear emergency situations. Umbelliferone (UMB) is a wide spread natural product of the coumarin family. It occurs in many plants from the Apiaceae family. In the present study radioprotective effect of UMB was investigated in vitro and in vivo. Anti genotoxic effect of Umbelliferone was tested by treating the splenic lymphocytes with various doses of UMB (6.5 μM - 50 μM) prior to radiation (6Gy) exposure. After the radiation exposure, extent of DNA damage was assessed by comet assay at 5 mm and two hours after radiation exposure. At both the time points, it was observed that the pretreatment of UMB reduced the radiation induced DNA damage to a significant extent in comparison to radiation control. UMB pretreatment also significantly reduced the radiation induced apoptosis enumerated by propidium iodide staining assay. Results of clonogenic survival assay using intestinal cell line showed that pretreatment with UMB significantly protected against radiation induced loss of colony forming units. To assess the anti genotoxic role of umbelliferone in vivo two different doses of UMB (20 mg/Kg and 40 mg/Kg of body weight) were injected into Swiss mice or with vehicle and exposed to radiation. Thirty minutes after the radiation comet assay was performed in peripheral leukocytes. Frequency of micro nucleated erythrocytes was scored in bone marrow cells. It was observed that UMB alone did not cause any significant increase in DNA damage in comparison to control. Animals which are exposed to radiation alone showed significant increase in DNA damage and micronuclei frequency. But animals treated with UMB prior to the radiation exposure showed significant decrease

  2. Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients.

    Science.gov (United States)

    Garçon, Loïc; Ge, Jingping; Manjunath, Shwetha H; Mills, Jason A; Apicella, Marisa; Parikh, Shefali; Sullivan, Lisa M; Podsakoff, Gregory M; Gadue, Paul; French, Deborah L; Mason, Philip J; Bessler, Monica; Weiss, Mitchell J

    2013-08-08

    Diamond Blackfan anemia (DBA) is a congenital disorder with erythroid (Ery) hypoplasia and tissue morphogenic abnormalities. Most DBA cases are caused by heterozygous null mutations in genes encoding ribosomal proteins. Understanding how haploinsufficiency of these ubiquitous proteins causes DBA is hampered by limited availability of tissues from affected patients. We generated induced pluripotent stem cells (iPSCs) from fibroblasts of DBA patients carrying mutations in RPS19 and RPL5. Compared with controls, DBA fibroblasts formed iPSCs inefficiently, although we obtained 1 stable clone from each fibroblast line. RPS19-mutated iPSCs exhibited defects in 40S (small) ribosomal subunit assembly and production of 18S ribosomal RNA (rRNA). Upon induced differentiation, the mutant clone exhibited globally impaired hematopoiesis, with the Ery lineage affected most profoundly. RPL5-mutated iPSCs exhibited defective 60S (large) ribosomal subunit assembly, accumulation of 12S pre-rRNA, and impaired erythropoiesis. In both mutant iPSC lines, genetic correction of ribosomal protein deficiency via complementary DNA transfer into the "safe harbor" AAVS1 locus alleviated abnormalities in ribosome biogenesis and hematopoiesis. Our studies show that pathological features of DBA are recapitulated by iPSCs, provide a renewable source of cells to model various tissue defects, and demonstrate proof of principle for genetic correction strategies in patient stem cells.

  3. Generation of induced pluripotent stem cells from peripheral blood CD34+ hematopoietic progenitors of a 31 year old healthy woman

    Directory of Open Access Journals (Sweden)

    Amornrat Tangprasittipap

    2017-04-01

    Full Text Available The MUi019-A human induced pluripotent stem cell line was generated from peripheral blood CD34+ hematopoietic progenitors of a healthy woman using a non-integrative reprogramming method. Episomal vectors carrying reprogramming factors OCT4, SOX2, KLF4, L-MYC, LIN28, and shRNA of TP53 and EBNA-1 were delivered using electroporation. The iPSC line can be used as a control in studying disease mechanisms. Furthermore, gene editing approaches can be used to introduce specific mutations into the MUi019-A to model disease while the cell type affected by the disease is inaccessible.

  4. Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells

    NARCIS (Netherlands)

    van Dijk, T. B.; van den Akker, E.; Amelsvoort, M. P.; Mano, H.; Löwenberg, B.; von Lindern, M.

    2000-01-01

    Stem cell factor (SCF) has an important role in the proliferation, differentiation, survival, and migration of hematopoietic cells. SCF exerts its effects by binding to cKit, a receptor with intrinsic tyrosine kinase activity. Activation of phosphatidylinositol 3'-kinase (PI3-K) by cKit was

  5. New experimental approach to treatment of radiation-induced bone marrow aplasia: ex vivo expansion of hematopoietic cells

    International Nuclear Information System (INIS)

    Herodin, F.; Mathieu, J.; Drouet, M.; Grenier, N.; Grange, L.; Bourin, P.; Vetillard, J.; Thierry, D.; Mestries, J.C.

    1995-01-01

    The management of bone marrow aplasia secondary to accidental exposure to high doses of ionizing radiations requires new therapeutic protocols in addition to cytokine therapy. The in vitro incubation of hematopoietic stem and progenitor cells from irradiated nonhuman primates with negative and positive regulators of hematopoiesis may lead to helpful products of transfusion. (author)

  6. On the Chemical Mixing Induced by Internal Gravity Waves

    Energy Technology Data Exchange (ETDEWEB)

    Rogers, T. M. [School of Mathematics, Statistics and Physics, Newcastle University, Newcastle upon Tyne (United Kingdom); McElwaine, J. N. [Planetary Science Institute, Tucson, AZ 85721 (United States)

    2017-10-10

    Detailed modeling of stellar evolution requires a better understanding of the (magneto)hydrodynamic processes that mix chemical elements and transport angular momentum. Understanding these processes is crucial if we are to accurately interpret observations of chemical abundance anomalies, surface rotation measurements, and asteroseismic data. Here, we use two-dimensional hydrodynamic simulations of the generation and propagation of internal gravity waves in an intermediate-mass star to measure the chemical mixing induced by these waves. We show that such mixing can generally be treated as a diffusive process. We then show that the local diffusion coefficient does not depend on the local fluid velocity, but rather on the wave amplitude. We then use these findings to provide a simple parameterization for this diffusion, which can be incorporated into stellar evolution codes and tested against observations.

  7. Protection of radiation-induced damage to the hematopoietic system, small intestine and salivary glands in rats by JNJ7777120 compound, a histamine H4 ligand.

    Directory of Open Access Journals (Sweden)

    Diego J Martinel Lamas

    Full Text Available Based on previous data on the histamine radioprotective effect on highly radiosensitive tissues, in the present work we aimed at investigating the radioprotective potential of the H4R ligand, JNJ7777120, on ionizing radiation-induced injury and genotoxic damage in small intestine, salivary glands and hematopoietic tissue. For that purpose, rats were divided into 4 groups. JNJ7777120 and JNJ7777120-irradiated groups received a daily subcutaneous JNJ7777120 injection (10 mg/kg starting 24 h before irradiation. Irradiated groups received a single dose of 5 Gy on whole-body using Cesium-137 source and were sacrificed 3 or 30 days after irradiation. Tissues were removed, fixed, stained with hematoxylin and eosin or PAS staining and histological characteristics were evaluated. Proliferative and apoptotic markers were studied by immunohistochemistry, while micronucleus assay was performed to evaluate DNA damage. Submandibular gland (SMG function was evaluated by methacholine-induced salivation. Results indicate that JNJ7777120 treatment diminished mucosal atrophy and preserved villi and the number of crypts after radiation exposure (240±8 vs. 165±10, P<0.01. This effect was associated to a reduced apoptosis and DNA damage in intestinal crypts. JNJ7777120 reduced radiation-induced aplasia, preserving medullar components and reducing formation of micronucleus and also it accelerated bone marrow repopulation. Furthermore, it reduced micronucleus frequency in peripheral blood (27±8 vs. 149±22, in 1,000 erythrocytes, P<0.01. JNJ7777120 completely reversed radiation-induced reduced salivation, conserving glandular mass with normal histological appearance and reducing apoptosis and atrophy of SMG. JNJ7777120 exhibits radioprotective effects against radiation-induced cytotoxic and genotoxic damages in small intestine, SMG and hematopoietic tissues and, thus, could be of clinical value for patients undergoing radiotherapy.

  8. Recombinant TAT-BMI-1 fusion protein induces ex vivo expansion of human umbilical cord blood-derived hematopoietic stem cells.

    Science.gov (United States)

    Codispoti, Bruna; Rinaldo, Nicola; Chiarella, Emanuela; Lupia, Michela; Spoleti, Cristina Barbara; Marafioti, Maria Grazia; Aloisio, Annamaria; Scicchitano, Stefania; Giordano, Marco; Nappo, Giovanna; Lucchino, Valeria; Moore, Malcolm A S; Zhou, Pengbo; Mesuraca, Maria; Bond, Heather Mandy; Morrone, Giovanni

    2017-07-04

    Transplantation of hematopoietic stem cells (HSCs) is a well-established therapeutic approach for numerous disorders. HSCs are typically derived from bone marrow or peripheral blood after cytokine-induced mobilization. Umbilical cord blood (CB) represents an appealing alternative HSC source, but the small amounts of the individual CB units have limited its applications. The availability of strategies for safe ex vivo expansion of CB-derived HSCs (CB-HSCs) may allow to extend the use of these cells in adult patients and to avoid the risk of insufficient engraftment or delayed hematopoietic recovery.Here we describe a system for the ex vivo expansion of CB-HSCs based on their transient exposure to a recombinant TAT-BMI-1 chimeric protein. BMI-1 belongs to the Polycomb family of epigenetic modifiers and is recognized as a central regulator of HSC self-renewal. Recombinant TAT-BMI-1 produced in bacteria was able to enter the target cells via the HIV TAT-derived protein transduction peptide covalently attached to BMI-1, and conserved its biological activity. Treatment of CB-CD34+ cells for 3 days with repeated addition of 10 nM purified TAT-BMI-1 significantly enhanced total cell expansion as well as that of primitive hematopoietic progenitors in culture. Importantly, TAT-BMI-1-treated CB-CD34+ cells displayed a consistently higher rate of multi-lineage long-term repopulating activity in primary and secondary xenotransplants in immunocompromised mice. Thus, recombinant TAT-BMI-1 may represent a novel, effective reagent for ex vivo expansion of CB-HSC for therapeutic purposes.

  9. Factors determining radiation-induced mixing at interfaces

    International Nuclear Information System (INIS)

    Collins, R.

    1986-01-01

    A review is given of the principal mechanisms contributing to atomic mixing produced by ion beams at initially well-defined interfaces between solid phases. Their relative importance is discussed in the light of available experimental evidence, and a critical survey is given of current mathematical models. The case of a thin interior implant layer is included. Those aspects of surface sputtering of direct relevance to the construction of the mixing equations are examined. Mixing mechanisms considered are ballistic relocation, diffusion, radiation-induced segregation, and drifts induced by chemical affinities of the elements concerned, together with constraints on all these from packing (Kirkendall) effects. Ballistic terms are subdivided into direct-recoil and cascade contributions. A brief review is given of the established methods of modelling them by using relocation integral cross-sections, and also the limitations and advantages of their approximation by differential equations of Fokker-Planck (diffusion) type. Genuinely diffusive mechanisms involved are thermal and radiation-enhanced diffusion; the question of the most appropriate form of Fick's law to use in each case is considered. The packing effects may be modelled either as a lattice relaxation to be imposed following each radiation dose increment, or as a continuously computed reversed collective current of atoms. These two approaches are discussed. (author)

  10. Protective Effect of Ginsenoside Rg1 on Hematopoietic Stem/Progenitor Cells through Attenuating Oxidative Stress and the Wnt/β-Catenin Signaling Pathway in a Mouse Model of d-Galactose-induced Aging.

    Science.gov (United States)

    Li, Jing; Cai, Dachuan; Yao, Xin; Zhang, Yanyan; Chen, Linbo; Jing, Pengwei; Wang, Lu; Wang, Yaping

    2016-06-09

    Stem cell senescence is an important and current hypothesis accounting for organismal aging, especially the hematopoietic stem cell (HSC). Ginsenoside Rg1 is the main active pharmaceutical ingredient of ginseng, which is a traditional Chinese medicine. This study explored the protective effect of ginsenoside Rg1 on Sca-1⁺ hematopoietic stem/progenitor cells (HSC/HPCs) in a mouse model of d-galactose-induced aging. The mimetic aging mouse model was induced by continuous injection of d-gal for 42 days, and the C57BL/6 mice were respectively treated with ginsenoside Rg1, Vitamin E or normal saline after 7 days of d-gal injection. Compared with those in the d-gal administration alone group, ginsenoside Rg1 protected Sca-1⁺ HSC/HPCs by decreasing SA-β-Gal and enhancing the colony forming unit-mixture (CFU-Mix), and adjusting oxidative stress indices like reactive oxygen species (ROS), total anti-oxidant (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-px) and malondialdehyde (MDA). In addition, ginsenoside Rg1 decreased β-catenin and c-Myc mRNA expression and enhanced the phosphorylation of GSK-3β. Moreover, ginsenoside Rg1 down-regulated advanced glycation end products (AGEs), 4-hydroxynonenal (4-HNE), phospho-histone H2A.X (r-H2A.X), 8-OHdG, p16(Ink4a), Rb, p21(Cip1/Waf1) and p53 in senescent Sca-1⁺ HSC/HPCs. Our findings indicated that ginsenoside Rg1 can improve the resistance of Sca-1⁺ HSC/HPCs in a mouse model of d-galactose-induced aging through the suppression of oxidative stress and excessive activation of the Wnt/β-catenin signaling pathway, and reduction of DNA damage response, p16(Ink4a)-Rb and p53-p21(Cip1/Waf1) signaling.

  11. Electromagnetically Induced Transparency in Four Wave Mixing Process

    International Nuclear Information System (INIS)

    Kucukkara, I.

    2008-01-01

    We have theoretically studied Four Wave Mixing (FWM) process in VUV (Vacuum Ultraviolet) region enhanced by Electromagnetically Induced Transparency in Krypton gas medium at room temperature. One of the mixing fields, in the ultraviolet region at 212.5 nm was in two-photon resonance with the 4p 6 1 S 0 -4p 5 5p[0,1/2] transition of Krypton and the second field (coupling field) at 759 nm was resonant with the 4p 5 5p[0,1/2]-4p 5 5s[1,1/2] transition in scheme. This coupling field produced an electromagnetically induced transparency and thus the efficiency of the generation of the field at 123.6 nm on the 4p 5 5s[1,1/2] to 4p 6 1 S 0 transition is enhanced. We modified the computer program previously written by changing some variables like pressure, interaction region length, UV energy, IR energy. As demonstrated by the intensity generated VUV light versus Krypton pressure graphic, the most efficient intensity value, which was approximately 4.2x10 1 6 arbitrary units, was obtained while IR energy was 3x10 - 4 J and the pressure was 2x10 - 3 bar

  12. Mixing processes in the vitreous chamber induced by eye rotations

    Energy Technology Data Exchange (ETDEWEB)

    Stocchino, Alessandro [Department of Civil, Environmental and Architectural Engineering, University of Genoa (Italy); Repetto, Rodolfo [Department of Engineering of Structures, Water and Soil, University of L' Aquila (Italy); Siggers, Jennifer H [Department of Bioengineering, Imperial College London, London SW7 2AZ (United Kingdom)], E-mail: jorma@diam.unige.it

    2010-01-21

    In this paper, we study a model of flow in the vitreous humour in the posterior chamber of the human eye, induced by saccadic eye rotations. We concentrate on the effect of the shape of the chamber upon the mixing properties of the induced flows. We make particle image velocimetry measurements of the fluid velocity in a transparent plastic (Perspex) model of the posterior chamber during sinusoidal torsional oscillations about a vertical axis. We use a Newtonian fluid to model the vitreous humour, which is most realistic when either the vitreous humour is liquefied or has been replaced by purely viscous tamponade fluids. The model of the posterior chamber is a sphere with an indentation, representing the effect of the lens. In spite of the purely periodic forcing, a steady streaming flow is generated, which plays a fundamental role in the mixing processes in the domain. The streaming flow differs markedly from that in a perfect sphere, and its topological characteristics change substantially as the frequency of oscillation varies. We discuss the flow characteristics in detail and show that, for physiological parameter values, the Peclet number (based on a suitable measure of the steady streaming velocity) is large, suggesting that advection strongly dominates over diffusion for mass transport phenomena. We also compute particle trajectories based on the streaming velocity and use these to investigate the stirring properties of the flow.

  13. Mixing processes in the vitreous chamber induced by eye rotations

    International Nuclear Information System (INIS)

    Stocchino, Alessandro; Repetto, Rodolfo; Siggers, Jennifer H

    2010-01-01

    In this paper, we study a model of flow in the vitreous humour in the posterior chamber of the human eye, induced by saccadic eye rotations. We concentrate on the effect of the shape of the chamber upon the mixing properties of the induced flows. We make particle image velocimetry measurements of the fluid velocity in a transparent plastic (Perspex) model of the posterior chamber during sinusoidal torsional oscillations about a vertical axis. We use a Newtonian fluid to model the vitreous humour, which is most realistic when either the vitreous humour is liquefied or has been replaced by purely viscous tamponade fluids. The model of the posterior chamber is a sphere with an indentation, representing the effect of the lens. In spite of the purely periodic forcing, a steady streaming flow is generated, which plays a fundamental role in the mixing processes in the domain. The streaming flow differs markedly from that in a perfect sphere, and its topological characteristics change substantially as the frequency of oscillation varies. We discuss the flow characteristics in detail and show that, for physiological parameter values, the Peclet number (based on a suitable measure of the steady streaming velocity) is large, suggesting that advection strongly dominates over diffusion for mass transport phenomena. We also compute particle trajectories based on the streaming velocity and use these to investigate the stirring properties of the flow.

  14. Does defibrotide induce a delay to polymorphonuclear neutrophil engraftment after hematopoietic stem cell transplantation? Observation in a pediatric population.

    Science.gov (United States)

    Maximova, Natalia; Pizzol, Antonio; Giurici, Nagua; Granzotto, Marilena

    2015-04-01

    In recent years, defibrotide (DFT) has emerged as a promising therapy for veno-occlusive disease (VOD). The aim of this study was to investigate whether DFT prophylaxis affects neutrophil engraftment in patients undergoing hematopoietic stem cell transplantation (HSCT). A cohort of 44 consecutive pediatric patients who underwent HSCT was retrospectively analyzed to see the role of DFT on engraftment. Patients were assigned into two groups based on the use or non-use of prophylaxis with DFT. The mean time to engraftment was statistically different between the two groups for both polymorphonuclear neutrophils (PMN) and white blood cells. Our study supports the hypothesis that prophylaxis with DFT for VOD leads to a delay to the engraftment of PMN in pediatric patients that underwent HSCT.

  15. Conditional and inducible transgene expression in endothelial and hematopoietic cells using Cre/loxP and tetracycline-off systems.

    Science.gov (United States)

    Liu, Ju; Deutsch, Urban; Fung, Iris; Lobe, Corrinne G

    2014-11-01

    In the present study, the tetracycline-off and Cre/ loxP systems were combined to gain temporal and spatial control of transgene expression. Mice were generated that carried three transgenes: Tie2-tTA, tet-O-Cre and either the ZEG or ZAP reporter. Tie2-tTA directs expression of tetracycline-controlled transactivator (tTA) in endothelial and hematopoietic cells under the control of the Tie2 promoter. Tet-O-Cre produces Cre recombinase from a minimal promoter containing the tet-operator (tetO). ZEG or ZAP contains a strong promoter and a loxP -flanked stop sequence, followed by an enhanced green fluorescence protein (EGFP) or human placental alkaline phosphatase (hPLAP) reporter. In the presence of tetracycline, the tTA transactivator produced by Tie-2-tTA is disabled and Cre is not expressed. In the absence of tetracycline, the tTA binds tet-O-Cre to drive the expression of Cre, which recombines the loxP sites of the ZEG or ZAP transgene and results in reporter gene expression. In the present study, the expression of the ZEG or ZAP reporter genes in embryos and adult animals with and without tetracycline treatment was examined. In the presence of tetracycline, no reporter gene expression was observed. When tetracycline was withdrawn, Cre excision was activated and the reporter genes were detected in endothelial and hematopoietic cells. These results demonstrate that this system may be used to bypass embryonic lethality and access adult phenotypes.

  16. Mixed organic solvents induce renal injury in rats.

    Directory of Open Access Journals (Sweden)

    Weisong Qin

    Full Text Available To investigate the injury effects of organic solvents on kidney, an animal model of Sprague-Dawley (SD rats treated with mixed organic solvents via inhalation was generated and characterized. The mixed organic solvents consisted of gasoline, dimethylbenzene and formaldehyde (GDF in the ratio of 2:2:1, and were used at 12,000 PPM to treat the rats twice a day, each for 3 hours. Proteinuria appeared in the rats after exposure for 5-6 weeks. The incidences of proteinuria in male and female rats after exposure for 12 weeks were 43.8% (7/16 and 25% (4/16, respectively. Urinary N-Acetyl-β-(D-Glucosaminidase (NAG activity was increased significantly after exposure for 4 weeks. Histological examination revealed remarkable injuries in the proximal renal tubules, including tubular epithelial cell detachment, cloud swelling and vacuole formation in the proximal tubular cells, as well as proliferation of parietal epithelium and tubular reflux in glomeruli. Ultrastructural examination found that brush border and cytoplasm of tubular epithelial cell were dropped, that tubular epithelial cells were partially disintegrated, and that the mitochondria of tubular epithelial cells were degenerated and lost. In addition to tubular lesions, glomerular damages were also observed, including segmental foot process fusion and loss of foot process covering on glomerular basement membrane (GBM. Immunofluorescence staining indicated that the expression of nephrin and podocin were both decreased after exposure of GDF. In contrast, increased expression of desmin, a marker of podocyte injury, was found in some areas of a glomerulus. TUNEL staining showed that GDF induced apoptosis in tubular cells and glomerular cells. These studies demonstrate that GDF can induce both severe proximal tubular damage and podocyte injury in rats, and the tubular lesions appear earlier than that of glomeruli.

  17. Mixed organic solvents induce renal injury in rats.

    Science.gov (United States)

    Qin, Weisong; Xu, Zhongxiu; Lu, Yizhou; Zeng, Caihong; Zheng, Chunxia; Wang, Shengyu; Liu, Zhihong

    2012-01-01

    To investigate the injury effects of organic solvents on kidney, an animal model of Sprague-Dawley (SD) rats treated with mixed organic solvents via inhalation was generated and characterized. The mixed organic solvents consisted of gasoline, dimethylbenzene and formaldehyde (GDF) in the ratio of 2:2:1, and were used at 12,000 PPM to treat the rats twice a day, each for 3 hours. Proteinuria appeared in the rats after exposure for 5-6 weeks. The incidences of proteinuria in male and female rats after exposure for 12 weeks were 43.8% (7/16) and 25% (4/16), respectively. Urinary N-Acetyl-β-(D)-Glucosaminidase (NAG) activity was increased significantly after exposure for 4 weeks. Histological examination revealed remarkable injuries in the proximal renal tubules, including tubular epithelial cell detachment, cloud swelling and vacuole formation in the proximal tubular cells, as well as proliferation of parietal epithelium and tubular reflux in glomeruli. Ultrastructural examination found that brush border and cytoplasm of tubular epithelial cell were dropped, that tubular epithelial cells were partially disintegrated, and that the mitochondria of tubular epithelial cells were degenerated and lost. In addition to tubular lesions, glomerular damages were also observed, including segmental foot process fusion and loss of foot process covering on glomerular basement membrane (GBM). Immunofluorescence staining indicated that the expression of nephrin and podocin were both decreased after exposure of GDF. In contrast, increased expression of desmin, a marker of podocyte injury, was found in some areas of a glomerulus. TUNEL staining showed that GDF induced apoptosis in tubular cells and glomerular cells. These studies demonstrate that GDF can induce both severe proximal tubular damage and podocyte injury in rats, and the tubular lesions appear earlier than that of glomeruli.

  18. Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Thys, Ryan G., E-mail: rthys@wakehealth.edu [Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1016 (United States); Lehman, Christine E., E-mail: clehman@wakehealth.edu [Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1016 (United States); Pierce, Levi C.T., E-mail: Levipierce@gmail.com [Human Longevity, Inc., San Diego, California 92121 (United States); Wang, Yuh-Hwa, E-mail: yw4b@virginia.edu [Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA 22908-0733 (United States)

    2015-09-15

    Highlights: • Environmental/chemotherapeutic agents cause DNA breakage in MLL and CBFB in HSPCs. • Diethylnitrosamine-induced DNA breakage at MLL and CBFB shown for the first time. • Chemical-induced DNA breakage occurs at topoisomerase II cleavage sites. • Chemical-induced DNA breaks display a pattern similar to those in leukemia patients. • Long-term exposures suggested to generate DNA breakage at leukemia-related genes. - Abstract: Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The

  19. Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells

    International Nuclear Information System (INIS)

    Thys, Ryan G.; Lehman, Christine E.; Pierce, Levi C.T.; Wang, Yuh-Hwa

    2015-01-01

    Highlights: • Environmental/chemotherapeutic agents cause DNA breakage in MLL and CBFB in HSPCs. • Diethylnitrosamine-induced DNA breakage at MLL and CBFB shown for the first time. • Chemical-induced DNA breakage occurs at topoisomerase II cleavage sites. • Chemical-induced DNA breaks display a pattern similar to those in leukemia patients. • Long-term exposures suggested to generate DNA breakage at leukemia-related genes. - Abstract: Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The

  20. Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD–induced myeloproliferation

    Science.gov (United States)

    Matsuoka, Sahoko; Thongjuea, Supat; Jamieson, Lauren; Atkinson, Deborah; Kharazi, Shabnam; Suda, Toshio

    2017-01-01

    Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment. Competitive transplantation experiments established that Flt3-ITD compromises HSCs through an extrinsically mediated mechanism of disrupting HSC-supporting bone marrow stromal cells, with reduced numbers of endothelial and mesenchymal stromal cells showing increased inflammation-associated gene expression. Tumor necrosis factor (TNF), a cell-extrinsic potent negative regulator of HSCs, was overexpressed in bone marrow niche cells from FLT3-ITD mice, and anti-TNF treatment partially rescued the HSC phenotype. These findings, which establish that Flt3-ITD–driven myeloproliferation results in cell-extrinsic suppression of the normal HSC reservoir, are of relevance for several aspects of acute myeloid leukemia biology. PMID:28637883

  1. Particle dispersion and mixing induced by breaking internal gravity waves

    Science.gov (United States)

    Bouruet-Aubertot, Pascale; Koudella, C.; Staquet, C.; Winters, K. B.

    2001-01-01

    The purpose of this paper is to analyze diapycnal mixing induced by the breaking of an internal gravity wave — the primary wave — either standing or propagating. To achieve this aim we apply two different methods. The first method consists of a direct estimate of vertical eddy diffusion from particle dispersion while the second method relies upon potential energy budgets [Winters, K.B., Lombard, P.N., Riley, J.J., D'Asaro, E.A., 1995. J. Fluid Mech. 289, 115-128; Winters, K.B., D'Asaro, E.A., 1996. J. Fluid Mech. 317, 179-193]. The primary wave we consider is of small amplitude and is statically stable, a case for which the breaking process involves two-dimensional instabilities. The dynamics of the waves have been previously analyzed by means of two-dimensional direct numerical simulations [Bouruet-Aubertot, P., Sommeria, J., Staquet, C., 1995. J. Fluid Mech. 285, 265-301; Bouruet-Aubertot, P., Sommeria, J., Staquet, C., 1996. Dyn. Atmos. Oceans 29, 41-63; Koudella, C., Staquet, C., 1998. In: Davis, P. (Ed.), Proceedings of the IMA Conference on Mixing and Dispersion on Stably-stratified Flows, Dundee, September 1996. IMA Publication]. High resolution three-dimensional calculations of the same wave are also reported here [Koudella, C., 1999]. A local estimate of mixing is first inferred from the time evolution of sets of particles released in the flow during the breaking regime. We show that, after an early evolution dominated by shear effects, a diffusion law is reached and the dispersion coefficient is fairly independent of the initial seeding location of the particles in the flow. The eddy diffusion coefficient, K, is then estimated from the diapycnal diffusive flux. A good agreement with the value inferred from particle dispersion is obtained. This finding is of particular interest regarding the interpretation of in situ estimates of K inferred either from tracer dispersion or from microstructure measurements. Computation of the Cox number, equal to the

  2. Self-induced neutrino flavor conversion without flavor mixing

    International Nuclear Information System (INIS)

    Chakraborty, S.; Izaguirre, I.; Raffelt, G.G.; Hansen, R. S.

    2016-01-01

    Neutrino-neutrino refraction in dense media can cause self-induced flavor conversion triggered by collective run-away modes of the interacting flavor oscillators. The growth rates were usually found to be of order a typical vacuum oscillation frequency Δ m 2 /2E. However, even in the simple case of a ν e beam interacting with an opposite-moving ν-bar e beam, and allowing for spatial inhomogeneities, the growth rate of the fastest-growing Fourier mode is of order μ=√2 G F  n ν , a typical ν–ν interaction energy. This growth rate is much larger than the vacuum oscillation frequency and gives rise to flavor conversion on a much shorter time scale. This phenomenon of 'fast flavor conversion' occurs even for vanishing Δ m 2 /2E and thus does not depend on energy, but only on the angle distributions. Moreover, it does not require neutrinos to mix or to have masses, except perhaps for providing seed disturbances. We also construct a simple homogeneous example consisting of intersecting beams and study a schematic supernova model proposed by Ray Sawyer, where ν e and ν-bar e emerge with different zenith-angle distributions, the key ingredient for fast flavor conversion. What happens in realistic astrophysical scenarios remains to be understood

  3. Hematopoietic chimerism and transplantation tolerance: a role for regulatory T cells

    Directory of Open Access Journals (Sweden)

    Lise ePasquet

    2011-12-01

    Full Text Available The major obstacle in transplantation medicine is rejection of donor tissues by the host’s immune system. Immunosuppressive drugs can delay but not prevent loss of transplants, and their efficiency is strongly impacted by inter-individual pharmacokinetic differences. Moreover, due to the global immunosuppression induced and to the broad distribution of their targets amongst human tissues, these drugs have severe side effects. Induction of donor-specific non-responsiveness (i.e. immunological tolerance to transplants would solve these problems and would substantially ameliorate patients’ quality of life. It is widely believed that bone marrow or hematopoietic stem cell transplantation, and resulting (mixed hematopoietic chimerism, invariably leads to immunological tolerance to organs of the same donor. A careful analysis of the literature, reviewed here, indeed shows that chimerism consistently prolongs allograft survival. However, in absence of additional conditioning leading to the development of active regulatory mechanisms, it does not prevent chronic rejection. A central role for active tolerance in transplantation-tolerance is also supported by recent data showing that genuine immunological tolerance to organ allografts can be achieved by combining induction of hematopoietic chimerism with infusion of regulatory T lymphocytes. Therefore, conditioning regimens that lead to the establishment of hematopoietic chimerism plus active regulatory mechanisms appear required for induction of genuine tolerance to allogeneic grafts.

  4. The therapeutic effect of a preparation extracted from tremella fuciformic berk (TFP) on the hematopoietic residual injury in mice induced by fractionated doses of 60Co γ-ray exposures

    International Nuclear Information System (INIS)

    Lu Shaoping; Yang Fengtong; Xu Chengxiong

    1989-01-01

    Hematopoietic residual injury, which is identified by the permanent defect of the blood forming system, could be induced in mice by repeated sublethal 60 Co γ-ray exposures. The number of hematopoietic stem cells (CFU-S) in mouse femora could be enhanced to a normal or near normal level if the 3 or 5 doses of 4.0 Gy irradiated mice were treated with a preparation extracted from an edible fungus Tremella Fuciformis Berk (TFP) 2 months after the irradiation. The number of endogenous spleen colonies and the spleen weight also increased markedly after the treatment. Because of the similarity found in the changes of hemaopoietic functions between the mice of residual injury and the patients of aplastic anemia, it is suggested that TFP may be useful to the patients of such blood disorder

  5. Clozapine-induced severe mixed hyperlipidemia: a case report.

    LENUS (Irish Health Repository)

    Ahmed, Mohamed

    2009-01-01

    To highlight the association between the use of clozapine and the early development of severe mixed hyperlipidemia, a condition that substantially increases the risk of cardiovascular events and other medical complications.

  6. In Utero Hematopoietic Cell Transplantation for Hemoglobinopathies

    Directory of Open Access Journals (Sweden)

    Tippi C. Mackenzie

    2015-01-01

    Full Text Available In utero hematopoietic cell transplantation (IUHCTx is a promising strategy to circumvent the challenges of postnatal hematopoietic stem cell (HSC transplantation. The goal of IUHCTx is to introduce donor cells into a naïve host prior to immune maturation, thereby inducing donor–specific tolerance. Thus, this technique has the potential of avoiding host myeloablative conditioning with cytotoxic agents. Over the past two decades, several attempts at IUHCTx have been made to cure numerous underlying congenital anomalies with limited success. In this review, we will briefly review the history of IUHCTx and give a perspective on alpha thalassemia major, one target disease for its clinical application.

  7. Inhibition of G1-phase arrest induced by ionizing radiation in hematopoietic cells by overexpression of genes involved in the G1/S-phase transition

    International Nuclear Information System (INIS)

    Epperly, M.; Berry, L.; Halloran, A.; Greenberger, J.S.

    1995-01-01

    D-type cyclins and cyclin-dependent kinase (cdk-4) are likely involved in regulating passage of cells through the G 1 phase of the cell cycle. A decrease in the proportion of cells in G 1 , a relatively radiation-sensitive phase of the cell cycle, should result in increased resistance to ionizing radiation; however, the effect of such overexpression on X-ray-induced G 1 -phase arrest is not known. Radiation survival curves were obtained at a dose rate of either 8 cGy/min or 1 Gy/min for subclones of the IL-3-dependent hematopoietic progenitor cell line 32D cl 3 expressing transgenes for either cyclin-D1, D2 or D3 or cdk-4. We compared the results to those with overexpression of the transgene for Bcl-2, whose expression enhances radiation survival and delays apoptosis. Cells overexpressing transgenes for each D-type cyclin or Bcl-2 had an increased number of cells in S phase compared to parent line 32D cl 3; however, overexpression of cdk-4 had no effect on cell cycle distribution. Cell death resulting from withdrawal of IL-3 was not affected by overexpression of D2, cdk-4 or Bcl-2. Flow cytometry 24 h after 5 Gy irradiation demonstrated that overexpression of each G 1 -phase regulatory transgene decreased the proportion of cells at the G 1 /S-phase border. Western analysis revealed induction of cyclin-D protein levels by irradiation, but no change in the D O , but a significant increase in the rvec n for cyclin-D or cdk-4 transgene-overexpressing clones at 1 Gy/min (P 1 /S-phase arrest. 31 refs., 4 figs., 4 tabs

  8. Turbulent mixing induced by Richtmyer-Meshkov instability

    Science.gov (United States)

    Krivets, V. V.; Ferguson, K. J.; Jacobs, J. W.

    2017-01-01

    Richtmyer-Meshkov instability is studied in shock tube experiments with an Atwood number of 0.7. The interface is formed in a vertical shock tube using opposed gas flows, and three-dimensional random initial interface perturbations are generated by the vertical oscillation of gas column producing Faraday waves. Planar Laser Mie scattering is used for flow visualization and for measurements of the mixing process. Experimental image sequences are recorded at 6 kHz frequency and processed to obtain the time dependent variation of the integral mixing layer width. Measurements of the mixing layer width are compared with Mikaelian's [1] model in order to extract the growth exponent θ where a fairly wide range of values is found varying from θ ≈ 0.2 to 0.6.

  9. Intermediate heat exchanger tube vibration induced by cross and parallel mixed flow

    International Nuclear Information System (INIS)

    Kawamura, Koji

    1986-01-01

    The characteristics of pool type LMFBR intermediate heat exchanger (IHX) tube vibrations induced by cross and parallel mixed flow were basically investigated. Secondary coolant in IHX tube bundle is mixed flow of parallel jit flow along the tube axis through flow holes in baffle plates and cross flow. By changing these two flow rate, flow distributions vary in the tube bundle. Mixed flow also induces vibrations which cause fretting wear and fatigue of tube. It is therefore very important to evaluate the tube vibration characteristics for estimating the tube integrity. The results show that the relationships between tube vibrations and flow distributions in the tube bundle were cleared, and mixed flow induced tube vibration could be evaluated on the base of the characteristics of both parallel and cross flow induced vibration. From these investigations it could be concluded that the characteristics of tube vibration for various flow distributions can be systematically evaluated. (author)

  10. Use of moisture induced stress testing to evaluate stripping potential of hot mix asphalt (HMA).

    Science.gov (United States)

    2012-07-01

    Stripping of hot mix asphalt (HMA) in the field is an ongoing issue for many Departments of Transportation : (DOTs). A leading cause of stripping is hydraulic scouring. The Moisture Induced Stress Tester (MIST) is a recently : developed technology th...

  11. Influence of thermal effects induced by nonlinear absorption on four-wave mixing in silicon waveguides

    DEFF Research Database (Denmark)

    Pu, Minhao; Chen, Yaohui; Yvind, Kresten

    2014-01-01

    Influence of thermal effects induced by nonlinear absorption on four-wave mixing in silicon waveguides is investigated. A conversion bandwidth reduction up to 63% is observed in simulation due to the thermal effects.......Influence of thermal effects induced by nonlinear absorption on four-wave mixing in silicon waveguides is investigated. A conversion bandwidth reduction up to 63% is observed in simulation due to the thermal effects....

  12. Formaldehyde and co-exposure with benzene induce compensation of bone marrow and hematopoietic stem/progenitor cells in BALB/c mice during post-exposure period

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Chenxi [Key Laboratory of Ecological Safety Monitoring and Evaluation, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan (China); Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China); Chen, Mouying [Key Laboratory of Ecological Safety Monitoring and Evaluation, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan (China); You, Huihui [Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China); Qiu, Feng [Key Laboratory of Ecological Safety Monitoring and Evaluation, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan (China); Wen, Huaxiao; Yuan, Junlin [Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China); Xiang, Shuanglin, E-mail: xshlin@hunnu.edu.cn [Key Laboratory of Ecological Safety Monitoring and Evaluation, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan (China); Yang, Xu, E-mail: yangxu@mail.ccnu.edu.cn [Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China)

    2017-06-01

    Formaldehyde (FA) is a human leukemogen. Since there is a latency period between initial FA exposure and the development of leukemia, the subsequent impact of FA on hematopoietic stem or progenitor cells (HSCs/HPCs) in post-exposure stage is crucial for a deep understanding of FA-induced hematotoxicity. BALB/c mice were exposed to 3 mg/m{sup 3} FA for 2 weeks, mimicking occupational exposure, and were monitored for another 7 days post-exposure. Meanwhile, we included benzene (BZ) as a positive control, separately and together with FA because co-exposure occurs frequently. After 7-day recovery, colonies of progenitors for CFU-GM and BFU-E, and nucleated bone marrow cells in FA-exposed mice were comparable to controls, although they were significantly reduced during exposure. Levels of reactive oxygen species (ROS) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in CFU-GM and BFU-E from FA-exposed mice were higher than controls, although the increase in 8-OHdG was not significant. Granulocyte-macrophage colony stimulating factor (GM-CSF) level in the FA group was lower than controls, but the expression level for the receptor was not upregulated. It suggests that HSCs/HPCs in FA-exposed mice respond to a small amount of GM-CSF and proliferate rapidly, which may cause a possible risk of expansion of abnormal stem/progenitor cell clones. FA co-exposure with BZ was more potent for promoting CFU-GM formation and inducing ROS in BFU-E and 8-OHdG in CFU-GM during the post-exposure period. The compensation of myeloid progenitors with elevated ROS and 8-OHdG may lead to a risk of transforming normal HSCs/HPCs to leukemic stem/progenitor cells. Thus, co-exposure may pose a greater leukemia risk. - Highlights: • Nucleated bone marrow cell count recovered after 7 days post-FA and/or BZ exposure. • CFU-GM showed an increase in colonies and 8-OHdG after 7 days post-FA + BZ exposure. • Levels of ROS in CFU-GM and BFU-E were increased by FA or FA + BZ during recovery. • Levels of

  13. Formaldehyde and co-exposure with benzene induce compensation of bone marrow and hematopoietic stem/progenitor cells in BALB/c mice during post-exposure period

    International Nuclear Information System (INIS)

    Wei, Chenxi; Chen, Mouying; You, Huihui; Qiu, Feng; Wen, Huaxiao; Yuan, Junlin; Xiang, Shuanglin; Yang, Xu

    2017-01-01

    Formaldehyde (FA) is a human leukemogen. Since there is a latency period between initial FA exposure and the development of leukemia, the subsequent impact of FA on hematopoietic stem or progenitor cells (HSCs/HPCs) in post-exposure stage is crucial for a deep understanding of FA-induced hematotoxicity. BALB/c mice were exposed to 3 mg/m 3 FA for 2 weeks, mimicking occupational exposure, and were monitored for another 7 days post-exposure. Meanwhile, we included benzene (BZ) as a positive control, separately and together with FA because co-exposure occurs frequently. After 7-day recovery, colonies of progenitors for CFU-GM and BFU-E, and nucleated bone marrow cells in FA-exposed mice were comparable to controls, although they were significantly reduced during exposure. Levels of reactive oxygen species (ROS) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in CFU-GM and BFU-E from FA-exposed mice were higher than controls, although the increase in 8-OHdG was not significant. Granulocyte-macrophage colony stimulating factor (GM-CSF) level in the FA group was lower than controls, but the expression level for the receptor was not upregulated. It suggests that HSCs/HPCs in FA-exposed mice respond to a small amount of GM-CSF and proliferate rapidly, which may cause a possible risk of expansion of abnormal stem/progenitor cell clones. FA co-exposure with BZ was more potent for promoting CFU-GM formation and inducing ROS in BFU-E and 8-OHdG in CFU-GM during the post-exposure period. The compensation of myeloid progenitors with elevated ROS and 8-OHdG may lead to a risk of transforming normal HSCs/HPCs to leukemic stem/progenitor cells. Thus, co-exposure may pose a greater leukemia risk. - Highlights: • Nucleated bone marrow cell count recovered after 7 days post-FA and/or BZ exposure. • CFU-GM showed an increase in colonies and 8-OHdG after 7 days post-FA + BZ exposure. • Levels of ROS in CFU-GM and BFU-E were increased by FA or FA + BZ during recovery. • Levels of GM

  14. Mycobacterium genavense-induced spindle cell pseudotumor in a pediatric hematopoietic stem cell transplant recipient: Case report and review of the literature.

    Science.gov (United States)

    Coelho, Ritika; Hanna, Rabi; Flagg, Aron; Stempak, Lisa M; Ondrejka, Sarah; Procop, Gary W; Harrington, Susan; Zembillas, Anthony; Kusick, Karissa; Gonzalez, Blanca E

    2017-04-01

    We describe the first reported pediatric patient to our knowledge with a spindle cell pseudotumor caused by Mycobacterium genavense in a hematopoietic stem cell transplant recipient, and review the literature of such an entity in the transplant population. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Mixed

    Directory of Open Access Journals (Sweden)

    Pau Baya

    2011-05-01

    Full Text Available Remenat (Catalan (Mixed, "revoltillo" (Scrambled in Spanish, is a dish which, in Catalunya, consists of a beaten egg cooked with vegetables or other ingredients, normally prawns or asparagus. It is delicious. Scrambled refers to the action of mixing the beaten egg with other ingredients in a pan, normally using a wooden spoon Thought is frequently an amalgam of past ideas put through a spinner and rhythmically shaken around like a cocktail until a uniform and dense paste is made. This malleable product, rather like a cake mixture can be deformed pulling it out, rolling it around, adapting its shape to the commands of one’s hands or the tool which is being used on it. In the piece Mixed, the contortion of the wood seeks to reproduce the plasticity of this slow heavy movement. Each piece lays itself on the next piece consecutively like a tongue of incandescent lava slowly advancing but with unstoppable inertia.

  16. Mixed chimerism to induce tolerance for solid organ transplantation

    International Nuclear Information System (INIS)

    Wren, S.M.; Nalesnik, M.; Hronakes, M.L.; Oh, E.; Ildstad, S.T.

    1991-01-01

    Chimerism, or the coexistence of tissue elements from more than one genetically different strain or species in an organism, is the only experimental state that results in the induction of donor-specific transplantation tolerance. Transplantation of a mixture of T-cell-depleted syngeneic (host-type) plus T-cell-depleted allogeneic (donor) bone marrow into a normal adult recipient mouse (A + B----A) results in mixed allogeneic chimerism. Recipient mice exhibit donor-specific transplantation tolerance, yet have full immunocompetence to recognize and respond to third-party transplantation antigens. After complete hematolymphopoietic repopulation at 28 days, animals accept a donor-specific skin graft but reject major histocompatibility complex (MHC) locus-disparate third-party grafts. We now report that permanent graft acceptance can also be achieved when the graft is placed at the time of bone marrow transplantation. Histologically, grafts were viable and had only minimal inflammatory changes. This model may have potential future clinical application for the induction of donor-specific transplantation tolerance

  17. Laser induced fluorescence measurements of the mixing of fuel oil with air

    Energy Technology Data Exchange (ETDEWEB)

    Arnold, A; Bombach, R; Hubschmid, W; Kaeppeli, B [Paul Scherrer Inst. (PSI), Villigen (Switzerland)

    1999-08-01

    We report on measurements of the mixing of fuel oil with air at atmospheric pressure in an industrial premixed gas turbine burner. The concentration of the vaporized fuel oil was measured with laser induced fluorescence. We reason that the fuel oil concentration can be considered with good accuracy as proportional to the fluorescence intensity. (author) 6 fig., 3 refs.

  18. Modeling of combined physical-mechanical moisture induced damage in asphaltic mixes

    NARCIS (Netherlands)

    Kringos, N.

    2007-01-01

    Moisture induced damage in asphaltic mixes is recognized as a major issue, resulting to the need for frequent maintenance operations. This does not only imply high maintenance costs, but also temporary closure of traffic and hence increased road congestion. Given the high costs for the road

  19. Tapak liman (Elephantopus scaber L) extract-induced CD4+ and CD8+ differentiation from hematopoietic stem cells and progenitor cell proliferation in mice (Mus musculus L)

    Science.gov (United States)

    Djati, Muhammad Sasmito; Habibu, Hindun; Jatiatmaja, Nabilah A.; Rifa'i, Muhaimin

    2017-11-01

    Tapak Liman (Elephantopus scaber L) is a traditional medicinal plant containing several active compounds that potentially affecting hematopoietic stem cells, such as epifrieelinol, lupeol, stigmasterol, triacontane-1-ol, dotriacontane-1-ol, lupeol acetate, deoxyelephan-topin, isodeoxyelephantopin, polyphenol luteolin-7, as well as various flavonoids and glucosides. The aim of this study was to elucidate the effect of leaf extract of Tapak Liman on hematopoietic stem cells in mice BALB/c, by observation of the relative number of cells expressing CD4/CD8, CD4/CD62L, and TER119/B220 in the spleen, and TER119/B220, TER119/VLA-4 and TER119/CD34 in bone marrow, after being administered leaf extract for 2 weeks. This experiment used 12 female mice, which were divided into three treatment groups, P1= 0.5 g.g bw-1.day-1, P2= 1.0 g.g bw-1.day-1 and P3=2.0 g.g bw-1.day-1 Tapak Liman leaf extract as well as a control. The relative numbers of cells expressing surface molecules were analyzed by flowcytometry and quantitative data were tested using one-way ANOVA. The results showed that the leaf extract of Tapak Liman has no significant effect on erythrocyte proliferation; on the other hand, it had a significant effect on both proliferation and differentiation of B lymphocytes (B220+) in bone marrow (p=0.044) and increased the expression of CD4+, CD8+ molecule in B cells (p=0.026) and erythroid cells in spleen and bone marrow, based on the estimation of cells that expressed TER119+VLA-4+, identified as important in the development pathway of erythrocytes. An increased cell percentage of TER11+VLA-4+ occurred for treatment P2, 12% higher than the control. The increased expression of TER119+VLA-4+ was assumed to be due to the iron content in Tapak Liman, which functioned to stimulate the progenitor hematopoietic cells to proliferate and differentiate into a precursor of erythroid cells (TER119+VLA-4+). There was an increasing number of cells expressing the surface molecules TER119

  20. Surface solitons of four-wave mixing in an electromagnetically induced lattice

    International Nuclear Information System (INIS)

    Zhang, Yanpeng; Yuan, Chenzhi; Zhang, Yiqi; Zheng, Huaibin; Chen, Haixia; Li, Changbiao; Wang, Zhiguo; Xiao, Min

    2013-01-01

    By creating lattice states with two-dimensional spatial periodic atomic coherence, we report an experimental demonstration of generating two-dimensional surface solitons of a four-wave mixing signal in an electromagnetically induced lattice composed of two electromagnetically induced gratings with different orientations in an atomic medium, each of which can support a one-dimensional surface soliton. The surface solitons can be well controlled by different experimental parameters, such as probe frequency, pump power, and beam incident angles, and can be affected by coherent induced defect states. (letter)

  1. Progress in understanding turbulent mixing induced by Rayleigh-Taylor and Richtmyer-Meshkov instabilities

    International Nuclear Information System (INIS)

    Zhou Ye; Remington, B.A.; Robey, H.F.; Cook, A.W.; Glendinning, S.G.; Dimits, A.; Buckingham, A.C.; Zimmerman, G.B.; Burke, E.W.; Peyser, T.A.; Cabot, W.; Eliason, D.

    2003-01-01

    Turbulent hydrodynamic mixing induced by the Rayleigh-Taylor (RT) and Richtmyer-Meshkov (RM) instabilities occurs in settings as varied as exploding stars (supernovae), inertial confinement fusion (ICF) capsule implosions, and macroscopic flows in fluid dynamics facilities such as shock tubes. Turbulence theory and modeling have been applied to RT and RM induced flows and developed into a quantitative description of turbulence from the onset to the asymptotic end-state. The treatment, based on a combined approach of theory, direct numerical simulation (DNS), and experimental data analysis, has broad generality. Three areas of progress will be reported. First, a robust, easy to apply criteria will be reported for the mixing transition in a time-dependent flow. This allows an assessment of whether flows, be they from supernova explosions or ICF experiments, should be mixed down to the molecular scale or not. Second, through DNS, the structure, scaling, and spectral evolution of the RT instability induced flow will be inspected. Finally, using these new physical insights, a two-scale, dynamic mix model has been developed that can be applied to simulations of ICF experiments and astrophysics situations alike

  2. Studies on mechanism of treatment of granulocyte colony-stimulating factor, recombinant human interleukin-11 and recombinant human interleukin-2 on hematopoietic injuries induced by 4.5 Gy γ-rays irradiation in beagles

    International Nuclear Information System (INIS)

    Li Ming; Ou Hongling; Xing Shuang; Huang Haixiao; Xiong Guolin; Xie Ling; Zhao Yanfang; Zhao Zhenhu; Wang Ning; Wang Jinxiang; Miao Jingcheng; Zhu Nankang; Luo Qingliang; Cong Yuwen; Zhang Xueguang

    2010-01-01

    Objective: To investigate the mechanism of treatment of granulocyte colony-stimulating factor (rhG-CSF), recombinant human interleukin-11 (rhIL-11) and recombinant human interleukin-2 (rhIL-2) on hematopoietic injuries induced by 4.5 Gy 60 Co γ-ray irradiation in beagles, and to provide experimental evidence for the clinical treatment of extremely severe myeloid acute radiation sickness (ARS). Methods: Sixteen beagle dogs were given 4.5 Gy 60 Co γ-ray total body irradiation (TBI), then randomly assigned into irradiation control group, supportive care group or cytokines + supportive care (abbreviated as cytokines) group. In addition to supportive care, rhG-CSF, rhIL-11 and rhIL-2 were administered subcutaneously to treat dogs in cytokines group. The percentage of CD34 + cells, cell cycle and apoptosis of nucleated cells in peripheral blood were examined by Flow cytometry. Results: After 4.5 Gy 60 Co γ-ray irradiation, the CD34 + cells in peripheral blood declined obviously (61.3% and 52.1% of baseline for irradiation control and supportive care group separately). The cell proportion of nucleated cells in G 0 /G 1 phase was increased notably notably (99.27% and 99.49% respectively). The rate of apoptosis (26.93% and 21.29% separately) and necrosis (3.27% and 4.14%, respectively) of nucleated cells were elevated significantly when compared with values before irradiation (P 0 /G 1 phase blockage of nucleated cells became more serious (99.71%). The rate of apoptosis (5.66%) and necrosis (1.60%) of nucleated cells were significantly lower than that of irradiation control and supportive care groups 1 d after exposure. Conclusions: Cytokines maybe mobilize CD34 + cells in bone marrow to peripheral blood, indce cell block at G 0 /G 1 phase and reduce apoptosis, and eventually cure hematopoietic injuries induced by irradiation. (authors)

  3. A novel serum-free monolayer culture for orderly hematopoietic differentiation of human pluripotent cells via mesodermal progenitors.

    Directory of Open Access Journals (Sweden)

    Akira Niwa

    Full Text Available Elucidating the in vitro differentiation of human embryonic stem (ES and induced pluripotent stem (iPS cells is important for understanding both normal and pathological hematopoietic development in vivo. For this purpose, a robust and simple hematopoietic differentiation system that can faithfully trace in vivo hematopoiesis is necessary. In this study, we established a novel serum-free monolayer culture that can trace the in vivo hematopoietic pathway from ES/iPS cells to functional definitive blood cells via mesodermal progenitors. Stepwise tuning of exogenous cytokine cocktails induced the hematopoietic mesodermal progenitors via primitive streak cells. These progenitors were then differentiated into various cell lineages depending on the hematopoietic cytokines present. Moreover, single cell deposition assay revealed that common bipotential hemoangiogenic progenitors were induced in our culture. Our system provides a new, robust, and simple method for investigating the mechanisms of mesodermal and hematopoietic differentiation.

  4. Rayleigh-Taylor and Richtmyer-Meshkov instability induced flow, turbulence, and mixing. I

    Science.gov (United States)

    Zhou, Ye

    2017-12-01

    Rayleigh-Taylor (RT) and Richtmyer-Meshkov (RM) instabilities play an important role in a wide range of engineering, geophysical, and astrophysical flows. They represent a triggering event that, in many cases, leads to large-scale turbulent mixing. Much effort has been expended over the past 140 years, beginning with the seminal work of Lord Rayleigh, to predict the evolution of the instabilities and of the instability-induced mixing layers. The objective of Part I of this review is to provide the basic properties of the flow, turbulence, and mixing induced by RT, RM, and Kelvin-Helmholtz (KH) instabilities. Historical efforts to study these instabilities are briefly reviewed, and the significance of these instabilities is discussed for a variety of flows, particularly for astrophysical flows and for the case of inertial confinement fusion. Early experimental efforts are described, and analytical attempts to model the linear, and nonlinear regimes of these mixing layers are examined. These analytical efforts include models for both single-mode and multi-mode initial conditions, as well as multi-scale models to describe the evolution. Comparisons of these models and theories to experimental and simulation studies are then presented. Next, attention is paid to the issue of the influence of stabilizing mechanisms (e.g., viscosity, surface tension, and diffuse interface) on the evolution of these instabilities, as well as the limitations and successes of numerical methods. Efforts to study these instabilities and mixing layers using group-theoretic ideas, as well as more formal notions of turbulence cascade processes during the later stages of the induced mixing layers, are inspected. A key element of the review is the discussion of the late-time self-similar scaling for the RT and RM growth factors, α and θ. These parameters are influenced by the initial conditions and much of the observed variation can be explained by this. In some cases, these instabilities

  5. Enhancement of four-wave mixing induced by interacting dark resonances

    International Nuclear Information System (INIS)

    Yang Weifeng; Gong Shangqing; Niu Yueping; Jin Shiqi; Xu Zhizhan

    2005-01-01

    We analyse a four-wave mixing (FWM) scheme in a five-level atomic system in which double-dark resonances are present. It is found that the enhancement of FWM in both electromagnetically induced transparency (EIT) windows can be obtained even without the condition of multiphoton resonance. Moreover, the conversion efficiency of FWM in one EIT window can be much larger than that in the other due to the presence of interacting dark resonances

  6. Semipermeable membrane devices concentrate mixed function oxygenase inducers from oil sands and refinery wastewaters

    International Nuclear Information System (INIS)

    Parrott, J.L.; Hewitt, L.M.

    2002-01-01

    The health of fish in the Athabasca River was examined to determine the effects of both natural and anthropogenic oil sands exposure on liver mixed function oxygenase (MFO) enzymes. Semipermeable membrane devices (SPMD) were used to concentrate bioavailable compounds that may result in MFO induction. The SPMDs were used for a period of 2 weeks in the Steepbank River as well as in oil refinery wastewater and intake ponds. They were then tested to see if they induced ethoxyresorufin-O-deethylase (EROD) activity in hepatoma cells, a cell line derived from a liver cancer of a small fish. SPMDs from the wastewater pond contained potent EROD inducers in fish liver cells. SPMDs from the Athabasca River exhibited some EROD inducers, but they were 1/100 as potent as those of the refinery wastewater. The characteristics of MFO inducers from refinery wastewater were different from natural inducers from the oil sands in the Athabasca and Steepbank Rivers. For instance, log Kow was less than 5 for refinery wastewater, but it was greater than 5 for Athabasca River wastewater and from natural oil sands exposure. In the case of the Steepbank River, the pattern of MFO induction was similar to the MFO induction seen in wild fish.The highest MFO inducers were found to be in the area of the mine, suggesting and anthropogenic pollution source. The less potent inducers were in the area of the natural and undisturbed oil sands. Very few inducers were found outside of the oil sands formation

  7. Studies on hematopoietic cell apoptosis and the relative gene expression in irradiated mouse bone marrow

    International Nuclear Information System (INIS)

    Peng Ruiyun; Wang Dewen; Xiong Chengqi; Gao Yabing; Yang Hong; Cui Yufang; Wang Baozhen

    2001-01-01

    Objective: To study apoptosis and expressions bcl-2 and p53 in irradiated mouse bone marrow. Methods: LACA mice were irradiated with 60 Co γ-rays. By means of in situ terminal labelling, in situ hybridization and image analysis, the authors studied radiation-induced apoptosis of hematopoietic cells and the expressions of bcl-2 and p53. Results: The characteristics of apoptosis appeared in hematopoietic cells at 6 hrs after irradiation. The expression of bcl-2 was obviously decreased when apoptosis of hematopoietic cells occurred, whereas it increased in the early recovery phase; p53 protein increased during both apoptosis of hematopoietic cells and the recovery phase, and mutant type p53 DNA was positive only in the recovery phase. Conclusion: Radiation may induced apoptosis of hematopoietic cells in a dose-dependent manner; Both bcl-2 and p53 genes play an important role in apoptosis and recovery phase

  8. Xenon-ion-induced and thermal mixing of Co/Si bilayers and their interplay

    Science.gov (United States)

    Novaković, M.; Zhang, K.; Popović, M.; Bibić, N.; Hofsäss, H.; Lieb, K. P.

    2011-05-01

    Studies on ion-irradiated transition-metal/silicon bilayers demonstrate that interface mixing and silicide phase formation depend sensitively on the ion and film parameters, including the structure of the metal/Si interface. Thin Co layers e-gun evaporated to a thickness of 50 nm on Si(1 0 0) wafers were bombarded at room temperature with 400-keV Xe + ions at fluences of up to 3 × 10 16 cm -2. We used either crystalline or pre-amorphized Si wafers the latter ones prepared by 1.0-keV Ar-ion implantation. The as-deposited or Xe-ion-irradiated samples were then isochronally annealed at temperatures up to 700 °C. Changes of the bilayer structures induced by ion irradiation and/or annealing were investigated with RBS, XRD and HRTEM. The mixing rate for the Co/c-Si couples, Δ σ2/ Φ = 3.0(4) nm 4, is higher than the value expected for ballistic mixing and about half the value typical for spike mixing. Mixing of pre-amorphized Si is much weaker relative to crystalline Si wafers, contrary to previous results obtained for Fe/Si bilayers. Annealing of irradiated samples produces very similar interdiffusion and phase formation patterns above 400 °C as in the non-irradiated Co/Si bilayers: the phase evolution follows the sequence Co 2Si → CoSi → CoSi 2.

  9. Xenon-ion-induced and thermal mixing of Co/Si bilayers and their interplay

    International Nuclear Information System (INIS)

    Novakovic, M.; Zhang, K.; Popovic, M.; Bibic, N.; Hofsaess, H.; Lieb, K.P.

    2011-01-01

    Studies on ion-irradiated transition-metal/silicon bilayers demonstrate that interface mixing and silicide phase formation depend sensitively on the ion and film parameters, including the structure of the metal/Si interface. Thin Co layers e-gun evaporated to a thickness of 50 nm on Si(1 0 0) wafers were bombarded at room temperature with 400-keV Xe + ions at fluences of up to 3 x 10 16 cm -2 . We used either crystalline or pre-amorphized Si wafers the latter ones prepared by 1.0-keV Ar-ion implantation. The as-deposited or Xe-ion-irradiated samples were then isochronally annealed at temperatures up to 700 o C. Changes of the bilayer structures induced by ion irradiation and/or annealing were investigated with RBS, XRD and HRTEM. The mixing rate for the Co/c-Si couples, Δσ 2 /Φ = 3.0(4) nm 4 , is higher than the value expected for ballistic mixing and about half the value typical for spike mixing. Mixing of pre-amorphized Si is much weaker relative to crystalline Si wafers, contrary to previous results obtained for Fe/Si bilayers. Annealing of irradiated samples produces very similar interdiffusion and phase formation patterns above 400 o C as in the non-irradiated Co/Si bilayers: the phase evolution follows the sequence Co 2 Si → CoSi → CoSi 2 .

  10. [Clinical roles of vitamins in hematopoietic disorders].

    Science.gov (United States)

    Matsuda, M; Kanamaru, A

    1999-10-01

    Vitamins are essential organisms which promote various metabolisms and physiological systems. Several vitamins play important roles in hematopoietic system. Vitamin B12, C and folic acid are associated with DNA synthesis of erythroid nucleus, the deficiency of which causes the megaloblastic anemia. Some megaloblatic anemia and sideroblastic anemia might response to vitamin B1 and B6, respectively. Vitamin K participates in some coagulation factors in coagulation-fibrinogenolysis system. It has been reported that vitamins A, D and K potentially differentiate leukemic cells and then induce the apoptosis, suggesting that they would be new therapeutic agents in acute leukemia.

  11. Mixed Herbal Medicine Induced Diffuse Infiltrative Lung Disease: The HRCT and Histopathologic Findings

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Gyu; Shin, Eun A [Sanggye Paik Hospital, Inje University College of Medicine, Seoul (Korea, Republic of); Kim, Joung Sook [Mokdong Hospital, Ewha Womans University College of Medicine, Seoul (Korea, Republic of)

    2010-12-15

    The purpose of this study was to evaluate the high-resolution CT (HRCT) and pathologic findings of mixed herbal medicine-induced diffuse interstitial lung disease. Eight patients (6 women and 2 men, age range: 31 to 81 years, mean age: 51.4 years) who presented with cough or dyspnea after taking mixed herbal medicine were included in this study. All the patients underwent plain chest radiography and HRCT. We obtained pathologic specimens from 7 patients via fluoroscopy guided large bore cutting needle biopsy and transbronchial lung biopsy. All the patients were treated with steroid therapy. The most common HRCT finding was bilateral diffuse ground glass opacity (n=7), followed by peribronchial consolidation (n=5) and inter- or intralobular septal thickening (n=2). For the disease distribution, the lower lung zone was dominantly involved. The pathologic results of 7 patients were nonspecific interstitial pneumonia (n=3), bronchiolitis obliterans organizing pneumonia (n=2), hypersensitivity pneumonitis (n=1) and eosinophilic pneumonia (n=1). Irrespective of the pathologic results, all 8 patients improved clinically and radiologically after steroid treatment. The HRCT findings of mixed herbal medicine-induced diffuse infiltrative lung disease were mainly bilateral diffuse ground glass opacity, peribronchial consolidation and dominant involvement of the lower lung zone. Those pathologic findings were nonspecific and the differential diagnosis could include interstitial pneumonia, bronchiolitis obliterans organizing pneumonia, hypersensitivity pneumonitis and eosinophilic pneumonia

  12. Mixed Herbal Medicine Induced Diffuse Infiltrative Lung Disease: The HRCT and Histopathologic Findings

    International Nuclear Information System (INIS)

    Kim, Tae Gyu; Shin, Eun A; Kim, Joung Sook

    2010-01-01

    The purpose of this study was to evaluate the high-resolution CT (HRCT) and pathologic findings of mixed herbal medicine-induced diffuse interstitial lung disease. Eight patients (6 women and 2 men, age range: 31 to 81 years, mean age: 51.4 years) who presented with cough or dyspnea after taking mixed herbal medicine were included in this study. All the patients underwent plain chest radiography and HRCT. We obtained pathologic specimens from 7 patients via fluoroscopy guided large bore cutting needle biopsy and transbronchial lung biopsy. All the patients were treated with steroid therapy. The most common HRCT finding was bilateral diffuse ground glass opacity (n=7), followed by peribronchial consolidation (n=5) and inter- or intralobular septal thickening (n=2). For the disease distribution, the lower lung zone was dominantly involved. The pathologic results of 7 patients were nonspecific interstitial pneumonia (n=3), bronchiolitis obliterans organizing pneumonia (n=2), hypersensitivity pneumonitis (n=1) and eosinophilic pneumonia (n=1). Irrespective of the pathologic results, all 8 patients improved clinically and radiologically after steroid treatment. The HRCT findings of mixed herbal medicine-induced diffuse infiltrative lung disease were mainly bilateral diffuse ground glass opacity, peribronchial consolidation and dominant involvement of the lower lung zone. Those pathologic findings were nonspecific and the differential diagnosis could include interstitial pneumonia, bronchiolitis obliterans organizing pneumonia, hypersensitivity pneumonitis and eosinophilic pneumonia

  13. Effect of Induced Magnetic Field on MHD Mixed Convection Flow in Vertical Microchannel

    Science.gov (United States)

    Jha, B. K.; Aina, B.

    2017-08-01

    The present work presents a theoretical investigation of an MHD mixed convection flow in a vertical microchannel formed by two electrically non-conducting infinite vertical parallel plates. The influence of an induced magnetic field arising due to motion of an electrically conducting fluid is taken into consideration. The governing equations of the motion are a set of simultaneous ordinary differential equations and their exact solutions in dimensionless form have been obtained for the velocity field, the induced magnetic field and the temperature field. The expressions for the induced current density and skin friction have also been obtained. The effects of various non-dimensional parameters such as rarefaction, fluid wall interaction, the Hartmann number and the magnetic Prandtl number on the velocity, the induced magnetic field, the temperature, the induced current density, and skin friction have been presented in a graphical form. It is found that the effect of the Hartmann number and magnetic Prandtl number on the induced current density is found to have a decreasing nature at the central region of the microchannel.

  14. Analysis of unstable chromosome alterations frequency induced by neutron-gamma mixed field radiation

    International Nuclear Information System (INIS)

    Souza, Priscilla L.G.; Brandao, Jose Odinilson de C.; Vale, Carlos H.F.P.; Santos, Joelan A.L.; Vilela, Eudice C.; Lima, Fabiana F.; Calixto, Merilane S.; Santos, Neide

    2009-01-01

    Nowadays monitoring chromosome alterations in peripheral blood lymphocytes have been used to access the radiation absorbed dose in individuals exposed accidental or occupationally to gamma radiation. However there are not many studies based on the effects of mixed field neutron-gamma. The radiobiology of neutrons has great importance because in nuclear factories worldwide there are several hundred thousand individuals monitored as potentially receiving doses of neutron. In this paper it was observed the frequencies of unstable chromosome alterations induced by a gamma-neutron mixed field. Blood was obtained from one healthy donor and exposed to mixed field neutron-gamma sources 241 AmBe (20 Ci) at the Neutron Calibration Laboratory (NCL-CRCN/NE-PE-Brazil). The chromosomes were observed at metaphase, following colcemid accumulation and 1000 well-spread metaphases were analyzed for the presence of chromosome alterations by two experienced scorers. The results suggest that there is the possibility of a directly proportional relationship between absorbed dose of neutron-gamma mixed field radiation and the frequency of unstable chromosome alterations analyzed in this paper. (author)

  15. Analysis of unstable chromosome alterations frequency induced by neutron-gamma mixed field radiation

    Energy Technology Data Exchange (ETDEWEB)

    Souza, Priscilla L.G.; Brandao, Jose Odinilson de C.; Vale, Carlos H.F.P.; Santos, Joelan A.L.; Vilela, Eudice C.; Lima, Fabiana F. [Centro Regional de Ciencias Nucleares (CRCN-NE/CNEN-PE), Recife, PE (Brazil)], e-mail: psouza@cnen.gov.br, e-mail: jodinilson@cnen.gov.br; Calixto, Merilane S.; Santos, Neide [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Genetica

    2009-07-01

    Nowadays monitoring chromosome alterations in peripheral blood lymphocytes have been used to access the radiation absorbed dose in individuals exposed accidental or occupationally to gamma radiation. However there are not many studies based on the effects of mixed field neutron-gamma. The radiobiology of neutrons has great importance because in nuclear factories worldwide there are several hundred thousand individuals monitored as potentially receiving doses of neutron. In this paper it was observed the frequencies of unstable chromosome alterations induced by a gamma-neutron mixed field. Blood was obtained from one healthy donor and exposed to mixed field neutron-gamma sources {sup 241}AmBe (20 Ci) at the Neutron Calibration Laboratory (NCL-CRCN/NE-PE-Brazil). The chromosomes were observed at metaphase, following colcemid accumulation and 1000 well-spread metaphases were analyzed for the presence of chromosome alterations by two experienced scorers. The results suggest that there is the possibility of a directly proportional relationship between absorbed dose of neutron-gamma mixed field radiation and the frequency of unstable chromosome alterations analyzed in this paper. (author)

  16. Successful Sequential Liver and Hematopoietic Stem Cell Transplantation in a Child With CD40 Ligand Deficiency and Cryptosporidium-Induced Liver Cirrhosis.

    Science.gov (United States)

    Quarello, Paola; Tandoi, Francesco; Carraro, Francesca; Vassallo, Elena; Pinon, Michele; Romagnoli, Renato; David, Ezio; Dell Olio, Dominic; Salizzoni, Mauro; Fagioli, Franca; Calvo, Pier Luigi

    2018-05-01

    Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a 7-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in 1 young adult to date. A closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft. Combined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur. Hopefully, this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child will encourage others to adapt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies.

  17. Effect of radiation on normal hematopoiesis and on viral induced cancers of the hematopoietic system. Technical progress report, August 1, 1974--May 1, 1975

    International Nuclear Information System (INIS)

    Okunewick, J.P.

    1975-01-01

    Studies carried out during the above period on viral leukemia have conclusively shown that the pluripotent hematopoietic colony forming stem cell (CFU-S) is a target cell for the leukemia virus. Treatment of this cell population with antiserum prepared in syngeneic mice against the disease resulted in inactivation of up to 50 percent of the CFU-S obtained from the spleens of viral leukemic mice. At the same time, normal serum had no effect on these cells, nor did the antiserum have any effect on normal CFU-S. Data indicated that a considerable time delay, on the order of a week, preceded the expression of the viral antigen in the leukemic CFU-S, but that it could be seen at all times after that up to the terminal point of the disease. We examined the effect of the virus on DNA synthesis (S-phase cells) in the CFU-S immediately after virus injection. The results showed that a doubling of the number of cells in S could be seen as early as four hours after introduction of the virus into the animal. Studies with ethidium bromide, an inhibitor of viral reverse transcriptase, were found to be in agreement with this observation. When given to viral leukemic animals in combination with fractionated exposure to x-ray, the data suggested that ethidium bromide did act to extend survival somewhat, but not much over that seen through the use of x-ray alone

  18. Evaluation of the risk factors associated with high-dose chemotherapy-induced dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation: possible usefulness of cryotherapy in dysgeusia prevention.

    Science.gov (United States)

    Okada, Naoto; Hanafusa, Takeshi; Abe, Shinji; Sato, Chiemi; Nakamura, Toshimi; Teraoka, Kazuhiko; Abe, Masahiro; Kawazoe, Kazuyoshi; Ishizawa, Keisuke

    2016-09-01

    Dysgeusia is one of the sporadic adverse effects induced by chemotherapy, but it remains poorly understood. The aim of this study was to retrospectively identify the risk factors related with dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation (AHSCT). Forty-eight patients with myeloma or lymphoma undergoing AHSCT were enrolled in this study. Data regarding dysgeusia and symptoms were collected by interviews conducted by medical workers. Patient characteristics and unfavorable effects induced by dysgeusia were obtained from medical records and analyzed. Logistic regression analysis was performed to identify the risk factors related with dysgeusia. Of the 48 patients, 20 (42 %) had dysgeusia after AHSCT. The total period of parenteral nutrition (TPN) administration and period of decreased oral intake in the dysgeusia group were statistically longer than those in the non-dysgeusia group. Multivariate analyses revealed that oral mucositis (odds ratio: 30.3; p cryotherapy was the independent suppressive factor of dysgeusia (odds ratio: 0.14; p cryotherapy was an independent suppressive factor for dysgeusia. Therefore, oral cryotherapy should be implemented into the regimen of supportive care management in patients undergoing AHSCT.

  19. OP9-Lhx2 stromal cells facilitate derivation of hematopoietic progenitors both in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Xiaoli Chen

    2015-09-01

    Full Text Available Generating engraftable hematopoietic stem cells (HSCs from pluripotent stem cells (PSCs is an ideal approach for obtaining induced HSCs for cell therapy. However, the path from PSCs to robustly induced HSCs (iHSCs in vitro remains elusive. We hypothesize that the modification of hematopoietic niche cells by transcription factors facilitates the derivation of induced HSCs from PSCs. The Lhx2 transcription factor is expressed in fetal liver stromal cells but not in fetal blood cells. Knocking out Lhx2 leads to a fetal hematopoietic defect in a cell non-autonomous role. In this study, we demonstrate that the ectopic expression of Lhx2 in OP9 cells (OP9-Lhx2 accelerates the hematopoietic differentiation of PSCs. OP9-Lhx2 significantly increased the yields of hematopoietic progenitor cells via co-culture with PSCs in vitro. Interestingly, the co-injection of OP9-Lhx2 and PSCs into immune deficient mice also increased the proportion of hematopoietic progenitors via the formation of teratomas. The transplantation of phenotypic HSCs from OP9-Lhx2 teratomas but not from the OP9 control supported a transient repopulating capability. The upregulation of Apln gene by Lhx2 is correlated to the hematopoietic commitment property of OP9-Lhx2. Furthermore, the enforced expression of Apln in OP9 cells significantly increased the hematopoietic differentiation of PSCs. These results indicate that OP9-Lhx2 is a good cell line for regeneration of hematopoietic progenitors both in vitro and in vivo.

  20. Xenon-ion-induced and thermal mixing of Co/Si bilayers and their interplay

    Energy Technology Data Exchange (ETDEWEB)

    Novakovic, M. [VINCA Institute of Nuclear Sciences, 11001 Belgrade (Serbia); II. Physikalisches Institut, Georg-August-Universitaet Goettingen, Friedrich-Hund-Platz 1, 37077 Goettingen (Germany); Zhang, K. [II. Physikalisches Institut, Georg-August-Universitaet Goettingen, Friedrich-Hund-Platz 1, 37077 Goettingen (Germany); Popovic, M.; Bibic, N. [VINCA Institute of Nuclear Sciences, 11001 Belgrade (Serbia); II. Physikalisches Institut, Georg-August-Universitaet Goettingen, Friedrich-Hund-Platz 1, 37077 Goettingen (Germany); Hofsaess, H. [II. Physikalisches Institut, Georg-August-Universitaet Goettingen, Friedrich-Hund-Platz 1, 37077 Goettingen (Germany); Lieb, K.P., E-mail: plieb@gwdg.d [II. Physikalisches Institut, Georg-August-Universitaet Goettingen, Friedrich-Hund-Platz 1, 37077 Goettingen (Germany)

    2011-05-01

    Studies on ion-irradiated transition-metal/silicon bilayers demonstrate that interface mixing and silicide phase formation depend sensitively on the ion and film parameters, including the structure of the metal/Si interface. Thin Co layers e-gun evaporated to a thickness of 50 nm on Si(1 0 0) wafers were bombarded at room temperature with 400-keV Xe{sup +} ions at fluences of up to 3 x 10{sup 16} cm{sup -2}. We used either crystalline or pre-amorphized Si wafers the latter ones prepared by 1.0-keV Ar-ion implantation. The as-deposited or Xe-ion-irradiated samples were then isochronally annealed at temperatures up to 700 {sup o}C. Changes of the bilayer structures induced by ion irradiation and/or annealing were investigated with RBS, XRD and HRTEM. The mixing rate for the Co/c-Si couples, {Delta}{sigma}{sup 2}/{Phi} = 3.0(4) nm{sup 4}, is higher than the value expected for ballistic mixing and about half the value typical for spike mixing. Mixing of pre-amorphized Si is much weaker relative to crystalline Si wafers, contrary to previous results obtained for Fe/Si bilayers. Annealing of irradiated samples produces very similar interdiffusion and phase formation patterns above 400 {sup o}C as in the non-irradiated Co/Si bilayers: the phase evolution follows the sequence Co{sub 2}Si {yields} CoSi {yields} CoSi{sub 2}.

  1. Kynurenic Acid Prevents Cytoskeletal Disorganization Induced by Quinolinic Acid in Mixed Cultures of Rat Striatum.

    Science.gov (United States)

    Pierozan, Paula; Biasibetti-Brendler, Helena; Schmitz, Felipe; Ferreira, Fernanda; Pessoa-Pureur, Regina; Wyse, Angela T S

    2018-06-01

    Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan known to modulate a number of mechanisms involved in neural dysfunction. Although its activity in the brain has been widely studied, the effect of KYNA counteracting the actions of quinolinic acid (QUIN) remains unknown. The present study aims at describing the ability of 100 μM KYNA preventing cytoskeletal disruption provoked by QUIN in astrocyte/neuron/microglia mixed culture. KYNA totally preserved cytoskeletal organization, cell morphology, and redox imbalance in mixed cultures exposed to QUIN. However, KYNA partially prevented morphological alteration in isolated primary astrocytes and failed to protect the morphological alterations of neurons caused by QUIN exposure. Moreover, KYNA prevented QUIN-induced microglial activation and upregulation of ionized calcium-binding adapter molecule 1 (Iba-1) and partially preserved tumor necrosis factor-α (TNF-α) level in mixed cultures. TNF-α level was also partially preserved in astrocytes. In addition to the mechanisms dependent on redox imbalance and microglial activation, KYNA prevented downregulation of connexin-43 and the loss of functionality of gap junctions (GJs), preserving cell-cell contact, cytoskeletal organization, and cell morphology in QUIN-treated cells. Furthermore, the toxicity of QUIN targeting the cytoskeleton of mixed cultures was not prevented by the N-methyl-D-aspartate (NMDA) antagonist MK-801. We suggest that KYNA protects the integrity of the cytoskeleton of mixed cultures by complex mechanisms including modulating microglial activation preventing oxidative imbalance and misregulated GJs leading to disrupted cytoskeleton in QUIN-treated cells. This study contributed to elucidate the molecular basis of KYNA protection against QUIN toxicity.

  2. Parametrically tunable soliton-induced resonant radiation by three-wave mixing

    DEFF Research Database (Denmark)

    Zhou, Binbin; Liu, Xing; Guo, Hairun

    2017-01-01

    We show that a temporal soliton can induce resonant radiation by three-wave mixing nonlinearities. This constitutes a new class of resonant radiation whose spectral positions are parametrically tunable. The experimental verification is done in a periodically poled lithium niobate crystal, where...... a femtosecond near-IR soliton is excited and resonant radiation waves are observed exactly at the calculated soliton phasematching wavelengths via the sum- and difference-frequency generation nonlinearities. This extends the supercontinuum bandwidth well into the mid IR to span 550–5000 nm, and the mid-IR edge...

  3. Fluorescence and Four-Wave Mixing in Electromagnetically Induced Transparency Windows

    International Nuclear Information System (INIS)

    Wang Zhi-Guo; Li Cheng; Zhang Zhao-Yang; Che Jun-Ling; Qin Meng-Zhe; He Jia-Nan; Zhang Yan-Peng

    2013-01-01

    We simultaneously compare the probe transmission, Four-Wave Mixing (FWM) and fluorescence signals with dressing effects in a four-level atomic system. The variation rules of three types of signals are exhibited by changing the frequency detuning and power of incident laser beams. The interplay between two ladder subsystems is investigated in the Y-type atomic system. In particular, the fluorescence signal with ultra-narrow linewidth is obtained due to being sheared twice by the electromagnetically induced transparency window. Such fluorescence with very high coherence and monochromaticity can be used for the quantum correlation and narrow linewidth laser

  4. Differentiation of embryonic stem cells towards hematopoietic cells: progress and pitfalls.

    Science.gov (United States)

    Tian, Xinghui; Kaufman, Dan S

    2008-07-01

    Hematopoietic development from embryonic stem cells has been one of the most productive areas of stem cell biology. Recent studies have progressed from work with mouse to human embryonic stem cells. Strategies to produce defined blood cell populations can be used to better understand normal and abnormal hematopoiesis, as well as potentially improve the generation of hematopoietic cells with therapeutic potential. Molecular profiling, phenotypic and functional analyses have all been utilized to demonstrate that hematopoietic cells derived from embryonic stem cells most closely represent a stage of hematopoiesis that occurs at embryonic/fetal developmental stages. Generation of hematopoietic stem/progenitor cells comparable to hematopoietic stem cells found in the adult sources, such as bone marrow and cord blood, still remains challenging. However, genetic manipulation of intrinsic factors during hematopoietic differentiation has proven a suitable approach to induce adult definitive hematopoiesis from embryonic stem cells. Concrete evidence has shown that embryonic stem cells provide a powerful approach to study the early stage of hematopoiesis. Multiple hematopoietic lineages can be generated from embryonic stem cells, although most of the evidence suggests that hematopoietic development from embryonic stem cells mimics an embryonic/fetal stage of hematopoiesis.

  5. Wave-mixing-induced transparency with zero phase shift in atomic vapors

    Science.gov (United States)

    Zhou, F.; Zhu, C. J.; Li, Y.

    2017-12-01

    We present a wave-mixing induced transparency that can lead to a hyper-Raman gain-clamping effect. This new type of transparency is originated from a dynamic gain cancellation effect in a multiphoton process where a highly efficient light field of new frequency is generated and amplified. We further show that this novel dynamic gain cancellation effect not only makes the medium transparent to a probe light field at appropriate frequency but also eliminates the probe field propagation phase shift. This gain-cancellation-based induced transparency holds for many potential applications on optical communication and may lead to effective suppression of parasitic Raman/hyper-Raman noise field generated in high intensity optical fiber transmissions.

  6. Experimental Investigation of Jet-Induced Mixing of a Large Liquid Hydrogen Storage Tank

    Science.gov (United States)

    Lin, C. S.; Hasan, M. M.; Vandresar, N. T.

    1994-01-01

    Experiments have been conducted to investigate the effect of fluid mixing on the depressurization of a large liquid hydrogen storage tank. The test tank is approximately ellipsoidal, having a volume of 4.89 m(exp 3) and an average wall heat flux of 4.2 W/m(exp 2) due to external heat input. A mixer unit was installed near the bottom of the tank to generate an upward directed axial jet flow normal to the liquid-vapor interface. Mixing tests were initiated after achieving thermally stratified conditions in the tank either by the introduction of hydrogen gas into the tank or by self-pressurization due to ambient heat leak through the tank wall. The subcooled liquid jet directed towards the liquid-vapor interface by the mixer induced vapor condensation and caused a reduction in tank pressure. Tests were conducted at two jet submergence depths for jet Reynolds numbers from 80,000 to 495,000 and Richardson numbers from 0.014 to 0.52. Results show that the rate of tank pressure change is controlled by the competing effects of subcooled jet flow and the free convection boundary layer flow due to external tank wall heating. It is shown that existing correlations for mixing time and vapor condensation rate based on small scale tanks may not be applicable to large scale liquid hydrogen systems.

  7. Heat transfer in tube bundles of heat exchangers with flow baffles induced forced mixing

    International Nuclear Information System (INIS)

    AbuRomia, M.M.; Chu, A.W.; Cho, S.M.

    1976-01-01

    Thermal analysis of shell-and-tube heat exchangers is being investigated through geometric modeling of the unit configuration in addition to considering the heat transfer processes taking place within the tube bundle. The governing equations that characterize the heat transfer from the shell side fluid to the tube side fluid across the heat transfer tubewalls are indicated. The equations account for the heat transfer due to molecular conduction, turbulent thermal diffusion, and forced fluid mixing among various shell side fluid channels. The analysis, though general in principle, is being applied to the Clinch River Breeder Reactor Plant-Intermediate Heat Exchanger, which utilizes flow baffles appropriately designed for induced forced fluid mixing in the tube bundle. The results of the analysis are presented in terms of the fluid and tube wall temperature distributions of a non-baffled and baffled tube bundle geometry. The former case yields axial flow in the main bundle region while the latter is associated with axial/cross flow in the bundle. The radial components of the axial/cross flow yield the necessary fluid mixing that results in reducing the thermal unbalance among the heat transfer to the allowable limits. The effect of flow maldistribution, present on the tube or shell sides of the heat exchangers, in altering the temperature field of tube bundles is also noted

  8. Tritium contamination of hematopoietic stem cells alters long-term hematopoietic reconstitution

    International Nuclear Information System (INIS)

    Di Giacomo, F.; Barroca, V.; Laurent, D.; Lewandowski, D.; Saintigny, Y.; Romeo, P.H.; Granotier, Ch.; Boussin, F.D.

    2011-01-01

    Purpose: In vivo effects of tritium contamination are poorly documented. Here, we study the effects of tritiated Thymidine ([ 3 H] Thymidine) or tritiated water (HTO) contamination on the biological properties of hematopoietic stem cells (HSC). Materials and methods: Mouse HSC were contaminated with concentrations of [ 3 H] Thymidine ranging from 0.37-37.03 kBq/ml or of HTO ranging from 5-50 kBq/ml. The biological properties of contaminated HSC were studied in vitro after HTO contamination and in vitro and in vivo after [ 3 H] Thymidine contamination. Results: Proliferation, viability and double-strand breaks were dependent on [ 3 H] Thymidine or HTO concentrations used for contamination but in vitro myeloid differentiation of HSC was not affected by [ 3 H] Thymidine contamination. [ 3 H] Thymidine contaminated HSC showed a compromised long-term capacity of hematopoietic reconstitution and competition experiments showed an up to two-fold decreased capacity of contaminated HSC to reconstitute hematopoiesis. These defects were not due to impaired homing in bone marrow but to an initial decreased proliferation rate of HSC. Conclusion: These results indicate that contaminations of HSC with doses of tritium that do not result in cell death, induce short-term effects on proliferation and cell cycle and long-term effects on hematopoietic reconstitution capacity of contaminated HSC. (authors)

  9. Fluid Flow and Mixing Induced by AC Continuous Electrowetting of Liquid Metal Droplet

    Directory of Open Access Journals (Sweden)

    Qingming Hu

    2017-04-01

    Full Text Available In this work, we proposed a novel design of a microfluidic mixer utilizing the amplified Marangoni chaotic advection induced by alternating current (AC continuous electrowetting of a metal droplet situated in electrolyte solution, due to the linear and quadratic voltage-dependence of flow velocity at small or large voltages, respectively. Unlike previous researchers exploiting the unidirectional surface stress with direct current (DC bias at droplet/medium interface for pumping of electrolytes where the resulting flow rate is linearly proportional to the field intensity, dominance of another kind of dipolar flow pattern caused by local Marangoni stress at the drop surface in a sufficiently intense AC electric field is demonstrated by both theoretical analysis and experimental observation, which exhibits a quadratic growth trend as a function of the applied voltage. The dipolar shear stress merely appears at larger voltages and greatly enhances the mixing performance by inducing chaotic advection between the neighboring laminar flow. The mixer design developed herein, on the basis of amplified Marangoni chaotic advection around a liquid metal droplet at larger AC voltages, has great potential for chemical reaction and microelectromechanical systems (MEMS actuator applications because of generating high-throughput and excellent mixing performance at the same time.

  10. Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen

    International Nuclear Information System (INIS)

    Sharabi, Y.; Sachs, D.H.

    1989-01-01

    The use of allogeneic bone marrow transplantation as a means of inducing donor-specific tolerance across MHC barriers could provide an immunologically specific conditioning regimen for organ transplantation. However, a major limitation to this approach is the toxicity of whole body irradiation as currently used to abrogate host resistance and permit marrow engraftment. The present study describes methodology for abrogating host resistance and permitting marrow engraftment without lethal irradiation. Our preparative protocol involves administration of anti-CD4 and anti-CD8 mAbs in vivo, 300-rad WBI, 700-rad thymic irradiation, and unmanipulated fully MHC-disparate bone marrow. B10 mice prepared by this regimen developed stable mixed lymphohematopoetic chimerism without any clinical evidence of graft-vs.-host disease. Engraftment was accompanied by induction of specific tolerance to donor skin grafts (B10.D2), while third-party skin grafts (B10.BR) were promptly rejected. Mice treated with the complete regimen without bone marrow transplantation appeared healthy and enjoyed long-term survival. This study therefore demonstrates that stable mixed chimerism with donor-specific tolerance can be induced across an MHC barrier after a nonlethal preparative regimen, without clinical GVHD and without the risk of aplasia

  11. Stimulation of murine stem cell proliferation by circulating activities produced during the recovery of a radiation-induced hematopoietic injury. Estimulacion proliferativa de celulas madre hematopoyeticas de raton por actividades circulantes producidas durante la recuperacion de un dano hematopoyetico radioinducido

    Energy Technology Data Exchange (ETDEWEB)

    Grande Azanedo, M.T.

    1989-02-01

    The proliferative activity of CFU-S, low in normal steady state, increases after treatment with different aggressors, i.e., radiation. This stimulation has been attributed in part to a local regulation system of stem cell proliferation, and at least in part to a humoral regulatory system. In the present work it has been investigated the role that circulating activities have in the CFU-S stimulation, by means of in vitro and in vivo incubation assays with diffusion chambers. The results show that bone marrow of mice irradiated with 5 Gy produces in vitro diffusible activities capable of stimulating the CFU-S proliferation. As well with this same dose circulating activities are also produced in vivo. In addition we have observed that these activities are only released during the periods of active hematopoietic regeneration that follow irradiation with moderate doses (1.5 and 5 Gy). In another set of experiments we saw that the stimulating activities are also detected in serum of mice irradiated with 5 Gy. These serum activities modify the proliferative state of very primitive precursors (12 d CFU-S). When the serum activities are added to long term bone marrow cultures the CFU-S are also stimulated to proliferate. Finally, we observed that the radiation-induced serum activities stimulate the proliferation of bone marrow CFU-S when injected into normal mice, suggesting that such activities are involved in the regulation of CFU-S proliferation.

  12. Plerixafor (a CXCR4 antagonist following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery

    Directory of Open Access Journals (Sweden)

    Michael M. B. Green

    2016-08-01

    Full Text Available Abstract Background The binding of CXCR4 with its ligand (stromal-derived factor-1 maintains hematopoietic stem/progenitor cells (HSPCs in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT promotes hematopoiesis by inducing HSC proliferation. Methods We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. Results Thirty patients received plerixafor following peripheral blood stem cell (n = 28 (PBSC or bone marrow (n = 2 transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04 and platelet recovery >20 K (p = 0.04 compared to the controls. Conclusions Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. Trial registration ClinicalTrials.gov NCT01280955

  13. Early viral replication and induced or constitutive immunity in rainbow trout families with differential resistance to Infectious hematopoietic necrosis virus (IHNV)

    Science.gov (United States)

    Purcell, M.K.; LaPatra, S.E.; Woodson, J.C.; Kurath, G.; Winton, J.R.

    2010-01-01

    The main objective of this study was to assess correlates of innate resistance in rainbow trout full-sibling families that differ in susceptibility to Infectious hematopoietic necrosis virus (IHNV). As part of a commercial breeding program, full-sibling families were challenged with IHNV by waterborne exposure at the 1 g size to determine susceptibility to IHNV. Progeny from select families (N = 7 families) that varied in susceptibility (ranging from 32 to 90% cumulative percent mortality (CPM)) were challenged again at the 10 g size by intra-peritoneal injection and overall mortality, early viral replication and immune responses were evaluated. Mortality challenges included 20–40 fish per family while viral replication and immune response studies included 6 fish per family at each time point (24, 48 and 72 h post-infection (hpi)). CPM at the 1 g size was significantly correlated with CPM at the 10 g size, indicating that inherent resistance was a stable trait irrespective of size. In the larger fish, viral load was measured by quantitative reverse-transcriptase PCR in the anterior kidney and was a significant predictor of family disease outcome at 48 hpi. Type I interferon (IFN) transcript levels were significantly correlated with an individual's viral load at 48 and 72 hpi, while type II IFN gene expression was significantly correlated with an individual's viral load at 24 and 48 hpi. Mean family type I but not type II IFN gene expression was weakly associated with susceptibility at 72 hpi. There was no association between mean family susceptibility and the constitutive expression of a range of innate immune genes (e.g. type I and II IFN pathway genes, cytokine and viral recognition receptor genes). The majority of survivors from the challenge had detectable serum neutralizing antibody titers but no trend was observed among families. This result suggests that even the most resistant families experienced sufficient levels of viral replication to trigger specific

  14. Stereo Imaging Velocimetry of Mixing Driven by Buoyancy Induced Flow Fields

    Science.gov (United States)

    Duval, W. M. B.; Jacqmin, D.; Bomani, B. M.; Alexander, I. J.; Kassemi, M.; Batur, C.; Tryggvason, B. V.; Lyubimov, D. V.; Lyubimova, T. P.

    2000-01-01

    Mixing of two fluids generated by steady and particularly g-jitter acceleration is fundamental towards the understanding of transport phenomena in a microgravity environment. We propose to carry out flight and ground-based experiments to quantify flow fields due to g-jitter type of accelerations using Stereo Imaging Velocimetry (SIV), and measure the concentration field using laser fluorescence. The understanding of the effects of g-jitter on transport phenomena is of great practical interest to the microgravity community and impacts the design of experiments for the Space Shuttle as well as the International Space Station. The aim of our proposed research is to provide quantitative data to the community on the effects of g-jitter on flow fields due to mixing induced by buoyancy forces. The fundamental phenomenon of mixing occurs in a broad range of materials processing encompassing the growth of opto-electronic materials and semiconductors, (by directional freezing and physical vapor transport), to solution and protein crystal growth. In materials processing of these systems, crystal homogeneity, which is affected by the solutal field distribution, is one of the major issues. The understanding of fluid mixing driven by buoyancy forces, besides its importance as a topic in fundamental science, can contribute towards the understanding of how solutal fields behave under various body forces. The body forces of interest are steady acceleration and g-jitter acceleration as in a Space Shuttle environment or the International Space Station. Since control of the body force is important, the flight experiment will be carried out on a tunable microgravity vibration isolation mount, which will permit us to precisely input the desired forcing function to simulate a range of body forces. To that end, we propose to design a flight experiment that can only be carried out under microgravity conditions to fully exploit the effects of various body forces on fluid mixing. Recent

  15. Investigation of radioprotective effect of indraline of hematopoietic system in different species of animal

    International Nuclear Information System (INIS)

    Vasin, M.V.; Antipov, V.V.; Chernov, G.A.

    1996-01-01

    The experiments were made on mice, guinea pigs and dogs. Radioprotector indraline increased radioresistant state of hematopoietic stem cells in vivo and in vitro, decreased the amount of post-radiation chromosome aberrations in marrow, induced more early and intensive post-radiation proliferative repair of marrow and spleen, faster regeneration of the initial amount of leukocytes thrombocytes and erytrocytes in blood of mice, guinea pigs and dogs. Antiradiation efficiency of indraline in hematopoietic system is equal to 1.5-2 by FMD. Radioprotective mechanism of indraline effect on hematopoietic system is discussed. 22 refs.; 8 figs.; 4 tabs

  16. Differential Requirements for c-Myc in Chronic Hematopoietic Hyperplasia and Acute Hematopoietic Malignancies in Pten-null Mice

    Science.gov (United States)

    Zhang, Jun; Xiao, Yechen; Guo, Yinshi; Breslin, Peter; Zhang, Shubin; Wei, Wei; Zhang, Zhou; Zhang, Jiwang

    2011-01-01

    Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten-knockout (Pten−/−) mice. The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs which developed in Pten−/− mice which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of PI3K/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. But due to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte-dominated to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies. PMID:21926961

  17. Molecular Signatures of Hepatitis C Virus (HCV-Induced Type II Mixed Cryoglobulinemia (MCII

    Directory of Open Access Journals (Sweden)

    Roberto Burioni

    2012-11-01

    Full Text Available The role of hepatitis C virus (HCV infection in the induction of type II mixed cryoglobulinemia (MCII and the possible establishment of related lymphoproliferative disorders, such as B-cell non-Hodgkin lymphoma (B-NHL, is well ascertained. However, the molecular pathways involved and the factors predisposing to the development of these HCV-related extrahepatic complications deserve further consideration and clarification. To date, several host- and virus-related factors have been implicated in the progression to MCII, such as the virus-induced expansion of selected subsets of B-cell clones expressing discrete immunoglobulin variable (IgV gene subfamilies, the involvement of complement factors and the specific role of some HCV proteins. In this review, we will analyze the host and viral factors taking part in the development of MCII in order to give a general outlook of the molecular mechanisms implicated.

  18. Controllable ultra-narrow fluorescence and six-wave mixing under double electromagnetically induced transparency

    International Nuclear Information System (INIS)

    Wang, Z G; Zhang, Z Y; Che, J L; Zhang, Y Z; Li, C B; Zheng, H B; Zhang, Y P

    2013-01-01

    We report the first observation of six-wave mixing (SWM) and fluorescence signals in an electromagnetically induced transparency (EIT) window. Several remarkable advantages are described. First, multiple bright and dark states are simultaneously observed due to enhancement or suppression of the SWM signal. Second, ultra-narrow fluorescence, much narrower than the EIT window, is experimentally obtained. Third, the ultra-narrow fluorescence can also generate Autler–Townes splitting on scanning the coupling beam. Fourth, a double-peak EIT window is obtained using the nest-dressing scheme. Such studies concerning SWM and fluorescence have applications in optical switching, multi-channel communication and narrowband and long-range quantum communication. (letter)

  19. Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin; Choi, Seung S. [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Li, Zhiguo [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina (United States); Chao, Nelson J. [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Department of Pathology, Duke University Medical Center, Durham, North Carolina (United States); Department of Immunology, Duke University Medical Center, Durham, North Carolina (United States); Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina (United States); Chen, Benny J., E-mail: chen0032@mc.duke.edu [Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina (United States); Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States)

    2013-03-15

    Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.

  20. Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

    International Nuclear Information System (INIS)

    Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin; Choi, Seung S.; Li, Zhiguo; Chao, Nelson J.; Chen, Benny J.

    2013-01-01

    Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells

  1. Effect of dehydroepiandrosterone administration on recovery from mix-type exercise training-induced muscle damage.

    Science.gov (United States)

    Liao, Yi-Hung; Liao, Kun-Fu; Kao, Chung-Lan; Chen, Chung-Yu; Huang, Chih-Yang; Chang, Wei-Hsiang; Ivy, John L; Bernard, Jeffrey R; Lee, Shin-Da; Kuo, Chia-Hua

    2013-01-01

    This study aimed to determine the role of DHEA-S in coping against the exercise training mixing aerobic and resistance components. During 5-day successive exercise training, 16 young male participants (19.2 ± 1.2 years) received either a placebo (flour capsule) or DHEA (100 mg/day) in a double-blinded and placebo-controlled design. Oral DHEA supplementation significantly increased circulating DHEA-S by 2.5-fold, but a protracted drop (~35 %) was observed from Day 3 during training. In the Placebo group, only a minimal DHEA-S reduction (~17 %) was observed. Changes in testosterone followed a similar pattern as DHEA-S. Muscle soreness was elevated significantly on Day 2 for both groups to a similar extent. Lower muscle soreness was observed in the DHEA-supplemented group on Day 3 and Day 6. In the Placebo group, training increased circulating creatine kinase (CK) levels by approximately ninefold, while only a threefold increase was observed in the DHEA-supplemented group. This mix-type exercise training improved glucose tolerance in both groups, while lowering the insulin response to the glucose challenge, but no difference between treatments was observed. Our results suggest that DHEA-S may play a role in protecting skeletal muscle from exercise training-induced muscle damage.

  2. CXC chemokine receptor 3 expression on CD34(+) hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor

    DEFF Research Database (Denmark)

    Jinquan, T; Quan, S; Jacobi, H H

    2000-01-01

    -induced CD34(+) progenitor chemotaxis. These chemotactic attracted CD34(+) progenitors are colony-forming units-granulocyte-macrophage. gamma IP-10 and Mig also induced GM-CSF-stimulated CD34(+) progenitor adhesion and aggregation by means of CXCR3, a finding confirmed by the observation that anti-CXCR3 m......Ab blocked these functions of gammaIP-10 and Mig but not of chemokine stromal cell-derived factor 1 alpha. gamma IP-10-induced and Mig-induced up-regulation of integrins (CD49a and CD49b) was found to play a crucial role in adhesion of GM-CSF-stimulated CD34(+) progenitors. Moreover, gamma IP-10 and Mig...... stimulated CXCR3 redistribution and cellular polarization in GM-CSF-stimulated CD34(+) progenitors. These results indicate that CXCR3-gamma IP-10 and CXCR3-Mig receptor-ligand pairs, as well as the effects of GM-CSF on them, may be especially important in the cytokine/chemokine environment...

  3. Development of hematopoietic stem and progenitor cells from human pluripotent stem cells.

    Science.gov (United States)

    Chen, Tong; Wang, Fen; Wu, Mengyao; Wang, Zack Z

    2015-07-01

    Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), provide a new cell source for regenerative medicine, disease modeling, drug discovery, and preclinical toxicity screening. Understanding of the onset and the sequential process of hematopoietic cells from differentiated hPSCs will enable the achievement of personalized medicine and provide an in vitro platform for studying of human hematopoietic development and disease. During embryogenesis, hemogenic endothelial cells, a specified subset of endothelial cells in embryonic endothelium, are the primary source of multipotent hematopoietic stem cells. In this review, we discuss current status in the generation of multipotent hematopoietic stem and progenitor cells from hPSCs via hemogenic endothelial cells. We also review the achievements in direct reprogramming from non-hematopoietic cells to hematopoietic stem and progenitor cells. Further characterization of hematopoietic differentiation in hPSCs will improve our understanding of blood development and expedite the development of hPSC-derived blood products for therapeutic purpose. © 2015 Wiley Periodicals, Inc.

  4. Instruction of hematopoietic lineage choice by cytokine signaling

    Energy Technology Data Exchange (ETDEWEB)

    Endele, Max; Etzrodt, Martin; Schroeder, Timm, E-mail: timm.schroeder@bsse.ethz.ch

    2014-12-10

    Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of already intrinsically lineage-committed cells has been debated over decades. Recent results demonstrated that cytokines can instruct lineage choice. However, the precise function of individual cytokine-triggered signaling molecules in inducing cellular events like proliferation, lineage choice, and differentiation remains largely elusive. Signal transduction pathways activated by different cytokine receptors are highly overlapping, but support the production of distinct hematopoietic lineages. Cellular context, signaling dynamics, and the crosstalk of different signaling pathways determine the cellular response of a given extrinsic signal. New tools to manipulate and continuously quantify signaling events at the single cell level are therefore required to thoroughly interrogate how dynamic signaling networks yield a specific cellular response. - Highlights: • Recent studies provided definite proof for lineage-instructive action of cytokines. • Signaling pathways involved in hematopoietic lineage instruction remain elusive. • New tools are emerging to quantitatively study dynamic signaling networks over time.

  5. Fetal liver stromal cells promote hematopoietic cell expansion

    International Nuclear Information System (INIS)

    Zhou, Kun; Hu, Caihong; Zhou, Zhigang; Huang, Lifang; Liu, Wenli; Sun, Hanying

    2009-01-01

    Future application of hematopoietic stem and progenitor cells (HSPCs) in clinical therapies largely depends on their successful expansion in vitro. Fetal liver (FL) is a unique hematopoietic organ in which hematopoietic cells markedly expand in number, but the mechanisms involved remain unclear. Stromal cells (StroCs) have been suggested to provide a suitable cellular environment for in vitro expansion of HSPCs. In this study, murine StroCs derived from FL at E14.5, with a high level of Sonic hedgehog (Shh) and Wnt expression, were found to have an increased ability to support the proliferation of HSPCs. This effect was inhibited by blocking Shh signaling. Supplementation with soluble Shh-N promoted the proliferation of hematopoietic cells by activating Wnt signaling. Our findings suggest that FL-derived StroCs support proliferation of HSPCs via Shh inducing an autocrine Wnt signaling loop. The use of FL-derived StroCs and regulation of the Shh pathway might further enhance HPSC expansion.

  6. Reversible photo-induced trap formation in mixed-halide hybrid perovskites for photovoltaics.

    Science.gov (United States)

    Hoke, Eric T; Slotcavage, Daniel J; Dohner, Emma R; Bowring, Andrea R; Karunadasa, Hemamala I; McGehee, Michael D

    2015-01-01

    We report on reversible, light-induced transformations in (CH 3 NH 3 )Pb(Br x I 1- x ) 3 . Photoluminescence (PL) spectra of these perovskites develop a new, red-shifted peak at 1.68 eV that grows in intensity under constant, 1-sun illumination in less than a minute. This is accompanied by an increase in sub-bandgap absorption at ∼1.7 eV, indicating the formation of luminescent trap states. Light soaking causes a splitting of X-ray diffraction (XRD) peaks, suggesting segregation into two crystalline phases. Surprisingly, these photo-induced changes are fully reversible; the XRD patterns and the PL and absorption spectra revert to their initial states after the materials are left for a few minutes in the dark. We speculate that photoexcitation may cause halide segregation into iodide-rich minority and bromide-enriched majority domains, the former acting as a recombination center trap. This instability may limit achievable voltages from some mixed-halide perovskite solar cells and could have implications for the photostability of halide perovskites used in optoelectronics.

  7. Asymptotic behavior of the mixed mass in Rayleigh–Taylor and Richtmyer–Meshkov instability induced flows

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Ye; Cabot, William H. [Lawrence Livermore National Laboratory, Livermore, California 94550 (United States); Thornber, Ben [The University of Sydney, School of Aerospace, Mechanical and Mechatronic Engineering, New South Wales 2006, Sydney (Australia)

    2016-05-15

    Rayleigh–Taylor instability (RTI) and Richtmyer–Meshkov instability (RMI) are serious practical issues in inertial confinement fusion research, and also have relevance to many cases of astrophysical fluid dynamics. So far, much of the attention has been paid to the late-time scaling of the mixed width, which is used as a surrogate to how well the fluids have been mixed. Yet, the actual amount of mixed mass could be viewed as a more direct indicator on the evolution of the mixing layers due to hydrodynamic instabilities. Despite its importance, there is no systematic study as yet on the scaling of the mixed mass for either the RTI or the RMI induced flow. In this article, the normalized mixed mass (Ψ) is introduced for measuring the efficiency of the mixed mass. Six large numerical simulation databases have been employed: the RTI cases with heavy-to-light fluid density ratios of 1.5, 3, and 9; the single shock RMI cases with density ratios of 3 and 20; and a reshock RMI case with density ratio of 3. Using simulated flow fields, the normalized mixed mass Ψ is shown to be more sensitive in discriminating the variation with Atwood number for the RTI flows. Moreover, Ψ is demonstrated to provide more consistent results for both the RTI and RMI flows when compared with the traditional mixedness parameters, Ξ and Θ.

  8. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency

    DEFF Research Database (Denmark)

    Qasim, Waseem; Cavazzana-Calvo, Marina; Davies, E Graham

    2009-01-01

    OBJECTIVES: Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 beta-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed...... of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/European Group for Blood and Marrow Transplantation, and the Center for International......, with full donor engraftment in 17 cases, mixed multilineage chimerism in 7 patients, and mononuclear cell-restricted chimerism in an additional 3 cases. CONCLUSIONS: Hematopoietic stem-cell transplantation offers long-term benefit in leukocyte adhesion deficiency and should be considered as an early...

  9. Aviation NOx-induced CH4 effect: Fixed mixing ratio boundary conditions versus flux boundary conditions

    Science.gov (United States)

    Khodayari, Arezoo; Olsen, Seth C.; Wuebbles, Donald J.; Phoenix, Daniel B.

    2015-07-01

    Atmospheric chemistry-climate models are often used to calculate the effect of aviation NOx emissions on atmospheric ozone (O3) and methane (CH4). Due to the long (∼10 yr) atmospheric lifetime of methane, model simulations must be run for long time periods, typically for more than 40 simulation years, to reach steady-state if using CH4 emission fluxes. Because of the computational expense of such long runs, studies have traditionally used specified CH4 mixing ratio lower boundary conditions (BCs) and then applied a simple parameterization based on the change in CH4 lifetime between the control and NOx-perturbed simulations to estimate the change in CH4 concentration induced by NOx emissions. In this parameterization a feedback factor (typically a value of 1.4) is used to account for the feedback of CH4 concentrations on its lifetime. Modeling studies comparing simulations using CH4 surface fluxes and fixed mixing ratio BCs are used to examine the validity of this parameterization. The latest version of the Community Earth System Model (CESM), with the CAM5 atmospheric model, was used for this study. Aviation NOx emissions for 2006 were obtained from the AEDT (Aviation Environmental Design Tool) global commercial aircraft emissions. Results show a 31.4 ppb change in CH4 concentration when estimated using the parameterization and a 1.4 feedback factor, and a 28.9 ppb change when the concentration was directly calculated in the CH4 flux simulations. The model calculated value for CH4 feedback on its own lifetime agrees well with the 1.4 feedback factor. Systematic comparisons between the separate runs indicated that the parameterization technique overestimates the CH4 concentration by 8.6%. Therefore, it is concluded that the estimation technique is good to within ∼10% and decreases the computational requirements in our simulations by nearly a factor of 8.

  10. Genetic and Epigenetic Mechanisms That Maintain Hematopoietic Stem Cell Function

    OpenAIRE

    Kosan, Christian; Godmann, Maren

    2015-01-01

    All hematopoiesis cells develop from multipotent progenitor cells. Hematopoietic stem cells (HSC) have the ability to develop into all blood lineages but also maintain their stemness. Different molecular mechanisms have been identified that are crucial for regulating quiescence and self-renewal to maintain the stem cell pool and for inducing proliferation and lineage differentiation. The stem cell niche provides the microenvironment to keep HSC in a quiescent state. Furthermore, several trans...

  11. Protective Effects of Hydrogen against Low-Dose Long-Term Radiation-Induced Damage to the Behavioral Performances, Hematopoietic System, Genital System, and Splenic Lymphocytes in Mice

    Directory of Open Access Journals (Sweden)

    Jiaming Guo

    2016-01-01

    Full Text Available Molecular hydrogen (H2 has been previously reported playing an important role in ameliorating damage caused by acute radiation. In this study, we investigated the effects of H2 on the alterations induced by low-dose long-term radiation (LDLTR. All the mice in hydrogen-treated or radiation-only groups received 0.1 Gy, 0.5 Gy, 1.0 Gy, and 2.0 Gy whole-body gamma radiation, respectively. After the last time of radiation exposure, all the mice were employed for the determination of the body mass (BM observation, forced swim test (FST, the open field test (OFT, the chromosome aberration (CA, the peripheral blood cells parameters analysis, the sperm abnormality (SA, the lymphocyte transformation test (LTT, and the histopathological studies. And significant differences between the treatment group and the radiation-only groups were observed, showing that H2 could diminish the detriment induced by LDLTR and suggesting the protective efficacy of H2 in multiple systems in mice against LDLTR.

  12. Mechanism of redox reactions induced by light and electron pulse in solutions of mixed ligand iron(II) complex cyanides

    International Nuclear Information System (INIS)

    Horvath, A.; Szoeke, J.; Wojnarovits, L.

    1991-01-01

    Redox reactions induced by light and electron pulse have been studied in aqueous solutions of mixed ligand iron(II) complex cyanides. The short lived intermediates have been identified by time resolved specroscopy, the results of detailed kinetic analysis have been discussed. (author) 6 refs.; 3 figs.; 2 tabs

  13. Continuum contribution to excitonic four-wave mixing due to interaction-induced nonlinearities: A numerical study

    DEFF Research Database (Denmark)

    Sayed, Karim El; Birkedal, Dan; Vadim, Lyssenko

    1997-01-01

    We present a theoretical investigation of ultrafast transient four-wave mixing (FWM) of GaAs quantum wells for coherent excitation of excitons and a large number of continuum states. It is shown that in this case the line shape of the FWM signal is drastically altered due to an interaction-induce...

  14. Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

    Science.gov (United States)

    Mori, Takehiko; Yamazaki, Rie; Aisa, Yoshinobu; Nakazato, Tomonori; Kudo, Masumi; Yashima, Tomoko; Kondo, Sakiko; Ikeda, Yasuo; Okamoto, Shinichiro

    2006-04-01

    We previously reported the efficacy of oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis. The purpose of this study was to evaluate whether the further shortening of the duration of oral cryotherapy could minimize its side effects while sparing its efficacy. Seventeen consecutive recipients of allogeneic hematopoieic stem cell transplant conditioned with high-dose melphalan in combination with fludarabine alone or with fludarabine and additional radiation were enrolled in the study. The severity of stomatitis was graded according to the National Cancer Institute-Common Toxicity Criteria. Patients were kept on oral cryotherapy shortly before, during, and for additional 30 min after the completion of melphalan administration (60-min oral cryotherapy). Patients who were also enrolled in our previous study received the same type of oral cryotherapy but for additional 90 min after the completion of melphalan administration (120-min oral cryotherapy), and they served as controls. Only 2 (11.8%) of 17 patients receiving 60-min oral cryotherapy and 2 (11.1%) of 18 patients receiving 120-min oral cryotherapy developed grade 2 or 3 stomatitis, respectively. The difference between groups was not statistically significant (P = 0.677). The incidence of unpleasant symptoms such as chills and nausea during oral cryotherapy decreased significantly with 60-min oral cryotherapy, as compared with that associated with 120-min oral cryotherapy (P cryotherapy is as effective as 120-min oral cryotherapy at preventing high-dose melphalan-induced stomatitis, and shorter treatment might have contributed to relieve patient discomfort during oral cryotherapy.

  15. Gas mixing under the influence of thermal-dynamic parameters such as buoyancy, jet momentum and fan-induced convection

    International Nuclear Information System (INIS)

    Chan, C.K.; Jones, S.C.A.

    1994-01-01

    Various scaling parameters for simulating mixing under the influence of buoyancy, jet momentum, and fan-induced convection were examined. Their significance was assessed by comparing the mixing of helium (a simulant for hydrogen) with air in a large-scale enclosure (1.8 m x 1.8 m x 1.8 m) to the mixing of salt-water with fresh-water in a small-scale enclosure (1/6 the size). The advantage of using the salt-water/freshwater technique is that it allows the characteristic flow regime (either turbulent or laminar flow) in the full-scale containment to be maintained in the reduced scale containment. A smoke technique for flow visualization was used to examine the mixing of the helium with air. For the small-scale salt-water/fresh-water experiment, fluorescent dye was used to provide a means to visualize the mixing process. The mixing behaviour in both sets of experiments were analyzed based on video records and concentration measurements in ten locations. Measurements showed that depending on the recirculation and jet flow rates, the injected salt-water (in small-scale experiments) and helium (in large-scale experiments) can disperse sufficiently quickly to produce an essentially 'well mixed' condition rendering the concentration measurements insensitive to the variation in the Froude or the Grashof Numbers. (author)

  16. Does the thermal spike affect low energy ion-induced interfacial mixing?

    International Nuclear Information System (INIS)

    Suele, P.; Menyhard, M.; Nordlund, K.

    2003-01-01

    Molecular dynamics simulations have been used to obtain the three-dimensional distribution of interfacial mixing and cascade defects in Ti/Pt multilayer system due to single 1 keV Ar + impact at grazing angle of incidence. The Ti/Pt system was chosen because of its relatively high heat of mixing in the binary alloy and therefore a suitable candidate for testing the effect of heat of mixing on ion-beam mixing. However, the calculated mixing profile is not sensitive to the heat of mixing. Therefore the thermal spike model of mixing is not fully supported under these irradiation conditions. Instead we found that the majority of mixing occurs after the thermal spike during the relaxation process. These conclusions are supported by liquid, vacancy as well as adatom analysis. The interfacial mixing is in various aspects anomalous in this system: the time evolution of mixing is leading to a phase delay for Ti mixing, and Pt exhibits an unexpected double peaked mixing evolution. The reasons to these effects are discussed

  17. The measurement of gamma ray induced heating in a mixed neutron and gamma ray environment

    International Nuclear Information System (INIS)

    Chiu, H.K.

    1991-10-01

    The problem of measuring the gamma heating in a mixed DT neutron and gamma ray environment was explored. A new detector technique was developed to make this measurement. Gamma heating measurements were made in a low-Z assembly irradiated with 14-Mev neutrons and (n, n') gammas produced by a Texas Nuclear Model 9400 neutron generator. Heating measurements were made in the mid-line of the lattice using a proportional counter operating in the Continuously-varied Bias-voltage Acquisition mode. The neutron-induced signal was separated from the gamma-induced signal by exploiting the signal rise-time differences inherent to radiations of different linear energy transfer coefficient, which are observable in a proportional counter. The operating limits of this measurement technique were explored by varying the counter position in the low-Z lattice, hence changing the irradiation spectrum observed. The experiment was modelled numerically to help interpret the measured results. The transport of neutrons and gamma rays in the assembly was modelled using the one- dimensional radiation transport code ANISN/PC. The cross-section set used for these calculations was derived from the ENDF/B-V library using the code MC 2 -2 for the case of DT neutrons slowing down in a low-Z material. The calculated neutron and gamma spectra in the slab and the relevant mass-stopping powers were used to construct weighting factors which relate the energy deposition in the counter fill-gas to that in the counter wall and in the surrounding material. The gamma energy deposition at various positions in the lattice is estimated by applying these weighting factors to the measured gamma energy deposition in the counter at those locations

  18. Hyperglycemia induces mixed M1/M2 cytokine profile in primary human monocyte-derived macrophages.

    Science.gov (United States)

    Moganti, Kondaiah; Li, Feng; Schmuttermaier, Christina; Riemann, Sarah; Klüter, Harald; Gratchev, Alexei; Harmsen, Martin C; Kzhyshkowska, Julia

    2017-10-01

    Hyperglycaemia is a key factor in diabetic pathology. Macrophages are essential regulators of inflammation which can be classified into two major vectors of polarisation: classically activated macrophages (M1) and alternatively activated macrophages (M2). Both types of macrophages play a role in diabetes, where M1 and M2-produced cytokines can have detrimental effects in development of diabetes-associated inflammation and diabetic vascular complications. However, the effect of hyperglycaemia on differentiation and programming of primary human macrophages was not systematically studied. We established a unique model to assess the influence of hyperglycaemia on M1 and M2 differentiation based on primary human monocyte-derived macrophages. The effects of hyperglycaemia on the gene expression and secretion of prototype M1 cytokines TNF-alpha and IL-1beta, and prototype M2 cytokines IL-1Ra and CCL18 were quantified by RT-PCR and ELISA. Hyperglycaemia stimulated production of TNF-alpha, IL-1beta and IL-1Ra during macrophage differentiation. The effect of hyperglycaemia on TNF-alpha was acute, while the stimulating effect on IL-1beta and IL-1Ra was constitutive. Expression of CCL18 was supressed in M2 macrophages by hyperglycaemia. However the secreted levels remained to be biologically significant. Our data indicate that hyperglycaemia itself, without additional metabolic factors induces mixed M1/M2 cytokine profile that can support of diabetes-associated inflammation and development of vascular complications. Copyright © 2016 Elsevier GmbH. All rights reserved.

  19. UV reactor flow visualization and mixing quantification using three-dimensional laser-induced fluorescence.

    Science.gov (United States)

    Gandhi, Varun; Roberts, Philip J W; Stoesser, Thorsten; Wright, Harold; Kim, Jae-Hong

    2011-07-01

    Three-dimensional laser-induced fluorescence (3DLIF) was applied to visualize and quantitatively analyze mixing in a lab-scale UV reactor consisting of one lamp sleeve placed perpendicular to flow. The recirculation zone and the von Karman vortex shedding that commonly occur in flows around bluff bodies were successfully visualized. Multiple flow paths were analyzed by injecting the dye at various heights with respect to the lamp sleeve. A major difference in these pathways was the amount of dye that traveled close to the sleeve, i.e., a zone of higher residence time and higher UV exposure. Paths away from the center height had higher velocities and hence minimal influence by the presence of sleeve. Approach length was also characterized in order to increase the probability of microbes entering the region around the UV lamp. The 3DLIF technique developed in this study is expected to provide new insight on UV dose delivery useful for the design and optimization of UV reactors. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. New experimental approach to treatment of radiation-induced bone marrow aplasia: ex vivo expansion of hematopoietic cells; Nouvelle approche experimentale du traitement de l`aplasie medullaire radio-induite

    Energy Technology Data Exchange (ETDEWEB)

    Herodin, F.; Mathieu, J.; Drouet, M.; Grenier, N.; Grange, L.; Bourin, P.; Vetillard, J.; Thierry, D.; Mestries, J.C.

    1995-12-31

    The management of bone marrow aplasia secondary to accidental exposure to high doses of ionizing radiations requires new therapeutic protocols in addition to cytokine therapy. The in vitro incubation of hematopoietic stem and progenitor cells from irradiated nonhuman primates with negative and positive regulators of hematopoiesis may lead to helpful products of transfusion. (author).

  1. Laser-induced breakdown spectroscopy for the real-time analysis of mixed waste samples containing Sr

    International Nuclear Information System (INIS)

    Barefield, J.E. II; Koskelo, A.C.; Multari, R.A.; Cremers, D.A.; Gamble, T.K.; Han, C.Y.

    1995-01-01

    In this report, the use of Laser-induced breakdown spectroscopy to analyze mixed waste samples containing Sr is discussed. The mixed waste samples investigated include vitrified waste glass and contaminated soil. Compared to traditional analysis techniques, the laser-based method is fast (i.e., analysis times on the order of minutes) and essentially waste free since little or no sample preparation is required. Detection limits on the order of pmm Sr were determined. Detection limits obtained using a fiber optic cable to deliver laser pulses to soil samples containing Cr, Zr, Pb, Be, Cu, and Ni will also be discussed

  2. Simulation of buoyancy induced gas mixing tests performed in a large scale containment facility using GOTHIC code

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Z.; Chin, Y.S. [Atomic Energy of Canada Limited, Chalk River, ON (Canada)

    2014-07-01

    This paper compares containment thermal-hydraulics simulations performed using GOTHIC against a past test set of large scale buoyancy induced helium-air-steam mixing experiments that had been performed at the AECL's Chalk River Laboratories. A number of typical post-accident containment phenomena, including thermal/gas stratification, natural convection, cool air entrainment, steam condensation on concrete walls and active local air cooler, were covered. The results provide useful insights into hydrogen gas mixing behaviour following a loss-of-coolant accident and demonstrate GOTHIC's capability in simulating these phenomena. (author)

  3. Simulation of buoyancy induced gas mixing tests performed in a large scale containment facility using GOTHIC code

    International Nuclear Information System (INIS)

    Liang, Z.; Chin, Y.S.

    2014-01-01

    This paper compares containment thermal-hydraulics simulations performed using GOTHIC against a past test set of large scale buoyancy induced helium-air-steam mixing experiments that had been performed at the AECL's Chalk River Laboratories. A number of typical post-accident containment phenomena, including thermal/gas stratification, natural convection, cool air entrainment, steam condensation on concrete walls and active local air cooler, were covered. The results provide useful insights into hydrogen gas mixing behaviour following a loss-of-coolant accident and demonstrate GOTHIC's capability in simulating these phenomena. (author)

  4. Mixed martial arts induces significant fatigue and muscle damage up to 24 hours post-combat.

    Science.gov (United States)

    Ghoul, Nihel; Tabben, Montassar; Miarka, Bianca; Tourny, Claire; Chamari, Karim; Coquart, Jeremy

    2017-06-22

    This study investigates the physiological/physical responses to a simulated mixed martial arts (MMA) competition over 24 hr. Twelve fighters performed a simulated MMA competition, consisting of three 5-min MMA matches. Physiological/physical data were assessed before (Trest), directly after round 1 (Trd1), round 2 (Trd2) and round 3 (Trd3), and then 30-min (Trecovery30min) and/or 24-hr (Trecovery24h) post-competition. Heart rate (HR), rating of perceived exertion (RPE) and blood lactate concentration ([La]) were assessed at Trest, Trd1, Trd2 and Trd3. Biological data were collected at Trest, Trd3, Trecovery30min and Trecovery24h. Physical tests were performed at Trest, Trecovery30min and Trecovery24h. HR, RPE and [La] were high during competition. Leukocytes, hemoglobin, total protein and glycemia were increased at Trd3 compared with all other time points (p<0.05). Cortisol was increased at Trd3 compared with Trest and Trecovery24h (p<0.05). Testosterone was higher at Trd3 and Trecovery30min than Trest (p<0.001). Higher values of uric acid were noted during recovery periods (p<0.001). Lactate dehydrogenase was lower at Trest compared with Trd3, Trecovery30min and Trecovery24h (p<0.05). Countermovement jump was higher at Trest than Trecovery30min (p=0.020). Consequently, MMA is a high-intensity intermittent combat sport that induces significant fatigue and muscle damage, both of which are still present 24-hr post-competition.

  5. Construction of PAH-degrading mixed microbial consortia by induced selection in soil.

    Science.gov (United States)

    Zafra, German; Absalón, Ángel E; Anducho-Reyes, Miguel Ángel; Fernandez, Francisco J; Cortés-Espinosa, Diana V

    2017-04-01

    Bioremediation of polycyclic aromatic hydrocarbons (PAHs)-contaminated soils through the biostimulation and bioaugmentation processes can be a strategy for the clean-up of oil spills and environmental accidents. In this work, an induced microbial selection method using PAH-polluted soils was successfully used to construct two microbial consortia exhibiting high degradation levels of low and high molecular weight PAHs. Six fungal and seven bacterial native strains were used to construct mixed consortia with the ability to tolerate high amounts of phenanthrene (Phe), pyrene (Pyr) and benzo(a)pyrene (BaP) and utilize these compounds as a sole carbon source. In addition, we used two engineered PAH-degrading fungal strains producing heterologous ligninolytic enzymes. After a previous selection using microbial antagonism tests, the selection was performed in microcosm systems and monitored using PCR-DGGE, CO 2 evolution and PAH quantitation. The resulting consortia (i.e., C1 and C2) were able to degrade up to 92% of Phe, 64% of Pyr and 65% of BaP out of 1000 mg kg -1 of a mixture of Phe, Pyr and BaP (1:1:1) after a two-week incubation. The results indicate that constructed microbial consortia have high potential for soil bioremediation by bioaugmentation and biostimulation and may be effective for the treatment of sites polluted with PAHs due to their elevated tolerance to aromatic compounds, their capacity to utilize them as energy source. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Hematopoietic stem cell expansion : challenges and opportunities

    NARCIS (Netherlands)

    Walasek, Marta A.; van Os, Ronald; de Haan, Gerald; Kanz, L; Fibbe, WE; Lengerke, C; Dick, JE

    2012-01-01

    Attempts to improve hematopoietic reconstitution and engraftment potential of ex vivo-expanded hematopoietic stem and progenitor cells (HSPCs) have been largely unsuccessful due to the inability to generate sufficient stem cell numbers and to excessive differentiation of the starting cell

  7. The biochemistry of hematopoietic stem cell development

    NARCIS (Netherlands)

    P. Kaimakis (Polynikis); M. Crisan (Mihaela); E.A. Dzierzak (Elaine)

    2013-01-01

    textabstractBackground: The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short

  8. Regulation of Hematopoietic Cell Development and Function Through Phosphoinositides

    Directory of Open Access Journals (Sweden)

    Mila Elich

    2018-05-01

    Full Text Available One of the most paramount receptor-induced signal transduction mechanisms in hematopoietic cells is production of the lipid second messenger phosphatidylinositol(3,4,5trisphosphate (PIP3 by class I phosphoinositide 3 kinases (PI3K. Defective PIP3 signaling impairs almost every aspect of hematopoiesis, including T cell development and function. Limiting PIP3 signaling is particularly important, because excessive PIP3 function in lymphocytes can transform them and cause blood cancers. Here, we review the key functions of PIP3 and related phosphoinositides in hematopoietic cells, with a special focus on those mechanisms dampening PIP3 production, turnover, or function. Recent studies have shown that beyond “canonical” turnover by the PIP3 phosphatases and tumor suppressors phosphatase and tensin homolog (PTEN and SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1/2, PIP3 function in hematopoietic cells can also be dampened through antagonism with the soluble PIP3 analogs inositol(1,3,4,5tetrakisphosphate (IP4 and inositol-heptakisphosphate (IP7. Other evidence suggests that IP4 can promote PIP3 function in thymocytes. Moreover, IP4 or the kinases producing it limit store-operated Ca2+ entry through Orai channels in B cells, T cells, and neutrophils to control cell survival and function. We discuss current models for how soluble inositol phosphates can have such diverse functions and can govern as distinct processes as hematopoietic stem cell homeostasis, neutrophil macrophage and NK cell function, and development and function of B cells and T cells. Finally, we will review the pathological consequences of dysregulated IP4 activity in immune cells and highlight contributions of impaired inositol phosphate functions in disorders such as Kawasaki disease, common variable immunodeficiency, or blood cancer.

  9. Bubble-induced mixing of two horizontal liquid layers with non-uniform gas injection at the bottom

    International Nuclear Information System (INIS)

    Cheung, F.B.; Pedersen, D.R.; Leinweber, G.

    1986-01-01

    During a postulated severe core meltdown accident in an LMFBR, a large amount of sodium coolant may spill into the reactor concrete cavity. A layer of liquid products may form as a result of the sodium-concrete reactions. The liquid product layer, which is highly viscous and much heavier than sodium, separates the concrete from the sodium pool. In general, the downward transport of sodium through the liquid product layer to the unreacted concrete surface, which controls the rate of chemical erosion of the concrete, depends strongly on the agitation induced by gas evolution from the heated concrete. In this study, experiments were conducted to explore the effect of non-uniform gas injection on mixing of two horizontal mutually soluble liquid layers. The liquid in the lower layer was chosen to be more viscous and heavier than the liquid in the upper layer. To simulate the reactor accident situation, gas was injected at the bottom of the liquid-liquid system through a circular hole that covered only the center portion of the bottom surface of the lower liquid layer. The bubble-induced mixing motions were observed and the rate of mixing was measured for different hole sizes and various gas flow rates. The results of this study clearly show that the rate of gas injection is not the only parameter controlling the mixing of the liquid-liquid system. The effect of non-uniform gas injection is important at high gas flow rates. Within the present experimental conditions, the reduction in the overall mixing rate can be as large as a factor of three

  10. Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche.

    Science.gov (United States)

    Mitroulis, Ioannis; Chen, Lan-Sun; Singh, Rashim Pal; Kourtzelis, Ioannis; Economopoulou, Matina; Kajikawa, Tetsuhiro; Troullinaki, Maria; Ziogas, Athanasios; Ruppova, Klara; Hosur, Kavita; Maekawa, Tomoki; Wang, Baomei; Subramanian, Pallavi; Tonn, Torsten; Verginis, Panayotis; von Bonin, Malte; Wobus, Manja; Bornhäuser, Martin; Grinenko, Tatyana; Di Scala, Marianna; Hidalgo, Andres; Wielockx, Ben; Hajishengallis, George; Chavakis, Triantafyllos

    2017-10-02

    Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by β3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.

  11. [Effect of inducers and inhibitors of mixed function oxidases on body resistance to endotoxins of gram-negative bacteria].

    Science.gov (United States)

    Liniuchev, M N; Zubik, T M; Kovelenov, A Iu; Bulyko, V I; Sergeev, V V

    1989-06-01

    Experimental typhoid intoxication in white mice leads to the inhibition of microsomal oxidation in the liver, which is manifested by the prolongation of hexenal-induced sleep and a decrease in the toxic action of parathion. Phenobarbital, capable of inducing oxidases with mixed function (OMF), enhances the process of the detoxification of endotoxin injected into the animals, which is manifested by the increase of its LD50. Soluble levomycetin succinate, widely used for the treatment of typhoid-paratyphoid infections, is a powerful inhibitor of OMF (as shown by the hexenal test). Benzonal, the analog of phenobarbital, removes the inhibitory effect of the antibiotic. Experimental studies carried out in the course of this investigation make it possible to substantiate the clinical trial of these preparations (OMF inducers) used in the complex therapy of typhoid-paratyphoid infections for the stimulation of natural detoxification mechanisms of the body. Benzonal is the preparation of choice for use in clinical practice.

  12. PARASITIC INFECTIONS IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    Isidro Jarque

    2016-07-01

    Full Text Available Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However, they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients.

  13. Bubble-induced mixing of two horizontal liquid layers with non-uniform gas injection at the bottom

    International Nuclear Information System (INIS)

    Cheung, F.B.; Leinweber, G.; Pedersen, D.R.

    1984-01-01

    During a postulated severe core meltdown accident in an LMFBR, a large amount of sodium coolant may spill into the reactor concrete cavity. A layer of liquid products may form as a result of the sodium-concrete reactions. The liquid product layer, which is highly viscous and much heavier than sodium, separates the concrete from the sodium pool. In general, the downward transport of sodium through the liquid product layer to the unreacted concrete surface, which controls the rate of chemical erosion of the concrete, depends strongly on the agitation induced by gas evolution from the heated concrete. In this study, experiments were conducted to explore the effect of non-uniform gas injection on mixing of two horizontal mutually soluble liquid layers. The liquid in the lower layer was chosen to be more viscous and heavier than the liquid in the upper layer. To simulate the reactor accident situation, gas was injected at the bottom of the liquid-liquid system through a circular hole that covered only the center portion of the bottom surface of the lower liquid layer. The bubble-induced mixing motions were observed and the rate of mixing was measured for different hole sizes and for various gas flow rates

  14. Accuracy Enhancement of Raman Spectroscopy Using Complementary Laser-Induced Breakdown Spectroscopy (LIBS) with Geologically Mixed Samples.

    Science.gov (United States)

    Choi, Soojin; Kim, Dongyoung; Yang, Junho; Yoh, Jack J

    2017-04-01

    Quantitative Raman analysis was carried out with geologically mixed samples that have various matrices. In order to compensate the matrix effect in Raman shift, laser-induced breakdown spectroscopy (LIBS) analysis was performed. Raman spectroscopy revealed the geological materials contained in the mixed samples. However, the analysis of a mixture containing different matrices was inaccurate due to the weak signal of the Raman shift, interference, and the strong matrix effect. On the other hand, the LIBS quantitative analysis of atomic carbon and calcium in mixed samples showed high accuracy. In the case of the calcite and gypsum mixture, the coefficient of determination of atomic carbon using LIBS was 0.99, while the signal using Raman was less than 0.9. Therefore, the geological composition of the mixed samples is first obtained using Raman and the LIBS-based quantitative analysis is then applied to the Raman outcome in order to construct highly accurate univariate calibration curves. The study also focuses on a method to overcome matrix effects through the two complementary spectroscopic techniques of Raman spectroscopy and LIBS.

  15. Radiation induced polymerization of MMA in imidazolium ionic liquids and their mixed solutions with organic solvents

    Energy Technology Data Exchange (ETDEWEB)

    Qi Mingying [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, P.O. Box 800-204, Shanghai 201800 (China); Graduate University of the Chinese Academy of Sciences, Beijing 100049 (China); Wu Guozhong [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, P.O. Box 800-204, Shanghai 201800 (China)], E-mail: wuguozhong@sinap.ac.cn; Sha Maolin; Liu Yusheng [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, P.O. Box 800-204, Shanghai 201800 (China); Graduate University of the Chinese Academy of Sciences, Beijing 100049 (China)

    2008-10-15

    Considerably higher molecular weight (M{sub w}) and multi-modal molecular weight distribution (MWD) of poly(methyl methacrylate) (PMMA) were observed in neat ionic liquids ([bmim][PF{sub 6}] and [bmim][BF{sub 4}]), as well as their mixed solutions with organic solvents, probably due to the high viscosity and inhomogeneity of ionic liquids. FTIR spectra for PMMA showed that a slight amount of ionic liquid remained in the resulting polymer, and DSC measurement indicated the increase of glass transition point of PMMA with increasing of ionic liquid fraction in mixed solutions.

  16. Observation of zone folding induced acoustic topological insulators and the role of spin-mixing defects

    Science.gov (United States)

    Deng, Yuanchen; Ge, Hao; Tian, Yuan; Lu, Minghui; Jing, Yun

    2017-11-01

    This article reports on the experimental realization of a flow-free, pseudospin-based acoustic topological insulator designed using the strategy of zone folding. Robust sound one-way propagation is demonstrated with the presence of non-spin-mixing defects. On the other hand, it is shown that spin-mixing defects, which break the geometric symmetry and therefore the pseudo-time-reversal symmetry, can open up nontrivial band gaps within the edge state frequency band, and their width can be tailored by the extent of the defect. This provides a possible route for realizing tunable acoustic topological insulators.

  17. Generation of axolotl hematopoietic chimeras

    Directory of Open Access Journals (Sweden)

    David Lopez

    2015-02-01

    Full Text Available Wound repair is an extremely complex process that requires precise coordination between various cell types including immune cells.  Unfortunately, in mammals this usually results in scar formation instead of restoration of the original fully functional tissue, otherwise known as regeneration.  Various animal models like frogs and salamanders are currently being studied to determine the intracellular and intercellular pathways, controlled by gene expression, that elicit cell proliferation, differentiation, and migration of cells during regenerative healing.  Now, the necessary genetic tools to map regenerative pathways are becoming available for the axolotl salamander, thus allowing comparative studies between scarring and regeneration.  Here, we describe in detail three methods to produce axolotl hematopoietic cell-tagged chimeras for the study of hematopoiesis and regeneration.

  18. Pretreatment with mixed-function oxidase inducers increases the sensitivity of the hepatocyte/DNA repair assay

    International Nuclear Information System (INIS)

    Shaddock, J.G.; Heflich, R.H.; McMillan, D.C.; Hinson, J.A.; Casciano, D.A.

    1989-01-01

    A recent National Toxicology Program evaluation indicates that the rat hepatocyte/DNA repair assay has a high false-negative rate and that it is insensitive to some genotoxic hepatocarcinogens as well as other species and organ-specific carcinogens. In this study, the authors examined whether the sensitivity of the hepatocyte/DNA repair assay might be increased through animal pretreatment with various hepatic mixed-function oxidase inducers, i.e., Aroclor 1254, phenobarbital, and 3,3',4,4'-tetrachloroazobenzene (TCAB). The effects on unscheduled DNA synthesis (UDS), a measured of DNA damage and repair, were studied in cultures exposed to known and/or potential carcinogens that had been evaluated as negative or questionable or that produced conflicting results with hepatocytes isolated from uninduced animals. 4,4'-Oxydianiline, 1-nitropy-rene, and TCAB produced concentration-dependent increases in UDS in hepatocytes from rats pretreated with Aroclor 1254. 4,4'-Oxydianiline and TCAB also induced a dose-dependent increase in DNA repair in hepatocytes from rats pretreated with phenobarbital, whereas 1-nitropyrene was negative. These data indicate that the limited sensitivity to chemical carcinogens displayed by the hepatocyte/DNA repair assay may be increased by using hepatocytes isolated from animals exposed to hepatic mixed-function oxidase inducers

  19. Pretreatment with mixed-function oxidase inducers increases the sensitivity of the hepatocyte/DNA repair assay

    Energy Technology Data Exchange (ETDEWEB)

    Shaddock, J.G.; Heflich, R.H.; McMillan, D.C.; Hinson, J.A.; Casciano, D.A. (National Center for Toxicological Research, Jefferson, AK (USA) Univ. of Arkansas for Medical Sciences, Little Rock (USA))

    1989-01-01

    A recent National Toxicology Program evaluation indicates that the rat hepatocyte/DNA repair assay has a high false-negative rate and that it is insensitive to some genotoxic hepatocarcinogens as well as other species and organ-specific carcinogens. In this study, the authors examined whether the sensitivity of the hepatocyte/DNA repair assay might be increased through animal pretreatment with various hepatic mixed-function oxidase inducers, i.e., Aroclor 1254, phenobarbital, and 3,3{prime},4,4{prime}-tetrachloroazobenzene (TCAB). The effects on unscheduled DNA synthesis (UDS), a measured of DNA damage and repair, were studied in cultures exposed to known and/or potential carcinogens that had been evaluated as negative or questionable or that produced conflicting results with hepatocytes isolated from uninduced animals. 4,4{prime}-Oxydianiline, 1-nitropy-rene, and TCAB produced concentration-dependent increases in UDS in hepatocytes from rats pretreated with Aroclor 1254. 4,4{prime}-Oxydianiline and TCAB also induced a dose-dependent increase in DNA repair in hepatocytes from rats pretreated with phenobarbital, whereas 1-nitropyrene was negative. These data indicate that the limited sensitivity to chemical carcinogens displayed by the hepatocyte/DNA repair assay may be increased by using hepatocytes isolated from animals exposed to hepatic mixed-function oxidase inducers.

  20. Heat-Induced Soluble Protein Aggregates from Mixed Pea Globulins and β-Lactoglobulin.

    Science.gov (United States)

    Chihi, Mohamed-Lazhar; Mession, Jean-luc; Sok, Nicolas; Saurel, Rémi

    2016-04-06

    The present work investigates the formation of protein aggregates (85 °C, 60 min incubation) upon heat treatment of β-lactoglobulin (βlg)-pea globulins (Glob) mixtures at pH 7.2 and 5 mM NaCl from laboratory-prepared protein isolates. Various βlg/Glob weight ratios were applied, for a total protein concentration of 2 wt % in admixture. Different analytical methods were used to determine the aggregation behavior of "mixed" aggregates, that is, surface hydrophobicity and also sulfhydryl content, protein interactions by means of SDS-PAGE electrophoresis, and molecule size distribution by DLS and gel filtration. The production of "mixed" thermal aggregates would involve both the formation of new disulfide bonds and noncovalent interactions between the denatured βlg and Glob subunits. The majority of "mixed" soluble aggregates displayed higher molecular weight and smaller diameter than those for Glob heated in isolation. The development of pea-whey protein "mixed" aggregates may help to design new ingredients for the control of innovative food textures.

  1. Family number non-conservation induced by the super-symmetric mixing of scalar leptons

    International Nuclear Information System (INIS)

    Levine, M.J.S.

    1987-01-01

    We examine a model of supersymmetry with soft breaking terms in the electroweak sector. Explicit mixing among the scalar leptons results in a number of effects, principally non-conservation of lepton family number. Comparison with experiment permits us to place constraints upon the model

  2. Redox-induced spin-state switching and mixed valency in quinonoid-bridged dicobalt complexes

    Czech Academy of Sciences Publication Activity Database

    Schweinfurth, D.; Rechkemmer, Y.; Hohloch, S.; Deibel, N.; Peremykin, I.; Fiedler, Jan; Marx, R.; Neugebauer, P.; van Slageren, J.; Sarkar, B.

    2014-01-01

    Roč. 20, č. 12 (2014), s. 3475-3486 ISSN 0947-6539 R&D Projects: GA ČR GA203/09/0705 Institutional support: RVO:61388955 Keywords : bridging ligand s * mixed -valent compounds * non-innocent ligand s Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 5.731, year: 2014

  3. A Study of Moisture Induced Material Loss of Hot Mix Asphalt (HMA)

    Science.gov (United States)

    2017-10-31

    Maine Department of Transportation has noticed the partial or complete loss of material within 2-3 years of construction in the traffic wheel path in the presence of moisture in few of their mixes. Regularly used moisture susceptibility tests are una...

  4. Mixed Lactobacillus plantarum Strains Inhibit Staphylococcus aureus Induced Inflammation and Ameliorate Intestinal Microflora in Mice.

    Science.gov (United States)

    Ren, Dayong; Gong, Shengjie; Shu, Jingyan; Zhu, Jianwei; Rong, Fengjun; Zhang, Zhenye; Wang, Di; Gao, Liangfeng; Qu, Tianming; Liu, Hongyan; Chen, Ping

    2017-01-01

    Objective . Staphylococcus aureus is an important pathogen that causes intestinal infection. We examined the immunomodulatory function of single and mixed Lactobacillus plantarum strains, as well as their impacts on the structure of the microbiome in mice infected with Staphylococcus aureus . The experiment was divided into three groups: protection, treatment, and control. Serum IFN- γ and IL-4 levels, as well as intestinal sIgA levels, were measured during and 1 week after infection with Staphylococcus aureus with and without Lactobacillus plantarum treatment. We used 16s rRNA tagged sequencing to analyze microbiome composition. IFN- γ /IL-4 ratio decreased significantly from infection to convalescence, especially in the mixed Lactobacillus plantarum group. In the mixed Lactobacillus plantarum group the secretion of sIgA in the intestine of mice (9.4-9.7 ug/mL) was significantly higher than in the single lactic acid bacteria group. The dominant phyla in mice are Firmicutes , Bacteroidetes , and Proteobacteria . Treatment with mixed lactic acid bacteria increased the anti-inflammatory factor and the secretion of sIgA in the intestine of mice infected with Staphylococcus aureus and inhibited inflammation.

  5. Mixing-induced groundwater denitrification beneath a manured field in southern Alberta, Canada

    International Nuclear Information System (INIS)

    McCallum, J.E.; Ryan, M.C.; Mayer, B.; Rodvang, S.J.

    2008-01-01

    Contamination of shallow groundwater by NO 3 - from manure may occur under fields where manure is spread as fertilizer and for disposal. Attenuation of NO 3 - in groundwater occurs through denitrification under certain conditions, or NO 3 - -contaminated younger groundwater may mix with older groundwater, lowering the NO 3 - concentration. In this study, δ 15 N and δ 18 O values of NO 3 - , and δ 18 O and δ 2 H values in groundwater under a manured field were evaluated to determine if groundwater NO 3 - concentrations were influenced through mixing of shallower, manure-impacted groundwater with older groundwater, or if denitrification was reducing NO 3 - concentrations. The younger groundwater showed clear evidence of manure impact with elevated Cl - (∼85 mg L -1 ) and NO 3 - concentrations (∼50 mg NO 3 -N L -1 ), and δ 15 N and δ 18 O values of NO 3 - consistent with a manure source. Vertical hydraulic gradients and δ 18 O and δ 2 H values in groundwater suggest older, more reduced groundwater is upwelling locally and mixing with the shallow groundwater. Decreasing NO 3 :Cl ratios, decreasing dissolved O 2 concentrations, and increasing δ 15 N and δ 18 O values of NO 3 - suggest that denitrification occurs locally in the aquifer. The extent of denitrification is proportional to the fraction of deeper groundwater in the aquifer. Denitrification apparently does not proceed in the younger, manure-impacted groundwater in the absence of mixing

  6. Continuum contribution to excitonic four-wave mixing due to interaction-induced nonlinearities

    DEFF Research Database (Denmark)

    Birkedal, Dan; Vadim, Lyssenko; Hvam, Jørn Märcher

    1996-01-01

    We present an experimental and theoretical investigation of ultrafast transient four-wave mixing of GaAs/AlxGa1-xAs quantum wells for coherent excitation of exciton and continuum states. The signal appears at the exciton resonance and is shown to consist of two contributions: an intense spectrall...

  7. Mixing induced by swift heavy ion irradiation at Fe/Si interface

    Indian Academy of Sciences (India)

    Unknown

    Experimental results show that high electronic excitation can also induce structural modifications in metallic sys- tems similar to those in non-metallic systems. This means that all Se-dependent effects induced in different materials are probably related to some basic energy transfer mecha- nism between the incident ion and ...

  8. Interferon-gamma impairs proliferation of hematopoietic stem cells in mice

    NARCIS (Netherlands)

    de Bruin, Alexander M.; Demirel, Özlem; Hooibrink, Berend; Brandts, Christian H.; Nolte, Martijn A.

    2013-01-01

    Balancing the processes of hematopoietic stem cell (HSC) differentiation and self-renewal is critical for maintaining a lifelong supply of blood cells. The bone marrow (BM) produces a stable output of newly generated cells, but immunologic stress conditions inducing leukopenia increase the demand

  9. A three-dimensional relaxation model for calculation of atomic mixing and topography changes induces by ion beams

    International Nuclear Information System (INIS)

    Collins, R.; Perez-Martin, A.M.C.; Dominguez-Vazquez, J.; Jimenez-Rodriguez, J.J.

    1994-01-01

    A simple model for three-dimensional material relaxation associated with atomic mixing is presented. The relaxation of the solid to accommodate the extra effective displacement volume Ω of an implanted or relocated atom is modelled by treating the surrounding solid as an incompressible medium. This leads to a tractable general formalism which can be used to predict implant distribution and changes in surface topography induced by ion beams, both in monatomic and multicomponent targets. The two-component case is discussed in detail. (orig.)

  10. Electron heating mode transition induced by mixing radio frequency and ultrahigh frequency dual frequency powers in capacitive discharges

    International Nuclear Information System (INIS)

    Sahu, B. B.; Han, Jeon G.

    2016-01-01

    Electron heating mode transitions induced by mixing the low- and high-frequency power in dual-frequency nitrogen discharges at 400 mTorr pressure are presented. As the low-frequency (13.56 MHz) power decreases and high-frequency (320 MHz) power increases for the fixed power of 200 W, there is a transition of electron energy distribution function (EEDF) from Druyvesteyn to bi-Maxwellian type characterized by a distinguished warm electron population. It is shown that this EEDF evolution is attributed to the transition from collisional to collisionless stochastic heating of the low-energy electrons.

  11. Generation of hematopoietic lineage cells from embryonic like cells

    Directory of Open Access Journals (Sweden)

    Gholam Reza Khamisipour

    2014-10-01

    Full Text Available Background: Epigenetic reprogramming of somatic cells into embryonic stem cells has attracted much attention, because of the potential for stem cell transplantation and compatibility with recipient. However, the therapeutic application of either nuclear transfer or nuclear fusion of somatic cell has been hindered by technical complications as well as ethical objections. Recently, a new method is reported whereby ectopic expression of embryonic specific transcription factors was shown to induce fibroblasts to become embryonic like SCs (induced pluripotent stem cells. A major limitation of this method is the use of potentially harmful genome integrating viruses such as reto- or lentivirus. The main aim of this investigation was generation of human hematopoietic stem cells from induced fibroblasts by safe adenovectors carrying embryonically active genes. Material and Methods: Isolated fibroblasts from foreskin were expanded and recombinant adenoviruses carrying human Sox2, Oct4, Klf4, cMyc genes were added to culture. After formation of embryonic like colonies and cell expansion, they were transferred to embryonic media without bFGF, and embryoid bodies were cultured on stromal and non-stromal differentiation media for 14 days. Results: Expression of CD34 gene and antigenic markers, CD34, CD38 & CD133 in stromal culture showed significant difference with non-differentiation and non-stromal media. Conclusion: These findings show high hematopoietic differentiation rate of Adeno-iPS cells in stromal culture and no need to use growth factors. While, there was no difference between non-differentiation and non-stromal media.

  12. Amplitude death induced by mixed attractive and repulsive coupling in the relay system

    Science.gov (United States)

    Zhao, Nannan; Sun, Zhongkui; Xu, Wei

    2018-01-01

    The amplitude death (AD) phenomenon is found in the relay system in the presence of the mixed couplings composed of attractive coupling and repulsive coupling. The generation mechanism of AD is revealed and shows that the middle oscillator achieving AD is a prerequisite to further suppress oscillation of the outermost oscillators for the paradigmatic Stuart-Landau and Rössler models. Moreover, regarding the Stuart-Landau relay system as a small motif of star network, we also observe that the mixed couplings can facilitate AD state of the whole network system. Particularly, the threshold of coupling strength is invariable with the change of network size. Our findings may shed a new insight to explore the effects of hybrid coupling on complex systems, also provide a new strategy to control dynamic behaviors in engineering science and neuroscience fields.

  13. New influence factor inducing difficulty in selective flotation separation of Cu-Zn mixed sulfide minerals

    Science.gov (United States)

    Deng, Jiu-shuai; Mao, Ying-bo; Wen, Shu-ming; Liu, Jian; Xian, Yong-jun; Feng, Qi-cheng

    2015-02-01

    Selective flotation separation of Cu-Zn mixed sulfides has been proven to be difficult. Thus far, researchers have found no satisfactory way to separate Cu-Zn mixed sulfides by selective flotation, mainly because of the complex surface and interface interaction mechanisms in the flotation solution. Undesired activation occurs between copper ions and the sphalerite surfaces. In addition to recycled water and mineral dissolution, ancient fluids in the minerals are observed to be a new source of metal ions. In this study, significant amounts of ancient fluids were found to exist in Cu-Zn sulfide and gangue minerals, mostly as gas-liquid fluid inclusions. The concentration of copper ions released from the ancient fluids reached 1.02 × 10-6 mol/L, whereas, in the cases of sphalerite and quartz, this concentration was 0.62 × 10-6 mol/L and 0.44 × 10-6 mol/L, respectively. As a result, the ancient fluid is a significant source of copper ions compared to mineral dissolution under the same experimental conditions, which promotes the unwanted activation of sphalerite. Therefore, the ancient fluid is considered to be a new factor that affects the selective flotation separation of Cu-Zn mixed sulfide ores.

  14. Reconstruction of hematopoietic inductive microenvironment after transplantation of VCAM-1-modified human umbilical cord blood stromal cells.

    Directory of Open Access Journals (Sweden)

    Yao Liu

    Full Text Available The hematopoietic inductive microenvironment (HIM is where hematopoietic stem/progenitor cells grow and develop. Hematopoietic stromal cells were the key components of the HIM. In our previous study, we had successfully cultured and isolated human cord blood-derived stromal cells (HUCBSCs and demonstrated that they could secret hemopoietic growth factors such as GM-CSF, TPO, and SCF. However, it is still controversial whether HUCBSCs can be used for reconstruction of HIM. In this study, we first established a co-culture system of HUCBSCs and cord blood CD34(+ cells and then determined that using HUCBSCs as the adherent layer had significantly more newly formed colonies of each hematopoietic lineage than the control group, indicating that HUCBSCs had the ability to promote the proliferation of hematopoietic stem cells/progenitor cells. Furthermore, the number of colonies was significantly higher in vascular cell adhesion molecule-1 (VCAM-1-modified HUCBSCs, suggesting that the ability of HUCBSCs in promoting the proliferation of hematopoietic stem cells/progenitor cells was further enhanced after having been modified with VCAM-1. Next, HUCBSCs were infused into a radiation-damaged animal model, in which the recovery of hematopoiesis was observed. The results demonstrate that the transplanted HUCBSCs were "homed in" to bone marrow and played roles in promoting the recovery of irradiation-induced hematopoietic damage and repairing HIM. Compared with the control group, the HUCBSC group had significantly superior effectiveness in terms of the recovery time for hemogram and myelogram, CFU-F, CFU-GM, BFU-E, and CFU-Meg. Such differences were even more significant in VCAM-1-modified HUCBSCs group. We suggest that HUCBSCs are able to restore the functions of HIM and promote the recovery of radiation-induced hematopoietic damage. VCAM-1 plays an important role in supporting the repair of HIM damage.

  15. s-Processing from MHD-induced mixing and isotopic abundances in presolar SiC grains

    Science.gov (United States)

    Palmerini, S.; Trippella, O.; Busso, M.; Vescovi, D.; Petrelli, M.; Zucchini, A.; Frondini, F.

    2018-01-01

    In the past years the observational evidence that s-process elements from Sr to Pb are produced by stars ascending the so-called Asymptotic Giant Branch (or "AGB") could not be explained by self-consistent models, forcing researchers to extensive parameterizations. The crucial point is to understand how protons can be injected from the envelope into the He-rich layers, yielding the formation of 13C and then the activation of the 13C (α,n)16O reaction. Only recently, attempts to solve this problem started to consider quantitatively physically-based mixing mechanisms. Among them, MHD processes in the plasma were suggested to yield mass transport through magnetic buoyancy. In this framework, we compare results of nucleosynthesis models for Low Mass AGB Stars (M≲ 3M⊙), developed from the MHD scenario, with the record of isotopic abundance ratios of s-elements in presolar SiC grains, which were shown to offer precise constraints on the 13C reservoir. We find that n-captures driven by magnetically-induced mixing can indeed account for the SiC data quite well and that this is due to the fact that our 13C distribution fulfils the above constraints rather accurately. We suggest that similar tests should be now performed using different physical models for mixing. Such comparisons would indeed improve decisively our understanding of the formation of the neutron source.

  16. Applications of Analytical Self-Similar Solutions of Reynolds-Averaged Models for Instability-Induced Turbulent Mixing

    Science.gov (United States)

    Hartland, Tucker; Schilling, Oleg

    2017-11-01

    Analytical self-similar solutions to several families of single- and two-scale, eddy viscosity and Reynolds stress turbulence models are presented for Rayleigh-Taylor, Richtmyer-Meshkov, and Kelvin-Helmholtz instability-induced turbulent mixing. The use of algebraic relationships between model coefficients and physical observables (e.g., experimental growth rates) following from the self-similar solutions to calibrate a member of a given family of turbulence models is shown. It is demonstrated numerically that the algebraic relations accurately predict the value and variation of physical outputs of a Reynolds-averaged simulation in flow regimes that are consistent with the simplifying assumptions used to derive the solutions. The use of experimental and numerical simulation data on Reynolds stress anisotropy ratios to calibrate a Reynolds stress model is briefly illustrated. The implications of the analytical solutions for future Reynolds-averaged modeling of hydrodynamic instability-induced mixing are briefly discussed. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

  17. Preliminary study about frequencies of unstable chromosome alterations induced by gamma beam and neutron-gamma mixed field

    International Nuclear Information System (INIS)

    Mendes, Mariana E.; Souza, Priscilla L.G.; Brandao, Jose Odinilson de C.; Santos, Joelan A.L.; Vilela, Eudice C.; Lima, Fabiana F.; Calixto, Merilane S.; Santos, Neide

    2011-01-01

    The estimate on approximate dose in exposed individual can be made through conventional cytogenetic analysis of dicentric, this technique has been used to support physical dosimetry. It is important to estimate the absorbed dose in case of accidents with the aim of developing an appropriate treatment and biological dosimetry can be very useful in case where the dosimetry is unavailable. Exposure to gamma and neutron radiation leads to the same biological effects such as chromosomal alterations and cancer. However, neutrons cause more genetic damage, such as mutation or more structural damage, such as chromosome alterations. The aim of research is to compare frequencies of unstable chromosome alterations induced by a gamma beam with those from neutron-gamma mixed field. Two blood samples were obtained from one healthy donor and irradiated at different sources. The first sample was exposed to mixed field neutron-gamma sources 241 AmBe at the Neutron Calibration Laboratory (NCL - CRCN/NE - PE - Brazil) and the second one was exposed to 137 Cs gamma rays at 137 Cs Laboratory (CRCN/NE - PE - Brazil), both exposures resulting in an absorbed dose of 0.66Gy. Mitotic metaphase cells were obtained by lymphocyte culture for chromosomal analysis and slides were stained with Giemsa 5%. These preliminary results showed a similarity in associated dicentrics frequency per cell (0.041 and 0.048) after 137 Cs and 241 AmBe sources irradiations, respectively. However, it was not observed centric rings frequency per cell (0.0 and 0.027). This study will be continue to verify the frequencies of unstable chromosome alterations induced by only gamma beam and neutron-gamma mixed field. (author)

  18. Preliminary study about frequencies of unstable chromosome alterations induced by gamma beam and neutron-gamma mixed field

    Energy Technology Data Exchange (ETDEWEB)

    Mendes, Mariana E.; Souza, Priscilla L.G.; Brandao, Jose Odinilson de C.; Santos, Joelan A.L.; Vilela, Eudice C.; Lima, Fabiana F. [Centro Regional de Ciencias Nucleares (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Calixto, Merilane S.; Santos, Neide [Universidade Federal de Pernanmbuco (CCB/UFPE), Recife, PE (Brazil). Centro de Ciencias Biologicas. Dept. de Genetica

    2011-07-01

    The estimate on approximate dose in exposed individual can be made through conventional cytogenetic analysis of dicentric, this technique has been used to support physical dosimetry. It is important to estimate the absorbed dose in case of accidents with the aim of developing an appropriate treatment and biological dosimetry can be very useful in case where the dosimetry is unavailable. Exposure to gamma and neutron radiation leads to the same biological effects such as chromosomal alterations and cancer. However, neutrons cause more genetic damage, such as mutation or more structural damage, such as chromosome alterations. The aim of research is to compare frequencies of unstable chromosome alterations induced by a gamma beam with those from neutron-gamma mixed field. Two blood samples were obtained from one healthy donor and irradiated at different sources. The first sample was exposed to mixed field neutron-gamma sources {sup 241}AmBe at the Neutron Calibration Laboratory (NCL - CRCN/NE - PE - Brazil) and the second one was exposed to {sup 137}Cs gamma rays at {sup 137}Cs Laboratory (CRCN/NE - PE - Brazil), both exposures resulting in an absorbed dose of 0.66Gy. Mitotic metaphase cells were obtained by lymphocyte culture for chromosomal analysis and slides were stained with Giemsa 5%. These preliminary results showed a similarity in associated dicentrics frequency per cell (0.041 and 0.048) after {sup 137}Cs and {sup 241}AmBe sources irradiations, respectively. However, it was not observed centric rings frequency per cell (0.0 and 0.027). This study will be continue to verify the frequencies of unstable chromosome alterations induced by only gamma beam and neutron-gamma mixed field. (author)

  19. Family number non-conservation induced by the supersymmetric mixing of scalar leptons

    International Nuclear Information System (INIS)

    Levine, M.J.S.

    1987-08-01

    The most egregious aspect of (N = 1) supersymmetric theories is that each particle state is accompanied by a 'super-partner', a state with identical quantum numbers save that it differs in spin by one half unit. For the leptons these are scalars and are called ''sleptons'', or scalar leptons. These consist of the charged sleptons (selectron, smuon, stau) and the scalar neutrinos ('sneutrinos'). We examine a model of supersymmetry with soft breaking terms in the electroweak sector. Explicit mixing among the scalar leptons results in a number of effects, principally non-conservation of lepton family number. Comparison with experiment permits us to place constraints upon the model. 49 refs., 12 figs

  20. Generation of stable mixed-compact-toroid rings by inducing plasma currents in strong E rings

    International Nuclear Information System (INIS)

    Jayakumar, R.; Taggart, D.P.; Parker, M.R.; Fleischmann, H.H.

    1989-01-01

    In the RECE-Christa device, hybrid-type compact toroid rings are generated by inducing large toroidal plasma currents I rho in strong electron rings using a thin induction coil positioned along the ring axis. Starting from field-reversal values δ ο = 50 - 120 percent of the original pure fast-electron ring, the induced plasma current I rho raises δ to a maximum value of up to 240 percent with I rho contributing more than 50 percent of the total ring current. Quite interestingly, the generated hybrid compact toroid configurations appear gross-stable during the full I rho pulse length (half-amplitude width about 100 μs)

  1. Mixed convection peristaltic flow of third order nanofluid with an induced magnetic field.

    Science.gov (United States)

    Noreen, Saima

    2013-01-01

    This research is concerned with the peristaltic flow of third order nanofluid in an asymmetric channel. The governing equations of third order nanofluid are modelled in wave frame of reference. Effect of induced magnetic field is considered. Long wavelength and low Reynolds number situation is tackled. Numerical solutions of the governing problem are computed and analyzed. The effects of Brownian motion and thermophoretic diffusion of nano particles are particularly emphasized. Physical quantities such as velocity, pressure rise, temperature, induced magnetic field and concentration distributions are discussed.

  2. Mixed convection peristaltic flow of third order nanofluid with an induced magnetic field.

    Directory of Open Access Journals (Sweden)

    Saima Noreen

    Full Text Available This research is concerned with the peristaltic flow of third order nanofluid in an asymmetric channel. The governing equations of third order nanofluid are modelled in wave frame of reference. Effect of induced magnetic field is considered. Long wavelength and low Reynolds number situation is tackled. Numerical solutions of the governing problem are computed and analyzed. The effects of Brownian motion and thermophoretic diffusion of nano particles are particularly emphasized. Physical quantities such as velocity, pressure rise, temperature, induced magnetic field and concentration distributions are discussed.

  3. Dissecting the hematopoietic microenvironment. V: Limitations of repair following damage to the hematopoietic support stroma

    Energy Technology Data Exchange (ETDEWEB)

    Wolf, N.S.

    1982-01-01

    Damage and repair of the hematopoietic microenvironment of the spleen was studied using X-irradiation, anoxic necrosis induced by splenic ligation, or a combination of the two, as the destructive agents. Spleen colony number, size and type, /sup 59/Fe uptake, and microscopic study of splenic structure were used as means of assessment. The most severe or least repaired damage was induced by high dose irradiation (4000 r), by 1000 r followed immediately by splenic ligation, and by two successive splenic ligations separated by a 30 day recovery period. It was seen that reduction of CFUlt. slashsub slt. slash lodgment, as measured by f factor, played a very major role in the lesser number of spleen colonies formed after either kind of damage. Following the several treatments, the numbers of spleen colonies formed, their size and their typing as erythrocytic or granulocytic varied independently of each other, suggesting that these functions of the microenvironment, and the cell types responsible for them, are independent of each other. The exhaustion of regenerative capacity displayed by repeatedly ligated spleens suggested a maximal limit for stromal cell replications commensurate with Hayflick's hypothesis.

  4. Biogenic mixing induced by intermediate Reynolds number swimming in stratified fluids

    Science.gov (United States)

    Wang, Shiyan; Ardekani, Arezoo M.

    2015-01-01

    We study fully resolved motion of interacting swimmers in density stratified fluids using an archetypal swimming model called “squirmer”. The intermediate Reynolds number regime is particularly important, because the vast majority of organisms in the aphotic ocean (i.e. regions that are 200 m beneath the sea surface) are small (mm-cm) and their motion is governed by the balance of inertial and viscous forces. Our study shows that the mixing efficiency and the diapycnal eddy diffusivity, a measure of vertical mass flux, within a suspension of squirmers increases with Reynolds number. The mixing efficiency is in the range of O(0.0001–0.04) when the swimming Reynolds number is in the range of O(0.1–100). The values of diapycnal eddy diffusivity and Cox number are two orders of magnitude larger for vertically swimming cells compared to horizontally swimming cells. For a suspension of squirmers in a decaying isotropic turbulence, we find that the diapycnal eddy diffusivity enhances due to the strong viscous dissipation generated by squirmers as well as the interaction of squirmers with the background turbulence. PMID:26628288

  5. Thermal fatigue analysis of vertical annulus with inner rotating cylinder induced by two temperature fluid mixing

    International Nuclear Information System (INIS)

    Miyano, Hiroshi; Narabayashi, Tadashi

    2011-01-01

    Mechanical seal for nuclear reactor coolant recirculation pump must purge the cold water supply from the outside. The cold purge water is flowing into the hot water zone in the pump through a narrow gap between pump shaft and casing over. On the mixing region of the cold purge water and hot water in the narrow gap, the random level temperature fluctuation occurs on the structural metal surface of casing cover and pump shaft. Then it could lead to cyclic thermal stress and fatigue damage. The experiments and analysis have done, made clear the mechanism of generation of temperature fluctuations. Also, it was studied how to measure the structure of the mixing zone temperature control and how to prevent the occurrence of a large temperature fluctuation. In addition, it is proposed the method of evaluating a random temperature fluctuation by using the envelope curve and its fatigue by OOR counting to applying to the evaluation of the similar random fluid temperature fluctuation problems. (author)

  6. MiRNAs and piRNAs from bone marrow mesenchymal stem cell extracellular vesicles induce cell survival and inhibit cell differentiation of cord blood hematopoietic stem cells: a new insight in transplantation.

    Science.gov (United States)

    De Luca, Luciana; Trino, Stefania; Laurenzana, Ilaria; Simeon, Vittorio; Calice, Giovanni; Raimondo, Stefania; Podestà, Marina; Santodirocco, Michele; Di Mauro, Lazzaro; La Rocca, Francesco; Caivano, Antonella; Morano, Annalisa; Frassoni, Francesco; Cilloni, Daniela; Del Vecchio, Luigi; Musto, Pellegrino

    2016-02-09

    Hematopoietic stem cells (HSC), including umbilical cord blood CD34+ stem cells (UCB-CD34+), are used for the treatment of several diseases. Although different studies suggest that bone marrow mesenchymal stem cells (BM-MSC) support hematopoiesis, the exact mechanism remains unclear. Recently, extracellular vesicles (EVs) have been described as a novel avenue of cell communication, which may mediate BM-MSC effect on HSC. In this work, we studied the interaction between UCB-CD34+ cells and BM-MSC derived EVs. First, by sequencing EV derived miRNAs and piRNAs we found that EVs contain RNAs able to influence UCB-CD34+ cell fate. Accordingly, a gene expression profile of UCB-CD34+ cells treated with EVs, identified about 100 down-regulated genes among those targeted by EV-derived miRNAs and piRNAs (e.g. miR-27b/MPL, miR-21/ANXA1, miR-181/EGR2), indicating that EV content was able to modify gene expression profile of receiving cells. Moreover, we demonstrated that UCB-CD34+ cells, exposed to EVs, significantly changed different biological functions, becoming more viable and less differentiated. UCB-CD34+ gene expression profile also identified 103 up-regulated genes, most of them codifying for chemokines, cytokines and their receptors, involved in chemotaxis of different BM cells, an essential function of hematopoietic reconstitution. Finally, the exposure of UCB-CD34+ cells to EVs caused an increased expression CXCR4, paralleled by an in vivo augmented migration from peripheral blood to BM niche in NSG mice. This study demonstrates the existence of a powerful cross talk between BM-MSC and UCB-CD34+ cells, mediated by EVs, providing new insight in the biology of cord blood transplantation.

  7. Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants

    OpenAIRE

    Strober, Samuel

    2016-01-01

    The goals of tolerance in patients with solid organ transplants are to eliminate the lifelong need for immunosuppressive (IS) drugs and to prevent graft loss due to rejection or drug toxicity. Tolerance with complete withdrawal of IS drugs has been achieved in recipients of HLA-matched and mismatched living donor kidney transplants in 3 medical centers using hematopoietic cell transplants to establish mixed or complete chimerism.

  8. Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants.

    Science.gov (United States)

    Strober, Samuel

    2016-03-24

    The goals of tolerance in patients with solid organ transplants are to eliminate the lifelong need for immunosuppressive (IS) drugs and to prevent graft loss due to rejection or drug toxicity. Tolerance with complete withdrawal of IS drugs has been achieved in recipients of HLA-matched and mismatched living donor kidney transplants in 3 medical centers using hematopoietic cell transplants to establish mixed or complete chimerism. © 2016 by The American Society of Hematology.

  9. Gamma-ray-induced polymerization of mixed liposomes consisting of 2,4-octadecadienoyl groups of phospholipids and unpolymerizable components

    Energy Technology Data Exchange (ETDEWEB)

    Akama, Kazuhiro; Awai, Kouji; Yano, Yoshihiro; Tokuyama, Satoru; Nakano, Yoshio [Tsukuba Research Laboratory, NOF Corporation, Tsukuba, Ibaraki (Japan); Hosoi, Fumio; Omichi, Hideki [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment

    2000-06-01

    We studied the {gamma}-ray-induced polymerization of two mixed-liposome systems containing 1,2-bis-[(2E,4E)-octadecadienoyl]-sn-glycero-3-phosphocholine (DODPC) to clarify its mechanism; (a) containing DODPC and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), or DODPC/DPPC liposome, and (b) containing DODPC, DPPC, Cholesterol (Chol), and stearic acid (SA), or DODPC/DPPC/Chol/SA liposomes was carried out. For each system, various molar ratios of DODPC/DPPC were studied. For DODPC/DPPC/Chol/SA liposomes, the molar ratio of phospholipid/Chol/SA was 7/7/2. Liposomes were prepared by extrusion through a 0.2-{mu}m-pore polycarbonate filter and polymerized by {gamma}-irradiation at a dose rate of 3.3 kGy/h at 4degC. Polymerization rate increased when DODPC/DPPC was 5/5 in DODPC/DPPC liposomes and when it was 9/1, 8/2, 7/3, and 5/5 in DODPC/DPPC/Chol/SA liposomes. The degree of polymerization at molar ratio 5/5 for each mixed-liposome system significantly increased compared with that of DODPC liposomes containing no DPPC. For polymerized mixed liposomes stability, mean diameter after one freeze-thaw cycle remained unchanged for molar ratios from 10/0 to 8/2 of either DODPC/DPPC or DODPC/DPPC/Chol/SA liposomes. {gamma}-Ray-induced polymerization of each mixed-liposome system was analyzed using kinetic treatment of polymerization. Although the rate of polymerization for either systems differed from that of DODPC liposomes, the polymerization mechanism was the same. Immiscibility between DODPC and unpolymerizable components was estimated based on the kinetic data of polymerization. Hydrophobic interactions of DPPC and/or Chol with DODPC significantly affected the conformation of DODPC, which rearranges into an easily polymerizable conformation. The rate and degree of polymerization thus increased. (author)

  10. Numerical simulation of bubble induced shear in membrane bioreactors: effects of mixed liquor rheology and membrane configuration.

    Science.gov (United States)

    Liu, Xuefei; Wang, Yuan; Waite, T David; Leslie, Greg

    2015-05-15

    A CFD model, incorporating an empirically determined rheology model and a porous media model, was developed to simulate bubble induced surface shear in membrane bioreactors configured with hollow fibre membranes with outer diameters ranging from 1.3 to 2.4 mm, arranged in vertically orientated modules with packing density from 200 to 560 m(2)/m(3). The rheology model was developed for mixed liquor suspended solids (MLSS) concentrations of 3 to 16 gL(-1) in the presence and absence of coagulant (generated by addition of a ferrous salt) for shear rates ranging from 0 to 500 s(-1). Experimentally determined particle relaxation times for the biological flocs in the mixed liquor, both in the absence and presence of iron, were negligible, consistent with an environment where positive buoyancy forces were greater than negative settling forces thereby allowing the sludge mixture to be modelled as a single continuous phase. The non-Newtonian behaviour of the mixed liquor was incorporated into the CFD simulations using an Ostwald-de Waele rheology model. Interactions between mixed liquor and hollow fibre membranes of different fibre size and packing density were described using a porous media model that was calibrated by empirical measurement of inertial loss coefficients over a range of viscosities (0.8 × 10(-3) to 2.1 × 10(-3) Pa.s) and velocities (0 to 0.35 m/s) typically encountered in full scale MBRs. Experimental results indicated that addition of iron salts resulted in an increase in MLSS and sludge viscosity. Shear stress is affected by both velocity and viscosity. The increase in sludge viscosity resulted in an increase in resistance to flow through the hollow fibre membrane bundles and, as a result, decreased the liquid flow velocities. CFD simulations provided insight on the effects of point of coagulant addition and MLSS concentration on bubble-induced shear over a range of industrially relevant conditions. A 12% increase in shear stress was observed when

  11. Family number non-conservation induced by the supersymmetric mixing of scalar leptons

    Energy Technology Data Exchange (ETDEWEB)

    Levine, M.J.S.

    1987-08-01

    The most egregious aspect of (N = 1) supersymmetric theories is that each particle state is accompanied by a 'super-partner', a state with identical quantum numbers save that it differs in spin by one half unit. For the leptons these are scalars and are called ''sleptons'', or scalar leptons. These consist of the charged sleptons (selectron, smuon, stau) and the scalar neutrinos ('sneutrinos'). We examine a model of supersymmetry with soft breaking terms in the electroweak sector. Explicit mixing among the scalar leptons results in a number of effects, principally non-conservation of lepton family number. Comparison with experiment permits us to place constraints upon the model. 49 refs., 12 figs.

  12. HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo

    Directory of Open Access Journals (Sweden)

    Parisa Imanirad

    2014-01-01

    Full Text Available Hypoxia affects many physiologic processes during early stages of mammalian ontogeny, particularly placental and vascular development. In the adult, the hypoxic bone marrow microenvironment plays a role in regulating hematopoietic stem cell (HSC function. HSCs are generated from the major vasculature of the embryo, but whether the hypoxic response affects the generation of these HSCs is as yet unknown. Here we examined whether Hypoxia Inducible Factor1-alpha (HIF1α, a key modulator of the response to hypoxia, is essential for HSC development. We found hypoxic cells in embryonic tissues that generate and expand hematopoietic cells (aorta, placenta and fetal liver, and specifically aortic endothelial and hematopoietic cluster cells. A Cre/loxP conditional knockout (cKO approach was taken to delete HIF1α in Vascular Endothelial-Cadherin expressing endothelial cells, the precursors to definitive hematopoietic cells. Functional assays show that HSC and hematopoietic progenitor cells (HPCs are significantly reduced in cKO aorta and placenta. Moreover, decreases in phenotypic aortic hematopoietic cluster cells in cKO embryos indicate that HIF1α is necessary for generation and/or expansion of HPCs and HSCs. cKO adult BM HSCs are also affected under transplantation conditions. Thus, HIF1α is a regulator of HSC generation and function beginning at the earliest embryonic stages.

  13. Cocaine induces a mixed lysosomal lipidosis in cultured fibroblasts, by inactivation of acid sphingomyelinase and inhibition of phospholipase A1

    International Nuclear Information System (INIS)

    Nassogne, Marie-Cecile; Lizarraga, Chantal; N'Kuli, Francisca; Van Bambeke, Francoise; Van Binst, Roger; Wallemacq, Pierre; Tulkens, Paul M.; Mingeot-Leclercq, Marie-Paule; Levade, Thierry; Courtoy, Pierre J.

    2004-01-01

    This paper reports that cocaine may induce a lysosomal storage disorder. Indeed, culture of Rat-1 fibroblasts with 250-500 μM cocaine induced after 2-3 days a major accumulation in lysosomes of electron-dense lamellar structures. By subcellular fractionation, this was reflected by a selective decrease of the buoyant density of several lysosomal enzymes, indicating lysosomal lipid overload. Biochemical analysis confirmed an increased cellular content of major phospholipids and sphingomyelin, but not of cholesterol. Cocaine, a membrane-permeant weak base, is concentrated by acidotropic sequestration, because its accumulation was abrogated by the proton ionophore, monensin and the vacuolar ATPase inhibitor, bafilomycin A 1 . At its estimated lysosomal concentration, cocaine almost completely inhibited phospholipase A 1 activity on liposomes. Cell incubation with cocaine, but not with its inactive metabolite, benzoylecgonine, rapidly inactivated acid sphingomyelinase, as reflected by a 10-fold decrease in V max with identical K m . Acid sphingomyelinase inactivation was fully prevented by the thiol proteinases inhibitors, leupeptin and E64, indicating that cocaine induces selective sphingomyelinase proteolysis. Upon cocaine removal, acid sphingomyelinase activity was rapidly restored, pointing to its fast turnover. In contrast, the cellular content of several other lysosomal hydrolases was increased up to 2-fold. Together, these data show that acidotropic accumulation of cocaine in lysosomes rapidly inhibits acid phospholipase A 1 and inactivates acid sphingomyelinase, which can explain induction of a mixed lysosomal lipidosis

  14. Activated H-Ras regulates hematopoietic cell survival by modulating Survivin

    International Nuclear Information System (INIS)

    Fukuda, Seiji; Pelus, Louis M.

    2004-01-01

    Survivin expression and Ras activation are regulated by hematopoietic growth factors. We investigated whether activated Ras could circumvent growth factor-regulated Survivin expression and if a Ras/Survivin axis mediates growth factor independent survival and proliferation in hematopoietic cells. Survivin expression is up-regulated by IL-3 in Ba/F3 and CD34 + cells and inhibited by the Ras inhibitor, farnesylthiosalicylic acid. Over-expression of constitutively activated H-Ras (CA-Ras) in Ba/F3 cells blocked down-modulation of Survivin expression, G 0 /G 1 arrest, and apoptosis induced by IL-3 withdrawal, while dominant-negative (DN) H-Ras down-regulated Survivin. Survivin disruption by DN T34A Survivin blocked CA-Ras-induced IL-3-independent cell survival and proliferation; however, it did not affect CA-Ras-mediated enhancement of S-phase, indicating that the anti-apoptotic activity of CA-Ras is Survivin dependent while its S-phase enhancing effect is not. These results indicate that CA-Ras modulates Survivin expression independent of hematopoietic growth factors and that a CA-Ras/Survivin axis regulates survival and proliferation of transformed hematopoietic cells

  15. Flow transport and mixing induced by horizontal jets impinging on a vertical wall of the multi-compartment PANDA facility

    International Nuclear Information System (INIS)

    Paladino, Domenico; Zboray, Robert; Andreani, Michele; Dreier, Joerg

    2010-01-01

    In the frame of the OECD/NEA SETH project an experimental campaign has been carried out in the PANDA facility to investigate gas transport and mixing induced by a plume or a jet in the large-scale multi-compartment PANDA facility. The paper summarizes the results of the horizontal jet test series consisting of eight tests. Horizontal jets impinging on a vertical wall of one of the cylindrical PANDA containment vessels have been generated by changing various parameters, such as: type of injected fluid (steam or a mixture of steam and helium), fluid injection velocity, elevation (with respect to the containment vessel) of the injection exit, initial fluid composition in the vessels, and location of the vent line. The initial jet Froude number has been varied between 17 and 36 and in one of the test condensation occurred. The paper shows the effect of these parameters variation on the test evolution with respect to jet impingement location in the vertical curved wall and variation of impingement location as a function of buoyancy variation. Fluid mixing and stratification, characteristics of gas transport between the compartment and the effect of condensation on the overall phenomena evolution are analyzed in the paper.

  16. Consequences of induced transparency in a double-Λ scheme: Destructive interference in four-wave mixing

    International Nuclear Information System (INIS)

    Payne, M.G.; Deng, L.

    2002-01-01

    We investigate a four-state system interacting with long and short laser pulses in a weak probe beam approximation. We show that when all lasers are tuned to the exact unperturbed resonances, part of the four-wave mixing (FWM) field is strongly absorbed. The part that is not absorbed has the exact intensity required to destructively interfere with the excitation pathway involved in producing the FWM state. We show that with this three-photon destructive interference, the conversion efficiency can still be as high as 25%. Contrary to common belief, our calculation shows that this process, where an ideal one-photon electromagnetically induced transparency is established, is not most suitable for high-efficiency conversion. With appropriate phase matching and propagation distance, and when the three-photon destructive interference does not occur, we show that the photon flux conversion efficiency is independent of probe intensity and can be close to 100%. In addition, we show clearly that the conversion efficiency is not determined by the maximum atomic coherence between two lower excited states, as commonly believed. It is the combination of phase matching and constructive interference involving the two terms arising in producing the mixing wave that is the key element for the optimized FWM generation. Indeed, in this scheme no appreciable excited state is produced, so that the atomic coherence between states vertical bar 0> and vertical bar 2> is always very small

  17. IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice

    Science.gov (United States)

    Siegemund, Sabine; Rigaud, Stephanie; Conche, Claire; Broaten, Blake; Schaffer, Lana; Westernberg, Luise; Head, Steven Robert

    2015-01-01

    Tight regulation of hematopoietic stem cell (HSC) homeostasis ensures lifelong hematopoiesis and prevents blood cancers. The mechanisms balancing HSC quiescence with expansion and differentiation into hematopoietic progenitors are incompletely understood. Here, we identify Inositol-trisphosphate 3-kinase B (Itpkb) as an essential regulator of HSC homeostasis. Young Itpkb−/− mice accumulated phenotypic HSC, which were less quiescent and proliferated more than wild-type (WT) controls. Itpkb−/− HSC downregulated quiescence and stemness associated, but upregulated activation, oxidative metabolism, protein synthesis, and lineage associated messenger RNAs. Although they had normal-to-elevated viability and no significant homing defects, Itpkb−/− HSC had a severely reduced competitive long-term repopulating potential. Aging Itpkb−/− mice lost hematopoietic stem and progenitor cells and died with severe anemia. WT HSC normally repopulated Itpkb−/− hosts, indicating an HSC-intrinsic Itpkb requirement. Itpkb−/− HSC showed reduced colony-forming activity and increased stem-cell-factor activation of the phosphoinositide-3-kinase (PI3K) effectors Akt/mammalian/mechanistic target of rapamycin (mTOR). This was reversed by treatment with the Itpkb product and PI3K/Akt antagonist IP4. Transcriptome changes and biochemistry support mTOR hyperactivity in Itpkb−/− HSC. Treatment with the mTOR-inhibitor rapamycin reversed the excessive mTOR signaling and hyperproliferation of Itpkb−/− HSC without rescuing colony forming activity. Thus, we propose that Itpkb ensures HSC quiescence and function through limiting cytokine-induced PI3K/mTOR signaling and other mechanisms. PMID:25788703

  18. Tomographic and Geodynamic Constraints on Convection-Induced Mixing in Earth's Deep Mantle

    Science.gov (United States)

    Hafter, D. P.; Forte, A. M.; Bremner, P. M.; Glisovic, P.

    2017-12-01

    Seismological studies reveal two large low-shear-velocity provinces (LLSVPs) in the lowermost mantle (e.g., Su et al. 1994; Wang & Wen 2007; He & Wen 2012), which may represent accumulations of subducted slabs at the CMB (Tan & Gurnis 2005; Christensen & Hoffman 1994) or primordial material generated in the early differentiation of Earth (e.g. Li et al. 2014). The longevity or stability of these large-scale heterogeneities in the deep mantle depends on the vigor and spatial distribution of the convective circulation, which is in turn dependent on the distribution of mantle buoyancy and viscosity (e.g. Glisovic & Forte 2015). Here we explore the state of convective mixing in the mantle using the ASPECT convection code (Kronbichler et al. 2012). A series of experiments are conducted to consider the geochemical and dynamical contributions of LLSVPs to deep-mantle upwellings and corresponding plume-sourced volcanism. The principal feature of these experiments is the use of particle tracers to track geochemical changes in the LLSVPs and mantle plumes in addition to identifying those parts of the mantle that may remain unmixed. We employ 3-D mantle density anomalies derived from joint inversions of seismic, geodynamic and mineral physics constraints and geodynamically-constrained viscosity distributions (Glisovic et al. 2015) to ensure that the predicted flow fields yield a good match to key geophysical constraints (e.g. heat flow, global gravity anomalies and plate velocities).

  19. Universality of Planck's constant and a constraint from the absence of ℏ-induced neutrino mixing

    Science.gov (United States)

    Llanes-Estrada, Felipe J.

    2014-03-01

    You have probably often set ℏ = 1 but for what particle? I revisit here the possibility of a non-universal Planck-constant. Anomaly cancellation suggests that all particles in the same family perceive the same ℏ at fixed charges e, gw, gs; the difference between the muon's and the electron's (and thus the first and second families) can be tightly constrained by the muon's anomalous magnetic moment, but constraints are weaker for the third family. Neutrino mixing could have proceeded a priori not only by the Lagrangian neutrino mass-term, but also by the kinetic term if Planck's constant was not equal for all three species. An experimental constraint follows as such contributions, characterized by oscillations proportional to the energy, as opposed to the inverse energy, have been generically analyzed in the past. This provides at the same time support for gauge invariance. On the other hand if ℏ differs among particles while fixing the fine structure constants αem, αs, etc. instead of the charges, it affects the muonic atom puzzle without much constrain from g - 2 . Based on arXiv:1312.3566. Supported by spanish grants FPA2011-27853-C02-01 and CPAN.

  20. Wave-induced mixing and transport of buoyant particles: application to the Statfjord A oil spill

    Directory of Open Access Journals (Sweden)

    M. Drivdal

    2014-12-01

    Full Text Available This study focuses on how wave–current and wave–turbulence interactions modify the transport of buoyant particles in the ocean. Here the particles can represent oil droplets, plastic particles, or plankton such as fish eggs and larvae. Using the General Ocean Turbulence Model (GOTM, modified to take surface wave effects into account, we investigate how the increased mixing by wave breaking and Stokes shear production, as well as the stronger veering by the Coriolis–Stokes force, affects the drift of the particles. The energy and momentum fluxes, as well as the Stokes drift, depend on the directional wave spectrum obtained from a wave model. As a first test, the depth and velocity scales from the model are compared with analytical solutions based on a constant eddy viscosity (i.e., classical Ekman theory. Secondly, the model is applied to a case in which we investigate the oil drift after an oil spill off the west coast of Norway in 2007. During this accident the average net drift of oil was observed to be both slower and more deflected away from the wind direction than predicted by oil-drift models. In this case, using wind and wave forcing from the ERA Interim archive it is shown that the wave effects are important for the resultant drift and have the potential to improve drift forecasting.

  1. ESTIMATING THE SIZE OF LATE VENEER IMPACTORS FROM IMPACT-INDUCED MIXING ON MERCURY

    International Nuclear Information System (INIS)

    Rivera-Valentin, E. G.; Barr, A. C.

    2014-01-01

    Late accretion of a ''veneer'' of compositionally diverse planetesimals may introduce chemical heterogeneity in the mantles of the terrestrial planets. The size of the late veneer objects is an important control on the angular momenta, eccentricities, and inclinations of the terrestrial planets, but current estimates range from meter-scale bodies to objects with diameters of thousands of kilometers. We use a three-dimensional global Monte Carlo model of impact cratering, excavation, and ejecta blanket formation to show that evidence of mantle heterogeneity can be preserved within ejecta blankets of mantle-exhuming impacts on terrestrial planets. Compositionally distinct provinces implanted at the time of the late veneer are most likely to be preserved in bodies whose subsequent geodynamical evolution is limited. Mercury may have avoided intensive mixing by solid-state convection during much of its history. Its subsequent bombardment may have then excavated evidence of primordial mantle heterogeneity introduced by the late veneer. Simple geometric arguments can predict the amount of mantle material in the ejecta blanket of mantle-exhuming impacts, and deviations in composition relative to geometric predictions can constrain the length-scale of chemical heterogeneities in the subsurface. A marked change in the relationship between mantle and ejecta composition occurs when chemically distinct provinces are ∼250 km in diameter; thus, evidence of bombardment by thousand-kilometer-sized objects should be readily apparent from the variation in compositions of ejecta blankets in Mercury's ancient cratered terrains

  2. TLR-mediated albuminuria needs TNFα-mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice

    Directory of Open Access Journals (Sweden)

    Nidhi Jain

    2016-06-01

    Full Text Available Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs in mice through engagement of Toll-like receptors (TLRs is widely studied as a partial model for some forms of human nephrotic syndrome (NS. In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development.

  3. Thermally induced growth of ZnO nanocrystals on mixed metal oxide surfaces.

    Science.gov (United States)

    Inayat, Alexandra; Makky, Ayman; Giraldo, Jose; Kuhnt, Andreas; Busse, Corinna; Schwieger, Wilhelm

    2014-06-23

    An in situ method for the growth of ZnO nanocrystals on Zn/Al mixed metal oxide (MMO) surfaces is presented. The key to this method is the thermal treatment of Zn/Al layered double hydroxides (Zn/Al LDHs) in the presence of nitrate anions, which results in partial demixing of the LDH/MMO structure and the subsequent crystallization of ZnO crystals on the surface of the forming MMO layers. In a first experimental series, thermal treatment of Zn/Al LDHs with different fractions of nitrate and carbonate in the interlayer space was examined by thermogravimetry coupled with mass spectrometry (TG-MS) and in situ XRD. In a second experimental series, Zn/Al LDHs with only carbonate in the interlayer space were thermally treated in the presence of different amounts of an external nitrate source (NH4NO3). All obtained Zn/Al MMO samples were analysed by electron microscopy, nitrogen physisorption and powder X-ray diffraction. The gas phase formed during nitrate decomposition turned out to be responsible for the formation of crystalline ZnO nanoparticles. Accordingly, both interlayer nitrate and the presence of ammonium nitrate led to the formation of supported ZnO nanocrystals with mean diameters between 100 and 400 nm, and both methods offer the possibility to tailor the amount and size of the ZnO crystals by means of the amount of nitrate. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Wave-induced ripple development in mixed clay-sand substrates

    Science.gov (United States)

    Wu, Xuxu; Parsons, Daniel; Baas, Jaco H.; Mouazé, Dominique; McLelland, Stuart; Amoudry, Laurent; Eggenhuisen, Jorris; Cartigny, Matthieu; Ruessink, Gerben

    2016-04-01

    for sediment dynamics in mixed-bed substrates are highlighted and discussed.

  5. Salinity-induced mixed and barrier layers in the southwestern tropical Atlantic Ocean off the northeast of Brazil

    Directory of Open Access Journals (Sweden)

    M. Araujo

    2011-01-01

    Full Text Available High-resolution hydrographic observations of temperature and salinity are used to analyze the formation and distribution of isothermal depth (ZT, mixed depth (ZM and barrier layer thickness (BLT in a section of the southwestern Atlantic (0°30´ N–14°00´ S; 31°24´–41°48´ W, adjacent to the northeastern Brazilian coast. Analyzed data consists of 279 CTD casts acquired during two cruises under the Brazilian REVIZEE Program. One occurred in late austral winter (August–October 1995 and another in austral summer (January–April 1997. Oceanic observations are compared to numerical modeling results obtained from the French Mercator-Coriolis Program. Results indicate that the intrusion of subtropical Salinity Maximum Waters (SMW is the major process contributing to the seasonal barrier layer formation. These waters are brought by the South Equatorial Current (SEC, from the subtropical region, into the western tropical Atlantic boundary. During late austral winter southeastern trade winds are more intense and ITCZ precipitations induce lower surface salinity values near the equator. During this period a 5–90 m thick BLT (median = 15 m is observed and BLT > 30 m is restricted to latitudes higher than 8° S, where the intrusion of salty waters between 8°–12.3° S creates shallow mixed layers over deep (ZT ≥ 90 m isothermal layers. During austral summer, shallow isothermal and mixed layers prevail, when northeasterly winds are predominant and evaporation overcomes precipitation, causing saltier waters at the surface/subsurface layers. During that period observed BLT varies from 5 to 70 m and presents thicker median value of 35 m, when comparing to the winter. Furthermore, BLT ≥ 30 m is observed not only in the southernmost part of the study area, as verified during late winter, but in the latitude range 2°–14° S, where near-surface salty waters are transported westward by the

  6. Immunomodulatory Effects of Kuseonwangdogo-Based Mixed Herbal Formula Extracts on a Cyclophosphamide-Induced Immunosuppression Mouse Model

    Directory of Open Access Journals (Sweden)

    Joo Wan Kim

    2018-01-01

    Full Text Available Aim. Kuseonwangdogo is a traditional Korean immunomodulatory polyherbal prescription. However, there are no systemic findings on its complex immunomodulatory effects on in vivo models. In this study, we observed the immunomodulatory effects of Kuseonwangdogo-based mixed herbal formula aqueous extracts (MHFe on cyclophosphamide- (CPA- induced immunosuppression mouse model. Methods. In total, 60 male 6-week-old ICR mice (10 mice/group were selected based on body weight 24 h after the second CPA treatment and used in this experiment. Twelve hours after the end of the last (fourth oral administration of MHFe, the animals were sacrificed. Results. Following CPA treatment, a noticeable decrease in the body, thymus, spleen, and submandibular lymph node (LN weights; white blood cell, red blood cell, platelet number, hemoglobin, and hematocrit concentrations; serum interferon-γ levels; splenic tumor necrosis factor-α, interleukin- (IL- 1β, and IL-10 content; and peritoneal and splenic natural killer cell activities was observed. Depletion of lymphoid cells in the thymic cortex, splenic white pulp, and submandibular LN-related atrophic changes were also observed. However, these CPA-induced myelosuppressive signs were markedly and dose-dependently inhibited by the oral administration of 125, 250, and 500 mg/kg MHFe. Conclusion. MHFe can be a promising, potent immunomodulatory therapeutic agent for various immune disorders.

  7. DNA damage induced by radiation plasmodial mixed + gamma thermal neutrons in the presence and absence of free radical scavenger

    International Nuclear Information System (INIS)

    Rodriguez Gual, Maritza; Mas Milian, Felix; Gouveia, Andreia; Deppman, Airton

    2010-01-01

    In this work is quantified the damage in DNA plasmid induced by mixed radiation (thermal neutron and gamma rays) for first time. For the study was used the pBs KS+ plasmid of 2961 bp in aqueous solution of the 88 ng/μL with 0, 2 and 20 mmol/L of glycerol which acts as a free radicals scavenger. This plasmid changes its form of supercoiled to circular when a simple strand break is produced, and passes to a linear form when a double strand break is produced in the chain. Quantifying the fractions that exist in each of these forms is possible to estimate the effect of radiation on DNA. The irradiations were carried out in the radial channel 3 at IEA-R1 research reactor of the Instituto de Pesquisas Energeticas y Nucleares in Sao Paulo, Brazil. DNA forms were separated by agarose gel electrophoresis. For quantification the program GelAnalis was used. The values of the fractions of DNA in various forms were plotted as a function of dose and fitted to exponential and linear functions to obtaining the probabilities of simple and double strand breaks normalized by dose and molecular mass. The results showed the protective action of free radical scavenger against damage induced for radiation which corroborates the previous results found with other ionizing radiations. Yields of SSB and DSB will be of interest for the validation of the different models that attempt to reproduce the experimental results

  8. Metabolism of benzene and phenol by a reconstituted purified phenobarbital induced rat liver mixed function oxidase system

    International Nuclear Information System (INIS)

    Griffiths, J.C.

    1986-01-01

    Cytochrome P-450 and the electron-donor, NADPH-cytochrome c reductase were isolated from phenobarbital induced rat liver microsomes. Both benzene and its primary metabolite phenol, were substrates for the reconstituted purified phenobarbital induced rat liver mixed function oxidase system. Benzene was metabolized to phenol and the polyhydroxylated metabolites; catechol, hydroquinone and 1,2,4 benzenetriol. Benzene elicited a Type I spectral change upon its interaction with the cytochrome P-450 while phenol's interaction with the cytochrome P-450 produced a reverse Type I spectra. The formation of phenol showed a pH optimum of 7.0 compared with 6.6-6.8 for the production of the polyhyrdoxylated metabolites. Cytochrome P-450 inhibitors, such as metyrapone and SKF 525A, diminished the production of phenol from benzene but not the production of the polyhydroxylated metabolites from phenol. The radical trapping agents, DMSO, KTBA and mannitol, decreased the recovery of polyhydroxylated metabolites, from 14 C-labeled benzene and/or phenol. As KTBA and DMSO interacted with OH. There was a concomitant release of ethylene and methane, which was measured. Desferrioxamine, an iron-chelator and catalase also depressed the recovery of polyhydroxylated metabolites. In summary, benzene and phenol were both substrates for this reconstituted purified enzyme system, but they differed in binding to cytochrome P-450, pH optima and mode of hydroxylation

  9. Diffusion-induced grain boundary migration during ion beam mixing of Au/Cu bilayers

    International Nuclear Information System (INIS)

    Alexander, D.E.; Baldo, P.M.; Rehn, L.E.

    1992-09-01

    Experiments were performed to evaluate the effect of 1.5 MeV Kr irradiation on diffusion-induced grain boundary migration (DIGM) in Au/Cu bilayers in the temperature range of 300≤T≤050K. The experimental results were consistent with DIGM occurring in bilayers both during irradiation and during annealing treatments. Rutherford backscattering spectrometry showed a nearly uniform distribution of Cu present through the entire thickness of appropriately prepared polycrystalline Au films irradiated or annealed at temperatures ≥400K. No parallel effect was seen in similarly treated single-crystal films. In each polycrystalline sample studied, irradiation resulted in greater amounts of Cu present uniformly in the Au compared to annealing-only. The magnitudes of measured Cu compositions were substantially greater than that expected solely from grain boundary diffusion. A simple analysis of the process indicated that ion irradiation affects DIGM by increasing the composition of Cu present in alloyed zones and/or by increasing the grain boundary velocity in the Au

  10. The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity.

    Science.gov (United States)

    Kraehenmann, Rainer; Schmidt, André; Friston, Karl; Preller, Katrin H; Seifritz, Erich; Vollenweider, Franz X

    2016-01-01

    Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual-limbic-prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

  11. The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

    Directory of Open Access Journals (Sweden)

    Rainer Kraehenmann

    2016-01-01

    Full Text Available Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

  12. Cellular memory and, hematopoietic stem cell aging

    NARCIS (Netherlands)

    Kamminga, Leonie M.; de Haan, Gerald

    Hematopoietic stem cells (HSCs) balance self-renewal and differentiation in order to sustain lifelong blood production and simultaneously maintain the HSC pool. However, there is clear evidence that HSCs are subject to quantitative and qualitative exhaustion. In this review, we briefly discuss

  13. Comparison of chemotherapy and hematopoietic stem cell ...

    African Journals Online (AJOL)

    2013-02-19

    Feb 19, 2013 ... scores before and after hematopoietic stem cell transplantation (HSCT) and chemotherapy. Materials and Methods: Thirty-six patients undergoing HSCT were included in the study. A pre-HSCT dental treatment protocol was implemented that consisted of restoration of all active carious lesions, treatment of ...

  14. Hematopoietic stem cell transplantation in multiple sclerosis

    DEFF Research Database (Denmark)

    Rogojan, C; Frederiksen, J L

    2009-01-01

    Intensive immunosuppresion followed by hematopoietic stem cell transplantation (HSCT) has been suggested as potential treatment in severe forms of multiple sclerosis (MS). Since 1995 ca. 400 patients have been treated with HSCT. Stabilization or improvement occurred in almost 70% of cases at least...

  15. Hematopoiesis and hematopoietic organs in arthropods.

    Science.gov (United States)

    Grigorian, Melina; Hartenstein, Volker

    2013-03-01

    Hemocytes (blood cells) are motile cells that move throughout the extracellular space and that exist in all clades of the animal kingdom. Hemocytes play an important role in shaping the extracellular environment and in the immune response. Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and the body cavity (mesothelia). In vertebrates and insects, common progenitors, called hemangioblasts, give rise to the endothelia and blood cells. In the adult animal, many differentiated hemocytes seem to retain the ability to proliferate; however, in most cases investigated closely, the bulk of hemocyte proliferation takes place in specialized hematopoietic organs. Hematopoietic organs provide an environment where undifferentiated blood stem cells are able to self-renew, and at the same time generate offspring that differentiate into different blood cell types. Hematopoiesis in vertebrates, taking place in the bone marrow, has been subject to intensive research by immunologists and stem cell biologists. Much less is known about blood cell formation in invertebrate animals. In this review, we will survey structural and functional properties of invertebrate hematopoietic organs, with a main focus on insects and other arthropod taxa. We will then discuss similarities, at the molecular and structural level, that are apparent when comparing the development of blood cells in hematopoietic organs of vertebrates and arthropods. Our comparative review is intended to elucidate aspects of the biology of blood stem cells that are more easily missed when focusing on one or a few model species.

  16. Molecular regulation of human hematopoietic stem cells

    NARCIS (Netherlands)

    van Galen, P.L.J.

    2014-01-01

    Peter van Galen focuses on understanding the determinants that maintain the stem cell state. Using human hematopoietic stem cells (HSCs) as a model, processes that govern self-renewal and tissue regeneration were investigated. Specifically, a role for microRNAs in balancing the human HSC

  17. Human hematopoietic cell culture, transduction, and analyses

    DEFF Research Database (Denmark)

    Bonde, Jesper; Wirthlin, Louisa; Kohn, Donald B

    2008-01-01

    This unit provides methods for introducing genes into human hematopoietic progenitor cells. The Basic Protocol describes isolation of CD34(+) cells, transduction of these cells with a retroviral vector on fibronectin-coated plates, assaying the efficiency of transduction, and establishing long-te...

  18. Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression.

    Science.gov (United States)

    Guo, Peipei; Poulos, Michael G; Palikuqi, Brisa; Badwe, Chaitanya R; Lis, Raphael; Kunar, Balvir; Ding, Bi-Sen; Rabbany, Sina Y; Shido, Koji; Butler, Jason M; Rafii, Shahin

    2017-12-01

    Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the homeostasis of HSPCs is unknown. Here, we show that under steady state, jagged-2 is differentially expressed in tissue-specific vascular beds, but its expression is induced in hematopoietic vascular niches after myelosuppressive injury. We used mice with EC-specific deletion of the gene encoding jagged-2 (Jag2) to demonstrate that while EC-derived jagged-2 was dispensable for maintaining the capacity of HSPCs to repopulate under steady-state conditions, by activating Notch2 it did contribute to the recovery of HSPCs in response to myelosuppressive conditions. Engraftment and/or expansion of HSPCs was dependent on the expression of endothelial-derived jagged-2 following myeloablation. Additionally, jagged-2 expressed in bone marrow ECs regulated HSPC cell cycle and quiescence during regeneration. Endothelial-deployed jagged-2 triggered Notch2/Hey1, while tempering Notch2/Hes1 signaling in HSPCs. Collectively, these data demonstrate that EC-derived jagged-2 activates Notch2 signaling in HSPCs to promote hematopoietic recovery and has potential as a therapeutic target to accelerate balanced hematopoietic reconstitution after myelosuppression.

  19. Hematopoietic stem cell transplantation monitoring in childhood. Hematological diseases in Serbia: STR-PCR techniques

    Directory of Open Access Journals (Sweden)

    Krstić Aleksandra D.

    2007-01-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is a very successful method of treatment for children with different aquired or inborn diseases. The main goal of post-transplantation chimerism monitoring in HSCT is to predict negative events (such as disease relapse and graft rejection, in order to intervene with appropriate therapy and improve the probability of long-term DFS (disease free survival. In this context, by quantifying the relative amounts of donor and recipient cells present in the peripheral blood sample, it can be determined if engraftment has taken place at all, or if full or mixed chimerism exists. In a group of patients who underwent hematopoietic stem cell transplantation at the Mother and Child Health Care Institute, we decided to use standard human identfication tests based on multiplex PCR analyses of short tandem repeats (STRs, as they are highly informative, sensitive, and fast and therefore represent an optimal methodological approach to engraftment analysis.

  20. The kinetic alteration of hematopoietic stem cells irradiated by ionizing radiation

    International Nuclear Information System (INIS)

    Ishikawa, Junya; Ojima, Mitsuaki; Kai, Michiaki

    2014-01-01

    Ionizing radiation (IR) brings oxidative stress, and can cause damages not only on DNA but also proteins and lipids in mammalian cells, and increases the mitochondria-dependent generation of reactive oxygen species (ROS), with the subsequent induction of cell death, cell cycle arrest, and stress related responses. It is well known that IR induces acute myeloid leukemia that originates in hematopoietic cells. However, the mechanisms of leukemogenesis following IR remain unclear. To clarify these mechanisms, it is necessary to quantify the several biological events induced by IR in hematopoietic stem/progenitor cells. In this review, we focus and summarize several recent findings, especially survival/clonogenic potential, cell cycle distribution, generation of ROS, DNA damage/repair, chromosomal abbreviation, and senescence. (author)

  1. Genetic and Epigenetic Mechanisms That Maintain Hematopoietic Stem Cell Function

    Science.gov (United States)

    Kosan, Christian; Godmann, Maren

    2016-01-01

    All hematopoiesis cells develop from multipotent progenitor cells. Hematopoietic stem cells (HSC) have the ability to develop into all blood lineages but also maintain their stemness. Different molecular mechanisms have been identified that are crucial for regulating quiescence and self-renewal to maintain the stem cell pool and for inducing proliferation and lineage differentiation. The stem cell niche provides the microenvironment to keep HSC in a quiescent state. Furthermore, several transcription factors and epigenetic modifiers are involved in this process. These create modifications that regulate the cell fate in a more or less reversible and dynamic way and contribute to HSC homeostasis. In addition, HSC respond in a unique way to DNA damage. These mechanisms also contribute to the regulation of HSC function and are essential to ensure viability after DNA damage. How HSC maintain their quiescent stage during the entire life is still matter of ongoing research. Here we will focus on the molecular mechanisms that regulate HSC function. PMID:26798358

  2. Silver nanoparticles of different sizes induce a mixed type of programmed cell death in human pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Zielinska, Ewelina; Zauszkiewicz-Pawlak, Agata; Wojcik, Michal; Inkielewicz-Stepniak, Iwona

    2018-01-01

    Pancreatic ductal adenocarcinoma, with the high resistance to chemotherapeutic agents, remains the fourth leading cause of cancer-death in the world. Due to the wide range of biological activity and unique properties, silver nanoparticles (AgNPs) are indicated as agents with potential to overcome barriers involved in chemotherapy failure. Therefore, in our study we decided to assess the ability of AgNPs to kill pancreatic cancer cells, and then to identify the molecular mechanism underlying this effect. Moreover, we evaluated the cytotoxicity of AgNPs against non-tumor cell of the same tissue (hTERT-HPNE cells) for comparison. Our results indicated that AgNPs with size of 2.6 and 18 nm decreased viability, proliferation and caused death of pancreatic cancer cells in a size- and concentration-dependent manner. Ultrastructural analysis identified that cellular uptake of AgNPs resulted in apoptosis, autophagy, necroptosis and mitotic catastrophe. These alterations were associated with increased pro-apoptotic protein Bax and decreased level of anti-apoptotic protein Bcl-2. Moreover, AgNPs significantly elevated the level of tumor suppressor p53 protein as well as necroptosis- and autophagy-related proteins: RIP-1, RIP-3, MLKL and LC3-II, respectively. In addition, we found that PANC-1 cells were more vulnerable to AgNPs-induced cytotoxicity compared to pancreatic non-tumor cells. In conclusion, AgNPs by inducing mixed type of programmed cell death in PANC-1 cells, could provide a new therapeutic strategy to overcome chemoresistance in one of the deadliest human cancer. PMID:29435134

  3. bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche

    Energy Technology Data Exchange (ETDEWEB)

    Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Schulz, Robert A., E-mail: rschulz@nd.edu

    2014-10-24

    Highlights: • bantam miRNA is endogenously expressed in the hematopoietic progenitor niche. • bantam is necessary and sufficient to induce cellular proliferation in the PSC. • bantam is upstream of the Insulin Receptor signaling pathway. • A model for positive regulation of hematopoietic niche growth is proposed. - Abstract: The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to lead to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche.

  4. bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche

    International Nuclear Information System (INIS)

    Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Schulz, Robert A.

    2014-01-01

    Highlights: • bantam miRNA is endogenously expressed in the hematopoietic progenitor niche. • bantam is necessary and sufficient to induce cellular proliferation in the PSC. • bantam is upstream of the Insulin Receptor signaling pathway. • A model for positive regulation of hematopoietic niche growth is proposed. - Abstract: The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to lead to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche

  5. The biochemistry of hematopoietic stem cell development.

    Science.gov (United States)

    Kaimakis, P; Crisan, M; Dzierzak, E

    2013-02-01

    The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short window of developmental time. In mammalian embryos, hematopoietic progenitor and HSC generation occurs within several extra- and intraembryonic microenvironments, most notably from 'hemogenic' endothelial cells lining the major vasculature. HSCs are made through a remarkable transdifferentiation of endothelial cells to a hematopoietic fate that is long-lived and self-renewable. Recent studies are beginning to provide an understanding of the biochemical signaling pathways and transcription factors/complexes that promote their generation. The focus of this review is on the biochemistry behind the generation of these potent long-lived self-renewing stem cells of the blood system. Both the intrinsic (master transcription factors) and extrinsic regulators (morphogens and growth factors) that affect the generation, maintenance and expansion of HSCs in the embryo will be discussed. The generation of HSCs is a stepwise process involving many developmental signaling pathways, morphogens and cytokines. Pivotal hematopoietic transcription factors are required for their generation. Interestingly, whereas these factors are necessary for HSC generation, their expression in adult bone marrow HSCs is oftentimes not required. Thus, the biochemistry and molecular regulation of HSC development in the embryo are overlapping, but differ significantly from the regulation of HSCs in the adult. HSC numbers for clinical use are limiting, and despite much research into the molecular basis of HSC regulation in the adult bone marrow, no panel of growth factors, interleukins and/or morphogens has been found to sufficiently increase the number of these important stem cells. An understanding of the biochemistry of HSC

  6. Optical refractive index and static permittivity of mixed Zr-Si oxide thin films prepared by ion beam induced CVD

    Energy Technology Data Exchange (ETDEWEB)

    Ferrer, F.J. [Centro Nacional de Aceleradores, Av. Thomas A. Edison, 7, 41092 Sevilla (Spain)], E-mail: fjferrer@us.es; Frutos, F. [E.T.S. de Ingenieria Informatica, Avda. Reina Mercedes, s/n, 41012 Sevilla (Spain); Garcia-Lopez, J. [Centro Nacional de Aceleradores, Av. Thomas A. Edison, 7, 41092 Sevilla (Spain); Gonzalez-Elipe, A.R.; Yubero, F. [Insituto de Ciencia de Materiales de Sevilla, c/ Americo vespucio, no. 49, 41092 Sevilla (Spain)

    2007-12-03

    Mixed oxides Zr{sub x}Si{sub 1-x}O{sub 2} (0 < x < 1) thin films have been prepared at room temperature by decomposition of (CH{sub 3}CH{sub 2}O){sub 3}SiH and Zr[OC(CH{sub 3}){sub 3}]{sub 4} volatile precursors induced by mixtures of O{sub 2}{sup +} and Ar{sup +} ions. The films were flat and amorphous independently of the Si/Zr ratio and did not present phase segregation of the pure single oxides (SiO{sub 2} and ZrO{sub 2}). A 10-23 at.% of H and 1-5 at.% of C atoms remained incorporated in the films depending on the mixture ratio of the Si and Zr precursors and the composition of the bombarding gas used during the deposition process. These impurities are mainly forming hydroxyl and carboxylic groups. Optical refractive index and static permittivity of the films were determined by reflection NIR-Vis spectroscopy and C-V electrical characterization, respectively. It is found that the refractive index increases non-linearly from 1.45 to 2.10 as the Zr content in the thin films increases. The static permittivity also increases non-linearly from {approx} 4 for pure SiO{sub 2} to {approx} 15 for pure ZrO{sub 2}. Optical and electrical characteristics of the films are justified by their impurity content and the available theories.

  7. Mixed Stimulus-Induced Mode Selection in Neural Activity Driven by High and Low Frequency Current under Electromagnetic Radiation

    Directory of Open Access Journals (Sweden)

    Lulu Lu

    2017-01-01

    Full Text Available The electrical activities of neurons are dependent on the complex electrophysiological condition in neuronal system, the three-variable Hindmarsh-Rose (HR neuron model is improved to describe the dynamical behaviors of neuronal activities with electromagnetic induction being considered, and the mode transition of electrical activities in neuron is detected when external electromagnetic radiation is imposed on the neuron. In this paper, different types of electrical stimulus impended with a high-low frequency current are imposed on new HR neuron model, and mixed stimulus-induced mode selection in neural activity is discussed in detail. It is found that mode selection of electrical activities stimulated by high-low frequency current, which also changes the excitability of neuron, can be triggered owing to adding the Gaussian white noise. Meanwhile, the mode selection of the neuron electrical activity is much dependent on the amplitude B of the high frequency current under the same noise intensity, and the high frequency response is selected preferentially by applying appropriate parameters and noise intensity. Our results provide insights into the transmission of complex signals in nerve system, which is valuable in engineering prospective applications such as information encoding.

  8. Protocol for the Differentiation of Human Induced Pluripotent Stem Cells into Mixed Cultures of Neurons and Glia for Neurotoxicity Testing.

    Science.gov (United States)

    Pistollato, Francesca; Canovas-Jorda, David; Zagoura, Dimitra; Price, Anna

    2017-06-09

    Human pluripotent stem cells can differentiate into various cell types that can be applied to human-based in vitro toxicity assays. One major advantage is that the reprogramming of somatic cells to produce human induced pluripotent stem cells (hiPSCs) avoids the ethical and legislative issues related to the use of human embryonic stem cells (hESCs). HiPSCs can be expanded and efficiently differentiated into different types of neuronal and glial cells, serving as test systems for toxicity testing and, in particular, for the assessment of different pathways involved in neurotoxicity. This work describes a protocol for the differentiation of hiPSCs into mixed cultures of neuronal and glial cells. The signaling pathways that are regulated and/or activated by neuronal differentiation are defined. This information is critical to the application of the cell model to the new toxicity testing paradigm, in which chemicals are assessed based on their ability to perturb biological pathways. As a proof of concept, rotenone, an inhibitor of mitochondrial respiratory complex I, was used to assess the activation of the Nrf2 signaling pathway, a key regulator of the antioxidant-response-element-(ARE)-driven cellular defense mechanism against oxidative stress.

  9. Continuum contribution to excitonic four-wave mixing due to interaction-induced nonlinearities: A numerical study

    Science.gov (United States)

    El Sayed, K.; Birkedal, D.; Lyssenko, V. G.; Hvam, J. M.

    1997-01-01

    We present a theoretical investigation of ultrafast transient four-wave mixing (FWM) of GaAs quantum wells for coherent excitation of excitons and a large number of continuum states. It is shown that in this case the line shape of the FWM signal is drastically altered due to an interaction-induced coupling of the exciton to all the excited continuum states. The signal is dominantly emitted at the spectral position of the exciton and decays, as a function of delay, on a time scale set by the duration of the laser pulse rather than by the intrinsic dephasing time. Nevertheless, the spectral width of the exciton line in the FWM spectrum and in the decay of the time-resolved FWM signal in real time are governed by the intrinsic excitonic dephasing rate. It is shown that for pulse durations of ~ 100 fs (for GaAs quantum wells) this behavior can be explained as the influence of the Coulomb exchange interaction, while for even shorter pulses this behavior is dominantly caused by nonlinear polarization decay.

  10. Ion collision-induced chemistry in pure and mixed loosely bound clusters of coronene and C60 molecules.

    Science.gov (United States)

    Domaracka, Alicja; Delaunay, Rudy; Mika, Arkadiusz; Gatchell, Michael; Zettergren, Henning; Cederquist, Henrik; Rousseau, Patrick; Huber, Bernd A

    2018-05-23

    Ionization, fragmentation and molecular growth have been studied in collisions of 22.5 keV He2+- or 3 keV Ar+-projectiles with pure loosely bound clusters of coronene (C24H12) molecules or with loosely bound mixed C60-C24H12 clusters by using mass spectrometry. The heavier and slower Ar+ projectiles induce prompt knockout-fragmentation - C- and/or H-losses - from individual molecules and highly efficient secondary molecular growth reactions before the clusters disintegrate on picosecond timescales. The lighter and faster He2+ projectiles have a higher charge and the main reactions are then ionization by ions that are not penetrating the clusters. This leads mostly to cluster fragmentation without molecular growth. However, here penetrating collisions may also lead to molecular growth but to a much smaller extent than with 3 keV Ar+. Here we present fragmentation and molecular growth mass distributions with 1 mass unit resolution, which reveals that the same numbers of C- and H-atoms often participate in the formation and breaking of covalent bonds inside the clusters. We find that masses close to those with integer numbers of intact coronene molecules, or with integer numbers of both intact coronene and C60 molecules, are formed where often one or several H-atoms are missing or have been added on. We also find that super-hydrogenated coronene is formed inside the clusters.

  11. Reactivity of inducer cell subsets and T8-cell activation during the human autologous mixed lymphocyte reaction.

    Science.gov (United States)

    Romain, P L; Morimoto, C; Daley, J F; Palley, L S; Reinherz, E L; Schlossman, S F

    1984-01-01

    To characterize the responding T cells in the autologous mixed lymphocyte reaction (AMLR), T cells were fractionated into purified subpopulations employing monoclonal antibodies and a variety of separation techniques including fluorescence-activated cell sorting. It was found that isolated T4 cells, but not T8 cells, proliferated in response to autologous non-T cells. More importantly, within the T4 subset, the autoreactive population was greatly enriched in a fraction reactive with an autoantibody from patients with juvenile chronic arthritis (JRA) or the monoclonal antibody anti-TQ1. Although T8 cells themselves were unable to proliferate in the AMLR, they could be induced to respond in the presence of either T4 cells or exogenous IL-2 containing medium. This was demonstrated by direct measurement of tritiated thymidine uptake by T8 cells during the course of the AMLR as well as by analysis of their relative DNA content. Taken together, these data indicate that the AMLR represents a complex pattern of immune responsiveness distinct from that observed in response to soluble antigen or alloantigen. The precise function of this T-cell circuit remains to be determined.

  12. The fps/fes proto-oncogene regulates hematopoietic lineage output.

    Science.gov (United States)

    Sangrar, Waheed; Gao, Yan; Zirngibl, Ralph A; Scott, Michelle L; Greer, Peter A

    2003-12-01

    The fps/fes proto-oncogene is abundantly expressed in myeloid cells, and the Fps/Fes cytoplasmic protein-tyrosine kinase is implicated in signaling downstream from hematopoietic cytokines, including interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin (EPO). Studies using leukemic cell lines have previously suggested that Fps/Fes contributes to granulomonocytic differentiation, and that it might play a more selective role in promoting survival and differentiation along the monocytic pathway. In this study we have used a genetic approach to explore the role of Fps/Fes in hematopoiesis. We used transgenic mice that tissue-specifically express a mutant human fps/fes transgene (fps(MF)) that was engineered to encode Fps/Fes kinase that is activated through N-terminal myristoylation (MFps). Hematopoietic function was assessed using lineage analysis, hematopoietic progenitor cell colony-forming assays, and biochemical approaches. fps(MF) transgenic mice displayed a skewed hematopoietic output reflected by increased numbers of circulating granulocytic and monocytic cells and a corresponding decrease in lymphoid cells. Bone marrow colony assays of progenitor cells revealed a significant increase in the number of both granulomonocytic and multi-lineage progenitors. A molecular analysis of signaling in mature monocytic cells showed that MFps promoted GM-CSF-induced STAT3, STAT5, and ERK1/2 activation. These observations support a role for Fps/Fes in signaling pathways that contribute to lineage determination at the level of multi-lineage hematopoietic progenitors as well as the more committed granulomonocytic progenitors.

  13. Role of reactive oxygen species in the radiation response of human hematopoietic stem/progenitor cells.

    Directory of Open Access Journals (Sweden)

    Masaru Yamaguchi

    Full Text Available Hematopoietic stem/progenitor cells (HSPCs, which are present in small numbers in hematopoietic tissues, can differentiate into all hematopoietic lineages and self-renew to maintain their undifferentiated phenotype. HSPCs are extremely sensitive to oxidative stressors such as anti-cancer agents, radiation, and the extensive accumulation of reactive oxygen species (ROS. The quiescence and stemness of HSPCs are maintained by the regulation of mitochondrial biogenesis, ROS, and energy homeostasis in a special microenvironment called the stem cell niche. The present study evaluated the relationship between the production of intracellular ROS and mitochondrial function during the proliferation and differentiation of X-irradiated CD34(+ cells prepared from human placental/umbilical cord blood HSPCs. Highly purified CD34(+ HSPCs exposed to X-rays were cultured in liquid and semi-solid medium supplemented with hematopoietic cytokines. X-irradiated CD34(+ HSPCs treated with hematopoietic cytokines, which promote their proliferation and differentiation, exhibited dramatically suppressed cell growth and clonogenic potential. The amount of intracellular ROS in X-irradiated CD34(+ HSPCs was significantly higher than that in non-irradiated cells during the culture period. However, neither the intracellular mitochondrial content nor the mitochondrial superoxide production was elevated in X-irradiated CD34(+ HSPCs compared with non-irradiated cells. Radiation-induced gamma-H2AX expression was observed immediately following exposure to 4 Gy of X-rays and gradually decreased during the culture period. This study reveals that X-irradiation can increase persistent intracellular ROS in human CD34(+ HSPCs, which may not result from mitochondrial ROS due to mitochondrial dysfunction, and indicates that substantial DNA double-strand breakage can critically reduce the stem cell function.

  14. Wnt5a regulates hematopoietic stem cell proliferation and repopulation through the Ryk receptor.

    Science.gov (United States)

    Povinelli, Benjamin J; Nemeth, Michael J

    2014-01-01

    Proper regulation of the balance between hematopoietic stem cell (HSC) proliferation, self-renewal, and differentiation is necessary to maintain hematopoiesis throughout life. The Wnt family of ligands has been implicated as critical regulators of these processes through a network of signaling pathways. Previously, we have demonstrated that the Wnt5a ligand can induce HSC quiescence through a noncanonical Wnt pathway, resulting in an increased ability to reconstitute hematopoiesis. In this study, we tested the hypothesis that the Ryk protein, a Wnt ligand receptor that can bind the Wnt5a ligand, regulated the response of HSCs to Wnt5a. We observed that inhibiting Ryk blocked the ability of Wnt5a to induce HSC quiescence and enhance short-term and long-term hematopoietic repopulation. We found that Wnt5a suppressed production of reactive oxygen species, a known inducer of HSC proliferation. The ability of Wnt5a to inhibit ROS production was also regulated by Ryk. From these data, we propose that Wnt5a regulates HSC quiescence and hematopoietic repopulation through the Ryk receptor and that this process is mediated by suppression of reactive oxygen species. © 2013 AlphaMed Press.

  15. Exogenous endothelial cells as accelerators of hematopoietic reconstitution

    Directory of Open Access Journals (Sweden)

    Mizer J

    2012-11-01

    Full Text Available Abstract Despite the successes of recombinant hematopoietic-stimulatory factors at accelerating bone marrow reconstitution and shortening the neutropenic period post-transplantation, significant challenges remain such as cost, inability to reconstitute thrombocytic lineages, and lack of efficacy in conditions such as aplastic anemia. A possible means of accelerating hematopoietic reconstitution would be administration of cells capable of secreting hematopoietic growth factors. Advantages of this approach would include: a ability to regulate secretion of cytokines based on biological need; b long term, localized production of growth factors, alleviating need for systemic administration of factors that possess unintended adverse effects; and c potential to actively repair the hematopoietic stem cell niche. Here we overview the field of hematopoietic growth factors, discuss previous experiences with mesenchymal stem cells (MSC in accelerating hematopoiesis, and conclude by putting forth the rationale of utilizing exogenous endothelial cells as a novel cellular therapy for acceleration of hematopoietic recovery.

  16. Hematopoietic stem cell origin of connective tissues.

    Science.gov (United States)

    Ogawa, Makio; Larue, Amanda C; Watson, Patricia M; Watson, Dennis K

    2010-07-01

    Connective tissue consists of "connective tissue proper," which is further divided into loose and dense (fibrous) connective tissues and "specialized connective tissues." Specialized connective tissues consist of blood, adipose tissue, cartilage, and bone. In both loose and dense connective tissues, the principal cellular element is fibroblasts. It has been generally believed that all cellular elements of connective tissue, including fibroblasts, adipocytes, chondrocytes, and bone cells, are generated solely by mesenchymal stem cells. Recently, a number of studies, including those from our laboratory based on transplantation of single hematopoietic stem cells, strongly suggested a hematopoietic stem cell origin of these adult mesenchymal tissues. This review summarizes the experimental evidence for this new paradigm and discusses its translational implications. Copyright 2010 ISEH - Society for Hematology and Stem Cells. All rights reserved.

  17. Recent advances in hematopoietic stem cell biology

    DEFF Research Database (Denmark)

    Bonde, Jesper; Hess, David A; Nolta, Jan A

    2004-01-01

    PURPOSE OF REVIEW: Exciting advances have been made in the field of hematopoietic stem cell biology during the past year. This review summarizes recent progress in the identification, culture, and in vivo tracking of hematopoietic stem cells. RECENT FINDINGS: The roles of Wnt and Notch proteins...... in regulating stem cell renewal in the microenvironment, and how these molecules can be exploited in ex vivo stem cell culture, are reviewed. The importance of identification of stem cells using functional as well as phenotypic markers is discussed. The novel field of nanotechnology is then discussed...... in the context of stem cell tracking in vivo. This review concludes with a section on the unexpected potential of bone marrow-derived stem cells to contribute to the repair of damaged tissues. The contribution of cell fusion to explain the latter phenomenon is discussed. SUMMARY: Because of exciting discoveries...

  18. Proliferative capacity of murine hematopoietic stem cells

    International Nuclear Information System (INIS)

    Hellman, S.; Botnick, L.E.; Hannon, E.C.; Vigneulle, R.M.

    1978-01-01

    The present study demonstrates a decrease in self-renewal capacity with serial transfer of murine hematopoietic stem cells. Production of differentiated cell progeny is maintained longer than stem cell self-renewal. In normal animals the capacity for self-renewal is not decreased with increasing donor age. The stem cell compartment in normal animals, both young and old, appears to be proliferatively quiescent. After apparent recovery from the alkylating agent busulfan, the probability of stem cell self-renewal is decreased, there is a permanent defect in the capacity of the bone marrow for serial transplantation, and the stem cells are proliferatively active. These findings support a model of the hematopoietic stem cell compartment as a continuum of cells with decreasing capacities for self-renewal, increasing likelihood for differentiation, and increasing proliferative activity. Cells progress in the continuum in one direction and such progression is not reversible

  19. Proteomic cornerstones of hematopoietic stem cell differentiation

    DEFF Research Database (Denmark)

    Klimmeck, Daniel; Hansson, Jenny; Raffel, Simon

    2012-01-01

    Regenerative tissues such as the skin epidermis, the intestinal mucosa or the hematopoietic system are organized in a hierarchical manner with stem cells building the top of this hierarchy. Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors...... which differentiate into lineage committed progenitors and subsequently mature cells. In this report, we applied an in-depth quantitative proteomic approach to analyze and compare the full proteomes of ex vivo isolated and FACS-sorted populations highly enriched for either multipotent hematopoietic stem....../progenitor cells (HSPCs, Lin(neg)Sca-1(+)c-Kit(+)) or myeloid committed precursors (Lin(neg)Sca-1(-)c-Kit(+)). By employing stable isotope dimethyl labeling and high-resolution mass spectrometry, more than 5,000 proteins were quantified. From biological triplicate experiments subjected to rigorous statistical...

  20. Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction

    Science.gov (United States)

    Tulpule, Asmin; Kelley, James M.; Lensch, M. William; McPherson, Jade; Park, In Hyun; Hartung, Odelya; Nakamura, Tomoka; Schlaeger, Thorsten M.; Shimamura, Akiko; Daley, George Q.

    2013-01-01

    Summary Shwachman-Diamond syndrome (SDS), a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematopoietic dysfunction, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. We created human pluripotent stem cell models of SDS by knock-down of SBDS in human embryonic stem cells (hESCs) and generation of induced pluripotent stem cell (iPSC) lines from two SDS patients. SBDS-deficient hESCs and iPSCs manifest deficits in exocrine pancreatic and hematopoietic differentiation in vitro, enhanced apoptosis and elevated protease levels in culture supernatants, which could be reversed by restoring SBDS protein expression through transgene rescue or by supplementing culture media with protease inhibitors. Protease-mediated auto-digestion provides a mechanistic link between the pancreatic and hematopoietic phenotypes in SDS, highlighting the utility of hESCs and iPSCs in obtaining novel insights into human disease. PMID:23602541

  1. Fanca-/- hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766.

    Science.gov (United States)

    Milsom, Michael D; Lee, Andrew W; Zheng, Yi; Cancelas, Jose A

    2009-07-01

    Fanconi anemia is a severe bone marrow failure syndrome resulting from inactivating mutations of Fanconi anemia pathway genes. Gene and cell therapy trials using hematopoietic stem cells and progenitors have been hampered by poor mobilization of HSC to peripheral blood in response to G-CSF. Using a murine model of Fanconi anemia (Fanca(-/-) mice), we found that the Fanca deficiency was associated with a profound defect in hematopoietic stem cells and progenitors mobilization in response to G-CSF in absence of bone marrow failure, which correlates with the findings of clinical trials in Fanconi anemia patients. This mobilization defect was overcome by co-administration of the Rac inhibitor NSC23766, suggesting that Rac signaling is implicated in the retention of Fanca(-/-) hematopoietic stem cells and progenitors in the bone marrow. In view of these data, we propose that targeting Rac signaling may enhance G-CSF-induced HSC mobilization in Fanconi anemia.

  2. Hematopoietic cell phosphatase is recruited to CD22 following B cell antigen receptor ligation

    NARCIS (Netherlands)

    Lankester, A. C.; van Schijndel, G. M.; van Lier, R. A.

    1995-01-01

    Hematopoietic cell phosphatase is a nonreceptor protein tyrosine phosphatase that is preferentially expressed in hematopoietic cell lineages. Motheaten mice, which are devoid of (functional) hematopoietic cell phosphatase, have severe disturbances in the regulation of B cell activation and

  3. Two Hemocyte Lineages Exist in Silkworm Larval Hematopoietic Organ

    OpenAIRE

    Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

    2010-01-01

    BACKGROUND: Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. METHODOLOGY/PRINCIPAL FINDINGS: To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocyto...

  4. Effect of deformation induced nucleation and phase mixing, a two phase model for the ductile deformation of rocks.

    Science.gov (United States)

    Bevillard, Benoit; Richard, Guillaume; Raimbourg, Hugues

    2017-04-01

    Rocks are complex materials and particularly their rheological behavior under geological stresses remains a long-standing question in geodynamics. To test large scale lithosphere dynamics numerical modeling is the main tool but encounter substantial difficulties to account for this complexity. One major unknown is the origin and development of the localization of deformation. This localization is observed within a large range of scales and is commonly characterized by sharp grain size reduction. These considerations argues for a control of the microscopical scale over the largest ones through one predominant variable: the mean grain-size. However, the presence of second phase and broad grain-size distribution may also have a important impact on this phenomenon. To address this question, we built a model for ductile rocks deformation based on the two-phase damage theory of Bercovici & Ricard 2012. We aim to investigate the role of grain-size reduction but also phase mixing on strain localization. Instead of considering a Zener-pining effect on damage evolution, we propose to take into account the effect of the grain-boundary sliding (GBS)-induced nucleation mechanism which is better supported by experimental or natural observations (Precigout et al 2016). This continuum theory allows to represent a two mineral phases aggregate with explicit log-normal grain-size distribution as a reasonable approximation for polymineralic rocks. Quantifying microscopical variables using a statistical approach may allow for calibration at small (experimental) scale. The general set of evolutions equations remains up-scalable provided some conditions on the homogenization scale. Using the interface density as a measure of mixture quality, we assume unlike Bercovici & Ricard 2012 that it may depend for some part on grain-size . The grain-size independent part of it is being represented by a "contact fraction" variable, whose evolution may be constrained by the dominant deformation

  5. Prostaglandin E2 regulates hematopoietic stem cell

    International Nuclear Information System (INIS)

    Wang Yingying; Zhou Daohong; Meng Aimin

    2013-01-01

    Prostaglandin E2 (PGE2) is a bioactive lipid molecule produced by cyclooxygenase (COX), which plays an important role on hematopoiesis. While it can block differentiation of myeloid progenitors but enhance proliferation of erythroid progenitors. Recent research found that PGE2 have the effects on hematopoietic stem cell (HSC) function and these effects were independent from effects on progenitor cells. Exposure of HSC cells to PGE2 in vitro can increase homing efficiency of HSC to the murine bone marrow compartment and decrease HSC apoptosis, meanwhile increase long-term stem cell engraftment. In-vivo treatment with PGE2 expands short-term HSC and engraftment in murine bone marrow but not long-term HSC.In addition, PGE2 increases HSC survival after radiation injury and enhance hematopoietic recovery, resulting maintains hematopoietic homeostasis. PGE2 regulates HSC homeostasis by reactive oxygen species and Wnt pathway. Clinical beneficial of 16, 16-dimethyl-prostaglandin E2 treatment to enhance engraftment of umbilical cord blood suggest important improvements to therapeutic strategies. (authors)

  6. Tuning the processability, morphology and biodegradability of clay incorporated PLA/LLDPE blends via selective localization of nanoclay induced by melt mixing sequence

    Directory of Open Access Journals (Sweden)

    S. H. Jafari

    2013-01-01

    Full Text Available Polylactic acid (PLA/linear low density polyethylene (LLDPE blend nanocomposites based on two different commercial-grade nanoclays, Cloisite® 30B and Cloisite® 15A, were produced via different melt mixing procedures in a counter-rotating twin screw extruder. The effects of mixing sequence and clay type on morphological and rheological behaviors as well as degradation properties of the blends were investigated. The X-ray diffraction (XRD results showed that generally the level of exfoliation in 30B based nanocomposites was better than 15A based nanocomposites. In addition, due to difference in hydrophilicity and kind of modifiers in these two clays, the effect of 30B on refinement of dispersed phase and enhancement of biodegradability of PLA/LLDPE blend was much more remarkable than that of 15A nanoclay. Unlike the one step mixing process, preparation of nanocomposites via a two steps mixing process improved the morphology. Based on the XRD and TEM (transmission electron microscopic results, it is found that the mixing sequence has a remarkable influence on dispersion and localization of the major part of 30B nanoclay in the PLA matrix. Owing to the induced selective localization of nanoclays in PLA phase, the nanocomposites prepared through a two steps mixing sequence exhibited extraordinary biodegradability, refiner morphology and better melt elasticity.

  7. A Mixed Flavonoid-Fish Oil Supplement Induces Immune-Enhancing and Anti-Inflammatory Transcriptomic Changes in Adult Obese and Overweight Women—A Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    Lynn Cialdella-Kam

    2016-05-01

    Full Text Available Flavonoids and fish oils have anti-inflammatory and immune-modulating influences. The purpose of this study was to determine if a mixed flavonoid-fish oil supplement (Q-Mix; 1000 mg quercetin, 400 mg isoquercetin, 120 mg epigallocatechin (EGCG from green tea extract, 400 mg n3-PUFAs (omega-3 polyunsaturated fatty acid (220 mg eicosapentaenoic acid (EPA and 180 mg docosahexaenoic acid (DHA from fish oil, 1000 mg vitamin C, 40 mg niacinamide, and 800 µg folic acid would reduce complications associated with obesity; that is, reduce inflammatory and oxidative stress markers and alter genomic profiles in overweight women. Overweight and obese women (n = 48; age = 40–70 years were assigned to Q-Mix or placebo groups using randomized double-blinded placebo-controlled procedures. Overnight fasted blood samples were collected at 0 and 10 weeks and analyzed for cytokines, C-reactive protein (CRP, F2-isoprostanes, and whole-blood-derived mRNA, which was assessed using Affymetrix HuGene-1_1 ST arrays. Statistical analysis included two-way ANOVA models for blood analytes and gene expression and pathway and network enrichment methods for gene expression. Plasma levels increased with Q-Mix supplementation by 388% for quercetin, 95% for EPA, 18% for DHA, and 20% for docosapentaenoic acid (DPA. Q-Mix did not alter plasma levels for CRP (p = 0.268, F2-isoprostanes (p = 0.273, and cytokines (p > 0.05. Gene set enrichment analysis revealed upregulation of pathways in Q-Mix vs. placebo related to interferon-induced antiviral mechanism (false discovery rate, FDR < 0.001. Overrepresentation analysis further disclosed an inhibition of phagocytosis-related inflammatory pathways in Q-Mix vs. placebo. Thus, a 10-week Q-Mix supplementation elicited a significant rise in plasma quercetin, EPA, DHA, and DPA, as well as stimulated an antiviral and inflammation whole-blood transcriptomic response in overweight women.

  8. s-PROCESSING IN AGB STARS REVISITED. II. ENHANCED {sup 13}C PRODUCTION THROUGH MHD-INDUCED MIXING

    Energy Technology Data Exchange (ETDEWEB)

    Trippella, O.; Busso, M.; Palmerini, S.; Maiorca, E. [Department of Physics, University of Perugia, and INFN, Section of Perugia, via A. Pascoli, I-06123 Perugia (Italy); Nucci, M. C., E-mail: oscar.trippella@fisica.unipg.it [Department of Mathematics and Informatics, University of Perugia, via Vanvitelli, I-06123 Perugia and INFN, Section of Perugia, via A. Pascoli, I-06123 Perugia (Italy)

    2016-02-20

    Slow neutron captures are responsible for the production of about 50% of elements heavier than iron, mainly occurring during the asymptotic giant branch phase of low-mass stars (1 ≲ M/M{sub ⊙} ≲ 3), where the main neutron source is the {sup 13}C(α, n){sup 16}O reaction. This last reaction is activated from locally produced {sup 13}C, formed by partial mixing of hydrogen into the He-rich layers. We present here the first attempt to describe a physical mechanism for the formation of the {sup 13}C reservoir, studying the mass circulation induced by magnetic buoyancy without adding new free parameters to those already involved in stellar modeling. Our approach represents the application to the stellar layers relevant for s-processing of recent exact analytical 2D and 3D models for magneto-hydrodynamic processes at the base of convective envelopes in evolved stars in order to promote downflows of envelope material for mass conservation during the occurrence of a dredge-up phenomenon. We find that the proton penetration is characterized by small concentrations, but is extended over a large fractional mass of the He-layers, thus producing {sup 13}C reservoirs of several 10{sup −3} M{sub ⊙}. The ensuing {sup 13}C-enriched zone has an almost flat profile, while only a limited production of {sup 14}N occurs. In order to verify the effects of our new findings we show how the abundances of the main s-component nuclei can be accounted for in solar proportions and how our large {sup 13}C-reservoir allows us to solve a few so far unexplained features in the abundance distribution of post-AGB objects.

  9. Todralazine protects zebra fish from lethal doses of ionizing radiation: role of hematopoietic stem cell expansion

    International Nuclear Information System (INIS)

    Dimri, Manali; Joshi, Jaidev; Indracanti, Prem Kumar

    2013-01-01

    Radiation induced cell killing and hematopoietic stem cell depletion leads to compromised immune functions and opportunistic infections which significantly affect the recovery and survival upon irradiation. Any agent which can expand residual hematopoietic stem cells in irradiated organism can render protection from the effects of lethal doses of ionizing radiation. Johns Hopkins Clinical compound library (JHCCL) was screened for protection against lethal doses of ionizing radiation using developing zebra fish as a model organism. Modulation of radiation induced reactive oxygen species by the small molecules were done by DCFDA staining and for visual identification and quantification of apoptosis acridine orange assay, flow cytometry were employed respectively. Hematopoietic stem cell expansion potential was assessed by quantifying runx1 expression, a marker for definitive stem cells, were done by RT-PCR and by the kinetics of recovery from chemically induced anaemia. Todralazine hydrochloride from JHCCL exhibited promising results with potential anti radiation effects. A dose of 5μM was found to be the most effective and has rendered significant organ and whole body protection (100% survival advantage over a period of 6 days) against 20 Gy. However todralazine did not modulated radiation induced free radicals (monitored within 2 h of irradiation) and apoptosis in zebra fish embryos analysed at 8 and 24h post irradiation. Flow cytometric quantification of pre G1 population suggested the same. Chemoinformatics approaches were further carried out to elucidate possible targets which are contributing to its radioprotection potential. Structural similarity search suggested several targets and possible hematopoietic stem cell expanding potential. Treatment of zebra fish embryos with todralazine has lead to significant proliferation of hematopoietic stem cell as indicated by increase in expression of runx1. HSC expanding potential of todralazine was further supported by

  10. The slippery slope of hematopoietic stem cell aging.

    Science.gov (United States)

    Wahlestedt, Martin; Bryder, David

    2017-12-01

    The late stages of life, in most species including humans, are associated with a decline in the overall maintenance and health of the organism. This applies also to the hematopoietic system, where aging is not only associated with an increased predisposition for hematological malignancies, but also identified as a strong comorbidity factor for other diseases. Research during the last two decades has proposed that alterations at the level of hematopoietic stem cells (HSCs) might be a root cause for the hematological changes observed with age. However, the recent realization that not all HSCs are alike with regard to fundamental stem cell properties such as self-renewal and lineage potential has several implications for HSC aging, including the synchrony and the stability of the aging HSC state. To approach HSC aging from a clonal perspective, we recently took advantage of technical developments in cellular barcoding and combined this with the derivation of induced pluripotent stem cells (iPSCs). This allowed us to selectively approach HSCs functionally affected by age. The finding that such iPSCs were capable of fully regenerating multilineage hematopoiesis upon morula/blastocyst complementation provides compelling evidence that many aspects of HSC aging can be reversed, which indicates that a central mechanism underlying HSC aging is a failure to uphold the epigenomes associated with younger age. Here we discuss these findings in the context of the underlying causes that might influence HSC aging and the requirements and prospects for restoration of the aging HSC epigenome. Copyright © 2017 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  11. Mixed allogeneic reconstitution (A+B----A) to induce donor-specific transplantation tolerance. Permanent acceptance of a simultaneous donor skin graft

    International Nuclear Information System (INIS)

    Ildstad, S.T.; Wren, S.M.; Oh, E.; Hronakes, M.L.

    1991-01-01

    Mixed allogeneic reconstitution, in which a mixture of T-cell-depleted bone marrow of syngeneic host and allogeneic donor type is transplanted into a lethally irradiated recipient (A+B----A), results in mixed lymphopoietic chimerism with engraftment of a mixture of both host and donor bone marrow elements. Recipients are specifically tolerant to donor both in vitro and in vivo. Donor-specific skin grafts survive indefinitely when they are placed after full bone marrow repopulation at 28 days, while third-party grafts are rapidly rejected. To determine whether a delay of a month or more for full bone marrow repopulation is required before a donor-specific graft can be placed, we have now examined whether tolerance induction can be achieved if a graft is placed at the time of bone marrow transplantation. Permanent acceptance of donor-specific B10.BR skin grafts occurred when mixed allogeneic chimerism (B10+B10.BR----B10) was induced and a simultaneous allogeneic donor graft placed. In vitro, mixed reconstituted recipients were specifically tolerant to the B10.BR donor lymphoid cells but fully reactive to MHC-disparate third-party (BALB/c; H-2dd) when assessed by mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. These data therefore indicate that a donor-specific graft placed at the time of mixed allogeneic reconstitution is permanently accepted without rejection. To determine whether an allogeneic skin graft alone without allogeneic bone marrow would be sufficient to induce tolerance, syngeneic reconstitution (B10----B10) was carried out, and a simultaneous B10.BR allogeneic skin graft placed. Although skin grafts were prolonged in all recipients, all grafts rejected when full lymphopoietic repopulation occurred at 28 days

  12. EFFECTS OF ROTATIONALLY INDUCED MIXING IN COMPACT BINARY SYSTEMS WITH LOW-MASS SECONDARIES AND IN SINGLE SOLAR-TYPE STARS

    International Nuclear Information System (INIS)

    Chatzopoulos, E.; Robinson, Edward L.; Wheeler, J. Craig

    2012-01-01

    Many population synthesis and stellar evolution studies have addressed the evolution of close binary systems in which the primary is a compact remnant and the secondary is filling its Roche lobe, thus triggering mass transfer. Although tidal locking is expected in such systems, most studies have neglected the rotationally induced mixing that may occur. Here we study the possible effects of mixing in mass-losing stars for a range of secondary star masses and metallicities. We find that tidal locking can induce rotational mixing prior to contact and thus affect the evolution of the secondary star if the effects of the Spruit-Tayler dynamo are included both for angular momentum and chemical transport. Once contact is made, the effect of mass transfer tends to be more rapid than the evolutionary timescale, so the effects of mixing are no longer directly important, but the mass-transfer strips matter to inner layers that may have been affected by the mixing. These effects are enhanced for secondaries of 1-1.2 M ☉ and for lower metallicities. We discuss the possible implications for the paucity of carbon in the secondaries of the cataclysmic variable SS Cyg and the black hole candidate XTE J1118+480 and for the progenitor evolution of Type Ia supernovae. We also address the issue of the origin of blue straggler stars in globular and open clusters. We find that for models that include rotation consistent with that observed for some blue straggler stars, evolution is chemically homogeneous. This leads to tracks in the H-R diagram that are brighter and bluer than the non-rotating main-sequence turn-off point. Rotational mixing could thus be one of the factors that contribute to the formation of blue stragglers.

  13. Formation and hematopoietic differentiation of human embryoid bodies by suspension and hanging drop cultures.

    Science.gov (United States)

    Cerdan, Chantal; Hong, Seok Ho; Bhatia, Mickie

    2007-10-01

    The in vitro aggregation of human embryonic stem cells (hESCs) into clusters termed embryoid bodies (EBs) allows for the spontaneous differentiation of cells representing endoderm, mesoderm, and ectoderm lineages. This stochastic process results however, in the generation of low numbers of differentiated cells, and can be enhanced to some extent by the addition of exogenous growth factors or overexpression of regulatory genes. In the authors' laboratory, the use of hematopoietic cytokines in combination with the mesoderm inducer bone morphogenetic protein-4 (BMP-4) was able to generate up to 90% of CD45(+) hematopoietic cells with colony-forming unit (CFU) activity. This unit describes two protocols that have been successfully applied in the authors' laboratory for the generation of EBs in (1) suspension and (2) hanging drop (HD) cultures from enzymatically digested clumps of undifferentiated hESC colonies.

  14. Cerebral salt-wasting syndrome after hematopoietic stem cell transplantation in adolescents: 3 case reports

    Directory of Open Access Journals (Sweden)

    Yeon Jin Jeon

    2015-12-01

    Full Text Available Cerebral salt-wasting syndrome (CSWS is a rare disease characterized by a extracellular volume depletion and hyponatremia induced by marked natriuresis. It is mainly reported in patients who experience a central nervous system insult, such as cerebral hemorrhage or encephalitis. The syndrome of inappropriate antidiuretic hormone secretion is a main cause of severe hyponatremia after hematopoietic stem cell transplantation, whereas CSWS is rarely reported. We report 3 patients with childhood acute leukemia who developed CSWS with central nervous system complication after hematopoietic stem cell transplantation. The diagnosis of CSW was made on the basis of severe hyponatremia accompanied by increased urine output with clinical signs of dehydration. All patients showed elevated natriuretic peptide and normal antidiuretic hormone. Aggressive water and sodium replacement treatment was instituted in all 3 patients and 2 of them were effectively recovered, the other one was required to add fludrocortisone administration.

  15. Large dimuon asymmetry in B{sub s}-B-bar{sub s} mixing from unparticle induced {Gamma}{sub s}{sup 12}

    Energy Technology Data Exchange (ETDEWEB)

    Ren Bo [INPAC, Department of Physics, Shanghai Jiao Tong University, Shanghai (China); He Xiaogang, E-mail: hexg@phys.ntu.edu.t [INPAC, Department of Physics, Shanghai Jiao Tong University, Shanghai (China); Department of Physics and Center for Theoretical Sciences, National Taiwan University, Taipei, Taiwan (China); Xie Peichu [INPAC, Department of Physics, Shanghai Jiao Tong University, Shanghai (China)

    2011-04-11

    Exchange of unparticle stuff of dimension d{sub U} with FCNC interaction can induce M{sup 12,u} and {Gamma}{sup 12,u} causing meson and antimeson mixing with the relation {Gamma}{sup 12,u}/M{sup 12,u}=2tan({pi}d{sub U}). We show that this type of unparticle contribution can provide the much needed large {Gamma}{sub s}{sup 12} to explain the recently observed anomalously large dimuon asymmetry in B{sub s}-B-bar{sub s} system reported by D0 Collaboration. The same interaction can also accommodate large mixing induced CP violation in B{sub s{yields}}J/{psi}{phi} indicated by CDF and D0 data. Experimental data can provide constraints on the unparticle dimension and scale.

  16. Brief Report: Human Acute Myeloid Leukemia Reprogramming to Pluripotency Is a Rare Event and Selects for Patient Hematopoietic Cells Devoid of Leukemic Mutations.

    Science.gov (United States)

    Lee, Jong-Hee; Salci, Kyle R; Reid, Jennifer C; Orlando, Luca; Tanasijevic, Borko; Shapovalova, Zoya; Bhatia, Mickie

    2017-09-01

    Induced pluripotent stem cell reprogramming has provided critical insights into disease processes by modeling the genetics and related clinical pathophysiology. Human cancer represents highly diverse genetics, as well as inter- and intra-patient heterogeneity, where cellular model systems capable of capturing this disease complexity would be invaluable. Acute myeloid leukemia (AML) represents one of most heterogeneous cancers and has been divided into genetic subtypes correlated with unique risk stratification over the decades. Here, we report our efforts to induce pluripotency from the heterogeneous population of human patients that represents this disease in the clinic. Using robust optimized reprogramming methods, we demonstrate that reprogramming of AML cells harboring leukemic genomic aberrations is a rare event with the exception of those with de novo mixed-lineage leukemia (MLL) mutations that can be reprogrammed and model drug responses in vitro. Our findings indicate that unlike hematopoietic cells devoid of genomic aberrations, AML cells harboring driver mutations are refractory to reprogramming. Expression of MLL fusion proteins in AML cells did not contribute to induced reprogramming success, which continued to select for patient derived cells devoid of AML patient-specific aberrations. Our study reveals that unanticipated blockades to achieving pluripotency reside within the majority of transformed AML patient cells. Stem Cells 2017;35:2095-2102. © 2017 AlphaMed Press.

  17. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report

    OpenAIRE

    Boucher, Alexander A.; Miller, Weston; Shanley, Ryan; Ziegler, Richard; Lund, Troy; Raymond, Gerald; Orchard, Paul J.

    2015-01-01

    Background Metachromatic Leukodystrophy (MLD) is a rare, fatal demyelinating disorder with limited treatment options. Published outcomes after hematopoietic stem cell transplantation (HSCT) are scant and mixed. We report survival and function following HSCT for a large, single-center MLD cohort. Methods Transplant-related data, survival and serial measures (brain MRI, nerve conduction velocity (NCV), neurologic and neuropsychology evaluations) were reviewed. When possible, parental interviews...

  18. Successful autologous hematopoietic stem cell transplantation for a patient with rapidly progressive localized scleroderma.

    Science.gov (United States)

    Nair, Velu; Sharma, Ajay; Sharma, Sanjeevan; Das, Satyaranjan; Bhakuni, Darshan S; Narayanan, Krishnan; Nair, Vivek; Shankar, Subramanian

    2015-03-01

    Autologous hematopoietic stem cell transplant (HSCT) for rapidly progressive disease has not been reported in localized scleroderma. Our patient, a 16-year-old girl had an aggressive variant of localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to immunosuppressive therapy and was causing rapid disfigurement. She was administered autologous HSCT in June 2011 and has maintained drug-free remission with excellent functional status at almost 3.5 years of follow-up. © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  19. Mobilization of hematopoietic stem and progenitor cells in mice

    NARCIS (Netherlands)

    Robinson, Simon N; van Os, Ronald P; Bunting, Kevin

    2008-01-01

    Animal models have added significantly to our understanding of the mechanism(s) of hematopoietic stem and progenitor cell (HSPC) mobilization. Such models suggest that changes in the interaction between the HSPC and the hematopoietic microenvironmental 'niche' (cellular and extracellular components)

  20. Normal hematopoietic stem cell function in mice with enforced expression of the Hippo signaling effector YAP1.

    Directory of Open Access Journals (Sweden)

    Lina Jansson

    Full Text Available The Hippo pathway has recently been implicated in the regulation of organ size and stem cells in multiple tissues. The transcriptional cofactor yes-associated protein 1 (Yap1 is the most downstream effector of Hippo signaling and is functionally repressed by the upstream components of the pathway. Overexpression of YAP1 stimulates proliferation of stem and progenitor cells in many tissues, consistent with inhibition of Hippo signaling. To study the role of Hippo signaling in hematopoietic stem cells (HSCs, we created a transgenic model with inducible YAP1 expression exclusively within the hematopoietic system. Following 3 months induction, examination of blood and bone marrow in the induced mice revealed no changes in the distribution of the hematopoietic lineages compared to control mice. Moreover, the progenitor cell compartment was unaltered as determined by colony forming assays and immunophenotyping. To address whether YAP1 affects the quantity and function of HSCs we performed competitive transplantation experiments. We show that ectopic YAP1 expression does not influence HSC function neither during steady state nor in situations of hematopoietic stress. This is in sharp contrast to effects seen on stem- and progenitor cells in other organs and suggests highly tissue specific functions of the Hippo pathway in regulation of stem cells.

  1. Complications of allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Arnaout, Karim; Patel, Nihar; Jain, Maneesh; El-Amm, Joelle; Amro, Farah; Tabbara, Imad A

    2014-08-01

    Infection, graft-versus-host disease (GVHD), and to a lesser extent sinusoidal obstructive syndrome (SOS) represent the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). During the last decade, progress in prevention and treatment of these complications led to improvement in the outcome of these patients. Despite the fact that nonmyeloablative regimens have been increasingly used in elderly patients and in patients with co-morbidities, the nonrelapse related mortality remains a challenge and long-term follow-up is required. The objective of this manuscript is to provide an updated concise review of the complications of AHSCT and of the available treatment interventions.

  2. Turnover of circulating hematopoietic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Dorie, M J; Maloney, M A; Patt, H M

    1979-10-01

    Short-term parabiosis of male and female CBA/CaJ mice was used to investigate the turnover of circulating hematopoietic stem cells. The change and subsequent disappearance of donor stem cells were monitored by spleen colony assay and chromosome analysis of individual colonies. The results revealed an exponential disappearance of pluripotent stem cells from blood with a characteristic half time of 1.7 h. Blood-borne stem cells were shown to be equilibrated with a subpopulation of marrow stem cells exhibiting a disappearance half time of 9.5 h. Splenectomy did not change the apparent rate of stem cell removal from the blood.

  3. Mechanism of hematopoietic stem cell homing

    International Nuclear Information System (INIS)

    Jiang Fuquan

    2000-01-01

    The clinical transplantation of hematopoietic stem cell (HSC) originating from many sources such as bone marrow, peripheral blood and cord blood has been widely applied in recent years. At the same time, the development of the study on the mechanism of HSC homing which involves multi-procedures has been achieved. And a lot of molecular and cytokines on the surface or in the microenvironment of HSC are functioning in homing. The purpose of is to review those molecular and cytokines on which more studies have been focused in the past

  4. Adriamycin-induced oxidative stress is prevented by mixed hydro-alcoholic extract of Nigella sativa and Curcuma longa in rat kidney.

    Science.gov (United States)

    Mohebbati, Reza; Shafei, Mohammad Naser; Soukhtanloo, Mohammad; Mohammadian Roshan, Noema; Khajavi Rad, Abolfazl; Anaeigoudari, Akbar; Hosseinian, Sara; Karimi, Sareh; Beheshti, Farimah

    2016-01-01

    Inflammation and oxidative stress is considered to have a crucial role in induction of nephropathy. Curcuma longa (C. longa) and Nigella sativa (N. sativa) have anti-inflammatory and antioxidant effects. This study was designed to investigate the effect of mixed hydro-alcoholic extract of N.sativa and C. longa on the oxidative stress induced by Adriamycin (ADR) in rat kidney. The animals were divided into 6 groups: control (CO), ADR, Adriamycin+ Vitamin C (ADR+VIT C), C. longa extract+ Adriamycin (C.LE+ADR), N. sativa extract+ Adriamycin (N.SE+ADR) and C. longa extract+ N. sativa extract + Adriamycin (N.S+C.L+ADR). ADR (5mg/kg) was injected intravenously, whereas VITC (100mg/kg) and extract of C. longa (1000mg/kg) and N. sativa (200mg/kg) were administrated orally. Finally, the renal tissue, urine and blood samples were collected and submitted to measure of redox markers, osmolarity and renal index. The renal content of total thiol and superoxide dismutase (SOD) activity significantly decreased and Malondialdehyde (MDA) concentration increased in Adriamycin group compared to control group. The renal content of total thiol and SOD activity significantly enhanced and MDA concentration reduced in treated-mixed extract of C. longa and N. sativa along with ADR group compared to ADR group. The mixed extract did not restore increased renal index percentage induced by ADR. There also was no significant difference in urine and serum osmolarity between the groups. hydro-alcoholic extracts of N.sativa and C.longa led to an improvement in ADR-induced oxidative stress and mixed administration of the extracts enhanced the aforementioned therapeutic effect.

  5. Unique Behavioral and Neurochemical Effects Induced by Repeated Adolescent Consumption of Caffeine-Mixed Alcohol in C57BL/6 Mice.

    Directory of Open Access Journals (Sweden)

    Meridith T Robins

    Full Text Available The number of highly caffeinated products has increased dramatically in the past few years. Among these products, highly caffeinated energy drinks are the most heavily advertised and purchased, which has resulted in increased incidences of co-consumption of energy drinks with alcohol. Despite the growing number of adolescents and young adults reporting caffeine-mixed alcohol use, knowledge of the potential consequences associated with co-consumption has been limited to survey-based results and in-laboratory human behavioral testing. Here, we investigate the effect of repeated adolescent (post-natal days P35-61 exposure to caffeine-mixed alcohol in C57BL/6 mice on common drug-related behaviors such as locomotor sensitivity, drug reward and cross-sensitivity, and natural reward. To determine changes in neurological activity resulting from adolescent exposure, we monitored changes in expression of the transcription factor ΔFosB in the dopaminergic reward pathway as a sign of long-term increases in neuronal activity. Repeated adolescent exposure to caffeine-mixed alcohol exposure induced significant locomotor sensitization, desensitized cocaine conditioned place preference, decreased cocaine locomotor cross-sensitivity, and increased natural reward consumption. We also observed increased accumulation of ΔFosB in the nucleus accumbens following repeated adolescent caffeine-mixed alcohol exposure compared to alcohol or caffeine alone. Using our exposure model, we found that repeated exposure to caffeine-mixed alcohol during adolescence causes unique behavioral and neurochemical effects not observed in mice exposed to caffeine or alcohol alone. Based on similar findings for different substances of abuse, it is possible that repeated exposure to caffeine-mixed alcohol during adolescence could potentially alter or escalate future substance abuse as means to compensate for these behavioral and neurochemical alterations.

  6. Quantitative assessment of hematopoietic chimerism by quantitative real-time polymerase chain reaction of sequence polymorphism systems after hematopoietic stem cell transplantation.

    Science.gov (United States)

    Qin, Xiao-ying; Li, Guo-xuan; Qin, Ya-zhen; Wang, Yu; Wang, Feng-rong; Liu, Dai-hong; Xu, Lan-ping; Chen, Huan; Han, Wei; Wang, Jing-zhi; Zhang, Xiao-hui; Li, Jin-lan; Li, Ling-di; Liu, Kai-yan; Huang, Xiao-jun

    2011-08-01

    Analysis of changes in recipient and donor hematopoietic cell origin is extremely useful to monitor the effect of hematopoietic stem cell transplantation (HSCT) and sequential adoptive immunotherapy by donor lymphocyte infusions. We developed a sensitive, reliable and rapid real-time PCR method based on sequence polymorphism systems to quantitatively assess the hematopoietic chimerism after HSCT. A panel of 29 selected sequence polymorphism (SP) markers was screened by real-time PCR in 101 HSCT patients with leukemia and other hematological diseases. The chimerism kinetics of bone marrow samples of 8 HSCT patients in remission and relapse situations were followed longitudinally. Recipient genotype discrimination was possible in 97.0% (98 of 101) with a mean number of 2.5 (1-7) informative markers per recipient/donor pair. Using serial dilutions of plasmids containing specific SP markers, the linear correlation (r) of 0.99, the slope between -3.2 and -3.7 and the sensitivity of 0.1% were proved reproducible. By this method, it was possible to very accurately detect autologous signals in the range from 0.1% to 30%. The accuracy of the method in the very important range of autologous signals below 5% was extraordinarily high (standard deviation real-time PCR method over short tandem repeat PCR chimerism assays is the absence of PCR competition and plateau biases, with demonstrated greater sensitivity and linearity. Finally, we prospectively analyzed bone marrow samples of 8 patients who received allografts and presented the chimerism kinetics of remission and relapse situations that illustrated the sensitivity level and the promising clinical application of this method. This SP-based real-time PCR assay provides a rapid, sensitive, and accurate quantitative assessment of mixed chimerism that can be useful in predicting graft rejection and early relapse.

  7. Hematopoietic stem cell fate through metabolic control.

    Science.gov (United States)

    Ito, Kyoko; Ito, Keisuke

    2018-05-25

    Hematopoietic stem cells (HSCs) maintain a quiescent state in the bone marrow to preserve their self-renewal capacity, but also undergo cell divisions as required. Organelles such as the mitochondria sustain cumulative damage during these cell divisions, and this damage may eventually compromise the cells' self-renewal capacity. HSC divisions result in either self-renewal or differentiation, with the balance between the two directly impacting hematopoietic homeostasis; but the heterogeneity of available HSC-enriched fractions, together with the technical challenges of observing HSC behavior, has long hindered the analysis of individual HSCs, and prevented the elucidation of this process. However, recent advances in genetic models, metabolomics analyses and single-cell approaches have revealed the contributions made to HSC self-renewal by metabolic cues, mitochondrial biogenesis, and autophagy/mitophagy, which have highlighted mitochondrial quality as a key control factor in the equilibrium of HSCs. A deeper understanding of precisely how specific modes of metabolism control HSC fate at the single cell level is therefore not only of great biological interest, but will have clear clinical implications for the development of therapies for hematological disease. Copyright © 2018. Published by Elsevier Inc.

  8. Epigenetic regulation of hematopoietic stem cell aging

    International Nuclear Information System (INIS)

    Beerman, Isabel; Rossi, Derrick J.

    2014-01-01

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging

  9. Epigenetic regulation of hematopoietic stem cell aging

    Energy Technology Data Exchange (ETDEWEB)

    Beerman, Isabel, E-mail: isabel.beerman@childrens.harvard.edu [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States); Rossi, Derrick J. [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States)

    2014-12-10

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.

  10. Doenjang prepared with mixed starter cultures attenuates azoxymethane and dextran sulfate sodium-induced colitis-associated colon carcinogenesis in mice

    Directory of Open Access Journals (Sweden)

    Ji-Kang Jeong

    2014-01-01

    Full Text Available Backgrounds: Doenjang is traditional Korean fermented soybean paste and widely known for its various health benefits including anticancer effect. In this study, we manufactured doenjang with the grain-type meju using probiotic mixed starter cultures of Aspegillus oryzae, Bacillus subtilis-SKm, and Lactococcus lactis-GAm to improve the qualities and beneficial properties of doenjang. Materials and Methods: The inhibitory effects of the doenjang prepared with the grain-type meju using mixed starter cultures were investigated in azoxymethane (AOM and dextran sulfate sodium (DSS-induced colon carcinogenesis mice model. AOM and DSS colon carcinogenesis was induced in female C57BL/6 mice, and doenjang was orally administered for 4 weeks. Body weight, colon length, and colon weight of mice were determined, and colonic tissues were histologically evaluated. The serum levels of proinflammatory cytokines as well as the expression of inflammation- and apoptosis-related genes in colonic tissue were also analyzed. Results: Administration of the doenjang using probiotic mixed starter cultures ameliorated the symptoms of colon cancer, and reduced the incidence of neoplasia, and reduced the levels of serum proinflammatory cytokines such as interleukin-6, and tumor necrosis factor-α and inducible nitric oxide synthase and cycloooxygenase-2 expression levels in colonic tissue. In addition, it increased Bax and reduced Bcl-2 expression levels and increased p21 and p53 expression in the colonic tissues. Conclusion: These findings indicate that the doenjang attenuated colon carcinogenesis induced by AOM and DSS by ameliorating the symptoms of colon cancer, reducing the occurrence of neoplasia, regulating proinflammatory cytokine levels, and controlling the expressions of inflammation- and apoptosis-related genes in the colonic tissue.

  11. Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress

    Science.gov (United States)

    Rissone, Alberto; Weinacht, Katja Gabriele; la Marca, Giancarlo; Bishop, Kevin; Giocaliere, Elisa; Jagadeesh, Jayashree; Felgentreff, Kerstin; Dobbs, Kerry; Al-Herz, Waleed; Jones, Marypat; Chandrasekharappa, Settara; Kirby, Martha; Wincovitch, Stephen; Simon, Karen Lyn; Itan, Yuval; DeVine, Alex; Schlaeger, Thorsten; Schambach, Axel; Sood, Raman

    2015-01-01

    Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD. PMID:26150473

  12. Pre-Transplantation Blockade of TNF-α-Mediated Oxygen Species Accumulation Protects Hematopoietic Stem Cells.

    Science.gov (United States)

    Ishida, Takashi; Suzuki, Sachie; Lai, Chen-Yi; Yamazaki, Satoshi; Kakuta, Shigeru; Iwakura, Yoichiro; Nojima, Masanori; Takeuchi, Yasuo; Higashihara, Masaaki; Nakauchi, Hiromitsu; Otsu, Makoto

    2017-04-01

    Hematopoietic stem cell (HSC) transplantation (HSCT) for malignancy requires toxic pre-conditioning to maximize anti-tumor effects and donor-HSC engraftment. While this induces bone marrow (BM)-localized inflammation, how this BM environmental change affects transplanted HSCs in vivo remains largely unknown. We here report that, depending on interval between irradiation and HSCT, residence within lethally irradiated recipient BM compromises donor-HSC reconstitution ability. Both in vivo and in vitro we demonstrate that, among inflammatory cytokines, TNF-α plays a role in HSC damage: TNF-α stimulation leads to accumulation of reactive oxygen species (ROS) in highly purified hematopoietic stem/progenitor cells (HSCs/HSPCs). Transplantation of flow-cytometry-sorted murine HSCs reveals damaging effects of accumulated ROS on HSCs. Short-term incubation either with an specific inhibitor of tumor necrosis factor receptor 1 signaling or an antioxidant N-acetyl-L-cysteine (NAC) prevents TNF-α-mediated ROS accumulation in HSCs. Importantly, pre-transplantation exposure to NAC successfully demonstrats protective effects in inflammatory BM on graft-HSCs, exhibiting better reconstitution capability than that of nonprotected control grafts. We thus suggest that in vivo protection of graft-HSCs from BM inflammation is a feasible and attractive approach, which may lead to improved hematopoietic reconstitution kinetics in transplantation with myeloablative conditioning that inevitably causes inflammation in recipient BM. Stem Cells 2017;35:989-1002. © 2016 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  13. Lipofectamine and related cationic lipids strongly improve adenoviral infection efficiency of primitive human hematopoietic cells.

    Science.gov (United States)

    Byk, T; Haddada, H; Vainchenker, W; Louache, F

    1998-11-20

    Adenoviral vectors have the potential to infect a large number of cell types including quiescent cells. Their use in hematopoietic cells is limited by the episomal form of their DNA, leading to transgene loss in the progeny cells. However, the use of this vector may be interesting for short-term in vitro modifications of primitive human hematopoietic cells. Therefore, we have investigated the ability of adenovirus to transduce cord blood CD34+ cells. Several promoters were tested using the lacZ reporter gene. The PGK and CMV promoters induced transgene expression in 18-25% of the cells, whereas the HTLV-I and especially the RSV promoter were almost inactive. To improve infection efficiency, adenovirus was complexed with cationic lipids. Lipofectamine, Cellfectin, and RPR120535b, but not Lipofectin, Lipofectace, or DOTAP, markedly improved transgene expression in CD34+ cells (from 19 to 35%). Lipofectamine strongly enhanced infection efficiency of the poorly infectable primitive CD34+CD38low cells (from 11 to 28%) whereas the more mature CD34+CD38+ cells were only slightly affected (from 24 to 31%). Lipofectamine tripled the infection of CFU-GMs and LTC-ICs derived from the CD34+CD38low cell fraction (from 4 to 12% and from 5 to 16%, respectively) and doubled that of BFU-Es (from 13 to 26%). We conclude that cationic lipids can markedly increase the efficiency of adenovirus-mediated gene transfer into primitive hematopoietic cells.

  14. Transformation of human mesenchymal cells and skin fibroblasts into hematopoietic cells.

    Directory of Open Access Journals (Sweden)

    David M Harris

    Full Text Available Patients with prolonged myelosuppression require frequent platelet and occasional granulocyte transfusions. Multi-donor transfusions induce alloimmunization, thereby increasing morbidity and mortality. Therefore, an autologous or HLA-matched allogeneic source of platelets and granulocytes is needed. To determine whether nonhematopoietic cells can be reprogrammed into hematopoietic cells, human mesenchymal stromal cells (MSCs and skin fibroblasts were incubated with the demethylating agent 5-azacytidine (Aza and the growth factors (GF granulocyte-macrophage colony-stimulating factor and stem cell factor. This treatment transformed MSCs to round, non-adherent cells expressing T-, B-, myeloid-, or stem/progenitor-cell markers. The transformed cells engrafted as hematopoietic cells in bone marrow of immunodeficient mice. DNA methylation and mRNA array analysis suggested that Aza and GF treatment demethylated and activated HOXB genes. Indeed, transfection of MSCs or skin fibroblasts with HOXB4, HOXB5, and HOXB2 genes transformed them into hematopoietic cells. Further studies are needed to determine whether transformed MSCs or skin fibroblasts are suitable for therapy.

  15. Long-term hematopoietic stem cell damage after external irradiation with X rays

    International Nuclear Information System (INIS)

    Grande, M.T.; Varas, F.; Bueren, J.A.

    1997-01-01

    We have investigated the functionality of the lympho-hematopoietic stem cells long-term (9 months) after the irradiation (X rays) of mice at different stages of development, by means of a competitive bone marrow repopulation assay. Our data revealed that a dose of 1 Gy was only capable of inducing significant long-term failures in the functionality of the primitive repopulating cells in mice irradiated at the young-adult stage (12 week-old), but not in mice irradiated at the late stages of foetus development (17 day-old fetuses) nor at the early development of the embryo (4 day-old embryos). The differential generation of long-term stem cell defects as a function of the age was confirmed in mice irradiated with 3 Gy. While no significant effects in the long-term repopulating cells were observed in 4 day-old embryos, significant repopulation deficiencies were observed in this population when mice were irradiated at the 17 day of foetus development, and more markedly at the adult stage of growth. These data offer new evidence about the influence of the developmental stage of the animal on the generation of residual hematopoietic dysfunctions by external irradiation, with particular relevance to the very primitive lympho-hematopoietic stem cells. (author)

  16. Response of hematopoietic stem cells to ionizing radiation

    International Nuclear Information System (INIS)

    Simonnet, A.

    2008-12-01

    Hematopoietic stem cells (HSCs) maintain blood and immune system throughout life and restore them after hematological injuries. Exposure of an organism to ionizing radiation (IR) causes rapid and acute myelosuppression and challenges the replenishment capacity of HSCs. Yet, the precise damages that are generated remain largely unexplored. To better understand these effects, phenotypic and functional changes in the stem/progenitor compartments of sublethally irradiated mice were monitored over a ten week period after radiation exposure. We report that shortly after sublethal IR-exposure, HSCs, defined by their repopulating ability, still segregate in the Hoechst dye excluding side population (SP); yet, their Sca-1 (S) and c-Kit (K) expression levels are increased and severely reduced, respectively, with a concurrent increase in the proportion of SP SK cells positive for established indicators of HSC presence: CD150 + and CD105 + . A great proportion of HSCs quickly but transiently enter the cell cycle to replenish the bone marrow of myelo-ablated mice. Ten weeks after, whereas bone marrow cellularity has recovered and hematopoietic homeostasis is restored, major phenotypic modifications can be observed within the Lin -/low Sca-1 + c-Kit + (LSK) stem/progenitor compartment: CD150 + /Flk2 - and CD150 - /Flk2 + LSK cell frequencies are increased and dramatically reduced, respectively. CD150 + LSK cells also show impaired reconstitution capacity, accrued number of γ-H2AX foci and increased tendency to apoptosis. This demonstrates that the LSK compartment is not properly restored 10 weeks after sublethal exposure, and that long-term IR-induced injury to the bone marrow proceeds, at least partially, through direct damage to the stem cell pool. Thrombopoietin (TPO) has been shown to promote the survival of lethally irradiated mice when administrated quickly after exposure. We investigated the mechanisms underlying this effect, and found in a competitive transplant

  17. Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

    Science.gov (United States)

    Gori, Jennifer L.; Butler, Jason M.; Chan, Yan-Yi; Chandrasekaran, Devikha; Poulos, Michael G.; Ginsberg, Michael; Nolan, Daniel J.; Elemento, Olivier; Wood, Brent L.; Adair, Jennifer E.; Rafii, Shahin; Kiem, Hans-Peter

    2015-01-01

    Pluripotent stem cells (PSCs) represent an alternative hematopoietic stem cell (HSC) source for treating hematopoietic disease. The limited engraftment of human PSC–derived (hPSC-derived) multipotent progenitor cells (MPP) has hampered the clinical application of these cells and suggests that MPP require additional cues for definitive hematopoiesis. We hypothesized that the presence of a vascular niche that produces Notch ligands jagged-1 (JAG1) and delta-like ligand-4 (DLL4) drives definitive hematopoiesis. We differentiated hes2 human embryonic stem cells (hESC) and Macaca nemestrina–induced PSC (iPSC) line-7 with cytokines in the presence or absence of endothelial cells (ECs) that express JAG1 and DLL4. Cells cocultured with ECs generated substantially more CD34+CD45+ hematopoietic progenitors compared with cells cocultured without ECs or with ECs lacking JAG1 or DLL4. EC-induced cells exhibited Notch activation and expressed HSC-specific Notch targets RUNX1 and GATA2. EC-induced PSC-MPP engrafted at a markedly higher level in NOD/SCID/IL-2 receptor γ chain–null (NSG) mice compared with cytokine-induced cells, and low-dose chemotherapy-based selection further increased engraftment. Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction were similar to levels achieved for cord blood–derived MPP and up to 20-fold higher than those achieved with hPSC-derived MPP engraftment. Our findings indicate that endothelial Notch ligands promote PSC-definitive hematopoiesis and production of long-term engrafting CD34+ cells, suggesting these ligands are critical for HSC emergence. PMID:25664855

  18. Dosimetry measurements using Timepix in mixed radiation fields induced by heavy ions; comparison with standard dosimetry methods

    Czech Academy of Sciences Publication Activity Database

    Ploc, Ondřej; Kubančák, Ján; Sihver, L.; Uchihori, Y.; Jakoubek, J.; Ambrožová, Iva; Molokanov, A. G.; Pinsky, L.

    2014-01-01

    Roč. 55, S1 (2014), i141-i142 ISSN 0449-3060 R&D Projects: GA MŠk(CZ) LG13031; GA MŠk LG14004 Institutional support: RVO:61389005 Keywords : LET spectrometry * heavy ions * mixed radiation field * pixel detector Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders Impact factor: 1.797, year: 2014

  19. Coordinated and unique functions of the E-selectin ligand ESL-1 during inflammatory and hematopoietic recruitment in mice.

    Science.gov (United States)

    Sreeramkumar, Vinatha; Leiva, Magdalena; Stadtmann, Anika; Pitaval, Christophe; Ortega-Rodríguez, Inés; Wild, Martin K; Lee, Brendan; Zarbock, Alexander; Hidalgo, Andrés

    2013-12-05

    Beyond its well-established roles in mediating leukocyte rolling, E-selectin is emerging as a multifunctional receptor capable of inducing integrin activation in neutrophils, and of regulating various biological processes in hematopoietic precursors. Although these effects suggest important homeostatic contributions of this selectin in the immune and hematologic systems, the ligands responsible for transducing these effects in different leukocyte lineages are not well defined. We have characterized mice deficient in E-selectin ligand-1 (ESL-1), or in both P-selectin glycoprotein-1 (PSGL-1) and ESL-1, to explore and compare the contributions of these glycoproteins in immune and hematopoietic cell trafficking. In the steady state, ESL-1 deficiency resulted in a moderate myeloid expansion that became more prominent when both glycoproteins were eliminated. During inflammation, PSGL-1 dominated E-selectin binding, rolling, integrin activation, and extravasation of mature neutrophils, but only the combined deficiency in PSGL-1 and ESL-1 completely abrogated leukocyte recruitment. Surprisingly, we find that the levels of ESL-1 were strongly elevated in hematopoietic progenitor cells. These elevations correlated with a prominent function of ESL-1 for E-selectin binding and for migration of hematopoietic progenitor cells into the bone marrow. Our results uncover dominant roles for ESL-1 in the immature compartment, and a functional shift toward PSGL-1 dependence in mature neutrophils.

  20. Correlation between mixed-function oxidase enzyme induction and aflatoxin B1-induced unscheduled DNA synthesis in the chick embryo, in vivo

    International Nuclear Information System (INIS)

    Hamilton, J.W.; Bloom, S.E.

    1984-01-01

    The unscheduled DNA synthesis (UDS) technique has been adapted for use in the chick embryo, in vivo, to determine the relationship between induction of the mixed-function oxidase (MFO) enzyme system and genetic damage from an indirect-acting mutagen-carcinogen. Embryos were injected at 6 days of incubation (DI) with either phenobarbital (PB), a specific inducer of P-450-associated enzyme activities, or 3,4,3',4'-tetrachlorobiphenyl (TCB), a specific inducer of P 1 -450-associated enzyme activities. Aflatoxin B 1 (AFB1) was injected 24 hr later (7 DI), followed by a 5-hr continuous 3 H-thymidine exposure. The livers were removed, prepared for autoradiography, and hepatocytes were scored for an increase in grains/nucleus, indicative of UDS. Aflatoxin B 1 caused a dose-related increase in UDS in all control and induction groups. Phenobarbital-induced embryos had an increased UDS response while TCB-induced embryos had a decreased UDS response, relative to noninduced embryos, for each dosage of AFB1. This suggests that the genotoxicity of an indirect-acting mutagen-carcinogen can be either increased or decreased, in vivo, depending on the inducer used. The chick embryo provides an excellent system for studying the effect of MFO induction on the genotoxicity of promutagen-carcinogens in a developing system

  1. Investigation of the bacteriophage community in induced lysates of undefined mesophilic mixed-strain DL-cultures using classical and metagenomic approaches.

    Science.gov (United States)

    Muhammed, Musemma K; Olsen, Mette L; Kot, Witold; Neve, Horst; Castro-Mejía, Josué L; Janzen, Thomas; Hansen, Lars H; Nielsen, Dennis S; Sørensen, Søren J; Heller, Knut J; Vogensen, Finn K

    2018-05-02

    To investigate the notion that starter cultures can be a reservoir of bacteriophages (phages) in the dairy environment, strains of three DL-starters (undefined mesophilic mixed-strain starters containing Lactococcus lactis subsp. lactis biovar. diacetylactis and Leuconostoc species) were selected and induced by mitomycin C, and the whole starters were induced spontaneously as well as by mitomycin C. Frequency of induction of 17%, 26% and 12% was estimated among the isolates of the three starters, with majority of the induced phages mostly showing morphological similarity to known P335 phages, and with a fraction of them showing atypical features. Sequences of P335 quasi-species phages were found to be the most frequent entities in almost all metaviromes derived from the induced lysates. However, sequences of Sk1virus phages (previously 936 phages) were emerged as the predominant entities following spontaneous induction of one of the starters, suggesting a phage-carrier state. Sequences of other phages such as 949, 1706, C2virus (previously c2 phages) and Leuconostoc species could also be observed but with a lower relative frequency. Taken together, the majority of the P335 quasi-species phages could represent the induced viral community of the starters and the remaining phage groups mainly represent the background ambient viral community. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Study of a High-Yield Cellulase System Created by Heavy-Ion Irradiation-Induced Mutagenesis of Aspergillus niger and Mixed Fermentation with Trichoderma reesei

    Science.gov (United States)

    Chen, Ji-Hong; Li, Wen-Jian; Liu, Jing; Hu, Wei; Xiao, Guo-Qing; Dong, Miao-Yin; Wang, Yu-Chen

    2015-01-01

    The aim of this study was to evaluate and validate the efficiency of 12C6+ irradiation of Aspergillus niger (A. niger) or mutagenesis via mixed Trichoderma viride (T. viride) culturing as well as a liquid cultivation method for cellulase production via mixed Trichoderma reesei (T. reesei) and A. niger culture fermentation. The first mutagenesis approach was employed to optimize yield from a cellulase-producing strain via heavy-ion mutagenesis and high-throughput screening, and the second was to effectively achieve enzymatic hydrolysis of cellulase from a mixed culture of mutant T. viride and A. niger. We found that 12C6+-ion irradiation induced changes in cellulase biosynthesis in A. niger but had no effect on the time course of the synthesis. It is notable that the exoglucanases (CBH) activities of A. niger strains H11-1 and H differed (6.71 U/mL vs. 6.01 U/mL) and were significantly higher than that of A. niger mutant H3-1. Compared with strain H, the filter paper assay (FPA), endoglucanase (EG) and β-glucosidase (BGL) activities of mutant strain H11-1 were increased by 250.26%, 30.26% and 34.91%, respectively. A mixed culture system was successfully optimized, and the best ratio of T. reesei to A. niger was 5:1 for 96 h with simultaneous inoculation. The BGL activity of the mixed culture increased after 72 h. At 96 h, the FPA and BGL activities of the mixed culture were 689.00 and 797.15 U/mL, respectively, significantly higher than those of monocultures, which were 408.70 and 646.98 U/mL for T. reesei and 447.29 and 658.89 U/mL for A. niger, respectively. The EG activity of the mixed culture was 2342.81 U/mL, a value that was significantly higher than that of monocultures at 2206.57 U/mL for T. reesei and 1727.62 U/mL for A. niger. In summary, cellulose production and hydrolysis yields were significantly enhanced by the proposed combination scheme. PMID:26656155

  3. Study of a High-Yield Cellulase System Created by Heavy-Ion Irradiation-Induced Mutagenesis of Aspergillus niger and Mixed Fermentation with Trichoderma reesei.

    Directory of Open Access Journals (Sweden)

    Shu-Yang Wang

    Full Text Available The aim of this study was to evaluate and validate the efficiency of 12C6+ irradiation of Aspergillus niger (A. niger or mutagenesis via mixed Trichoderma viride (T. viride culturing as well as a liquid cultivation method for cellulase production via mixed Trichoderma reesei (T. reesei and A. niger culture fermentation. The first mutagenesis approach was employed to optimize yield from a cellulase-producing strain via heavy-ion mutagenesis and high-throughput screening, and the second was to effectively achieve enzymatic hydrolysis of cellulase from a mixed culture of mutant T. viride and A. niger. We found that 12C6+-ion irradiation induced changes in cellulase biosynthesis in A. niger but had no effect on the time course of the synthesis. It is notable that the exoglucanases (CBH activities of A. niger strains H11-1 and H differed (6.71 U/mL vs. 6.01 U/mL and were significantly higher than that of A. niger mutant H3-1. Compared with strain H, the filter paper assay (FPA, endoglucanase (EG and β-glucosidase (BGL activities of mutant strain H11-1 were increased by 250.26%, 30.26% and 34.91%, respectively. A mixed culture system was successfully optimized, and the best ratio of T. reesei to A. niger was 5:1 for 96 h with simultaneous inoculation. The BGL activity of the mixed culture increased after 72 h. At 96 h, the FPA and BGL activities of the mixed culture were 689.00 and 797.15 U/mL, respectively, significantly higher than those of monocultures, which were 408.70 and 646.98 U/mL for T. reesei and 447.29 and 658.89 U/mL for A. niger, respectively. The EG activity of the mixed culture was 2342.81 U/mL, a value that was significantly higher than that of monocultures at 2206.57 U/mL for T. reesei and 1727.62 U/mL for A. niger. In summary, cellulose production and hydrolysis yields were significantly enhanced by the proposed combination scheme.

  4. Compassionate presence: The meaning of hematopoietic stem cell transplant nursing.

    Science.gov (United States)

    Sabo, Brenda M

    2011-04-01

    Within oncology, working with patients who are suffering or at end-of-life has been recognized repeatedly as stress-inducing, yet there is little agreement on what specifically nurses may experience as a result of their work. Further, research focused on caring work within the context of hematopoietic stem cell transplant (HSCT) nursing is almost non-existent. In light of the gap, this interpretative phenomenological study focused on enhancing the knowledge and understanding of the effect(s) of nursing work on the psychosocial health and well being of HSCT nurses. An interpretative phenomenological design grounded in the work of Heidegger and van Manen was used to explore nursing work among HSCT nurses. Twelve nurses from three Canadian tertiary healthcare facilities participated in multiple interviews and focus groups. Thematic analysis resulted in the emergence of four core themes and one overarching novel theme, compassionate presence. The discussion provides an overview of the novel finding, compassionate presence, which challenges the notion that working with individuals who are suffering or at end-of-life inevitably leads to adverse psychosocial effects. Implications for practice, education and research are also provided. Compassionate presence emerged to suggest a potential buffering effect against adverse consequences of HSCT nursing work. This finding underscored the value of the relationship as an integral component of nursing work. Copyright © 2010 Elsevier Ltd. All rights reserved.

  5. Genetic and Epigenetic Mechanisms That Maintain Hematopoietic Stem Cell Function

    Directory of Open Access Journals (Sweden)

    Christian Kosan

    2016-01-01

    Full Text Available All hematopoiesis cells develop from multipotent progenitor cells. Hematopoietic stem cells (HSC have the ability to develop into all blood lineages but also maintain their stemness. Different molecular mechanisms have been identified that are crucial for regulating quiescence and self-renewal to maintain the stem cell pool and for inducing proliferation and lineage differentiation. The stem cell niche provides the microenvironment to keep HSC in a quiescent state. Furthermore, several transcription factors and epigenetic modifiers are involved in this process. These create modifications that regulate the cell fate in a more or less reversible and dynamic way and contribute to HSC homeostasis. In addition, HSC respond in a unique way to DNA damage. These mechanisms also contribute to the regulation of HSC function and are essential to ensure viability after DNA damage. How HSC maintain their quiescent stage during the entire life is still matter of ongoing research. Here we will focus on the molecular mechanisms that regulate HSC function.

  6. Stepwise development of hematopoietic stem cells from embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Kenji Matsumoto

    Full Text Available The cellular ontogeny of hematopoietic stem cells (HSCs remains poorly understood because their isolation from and their identification in early developing small embryos are difficult. We attempted to dissect early developmental stages of HSCs using an in vitro mouse embryonic stem cell (ESC differentiation system combined with inducible HOXB4 expression. Here we report the identification of pre-HSCs and an embryonic type of HSCs (embryonic HSCs as intermediate cells between ESCs and HSCs. Both pre-HSCs and embryonic HSCs were isolated by their c-Kit(+CD41(+CD45(- phenotype. Pre-HSCs did not engraft in irradiated adult mice. After co-culture with OP9 stromal cells and conditional expression of HOXB4, pre-HSCs gave rise to embryonic HSCs capable of engraftment and long-term reconstitution in irradiated adult mice. Blast colony assays revealed that most hemangioblast activity was detected apart from the pre-HSC population, implying the early divergence of pre-HSCs from hemangioblasts. Gene expression profiling suggests that a particular set of transcripts closely associated with adult HSCs is involved in the transition of pre-HSC to embryonic HSCs. We propose an HSC developmental model in which pre-HSCs and embryonic HSCs sequentially give rise to adult types of HSCs in a stepwise manner.

  7. Interleukin-21 promotes thymopoiesis recovery following hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Aurélie Tormo

    2017-06-01

    Full Text Available Abstract Background Impaired T cell reconstitution remains a major deterrent in the field of bone marrow (BM transplantation (BMT due to pre-conditioning-induced damages inflicted to the thymi of recipient hosts. Given the previously reported thymo-stimulatory property of interleukin (IL-21, we reasoned that its use post-BMT could have a profound effect on de novo T cell development. Methods To evaluate the effect of IL-21 on de novo T cell development in vivo, BM derived from RAG2p-GFP mice was transplanted into LP/J mice. Lymphocyte reconstitution was first assessed using a hematological analyzer and a flow cytometer on collected blood samples. Detailed flow cytometry analysis was then performed on the BM, thymus, and spleen of transplanted animals. Finally, the effect of human IL-21 on thymopoiesis was validated in humanized mice. Results Using a major histocompatibility complex (MHC-matched allogeneic BMT model, we found that IL-21 administration improves immune reconstitution by triggering the proliferation of BM Lin−Sca1+c-kit+ (LSK subsets. The pharmacological effect of IL-21 also culminates in the recovery of both hematopoietic (thymocytes and non-hematopoietic (stromal cells within the thymi of IL-21-treated recipient animals. Although T cells derived from all transplanted groups proliferate, secrete various cytokines, and express granzyme B similarly in response to T cell receptor (TCR stimulation, full regeneration of peripheral naïve CD4+ and CD8+ T cells and normal TCRvβ distribution could only be detected in IL-21-treated recipient mice. Astonishingly, none of the recipient mice who underwent IL-21 treatment developed graft-versus-host disease (GVHD in the MHC-matched allogeneic setting while the graft-versus-tumor (GVT effect was strongly retained. Inhibition of GVHD onset could also be attributed to the enhanced generation of regulatory B cells (B10 observed in the IL-21, but not PBS, recipient mice. We also tested the

  8. Impacts of Extreme Events on Phenology: Drought-Induced Changes in Productivity of Mixed Woody-Herbaceous Ecosystems

    Science.gov (United States)

    Rich, P. M.; Breshears, D. D.; White, A. B.

    2006-12-01

    Ecosystem responses to key climate drivers are reflected in phenological dynamics such as the timing and degree of "greenup" that integrate responses over spatial scales from individual plants to ecosystems. This integration is clearest in ecosystems dominated by a single species or life form, such as seasonally dynamic grasslands or more temporally constant evergreen forests. Yet many ecosystems have substantial contribution of cover from both herbaceous and woody evergreen plants. Responses of mixed woody- herbaceous ecosystems to climate are of increasing concern due to their extensive nature, the potential for such systems to yield more complex responses than those dominated by a single life form, and projections that extreme climate and weather events will increase in frequency and intensity with global warming. We present responses of a mixed woody-herbaceous ecosystem type to an extreme event: regional scale piñon pine mortality following an extended drought and the subsequent herbaceous greenup following the first wet period after the drought. This example highlights how reductions in greenness of the slower, more stable evergreen woody component can rapidly be offset by increases associated with resources made available to the relatively more responsive herbaceous component. We hypothesize that such two-phase phenological responses to extreme events are characteristic of many mixed woody-herbaceous ecosystems.

  9. Features of neutrino mixing

    Science.gov (United States)

    Chiu, S. H.; Kuo, T. K.

    2018-03-01

    The elements (squared) of the neutrino mixing matrix are found to satisfy, as functions of the induced mass, a set of differential equations. They show clearly the dominance of pole terms when the neutrino masses "cross." Using the known vacuum mixing parameters as initial conditions, it is found that these equations have very good approximate solutions, for all values of the induced mass. The results are applicable to long baseline experiments.

  10. Hydrostatic-pressure-induced GAMMA-X mixing in delta-doped Al{sub x}Ga{sub 1-x}As

    Energy Technology Data Exchange (ETDEWEB)

    Mora-Ramos, M E [Facultad de Ciencias, Universidad Autonoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa, CP 62209 Cuernavaca, MOR. (Mexico); Duque, C A, E-mail: memora@buzon.uaem.m [Instituto de Fisica, Universidad de Antioquia, AA 1226, Medellin (Colombia)

    2009-05-01

    The mixing between GAMMA and X points in the conduction band is known to manifest in GaAs/Al{sub x}Ga{sub 1-x}As heterostructures. Application of hydrostatic pressure leads to the variation of both the GAMMA- and X-energy gaps in such a way that around P = 39 kbar, the GaAs becomes an indirect gap one. Within a narrow interval of P around this value, both minima remain almost energetically aligned. Therefore, it can be expected that some kind of mixing between the states corresponding to the delta-quantum-wells formed at those points should manifest. In this work, we investigate the occurrence of GAMMA-X mixing induced by the application of hydrostatic pressure in n-type delta doped Al{sub x}Ga{sub 1-x}As, by means of a variational scheme that uses a 2x2 Hamiltonian with the off-diagonal element being a variational potential energy. Diagonal Schroedinger-like effective mass elements are written with potential functions given by the Thomas-Fermi approximation. The effect of the hydrostatic pressure is incorporated via the dependence on P of the different input parameters in the system: energy gaps, effective masses and dielectric constant. We report the variation of the ground state of the system as a function of P.

  11. Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1

    NARCIS (Netherlands)

    Oostvogels, R.; Minnema, M. C.; van Elk, M.; Spaapen, R. M.; te Raa, G. D.; Giovannone, B.; Buijs, A.; van Baarle, D.; Kater, A. P.; Griffioen, M.; Spierings, E.; Lokhorst, H. M.; Mutis, T.

    2013-01-01

    Donor T cells directed at hematopoietic system-specific minor histoconnpatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the

  12. Lhx2 expression promotes self-renewal of a distinct multipotential hematopoietic progenitor cell in embryonic stem cell-derived embryoid bodies.

    Directory of Open Access Journals (Sweden)

    Lina Dahl

    Full Text Available The molecular mechanisms regulating the expansion of the hematopoietic system including hematopoietic stem cells (HSCs in the fetal liver during embryonic development are largely unknown. The LIM-homeobox gene Lhx2 is a candidate regulator of fetal hematopoiesis since it is expressed in the fetal liver and Lhx2(-/- mice die in utero due to severe anemia. Moreover, expression of Lhx2 in embryonic stem (ES cell-derived embryoid bodies (EBs can lead to the generation of HSC-like cell lines. To further define the role of this transcription factor in hematopoietic regulation, we generated ES cell lines that enabled tet-inducible expression of Lhx2. Using this approach we observed that Lhx2 expression synergises with specific signalling pathways, resulting in increased frequency of colony forming cells in developing EB cells. The increase in growth factor-responsive progenitor cells directly correlates to the efficiency in generating HSC-like cell lines, suggesting that Lhx2 expression induce self-renewal of a distinct multipotential hematopoietic progenitor cell in EBs. Signalling via the c-kit tyrosine kinase receptor and the gp130 signal transducer by IL-6 is necessary and sufficient for the Lhx2 induced self-renewal. While inducing self-renewal of multipotential progenitor cells, expression of Lhx2 inhibited proliferation of primitive erythroid precursor cells and interfered with early ES cell commitment, indicating striking lineage specificity of this effect.

  13. FAM20: an evolutionarily conserved family of secreted proteins expressed in hematopoietic cells

    Directory of Open Access Journals (Sweden)

    Cobos Everardo

    2005-01-01

    Full Text Available Abstract Background Hematopoiesis is a complex developmental process controlled by a large number of factors that regulate stem cell renewal, lineage commitment and differentiation. Secreted proteins, including the hematopoietic growth factors, play critical roles in these processes and have important biological and clinical significance. We have employed representational difference analysis to identify genes that are differentially expressed during experimentally induced myeloid differentiation in the murine EML hematopoietic stem cell line. Results One identified clone encoded a previously unidentified protein of 541 amino acids that contains an amino terminal signal sequence but no other characterized domains. This protein is a member of family of related proteins that has been named family with sequence similarity 20 (FAM20 with three members (FAM20A, FAM20B and FAM20C in mammals. Evolutionary comparisons revealed the existence of a single FAM20 gene in the simple vertebrate Ciona intestinalis and the invertebrate worm Caenorhabditis elegans and two genes in two insect species, Drosophila melanogaster and Anopheles gambiae. Six FAM20 family members were identified in the genome of the pufferfish, Fugu rubripes and five members in the zebrafish, Danio rerio. The mouse Fam20a protein was ectopically expressed in a mammalian cell line and found to be a bona fide secreted protein and efficient secretion was dependent on the integrity of the signal sequence. Expression analysis revealed that the Fam20a gene was indeed differentially expressed during hematopoietic differentiation and that the other two family members (Fam20b and Fam20c were also expressed during hematcpoiesis but that their mRNA levels did not vary significantly. Likewise FAM20A was expressed in more limited set of human tissues than the other two family members. Conclusions The FAM20 family represents a new family of secreted proteins with potential functions in regulating

  14. Biology and flow cytometry of proangiogenic hematopoietic progenitors cells.

    Science.gov (United States)

    Rose, Jonathan A; Erzurum, Serpil; Asosingh, Kewal

    2015-01-01

    During development, hematopoiesis and neovascularization are closely linked to each other via a common bipotent stem cell called the hemangioblast that gives rise to both hematopoietic cells and endothelial cells. In postnatal life, this functional connection between the vasculature and hematopoiesis is maintained by a subset of hematopoietic progenitor cells endowed with the capacity to differentiate into potent proangiogenic cells. These proangiogenic hematopoietic progenitors comprise a specific subset of bone marrow (BM)-derived cells that homes to sites of neovascularization and possess potent paracrine angiogenic activity. There is emerging evidence that this subpopulation of hematopoietic progenitors plays a critical role in vascular health and disease. Their angiogenic activity is distinct from putative "endothelial progenitor cells" that become structural cells of the endothelium by differentiation into endothelial cells. Proangiogenic hematopoietic progenitor cell research requires multidisciplinary expertise in flow cytometry, hematology, and vascular biology. This review provides a comprehensive overview of proangiogenic hematopoietic progenitor cell biology and flow cytometric methods to detect these cells in the peripheral blood circulation and BM. © 2014 International Society for Advancement of Cytometry.

  15. The Role of Toll Like Receptors in Hematopoietic Malignancies

    Directory of Open Access Journals (Sweden)

    Darlene Monlish

    2016-09-01

    Full Text Available Toll-like receptors (TLRs are a family of pattern recognition receptors (PRRs that shape the innate immune system by identifying pathogen-associated molecular patterns (PAMPS and host-derived damage associated molecular patterns (DAMPS. TLRs are widely expressed on both immune cells and non-immune cells, including hematopoietic stem and progenitor cells, effector immune cell populations, and endothelial cells. In addition to their well-known role in the innate immune response to acute infection or injury, accumulating evidence supports a role for TLRs in the development of hematopoietic and other malignancies. Several hematopoietic disorders, including lymphoproliferative disorders and myelodysplastic syndromes, which possess a high risk of transformation to leukemia, have been linked to aberrant TLR signaling. Furthermore, activation of TLRs leads to the induction of a number of pro-inflammatory cytokines and chemokines, which can promote tumorigenesis by driving cell proliferation and migration and providing a favorable microenvironment for tumor cells. Beyond hematopoietic malignancies, the upregulation of a number of TLRs has been linked to promoting tumor cell survival, proliferation, and metastasis in a variety of cancers, including those of the colon, breast, and lung. This review focuses on the contribution of TLRs to hematopoietic malignancies, highlighting the known direct and indirect effects of TLR signaling on tumor cells and their microenvironment. In addition, the utility of TLR agonists and antagonists as potential therapeutics in the treatment of hematopoietic malignancies is discussed.

  16. Increased radiosensitivity and radiation-induced apoptosis in SRC-3 knockout mice

    International Nuclear Information System (INIS)

    Jin Jie; Wang Yu; Xu Yang; Chen Shilei; Wang Junping; Ran Xinze; Su Yongping; Wang Jin

    2014-01-01

    Steroid receptor coactivator-3 (SRC-3), a multifunctional transcriptional coactivator, plays an important role in regulation of cell apoptosis in chemoresistant cancer cells. However, its role in radiation-induced apoptosis in hematopoietic cells is still unclear. In this study, we used SRC-3 knockout (SRC-3 -/- ) mice to assess the role of SRC-3 in radiation-induced hematopoietic injury in vivo. After a range of doses of irradiation, SRC-3 -/- mice exhibited lower counts of peripheral blood cells and bone marrow (BM) mononuclear cells and excessive BM depression, which resulted in a significantly higher mortality compared with wildtype mice. Moreover, BM mononuclear cells obtained from SRC-3 -/- mice showed a remarkable increase in radiation-induced apoptosis. Collectively, our data demonstrate that SRC-3 plays a role in radiation-induced apoptosis of BM hematopoietic cells. Regulation of SRC-3 might influence the radiosensitivity of hematopoietic cells, which highlights a potential therapeutic target for radiation-induced hematopoietic injury. (author)

  17. Hematopoietic Acute Radiation Syndrome (Bone marrow syndrome, Aplastic Anemia): Molecular Mechanisms of Radiation Toxicity.

    Science.gov (United States)

    Popov, Dmitri

    Radiation Toxins (SRD-4) to radiation naive animals in doses 0.1 mg/kg; 0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg up to 30 mg/kg. Results: After I/V or I/M administration of Hematotoxic Radiation Toxins to radiation -naive animals the induction of specific clinical signs was observed- including thrombocytopenia, lymphocytosis followed by lymphocytopenia, granulocytopenia , aplastic anemia, and the clinical manifestations- ecchymosis, hemorrhage and coagulopathy. These observed clinical signs mimic the acute/hematopoietic acute radiation syndrome. Conclusions: Administration of Hematopoietic Radiation Toxins (SRD-4) to radiation naive animals in doses 0.1 mg/kg;0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg up to 30 mg/kg produced specific toxic reactions with the development of signs and symptoms consistent with the hematological form of Acute Radiation Syndromes. Administration of high doses of Hematopoietic Radiation Toxins developed a clinical picture identical to severe Acute Radiation Exposure Syndrome and induces Toxic Multiple Organ Failure (TMOF) and Toxic Multiple Organ Involvement (TMOI) {i.e. pneumonitis, renal failure, renal hypo-perfusion, acute tubular necrosis, hepatic failure, etc.} essentially as which occurs as an acute consequence of radiation toxemia. Aplastic anemia is an important clinical and pathological process which develops after animals receive high doses of both radiation and administered radiation toxins.

  18. Dysregulation of the DNA Damage Response and KMT2A Rearrangement in Fetal Liver Hematopoietic Cells.

    Directory of Open Access Journals (Sweden)

    Mai Nanya

    Full Text Available Etoposide, a topoisomerase 2 (TOP2 inhibitor, is associated with the development of KMT2A (MLL-rearranged infant leukemia. An epidemiological study suggested that in utero exposure to TOP2 inhibitors may be involved in generation of KMT2A (MLL rearrangement. The present study examined the mechanism underlying the development of KMT2A (MLL-rearranged infant leukemia in response to in utero exposure to etoposide in a mouse model. Fetal liver hematopoietic stem cells were more susceptible to etoposide than maternal bone marrow mononuclear cells. Etoposide-induced Kmt2a breakage was detected in fetal liver hematopoietic stem cells using a newly developed chromatin immunoprecipitation (ChIP assay. Assessment of etoposide-induced chromosomal translocation by next-generation RNA sequencing (RNA-seq identified several chimeric fusion messenger RNAs that were generated by etoposide treatment. However, Kmt2a (Mll-rearranged fusion mRNA was detected in Atm-knockout mice, which are defective in the DNA damage response, but not in wild-type mice. The present findings suggest that in utero exposure to TOP2 inhibitors induces Kmt2a rearrangement when the DNA damage response is defective.

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

    Science.gov (United States)

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

    2016-01-01

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

  20. Therapeutic approaches of hematopoietic syndrome after serious accidental global irradiation. Ex vivo expansion interest of hematopoietic cells

    International Nuclear Information System (INIS)

    Thierry, D.

    1994-01-01

    Aplasia is one of the main syndrome, appearing after one global accidental irradiation by one ionizing radiation source. The hematopoietic syndrome is characterized by a peripheric blood cell number fall; the cell marrow is reduced too

  1. System and method for regeneration and recirculation of a reducing agent using highly exothermic reactions induced by mixed industrial slags

    Science.gov (United States)

    Nakano, Jinichiro; Bennett, James P.; Nakano, Anna

    2017-12-12

    Embodiments relate to systems and methods for regenerating and recirculating a CO, H.sub.2 or combinations thereof utilized for metal oxide reduction in a reduction furnace. The reduction furnace receives the reducing agent, reduces the metal oxide, and generates an exhaust of the oxidized product. The oxidized product is transferred to a mixing vessel, where the oxidized product, a calcium oxide, and a vanadium oxide interact to regenerate the reducing agent from the oxidized product. The regenerated reducing agent is transferred back to the reduction furnace for continued metal oxide reductions.

  2. Reactive oxygen species-dependent Toll/NF-κB activation in the Drosophila hematopoietic niche confers resistance to wasp parasitism.

    Science.gov (United States)

    Louradour, Isabelle; Sharma, Anurag; Morin-Poulard, Ismael; Letourneau, Manon; Vincent, Alain; Crozatier, Michèle; Vanzo, Nathalie

    2017-11-01

    Hematopoietic stem/progenitor cells in the adult mammalian bone marrow ensure blood cell renewal. Their cellular microenvironment, called 'niche', regulates hematopoiesis both under homeostatic and immune stress conditions. In the Drosophila hematopoietic organ, the lymph gland, the posterior signaling center (PSC) acts as a niche to regulate the hematopoietic response to immune stress such as wasp parasitism. This response relies on the differentiation of lamellocytes, a cryptic cell type, dedicated to pathogen encapsulation and killing. Here, we establish that Toll/NF-κB pathway activation in the PSC in response to wasp parasitism non-cell autonomously induces the lymph gland immune response. Our data further establish a regulatory network where co-activation of Toll/NF-κB and EGFR signaling by ROS levels in the PSC/niche controls lymph gland hematopoiesis under parasitism. Whether a similar regulatory network operates in mammals to control emergency hematopoiesis is an open question.

  3. Fanca−/− hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766

    Science.gov (United States)

    Milsom, Michael D.; Lee, Andrew W.; Zheng, Yi; Cancelas, Jose A.

    2009-01-01

    Fanconi anemia is a severe bone marrow failure syndrome resulting from inactivating mutations of Fanconi anemia pathway genes. Gene and cell therapy trials using hematopoietic stem cells and progenitors have been hampered by poor mobilization of HSC to peripheral blood in response to G-CSF. Using a murine model of Fanconi anemia (Fanca−/− mice), we found that the Fanca deficiency was associated with a profound defect in hematopoietic stem cells and progenitors mobilization in response to G-CSF in absence of bone marrow failure, which correlates with the findings of clinical trials in Fanconi anemia patients. This mobilization defect was overcome by co-administration of the Rac inhibitor NSC23766, suggesting that Rac signaling is implicated in the retention of Fanca−/− hematopoietic stem cells and progenitors in the bone marrow. In view of these data, we propose that targeting Rac signaling may enhance G-CSF-induced HSC mobilization in Fanconi anemia. PMID:19491337

  4. Cadmium modulates hematopoietic stem and progenitor cells and skews toward myelopoiesis in mice

    International Nuclear Information System (INIS)

    Zhang, Yandong; Yu, Xinchun; Sun, Shuhui; Li, Qian; Xie, Yunli; Li, Qiang; Zhao, Yifan; Pei, Jianfeng; Zhang, Wenmin; Xue, Peng; Zhou, Zhijun; Zhang, Yubin

    2016-01-01

    The heavy metal cadmium (Cd) is known to modulate immunity and cause osteoporosis. However, how Cd influences on hematopoiesis remain largely unknown. Herein, we show that wild-type C57BL/6 (B6) mice exposed to Cd for 3 months had expanded bone marrow (BM) populations of long-term hematopoietic stem cells (LT-HSCs), common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs), while having reduced populations of multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). A competitive mixed BM transplantation assay indicates that BM from Cd-treated mice had impaired LT-HSC ability to differentiate into mature cells. In accordance with increased myeloid progenitors and decreased lymphoid progenitors, the BM and spleens of Cd-treated mice had more monocytes and/or neutrophils and fewer B cells and T cells. Cd impaired the ability of the non-hematopoietic system to support LT-HSCs, in that lethally irradiated Cd-treated recipients transplanted with normal BM cells had reduced LT-HSCs after the hematopoietic system was fully reconstituted. This is consistent with reduced osteoblasts, a known critical component for HSC niche, observed in Cd-treated mice. Conversely, lethally irradiated control recipients transplanted with BM cells from Cd-treated mice had normal LT-HSC reconstitution. Furthermore, both control mice and Cd-treated mice that received Alendronate, a clinical drug used for treating osteoporosis, had BM increases of LT-HSCs. Thus, the results suggest Cd increase of LT-HSCs is due to effects on HSCs and not on osteoblasts, although, Cd causes osteoblast reduction and impaired niche function for maintaining HSCs. Furthermore, Cd skews HSCs toward myelopoiesis. - Highlights: • Cd increases the number of LT-HSCs but impairs their development. • Cd-treated hosts have compromised ability to support LT-HSCs. • Cd promotes myelopoiesis at the expense of lymphopoiesis at the MPP level.

  5. Cadmium modulates hematopoietic stem and progenitor cells and skews toward myelopoiesis in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yandong; Yu, Xinchun [School of Public Health and Key Laboratory of Public Health, MOE, Fudan University, Shanghai 200032 (China); Sun, Shuhui [Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Li, Qian [School of Public Health and Key Laboratory of Public Health, MOE, Fudan University, Shanghai 200032 (China); Xie, Yunli [Insititute of Brain Sciences, Fudan University, Shanghai 200032 (China); Li, Qiang [Putuo District Center for Disease Control and Prevention, Shanghai 200062 (China); Zhao, Yifan; Pei, Jianfeng; Zhang, Wenmin; Xue, Peng; Zhou, Zhijun [School of Public Health and Key Laboratory of Public Health, MOE, Fudan University, Shanghai 200032 (China); Zhang, Yubin, E-mail: yz001@fudan.edu.cn [School of Public Health and Key Laboratory of Public Health, MOE, Fudan University, Shanghai 200032 (China)

    2016-12-15

    The heavy metal cadmium (Cd) is known to modulate immunity and cause osteoporosis. However, how Cd influences on hematopoiesis remain largely unknown. Herein, we show that wild-type C57BL/6 (B6) mice exposed to Cd for 3 months had expanded bone marrow (BM) populations of long-term hematopoietic stem cells (LT-HSCs), common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs), while having reduced populations of multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). A competitive mixed BM transplantation assay indicates that BM from Cd-treated mice had impaired LT-HSC ability to differentiate into mature cells. In accordance with increased myeloid progenitors and decreased lymphoid progenitors, the BM and spleens of Cd-treated mice had more monocytes and/or neutrophils and fewer B cells and T cells. Cd impaired the ability of the non-hematopoietic system to support LT-HSCs, in that lethally irradiated Cd-treated recipients transplanted with normal BM cells had reduced LT-HSCs after the hematopoietic system was fully reconstituted. This is consistent with reduced osteoblasts, a known critical component for HSC niche, observed in Cd-treated mice. Conversely, lethally irradiated control recipients transplanted with BM cells from Cd-treated mice had normal LT-HSC reconstitution. Furthermore, both control mice and Cd-treated mice that received Alendronate, a clinical drug used for treating osteoporosis, had BM increases of LT-HSCs. Thus, the results suggest Cd increase of LT-HSCs is due to effects on HSCs and not on osteoblasts, although, Cd causes osteoblast reduction and impaired niche function for maintaining HSCs. Furthermore, Cd skews HSCs toward myelopoiesis. - Highlights: • Cd increases the number of LT-HSCs but impairs their development. • Cd-treated hosts have compromised ability to support LT-HSCs. • Cd promotes myelopoiesis at the expense of lymphopoiesis at the MPP level.

  6. Reciprocal upregulation of Notch signaling molecules in hematopoietic progenitor and mesenchymal stromal cells

    Directory of Open Access Journals (Sweden)

    Kikuchi Y

    2011-01-01

    Full Text Available Although mesenchymal stem cells (MSCs play pivotal supportive roles in hematopoiesis, how they interact with hematopoietic stem cells (HSCs is not well understood. We investigated the interaction between HSCs and surrogate MSCs (C3H10T1/2 stromal cells, focusing on the molecular events induced by cell contact of these bipartite populations. C3H10T1/2 is a mesenchymal stromal cell line that can be induced to differentiate into preadipocytes (A54 and myoblasts (M1601. The stromal cell derivatives were cocultured with murine HSCs (Lineage-Sca1+, and gene expression profiles in stromal cells and HSCs were compared before and after the coculture. HSCs gave rise to cobblestone areas only on A54 cells, with ninefold more progenitors than on M1601 or undifferentiated C3H10T1/2 cells. Microarray-based screening and a quantitative reverse transcriptase directed-polymerase chain reaction showed that the levels of Notch ligands (Jagged1 and Delta-like 3 were increased in A54 cells upon interaction with HSCs. On the other hand, the expression of Notch1 and Hes1 was upregulated in the HSCs cocultured with A54 cells. A transwell assay revealed that the reciprocal upregulation was dependent on cell-to-cell contact. The result suggested that in the hematopoietic niche, HSCs help MSCs to produce Notch ligands, and in turn, MSCs help HSCs to express Notch receptor. Such a reciprocal upregulation would reinforce the downstream signaling to determine the fate of hematopoietic cell lineage. Clarification of the initiating events on cell contact should lead to the identification of specific molecular targets to facilitate HSC engraftment in transplantation therapy.

  7. Inhibitory effects of meju prepared with mixed starter cultures on azoxymethane and dextran sulfate sodium-induced colon carcinogenesis in mice

    Directory of Open Access Journals (Sweden)

    Ji-Kang Jeong

    2012-01-01

    Full Text Available Backgrounds: Meju is the main ingredient and the starter culture of traditional Korean fermented soybean foods; these fermented soybean products are well-known for their various health benefits, including anticancer effects. We developed the grain-type meju using probiotic mixed starter cultures to improve the qualities and functionalities of fermented soybean products, as well as the meju itself. In this study, the inhibitory effects of the grain-type meju were investigated in azoxymethane (AOM and dextran sulfate sodium (DSS-induced colon carcinogenesis mice model. Materials and Methods: AOM and DSS colon carcinogenesis was induced in female C57BL/6 mice and meju was orally administered for 4 weeks. The body weight, colon length, and colon weight of mice were determined, and colonic tissues were histologically observed. The serum levels of proinflammatory cytokines and the levels of inflammation- and apoptosis-related genes in colonic tissue were also analyzed. Results: The administration of meju using probiotic mixed starter cultures ameliorated the symptoms of colon cancer and reduced number of neoplasia, and reduced serum proinflammatory cytokine levels and iNOS and COX-2 expression levels in colonic tissue. It increased Bax and reduced Bcl-2 expression levels and increased p21 and p53 expression in colonic tissues. Conclusion: The meju showed inhibitory effects on the progression of colon cancer induced by AOM and DSS by ameliorating the symptoms of colon cancer, reducing the number of neoplasias and regulating proinflammatory cytokine levels and the expressions of inflammation- and apoptosis-related genes in the colonic tissue.

  8. Effects of Fermented Milk with Mixed Strains as a Probiotic on the Inhibition of Loperamide-Induced Constipation.

    Science.gov (United States)

    Kim, Byoung-Kook; Choi, In Suk; Kim, Jihee; Han, Sung Hee; Suh, Hyung Joo; Hwang, Jae-Kwan

    2017-01-01

    To investigate the effects of a single bacterium and a mixture of bacteria as probiotics in loperamide-treated animal models, loperamide (3 mg/kg) was administered to SD rats to induce constipation. The individual lactic acid bacterial doses, Enterococcus faecium (EF), Lactobacillus acidophilus (LA), Streptococcus thermophilus (ST), Bifidobacterium bifidum (BB), Bifidobacterium lactis (BL), Pediococcus pentosaceus (PP), and a mixture of the bacteria were orally administered to loperamide-induced constipated rats at a concentration of 10 8 CFU/kg for 14 days. The weights and water contents of their stools were found to be significantly higher in PP, CKDB (mixture of 5 strains except PP), and CKDBP (CKDB+PP) groups than in the normal (constipation not induced) and the control (constipation-induced) groups ( p mucus secretion were significantly improved in all probiotic-treated-groups, as compared to that in the control group, and the CKDBP group was found to be the most effective according to immunohistochemistry (IHC) staining and total short chain fatty acid content analysis ( p <0.05). Lastly, PP, CKDB, and CKDBP showed relatively higher Lactobacillus sp. ratios of 61.94%, 60.31% and 51.94%, respectively, compared to the other groups, based on metagenomic analysis.

  9. In vitro and in vivo assessment of direct effects of simulated solar and galactic cosmic radiation on human hematopoietic stem/progenitor cells.

    Science.gov (United States)

    Rodman, C; Almeida-Porada, G; George, S K; Moon, J; Soker, S; Pardee, T; Beaty, M; Guida, P; Sajuthi, S P; Langefeld, C D; Walker, S J; Wilson, P F; Porada, C D

    2017-06-01

    Future deep space missions to Mars and near-Earth asteroids will expose astronauts to chronic solar energetic particles (SEP) and galactic cosmic ray (GCR) radiation, and likely one or more solar particle events (SPEs). Given the inherent radiosensitivity of hematopoietic cells and short latency period of leukemias, space radiation-induced hematopoietic damage poses a particular threat to astronauts on extended missions. We show that exposing human hematopoietic stem/progenitor cells (HSC) to extended mission-relevant doses of accelerated high-energy protons and iron ions leads to the following: (1) introduces mutations that are frequently located within genes involved in hematopoiesis and are distinct from those induced by γ-radiation; (2) markedly reduces in vitro colony formation; (3) markedly alters engraftment and lineage commitment in vivo; and (4) leads to the development, in vivo, of what appears to be T-ALL. Sequential exposure to protons and iron ions (as typically occurs in deep space) proved far more deleterious to HSC genome integrity and function than either particle species alone. Our results represent a critical step for more accurately estimating risks to the human hematopoietic system from space radiation, identifying and better defining molecular mechanisms by which space radiation impairs hematopoiesis and induces leukemogenesis, as well as for developing appropriately targeted countermeasures.

  10. Examining fire-induced forest changes using novel remote sensing technique: a case study in a mixed pine-oak forest

    Science.gov (United States)

    Meng, R.; Wu, J.; Zhao, F. R.; Cook, B.; Hanavan, R. P.; Serbin, S.

    2017-12-01

    Fire-induced forest changes has long been a central focus for forest ecology and global carbon cycling studies, and is becoming a pressing issue for global change biologists particularly with the projected increases in the frequency and intensity of fire with a warmer and drier climate. Compared with time-consuming and labor intensive field-based approaches, remote sensing offers a promising way to efficiently assess fire effects and monitor post-fire forest responses across a range of spatial and temporal scales. However, traditional remote sensing studies relying on simple optical spectral indices or coarse resolution imagery still face a number of technical challenges, including confusion or contamination of the signal by understory dynamics and mixed pixels with moderate to coarse resolution data (>= 30 m). As such, traditional remote sensing may not meet the increasing demand for more ecologically-meaningful monitoring and quantitation of fire-induced forest changes. Here we examined the use of novel remote sensing technique (i.e. airborne imaging spectroscopy and LiDAR measurement, very high spatial resolution (VHR) space-borne multi-spectral measurement, and high temporal-spatial resolution UAS-based (Unmanned Aerial System) imagery), in combination with field and phenocam measurements to map forest burn severity across spatial scales, quantify crown-scale post-fire forest recovery rate, and track fire-induced phenology changes in the burned areas. We focused on a mixed pine-oak forest undergoing multiple fire disturbances for the past several years in Long Island, NY as a case study. We demonstrate that (1) forest burn severity mapping from VHR remote sensing measurement can capture crown-scale heterogeneous fire patterns over large-scale; (2) the combination of VHR optical and structural measurements provides an efficient means to remotely sense species-level post-fire forest responses; (3) the UAS-based remote sensing enables monitoring of fire-induced

  11. Time Dependent MHD Nano-Second Grade Fluid Flow Induced by Permeable Vertical Sheet with Mixed Convection and Thermal Radiation.

    Directory of Open Access Journals (Sweden)

    Muhammad Ramzan

    Full Text Available The aim of present paper is to study the series solution of time dependent MHD second grade incompressible nanofluid towards a stretching sheet. The effects of mixed convection and thermal radiation are also taken into account. Because of nanofluid model, effects Brownian motion and thermophoresis are encountered. The resulting nonlinear momentum, heat and concentration equations are simplified using appropriate transformations. Series solutions have been obtained for velocity, temperature and nanoparticle fraction profiles using Homotopy Analysis Method (HAM. Convergence of the acquired solution is discussed critically. Behavior of velocity, temperature and concentration profiles on the prominent parameters is depicted and argued graphically. It is observed that temperature and concentration profiles show similar behavior for thermophoresis parameter Νt but opposite tendency is noted in case of Brownian motion parameter Νb. It is further analyzed that suction parameter S and Hartman number Μ depict decreasing behavior on velocity profile.

  12. Stress analysis of mixing of non-newtonian flows in cylindrical vessel induced by co-rotating stirrers

    International Nuclear Information System (INIS)

    Memon, R.A.; Solangi, M.A.

    2013-01-01

    The impacts of rotational velocity and inertia on velocity gradients and stresses are addressed under present study. The non-Newtonian behaviour of inelastic rotating flows is predicted by employing Power law model. A numerical model has been developed for mixing flow within a cylindrical vessel along a couple of stirrers. A time marching FEM (Finite Element Method) is employed to predict the required solution. Predicted solutions are presented for minimum to maximum values in terms of contour plots of velocity gradients and shear stresses, over the range. The long term application of this research will be used to improve the design of mixers and processing products. The predicted results are used to generate the capability and are in good agreement with numerical results to the mixer design that will ultimately effect the processing of dough products. (author)

  13. Hematopoietic tissue repair under chronic low daily dose irradiation

    International Nuclear Information System (INIS)

    Seed, T.M.

    1994-01-01

    The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). We have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d -1 ). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup (1), the failure to augment basic m-pair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments particularly marked within erythroid compartments. that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccomodated and either prone- or not prone to ML, subgroup 2 ampersand 3 appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high- tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity

  14. Swift heavy-ion induced trap generation and mixing at Si/SiO{sub 2} interface in depletion n-MOS

    Energy Technology Data Exchange (ETDEWEB)

    Shinde, N. [Ecotopia Science Institute, Division of Energy Science, Nagoya University, Nagoya 464-8603 (Japan) and Department of Physics, University of Pune, Pune 411 007 (India)]. E-mail: nss@nucl.nagoya-u.ac.jp; Bhoraskar, V.N. [Department of Physics, University of Pune, Pune 411 007 (India); Dhole, S.D. [Department of Physics, University of Pune, Pune 411 007 (India)

    2006-01-15

    Large channel depletion n-channel MOSFET (Metal oxide semiconductor field effect transistor) is a basic Si-SiO{sub 2} structure to understand irradiation-induced modifications. The contribution of interface and oxide states denoted as {delta}N {sub IT} and {delta}N {sub OT}, respectively, was separated out by using I {sub D}-V {sub DS}, I {sub D}-V {sub GS} measurements. The threshold voltage shift {delta}V {sub T} (V {sub T-irrad} - V {sub T-virgin}) increased for all ions (50 MeV Li, B, F, P and Ni) over the fluence of 2 x 10{sup 11}-2 x 10{sup 13} ions/cm{sup 2}. The increase in {delta}N {sub IT} was associated to trap generation at Si-SiO{sub 2} interface, but a small change in {delta}N {sub OT} indicate less charge trapping in oxide. The electronic energy loss S {sub e} induced increase in {delta}N {sub IT} is not adequate to explain the large shift in threshold voltage. A rough estimate shows that the channel width, W should decrease by 40% for a large increase in {delta}N {sub IT}. Thus, the possible factor affecting reduction of W may be ion beam mixing induced broadening of Si-SiO{sub 2} interface.

  15. Hematopoietic differentiative properties of murine spleen implanted in the omenta of irradiated and nonirradiated hosts

    Energy Technology Data Exchange (ETDEWEB)

    Haley, J E; Tjio, J H; Smith, W W; Brecher, G [California Univ., San Francisco (USA); National Inst. of Arthritis, Metabolism, and Digestive Diseases, Bethesda, Md. (USA); National Cancer Inst., Bethesda, Md. (USA). Lab. of Viral Oncology)

    1975-01-01

    Whole body irradiation of the recipients of syngeneic splenic implants into the omentum greatly enhances hematopoiesis and permits survival of and repopulation by stem cells of donor origin. Donor hematopoietic stem cells do not survive in spleen implants of the nonirradiated host.Irradiated hosts were therefore used in the bulk of the experiments. Differentiation in the implants of splenic fragments is predominantly erythrocytic at 10 days and shifts to predominantly granulocytic differentiation at 21 days. Suspensions of spleen cells injected into the omentum are predominantly granulocytopoietic at 10 days. The differentiation in fragments of spleen depleted of stem cells by irradiation, seeded with bone marrow cells and implanted into the omentum results in mixed erythrocytic and granulocytic hematopoiesis, with granulocytic predominance. Lymphocytic cells appeared late in the implants of irradiated recipients even at a time of prolific lymphocytopoiesis in the hosts' own spleens. The cause of the delay in the implants is not clear. The data are consistent with the concept that differentiation of hematopoietic stem cells is influenced by the stromal cells of the parent organ. The erythrocytic inductive capacity of the stromal cells may belost by mechanical disruption or modified by irradiation or a prolonged period of implantation.

  16. Hematopoietic stem cell function in motheaten mice

    International Nuclear Information System (INIS)

    Shultz, L.D.; Bailey, C.L.; Coman, D.R.

    1983-01-01

    Mice homozygous for the autosomal recessive mutation ''motheaten'' have normal numbers of multipotential hematopoietic stem cells in the bone marrow and spleen as determined by spleen colony assay. Histologic examination shows no qualitative abnormality in morphology of stem cell colonies in recipients of bone marrow or spleen cells from motheaten mice. Despite the apparently normal ontogeny, distribution, and differentiative capacity of CFU stem cells, bone marrow and spleen cells from motheaten mice fail to save congenic +/+ lethally gamma-irradiated hosts. This impaired lifesparing capacity is not due to defective self-renewal but appears to be due in part to pulmonary hemorrhage from alveolar capillaries in the gamma-irradiated hosts. Treatment of motheaten mice with 500 R gamma-irradiation followed by reconstitution with normal bone marrow cells increases the lifespan of this mutant to 10 months of age. The early onset of pneumonitis and subsequent short lifespan of motheaten mice is determined at the level of progenitor cells in the bone marrow

  17. Hematopoietic Stem Cell Therapy to Countermeasure Cancer in Astronauts during Exploration of Deep Space

    Science.gov (United States)

    Ohi, S.; Kindred, R. P.; Roach, A-N.; Edossa, A.; Kim, B. C.; Gonda, S. R.; Emami, K.

    2004-01-01

    Exposure to cosmic radiation can cause chromosomal mutations, which may lead to cancer in astronauts engaged in space exploration. Therefore, our goals are to develop countermeasures to prevent space-induced cancer using hematopoietic stem cell therapy (HSCT) and gene therapy. This presentation focuses on HSCT for cancer. Our previous experiments on a simulated, space-induced immuno-deficiency model (mouse hind limb unloading ) indicated that transplanted hematopoietic stem cells (HSCs) could enhance the host's immunity by effectively eliminating bacterial infection (Ohi S, et. al. J Grav Physiol 10, P63-64, 2003; Ohi S, et. al. Proceedings of the Space Technology and Applications International Forum (STAIF) . American Institute of Physics, New York, pp. 938-950, 2004). Hence, we hypothesized that the HSCs might be effective in combating cancer as well. Studies of cocultured mouse HSCs with beta-galactosidase marked rat gliosarcoma spheroids (9L/lacZ), a cancer model, indicated antagonistic interactions , resulting in destruction of the spheroids by HSCs. Trypan Blue dye-exclusion assays were consistent with the conclusion. These results show potential usehlness of HSCT for cancer. Currently, the NASA Hydrodynamic Focusing Bioreactor (HFB), a space analog tissue/cell culture system, is being used to study invasion of the gliosarcoma (GS) spheroids into mouse brain with or without co-cultured HSCs. This may simulate the metastasis of gliosarcoma to brain. There is a tendency for the HSCs to inhibit invasion of GS spheroids into brain, as evidenced by the X-gal staining.

  18. Cellular players of hematopoietic stem cell mobilization in the bone marrow niche.

    Science.gov (United States)

    Tay, Joshua; Levesque, Jean-Pierre; Winkler, Ingrid G

    2017-02-01

    Hematopoietic stem cells (HSC) reside in perivascular regions of the bone marrow (BM) embedded within a complex regulatory unit called the niche. Cellular components of HSC niches include vascular endothelial cells, mesenchymal stromal progenitor cells and a variety of mature hematopoietic cells such as macrophages, neutrophils, and megakaryocytes-further regulated by sympathetic nerves and complement components as described in this review. Three decades ago the discovery that cytokines induce a large number of HSC to mobilize from the BM into the blood where they are easily harvested, revolutionised the field of HSC transplantation-curative for immune-deficiencies and some malignancies. However, despite now routine use of granulocyte-colony stimulating factor (G-CSF) to mobilise HSC for transplant, only in last 15 years has research on the mechanisms behind why and how HSC can be induced to move into the blood began. These studies have revealed the complexity of the niche that retains HSC in the BM. This review describes how BM niches and HSC themselves change during administration of G-CSF-or in the recovery phase of chemotherapy-to facilitate movement of HSC into the blood, and research now leading to development of novel therapeutics to further boost HSC mobilization and transplant success.

  19. Chemotaxis of primitive hematopoietic cells in response to stromal cell–derived factor-1

    Science.gov (United States)

    Jo, Deog-Yeon; Rafii, Shahin; Hamada, Tsuneyoshi; Moore, Malcolm A.S.

    2000-01-01

    Stromal cell–derived factor-1 (SDF-1) provides a potent chemotactic stimulus for CD34+ hematopoietic cells. We cultured mobilized peripheral blood (PB) and umbilical cord blood (CB) for up to 5 weeks and examined the migratory activity of cobblestone area–forming cells (CAFCs) and long-term culture–initiating cells (LTC-ICs) in a transwell assay. In this system, SDF-1 or MS-5 marrow stromal cells placed in the lower chamber induced transmembrane and transendothelial migration by 2- and 5-week-old CAFCs and LTC-ICs in 3 hours. Transmigration was blocked by preincubation of input CD34+ cells with antibody to CXCR4. Transendothelial migration of CB CAFCs and LTC-ICs was higher than that of PB. We expanded CD34+ cells from CB in serum-free medium with thrombopoietin, flk-2 ligand, and c-kit ligand, with or without IL-3 and found that CAFCs cultured in the absence of IL-3 had a chemotactic response equivalent to noncultured cells, even after 5 weeks. However, addition of IL-3 to the culture reduced this response by 20–50%. These data indicate that SDF-1 induces chemotaxis of primitive hematopoietic cells signaling through CXCR4 and that the chemoattraction could be downmodulated by culture ex vivo. PMID:10619866

  20. Radioprotective effect of hematopoietic growth factor gene therapy regulated by Egr-1 promoter on radiation injury of SCID mice

    International Nuclear Information System (INIS)

    Du Nan; Pei Xuetao; Luo Chengji; Su Yongping; Cheng Tianmin

    2002-01-01

    Objective: To explore the radioprotective effect of the expression of hematopoietic growth factors regulated by radio-inducible promoter on radiation injury. Methods: The human FL cDNA and EGFP cDNA were linked together with an internal ribosome entry site (IRES) and then inserted into the eukaryotic expression vector pCI-neo with the Egr-1 promoter (Egr-EF), and further transduced into bone marrow stromal cell lines HFCL (HFCL/EF). The HFCL/EF and CD34 + cells from human umbilical cord blood were transplanted i.v. one after the other into sublethally irradiated severe combined immunodeficient (SCID) mice. The number of peripheral blood WBC and human cells engrafted in recipient mice were detected by flow cytometry and CFU-GM assay. Results: In contrast to two control groups (HFCL and HFCL/F), HFCL/EF (the Egr-1 regulatory element-driven expression of FL gene therapy) resulted in a proportionally obvious increase in the number of the WBC at early stage after irradiation. Significant differences were found for CD45 + , CD34 + , CFU-GM, and nucleated cells in the bone marrow. Conclusion: Hematopoietic growth factor gene therapy regulated by radio-inducible promoter has radioprotective effect on radiation hematopoietic injury

  1. HCV Proteins and Immunoglobulin Variable Gene (IgV Subfamilies in HCV-Induced Type II Mixed Cryoglobulinemia: A Concurrent Pathogenetic Role

    Directory of Open Access Journals (Sweden)

    Giuseppe Sautto

    2012-01-01

    Full Text Available The association between hepatitis C virus (HCV infection and type II mixed cryoglobulinemia (MCII is well established, but the role played by distinct HCV proteins and by specific components of the anti-HCV humoral immune response remains to be clearly defined. It is widely accepted that HCV drives the expansion of few B-cell clones expressing a restricted pool of selected immunoglobulin variable (IgV gene subfamilies frequently endowed with rheumatoid factor (RF activity. Moreover, the same IgV subfamilies are frequently observed in HCV-transformed malignant B-cell clones occasionally complicating MCII. In this paper, we analyze both the humoral and viral counterparts at the basis of cryoglobulins production in HCV-induced MCII, with particular attention reserved to the single IgV subfamilies most frequently involved.

  2. HCV proteins and immunoglobulin variable gene (IgV) subfamilies in HCV-induced type II mixed cryoglobulinemia: a concurrent pathogenetic role.

    Science.gov (United States)

    Sautto, Giuseppe; Mancini, Nicasio; Solforosi, Laura; Diotti, Roberta A; Clementi, Massimo; Burioni, Roberto

    2012-01-01

    The association between hepatitis C virus (HCV) infection and type II mixed cryoglobulinemia (MCII) is well established, but the role played by distinct HCV proteins and by specific components of the anti-HCV humoral immune response remains to be clearly defined. It is widely accepted that HCV drives the expansion of few B-cell clones expressing a restricted pool of selected immunoglobulin variable (IgV) gene subfamilies frequently endowed with rheumatoid factor (RF) activity. Moreover, the same IgV subfamilies are frequently observed in HCV-transformed malignant B-cell clones occasionally complicating MCII. In this paper, we analyze both the humoral and viral counterparts at the basis of cryoglobulins production in HCV-induced MCII, with particular attention reserved to the single IgV subfamilies most frequently involved.

  3. Influence of Dzyaloshinskii–Moriya interaction on measurement-induced disturbance in a mixed-spin Heisenberg XXZ model with an inhomogeneous magnetic field

    International Nuclear Information System (INIS)

    Zhou, Chao-Biao; Xiao, Shu-Yuan; Zhang, Cong; Wu, Gang; Ran, Yang-Qiang

    2015-01-01

    In this paper, by comparing with the thermal entanglement measured by negativity (N), we investigate the measurement-induced disturbance (MID) in a mixed-spin (1/2, 3/2) Heisenberg XXZ model with Dzyaloshinskii–Moriya (DM) interaction and an inhomogeneous external magnetic field. We make a comparison between MID and N, and find that their behaviors present obvious differences following the changes of the exchange constant J, DM interaction D, the uniform magnetic field B and the inhomogeneity of magnetic field b. It is found that J and D broaden the region of MID. At the same time, we notice that, for the case of small D, MID can detect the quantum phase transition near J=0, but not for N. It is also observed that DM interaction and the inhomogeneous external magnetic field play competing roles in enhancing the N and MID in our system. Moreover, we also note D is a more efficient parameter than B and b when adjusting MID under the higher temperature. In addition, we discover that, for the same parameters, the region of MID in our system is larger than the result in mixed-spin (1/2, 1) system.

  4. Thermoluminescence induced by UV radiation in ZrO2-La2O3 and ZrO2-CeO2 mixed systems

    International Nuclear Information System (INIS)

    Estrada G, R.; Salas C, P.; Mendoza A, D.; Gonzalez, P.R.

    2002-01-01

    Nowadays, the development of catalytic materials by means of pure or mixed oxides mainly as TiO 2 , Al 2 O 3 , ZrO 2 , La 2 O 3 and CeO 2 used as support or active phases, are widely used in oxidation-reduction reactions in the chemical industry and in petroleum refining processes. the cerium and lanthanum oxides in zircon, have been studied recently in processes for reduction of pollutant gases (SO x , NO x , etc.). They result very interesting for resolving the problems of environmental pollution. Moreover, it has been observed that some of these materials are highly sensitive to ultraviolet radiation (UV), characteristic that can be took in advantage for detecting this type of radiation. In this work the preliminary obtained results on the thermoluminescent response (Tl) induced by the UV radiation in ZrO 2 -La 2 O 3 and ZrO 2 -CeO 2 mixed systems obtained by the sol-gel method are presented. The results show that the first system has a high sensitivity to UV radiation with a Tl curve composed by three peaks, two ones of greater intensity located in 70 and 140 Centigrade degrees. Likewise it was observed that for both materials, the peak located at low temperature is fadeout in few minutes after irradiation, while that the second one peak presented very good stability, resulting promising for dosimetric applications in UV radiation fields. (Author)

  5. Temperature dependence of He(2 3PJ) reactions: Collision-induced mixing and conversion to He2( 3Πg) molecules

    International Nuclear Information System (INIS)

    Zhao, X.; Soletsky, P.A.; Bryan, W.H.; Dunning, F.B.; Walters, G.K.

    1993-01-01

    The rate coefficients for mixing between He(2 3 P J, MJ) levels during collisions with ground-state helium atoms and for conversion of He(2 3 P J ) atoms to He 2 (b 3 Π g ) molecules via three-body reactions in helium gas have been investigated over the temperature range 1.6--300 K. The measured rate coefficients for collisionally induced P-state mixing decrease slowly with decreasing temperature, from (1.8±0.5)x10 -9 cm 3 s -1 at 300 K to (4.5±0.5)x10 -10 cm 3 s -1 at 4.2 K. The rate coefficients for the production of He 2 (b 3 Π g ) molecules via three-body reactions are observed to increase with decreasing temperature and are described by the relation k P congruent(2.5+267T -1 )x10 -32 cm 6 s -1 . This behavior, which is very different from that noted in earlier studies of the conversion of He(2 3 S 1 ) atoms to He 2 (a 3 Σ u + ) molecules through three-body reactions, suggests that the reaction is not thermally activated

  6. Direct observation of hematopoietic progenitor chimerism in fetal freemartin cattle

    Directory of Open Access Journals (Sweden)

    Taponen Juhani

    2007-11-01

    Full Text Available Abstract Background Cattle twins are well known as blood chimeras. However, chimerism in the actual hematopoietic progenitor compartment has not been directly investigated. Here, we analyzed fetal liver of chimeric freemartin cattle by combining a new anti-bovine CD34 antibody and Y-chromosome specific in situ hybridization. Results Bull-derived CD34+ cells were detected in the liver of the female sibling (freemartin at 60 days gestation. The level of bull-derived CD34+ cells was lower in the freemartin than in its male siblings. Bull (Y+ and cow hematopoietic cells often occurred in separate clusters. Around clusters of Y+CD34+ cells, Y+CD34- cells were typically observed. The thymi were also strongly chimeric at 60 days of gestation. Conclusion The fetal freemartin liver contains clusters of bull-derived hematopoietic progenitors, suggesting clonal expansion and differentiation. Even the roots of the hematopoietic system in cattle twins are thus strongly chimeric from the early stages of fetal development. However, the hematopoietic seeding of fetal liver apparently started already before the onset of functional vascular anastomosis.

  7. Hematopoietic defects in response to reduced Arhgap21

    Directory of Open Access Journals (Sweden)

    Juliana Xavier-Ferrucio

    2018-01-01

    Full Text Available Arhgap21 is a member of the Rho GTPase activating protein (RhoGAP family, which function as negative regulators of Rho GTPases. Arhgap21 has been implicated in adhesion and migration of cancer cells. However, the role of Arhgap21 has never been investigated in hematopoietic cells. Herein, we evaluated functional aspects of hematopoietic stem and progenitor cells (HSPC using a haploinsufficient (Arhgap21+/− mouse. Our results show that Arhgap21+/− mice have an increased frequency of phenotypic HSC, impaired ability to form progenitor colonies in vitro and decreased hematopoietic engraftment in vivo, along with a decrease in LSK cell frequency during serial bone marrow transplantation. Arhgap21+/− hematopoietic progenitor cells have impaired adhesion and enhanced mobilization of immature LSK and myeloid progenitors. Arhgap21+/− mice also exhibit reduced erythroid commitment and differentiation, which was recapitulated in human primary cells, in which knockdown of ARHGAP21 in CMP and MEP resulted in decreased erythroid commitment. Finally, we observed enhanced RhoC activity in the bone marrow cells of Arhgap21+/− mice, indicating that Arhgap21 functions in hematopoiesis may be at least partially mediated by RhoC inactivation. Keywords: Arhgap21, Hematopoiesis, Erythroid cells, Hematopoietic stem and progenitor cells, Fate decision

  8. Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment

    Science.gov (United States)

    Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Fahey, Frederic; Daley, George Q.

    2009-01-01

    Osteoblasts and endothelium constitute functional niches that support hematopoietic stem cells (HSC) in mammalian bone marrow (BM) 1,2,3 . Adult BM also contains adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. Fatty infiltration of hematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia 4. To explore whether adipocytes influence hematopoiesis or simply fill marrow space, we compared the hematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. By flow cytometry, colony forming activity, and competitive repopulation assay, HSCs and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 “fatless” mice, which are genetically incapable of forming adipocytes8, and in mice treated with the PPARγ inhibitor Bisphenol-A-DiGlycidyl-Ether (BADGE), which inhibits adipogenesis9, post-irradiation marrow engraftment is accelerated relative to wild type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone marrow microenvironment, and suggest that antagonizingmarrow adipogenesis may enhance hematopoietic recovery in clinical bone marrow transplantation. PMID:19516257

  9. DDA/TDB liposomes containing soluble Leishmania major antigens induced a mixed Th1/Th2 immune response in BALB/c mice

    Directory of Open Access Journals (Sweden)

    Mansure Hojatizade

    2017-04-01

    Full Text Available Objective(s: Leishmaniasis is a complex parasitic disease that represents a major public health problem. Despite numerous attempts over the past decades, yet there is no effective vaccine against human leishmaniasis probably due to the lack of suitable adjuvants. In this study, a first generation liposomal-based Leishmania vaccine was developed using soluble Leishmania major antigens (SLA and á, Ü-trehalose6, 6'-dibehenat (TDB as an immunostimulatory adjuvant. In this liposome structure, the cationic lipid Dimethyldioctadecylammonium (DDA provides intrinsic adjuvant activity and cholesterol was added as a membrane stabilizer. Liposomes containing SLA were prepared.Materials and Methods: BALB/c mice were subcutaneously (sc immunized with Lip (DDA/TDB/CHOL-SLA+, Lip (DDA/TDB-SLA+, Lip (DDA-SLA+, Lip (DDA/CHOL-SLA+, SLA or Tris-HCl buffer. Immunization was done every two weeks for three weeks. The immunized mice were then challenged sc in the left footpad with 1×106 stationary phase L. major promastigotes (50 ìl, at 2 weeks after last booster injection.Results: mice immunized with any of the liposomal formulations containing SLA (Lip-SLA+, substantially increased footpad swelling and parasite loads of foot and spleen with no significant difference compared to Tris-HCl buffer or SLA alone. Lip-SLA+ formulations induced a mixed Th1/Th2 immune response characterized by IFN-ã and IL-4 production as well as high levels of IgG1 anti-Leishmania antibody. Conclusion: immunization with liposomes containing DDA and/or TDB in combination with SLA induces a mixed Th1/Th2 immune response and is not an appropriate strategy for preferential induction of a Th1 response and protection against leishmaniasis.

  10. Experimental study on vapor explosion induced by pressure pulse in coarse mixing of hot molten metal and water

    International Nuclear Information System (INIS)

    Inoue, A.; Tobita, Y.; Aritomi, M.; Takahashi, M.; Matsuzaki, M.

    2004-01-01

    An experimental study was done to investigate characteristics of metal-water interaction, when a mount of hot liquid metal is injected into the water. The test section is a vertical shock tube of 60mm in inner diameter and 1200mm in length. A special injector which is designed to inject hot metal of controlled volume and flow rate is attached at the top of the tube. When the hot metal is injected in the water and comes down at a position of the test vessel, a trigger pressure pulse is generated at the bottom of the test tube. Local transient pressures along the tube are measured by piezo pressure transducers. The following items were investigated in the experiment; 1) The criteria to cause a vapor explosion, 2) Transient behaviors and propagation characteristics of pressure wave in the mixing region. 3) Effects of triggering pulse, injection temperature and mass of hot molten metal on the peak pressure. The probability of the vapor explosion jumped when the interface temperature at the molten metal-water direct contact is higher than the homogeneous nucleation temperature of water and the triggering pulse becomes larger than 0.9MPa. Two types of the pressure propagation modes are observed, one is the detonative mode with a sharp rise and other is usual pressure mode with a mild rise. (author)

  11. Gene expression profiling in the inductive human hematopoietic microenvironment

    International Nuclear Information System (INIS)

    Zhao Yongjun; Chen, Edwin; Li Liheng; Gong Baiwei; Xie Wei; Nanji, Shaherose; Dube, Ian D.; Hough, Margaret R.

    2004-01-01

    Human hematopoietic stem cells (HSCs) and their progenitors can be maintained in vitro in long-term bone marrow cultures (LTBMCs) in which constituent HSCs can persist within the adherent layers for up to 2 months. Media replenishment of LTBMCs has been shown to induce transition of HSCs from a quiescent state to an active cycling state. We hypothesize that the media replenishment of the LTBMCs leads to the activation of important regulatory genes uniquely involved in HSC proliferation and differentiation. To profile the gene expression changes associated with HSC activation, we performed suppression subtractive hybridization (SSH) on day 14 human LTBMCs following 1-h media replenishment and on unmanipulated controls. The generated SSH library contained 191 differentially up-regulated expressed sequence tags (ESTs), the majority corresponding to known genes related to various intracellular processes, including signal transduction pathways, protein synthesis, and cell cycle regulation. Nineteen ESTs represented previously undescribed sequences encoding proteins of unknown function. Differential up-regulation of representative genes, including IL-8, IL-1, putative cytokine 21/HC21, MAD3, and a novel EST was confirmed by semi-quantitative RT-PCR. Levels of fibronectin, G-CSF, and stem cell factor also increased in the conditioned media of LTBMCs as assessed by ELISA, indicating increased synthesis and secretion of these factors. Analysis of our library provides insights into some of the immediate early gene changes underlying the mechanisms by which the stromal elements within the LTBMCs contribute to the induction of HSC activation and provides the opportunity to identify as yet unrecognized factors regulating HSC activation in the LTBMC milieu

  12. Reduced Erg Dosage Impairs Survival of Hematopoietic Stem and Progenitor Cells.

    Science.gov (United States)

    Xie, Ying; Koch, Mia Lee; Zhang, Xin; Hamblen, Melanie J; Godinho, Frank J; Fujiwara, Yuko; Xie, Huafeng; Klusmann, Jan-Henning; Orkin, Stuart H; Li, Zhe

    2017-07-01

    ERG, an ETS family transcription factor frequently overexpressed in human leukemia, has been implicated as a key regulator of hematopoietic stem cells. However, how ERG controls normal hematopoiesis, particularly at the stem and progenitor cell level, and how it contributes to leukemogenesis remain incompletely understood. Using homologous recombination, we generated an Erg knockdown allele (Erg kd ) in which Erg expression can be conditionally restored by Cre recombinase. Erg kd/kd animals die at E10.5-E11.5 due to defects in endothelial and hematopoietic cells, but can be completely rescued by Tie2-Cre-mediated restoration of Erg in these cells. In Erg kd/+ mice, ∼40% reduction in Erg dosage perturbs both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin - Sca-1 + c-Kit + (LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we find that Erg-restored HSPCs outcompete Erg kd/+ HSPCs for contribution to adult hematopoiesis in vivo. This defect is in part due to increased apoptosis of HSPCs with reduced Erg dosage, a phenotype that becomes more drastic during 5-FU-induced stress hematopoiesis. Expression analysis reveals that reduced Erg expression leads to changes in expression of a subset of ERG target genes involved in regulating survival of HSPCs, including increased expression of a pro-apoptotic regulator Bcl2l11 (Bim) and reduced expression of Jun. Collectively, our data demonstrate that ERG controls survival of HSPCs, a property that may be used by leukemic cells. Stem Cells 2017;35:1773-1785. © 2017 AlphaMed Press.

  13. Angiotensin II Regulation of Proliferation, Differentiation, and Engraftment of Hematopoietic Stem Cells.

    Science.gov (United States)

    Kim, Seungbum; Zingler, Michael; Harrison, Jeffrey K; Scott, Edward W; Cogle, Christopher R; Luo, Defang; Raizada, Mohan K

    2016-03-01

    Emerging evidence indicates that differentiation and mobilization of hematopoietic cell are critical in the development and establishment of hypertension and hypertension-linked vascular pathophysiology. This, coupled with the intimate involvement of the hyperactive renin-angiotensin system in hypertension, led us to investigate the hypothesis that chronic angiotensin II (Ang II) infusion affects hematopoietic stem cell (HSC) regulation at the level of the bone marrow. Ang II infusion resulted in increases in hematopoietic stem/progenitor cells (83%) and long-term HSC (207%) in the bone marrow. Interestingly, increases of HSCs and long-term HSCs were more pronounced in the spleen (228% and 1117%, respectively). Furthermore, we observed higher expression of C-C chemokine receptor type 2 in these HSCs, indicating there was increased myeloid differentiation in Ang II-infused mice. This was associated with accumulation of C-C chemokine receptor type 2(+) proinflammatory monocytes in the spleen. In contrast, decreased engraftment efficiency of GFP(+) HSC was observed after Ang II infusion. Time-lapse in vivo imaging and in vitro Ang II pretreatment demonstrated that Ang II induces untimely proliferation and differentiation of the donor HSC resulting in diminished HSC engraftment and bone marrow reconstitution. We conclude that (1) chronic Ang II infusion regulates HSC proliferation, mediated by angiotensin receptor type 1a, (2) Ang II accelerates HSC to myeloid differentiation resulting in accumulation of C-C chemokine receptor type 2(+) HSCs and inflammatory monocytes in the spleen, and (3) Ang II impairs homing and reconstitution potentials of the donor HSCs. These observations highlight the important regulatory roles of Ang II on HSC proliferation, differentiation, and engraftment. © 2016 American Heart Association, Inc.

  14. Hematopoietic (stem) cell development — how divergent are the roads taken?

    NARCIS (Netherlands)

    M.-L. Kauts (Mari-Liis); C.S. Vink (Chris); E.A. Dzierzak (Elaine)

    2016-01-01

    textabstractThe development of the hematopoietic system during early embryonic stages occurs in spatially and temporally distinct waves. Hematopoietic stem cells (HSC), the most potent and self-renewing cells of this system, are produced in the final ‘definitive’ wave of hematopoietic cell

  15. Wall-cooling-induced mixed-convection flow recirculation in a vertical square-array multi-rod channel

    International Nuclear Information System (INIS)

    Luangdilok, W.; Todreas, N.E.

    1989-01-01

    This work investigated the structure of penetrative flow recirculation and associated flow conditions in a multi-rod channel induced by interassembly heat transfer that causes cooling through channel walls. Three investigation approaches, experimental, numerical, and analytical were employed in a complimentary fashion. Physical experiments involved water flow visualization and temperature measurement in a 4x4 rod square channel. Numerical experiments involved 3-dimensional simulations of water and sodium flow in a 2x2-rod channels. An approximate reverse flow model including Prandtl number effect was developed. A correlating equation based on the model and experiments was verified for water to correctly predict the trend of the 4x4-rod experimental penetration depth data. (orig.)

  16. Integrated analysis of hematopoietic differentiation outcomes and molecular characterization reveals unbiased differentiation capacity and minor transcriptional memory in HPC/HSC-iPSCs.

    Science.gov (United States)

    Gao, Shuai; Hou, Xinfeng; Jiang, Yonghua; Xu, Zijian; Cai, Tao; Chen, Jiajie; Chang, Gang

    2017-01-23

    Transcription factor-mediated reprogramming can reset the epigenetics of somatic cells into a pluripotency compatible state. Recent studies show that induced pluripotent stem cells (iPSCs) always inherit starting cell-specific characteristics, called epigenetic memory, which may be advantageous, as directed differentiation into specific cell types is still challenging; however, it also may be unpredictable when uncontrollable differentiation occurs. In consideration of biosafety in disease modeling and personalized medicine, the availability of high-quality iPSCs which lack a biased differentiation capacity and somatic memory could be indispensable. Herein, we evaluate the hematopoietic differentiation capacity and somatic memory state of hematopoietic progenitor and stem cell (HPC/HSC)-derived-iPSCs (HPC/HSC-iPSCs) using a previously established sequential reprogramming system. We found that HPC/HSCs are amenable to being reprogrammed into iPSCs with unbiased differentiation capacity to hematopoietic progenitors and mature hematopoietic cells. Genome-wide analyses revealed that no global epigenetic memory was detectable in HPC/HSC-iPSCs, but only a minor transcriptional memory of HPC/HSCs existed in a specific tetraploid complementation (4 N)-incompetent HPC/HSC-iPSC line. However, the observed minor transcriptional memory had no influence on the hematopoietic differentiation capacity, indicating the reprogramming of the HPC/HSCs was nearly complete. Further analysis revealed the correlation of minor transcriptional memory with the aberrant distribution of H3K27me3. This work provides a comprehensive framework for obtaining high-quality iPSCs from HPC/HSCs with unbiased hematopoietic differentiation capacity and minor transcriptional memory.

  17. The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice

    Directory of Open Access Journals (Sweden)

    Xiaoying Zhou

    2015-07-01

    Full Text Available Prior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modified mice. Here we used a genome-wide association study (GWAS strategy with the hybrid mouse diversity panel to identify the genetic determinants of hematopoietic stem/progenitor cell (HSPC frequency. Among 108 strains, we observed ∼120- to 300-fold variation in three HSPC populations. A GWAS analysis identified several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 harboring the homeodomain-only protein gene (Hopx. Hopx previously had been implicated in cardiac development but was not known to influence HSPC biology. Analysis of the HSPC pool in Hopx−/− mice demonstrated significantly reduced cell frequencies and impaired engraftment in competitive repopulation assays, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identify genetic determinants of the hematopoietic system.

  18. Neural Crossroads in the Hematopoietic Stem Cell Niche.

    Science.gov (United States)

    Agarwala, Sobhika; Tamplin, Owen J

    2018-05-29

    The hematopoietic stem cell (HSC) niche supports steady-state hematopoiesis and responds to changing needs during stress and disease. The nervous system is an important regulator of the niche, and its influence is established early in development when stem cells are specified. Most research has focused on direct innervation of the niche, however recent findings show there are different modes of neural control, including globally by the central nervous system (CNS) and hormone release, locally by neural crest-derived mesenchymal stem cells, and intrinsically by hematopoietic cells that express neural receptors and neurotransmitters. Dysregulation between neural and hematopoietic systems can contribute to disease, however new therapeutic opportunities may be found among neuroregulator drugs repurposed to support hematopoiesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  19. Proton MR spectroscopy of hyperplastic hematopoietic marrow in aplastic anemia

    Energy Technology Data Exchange (ETDEWEB)

    Amano, Yasuo; Kumazaki, Tatsuo [Nippon Medical School, Tokyo (Japan); Arai, Nobuyuki

    1997-04-01

    The purpose of this study was to compare the findings of magnetic resonance (MR) spectroscopy of hyperplastic hematopoietic marrow with those of normal bone marrow. Twenty-four samples of normal marrow from eight control subjects and 19 samples of hyperplastic marrow in aplastic anemia were examined with a 1.5 T MR unit. The former showed low intensity on opposed-phase T1-weighted images, while the latter showed high intensity on both fast STIR and opposed-phase T1-weighted images. MR spectroscopy quantitatively confirmed that the water; fat ratio was increased and the transverse relaxation time of water was changed in hyperplastic bone marrow, compared with normal bone marrow. In summary, MR imaging is able to detect hematopoietic regions among a wide range of bone marrow of aplastic anemia, while MR spectroscopy allowed us to quantitatively analyze the cell population of hyperplastic hematopoietic marrow in aplastic anemia. (author)

  20. Proton MR spectroscopy of hyperplastic hematopoietic marrow in aplastic anemia

    International Nuclear Information System (INIS)

    Amano, Yasuo; Kumazaki, Tatsuo; Arai, Nobuyuki.

    1997-01-01

    The purpose of this study was to compare the findings of magnetic resonance (MR) spectroscopy of hyperplastic hematopoietic marrow with those of normal bone marrow. Twenty-four samples of normal marrow from eight control subjects and 19 samples of hyperplastic marrow in aplastic anemia were examined with a 1.5 T MR unit. The former showed low intensity on opposed-phase T1-weighted images, while the latter showed high intensity on both fast STIR and opposed-phase T1-weighted images. MR spectroscopy quantitatively confirmed that the water; fat ratio was increased and the transverse relaxation time of water was changed in hyperplastic bone marrow, compared with normal bone marrow. In summary, MR imaging is able to detect hematopoietic regions among a wide range of bone marrow of aplastic anemia, while MR spectroscopy allowed us to quantitatively analyze the cell population of hyperplastic hematopoietic marrow in aplastic anemia. (author)

  1. Complications of hematopoietic stem transplantation: Fungal infections.

    Science.gov (United States)

    Omrani, Ali S; Almaghrabi, Reem S

    2017-12-01

    Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole. Copyright © 2017

  2. Plaquing procedure for infectious hematopoietic necrosis virus

    Science.gov (United States)

    Burke, J.A.; Mulcahy, D.

    1980-01-01

    A single overlay plaque assay was designed and evaluated for infectious hematopoietic necrosis virus. Epithelioma papillosum carpio cells were grown in normal atmosphere with tris(hydroxymethyl)aminomethane- or HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid)-buffered media. Plaques were larger and formed more quickly on 1- to 3-day-old cell monolayers than on older monolayers. Cell culture medium with a 10% addition of fetal calf serum (MEM 10) or without serum (MEM 0) were the most efficient virus diluents. Dilution with phosphate-buffered saline, saline, normal broth, or deionized water reduced plaque numbers. Variations in the pH (7.0 to 8.0) of a MEM 0 diluent did not affect plaque numbers. Increasing the volume of viral inoculum above 0.15 ml (15- by 60-mm plate) decreased plaquing efficiency. Significantly more plaques occurred under gum tragacanth and methylcellulose than under agar or agarose overlays. Varying the pH (6.8 to 7.4) of methylcellulose overlays did not significantly change plaque numbers. More plaques formed under the thicker overlays of both methylcellulose and gum tragacanth. Tris(hydroxymethyl)aminomethane and HEPES performed equally well, buffering either medium or overlay. Plaque numbers were reduced when cells were rinsed after virus adsorption or less than 1 h was allowed for adsorption. Variation in adsorption time between 60 and 180 min did not change plaque numbers. The mean plaque formation time was 7 days at 16 degrees C. The viral dose response was linear when the standardized assay was used.

  3. Strength Training Following Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Hacker, Eileen Danaher; Larson, Janet; Kujath, Amber; Peace, David; Rondelli, Damiano; Gaston, Lisa

    2010-01-01

    Background Patients receiving high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT) experience considerable reductions in physical activity and deterioration of their health status. Objective The purpose of this pilot study was to test the effects of strength training compared to usual activity on physical activity, muscle strength, fatigue, health status perceptions, and quality of life following HSCT. Interventions/Methods Nineteen subjects were randomized to the exercise or control group. Moderate intensity strength training began following discharge from the hospital. Dependent variables included physical activity, muscle strength, fatigue, health status perceptions and quality of life. Variables were measured prior to admission to the hospital for HSCT, day 8 following HSCT, and six weeks following discharge from the hospital. Results Significant time effects were noted for many variables with anticipated declines in physical activity, muscle strength, fatigue, and health status perceptions immediately after HSCT with subsequent improvements six weeks following hospital discharge. One group effect was noted with subjects in the exercise group reporting less fatigue than subjects in the control group. Although no significant interactions were detected, the trends suggest that the exercise group may be more physically active following the intervention compared to the usual activity group. Conclusions This study demonstrates the potential positive effects of strength training on physical activity, fatigue, and quality of life in people receiving high-dose chemotherapy and HSCT. Implications for Practice Preliminary evidence is provided for using strength training to enhance early recovery following HSCT. Elastic resistance bands are easy to use and relatively inexpensive. PMID:21116175

  4. Sneutrino mixing

    International Nuclear Information System (INIS)

    Grossman, Y.

    1997-10-01

    In supersymmetric models with nonvanishing Majorana neutrino masses, the sneutrino and antisneutrino mix. The conditions under which this mixing is experimentally observable are studied, and mass-splitting of the sneutrino mass eigenstates and sneutrino oscillation phenomena are analyzed

  5. Sonic Hedgehog Signaling Regulates Hematopoietic Stem/Progenitor Cell Activation during the Granulopoietic Response to Systemic Bacterial Infection.

    Science.gov (United States)

    Shi, Xin; Wei, Shengcai; Simms, Kevin J; Cumpston, Devan N; Ewing, Thomas J; Zhang, Ping

    2018-01-01

    Activation and reprogramming of hematopoietic stem/progenitor cells play a critical role in the granulopoietic response to bacterial infection. Our current study determined the significance of Sonic hedgehog (SHH) signaling in the regulation of hematopoietic precursor cell activity during the host defense response to systemic bacterial infection. Bacteremia was induced in male Balb/c mice via intravenous injection (i.v.) of Escherichia coli (5 × 10 7 CFUs/mouse). Control mice received i.v. saline. SHH protein level in bone marrow cell (BMC) lysates was markedly increased at both 24 and 48 h of bacteremia. By contrast, the amount of soluble SHH ligand in marrow elutes was significantly reduced. These contrasting alterations suggested that SHH ligand release from BMCs was reduced and/or binding of soluble SHH ligand to BMCs was enhanced. At both 12 and 24 h of bacteremia, SHH mRNA expression by BMCs was significantly upregulated. This upregulation of SHH mRNA expression was followed by a marked increase in SHH protein expression in BMCs. Activation of the ERK1/2-SP1 pathway was involved in mediating the upregulation of SHH gene expression. The major cell type showing the enhancement of SHH expression in the bone marrow was lineage positive cells. Gli1 positioned downstream of the SHH receptor activation serves as a key component of the hedgehog (HH) pathway. Primitive hematopoietic precursor cells exhibited the highest level of baseline Gli1 expression, suggesting that they were active cells responding to SHH ligand stimulation. Along with the increased expression of SHH in the bone marrow, expression of Gli1 by marrow cells was significantly upregulated at both mRNA and protein levels following bacteremia. This enhancement of Gli1 expression was correlated with activation of hematopoietic stem/progenitor cell proliferation. Mice with Gli1 gene deletion showed attenuation in activation of marrow hematopoietic stem/progenitor cell proliferation and inhibition

  6. Induction of various immune modulatory molecules in CD34(+) hematopoietic cells

    DEFF Research Database (Denmark)

    Umland, Oliver; Heine, Holger; Miehe, Michaela

    2004-01-01

    revealed that T cell proliferation can be induced by TNF-alpha-stimulated KG-1a cells, which is preventable by blocking anti-ICAM-1 monoclonal antibodies. Our results demonstrate that CD34(+) HCs have the potential to express a variety of immune-regulatory mediators upon stimulation by inflammatory......Lipopolysaccharide (LPS) has been shown to induce proliferation of human T-lymphocytes only in the presence of monocytes and CD34(+) hematopoietic cells (HCs) from peripheral blood. This finding provided evidence of an active role of CD34(+) HCs during inflammation and immunological events....... To investigate mechanisms by which CD34(+) HCs become activated and exert their immune-modulatory function, we used the human CD34(+) acute myeloid leukemia cell line KG-1a and CD34(+) bone marrow cells (BMCs). We showed that culture supernatants of LPS-stimulated mononuclear cells (SUP(LPS)) as well as tumor...

  7. Hematopoietic Gene Therapies for Metabolic and Neurologic Diseases.

    Science.gov (United States)

    Biffi, Alessandra

    2017-10-01

    Increasingly, patients affected by metabolic diseases affecting the central nervous system and neuroinflammatory disorders receive hematopoietic cell transplantation (HCT) in the attempt to slow the course of their disease, delay or attenuate symptoms, and improve pathologic findings. The possible replacement of brain-resident myeloid cells by the transplanted cell progeny contributes to clinical benefit. Genetic engineering of the cells to be transplanted (hematopoietic stem cell) may endow the brain myeloid progeny of these cells with enhanced or novel functions, contributing to therapeutic effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Analysis of the hematopoietic tissue in Pleurodeles waltl newts exposed to 2 g hypergravity

    Science.gov (United States)

    Domaratskaya, Elena; Nikonova, Tatyana M.; Grigoryan, Eleonora N.; Dvorochkin, Natalya; Yousuf, Rukhsana; Almeida, Eduardo; Butorina, Nina N.

    2012-07-01

    Gravity is an important factor in creating biologically-relevant mechanical loads, and in spaceflight living organisms encounter both microgravity as well as hypergravity conditions. Here we studied the influence of hypergravity on the hematopoietic tissue of P. waltl newts in parallel with tissue regeneration experiments of the newt lens and tail. At day 9 post-surgery one group of newts was subjected to centrifugation at 2 g (2G, 12 days), while another was kept at 1 g. In addition, a basal control in wet mats, at 1g, (BC, 1G), and an aquarium control, neutrally buoyant, (AC, low G), were also performed. Differential blood counts and histological analysis of the spleen and liver were carried out in experimental and control groups of animals. At day 21 post-surgery in all groups (AC, 1G, and 2G), the number of neutrophils in the blood was significantly lower than in BC indicating a decrease in the inflammation induced by surgery. The 2G group however, showed numbers of neutrophils significantly higher than AC (neutrally buoyant) animals. This result suggests that post-operative inflammation can persist longer at 2 g that under unloaded aquarium conditions. In contrast we did not observe any significant differences in lymphocyte numbers between any experimental and control groups. Histological examination of the liver and spleen also did not show any significant morphological alterations due to hypergravity. These results indicate that 12 day exposure to hypergravity at 2 g, had only partial influence on newt hematopoiesis, possibly extending the duration of surgery-related inflammatory responses. Data obtained with newts in our previous experiments on Foton-M2 and Foton-M3 flights in microgravity also showed only slight effect on blood cells. Furthermore microgravity also did not cause any morphological changes in the hematopoietic and lymphoid tissues, and did not impair the proliferative capacity of newt hematopoietic cells. In sum these results indicate the

  9. 28Si total body irradiation injures bone marrow hematopoietic stem cells via induction of cellular apoptosis

    Science.gov (United States)

    Chang, Jianhui; Feng, Wei; Wang, Yingying; Allen, Antiño R.; Turner, Jennifer; Stewart, Blair; Raber, Jacob; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian

    2017-05-01

    Long-term space mission exposes astronauts to a radiation environment with potential health hazards. High-energy charged particles (HZE), including 28Si nuclei in space, have deleterious effects on cells due to their characteristics with high linear energy transfer and dense ionization. The influence of 28Si ions contributes more than 10% to the radiation dose equivalent in the space environment. Understanding the biological effects of 28Si irradiation is important to assess the potential health hazards of long-term space missions. The hematopoietic system is highly sensitive to radiation injury and bone marrow (BM) suppression is the primary life-threatening injuries after exposure to a moderate dose of radiation. Therefore, in the present study we investigated the acute effects of low doses of 28Si irradiation on the hematopoietic system in a mouse model. Specifically, 6-month-old C57BL/6 J mice were exposed to 0.3, 0.6 and 0.9 Gy 28Si (600 MeV) total body irradiation (TBI). The effects of 28Si TBI on BM hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were examined four weeks after the exposure. The results showed that exposure to 28Si TBI dramatically reduced the frequencies and numbers of HSCs in irradiated mice, compared to non-irradiated controls, in a radiation dose-dependent manner. In contrast, no significant changes were observed in BM HPCs regardless of radiation doses. Furthermore, irradiated HSCs exhibited a significant impairment in clonogenic ability. These acute effects of 28Si irradiation on HSCs may be attributable to radiation-induced apoptosis of HSCs, because HSCs, but not HPCs, from irradiated mice exhibited a significant increase in apoptosis in a radiation dose-dependent manner. However, exposure to low doses of 28Si did not result in an increased production of reactive oxygen species and DNA damage in HSCs and HPCs. These findings indicate that exposure to 28Si irradiation leads to acute HSC damage.

  10. Mechanistic Investigation on Grinding-Induced Subvisible Particle Formation during Mixing and Filling of Monoclonal Antibody Formulations.

    Science.gov (United States)

    Gikanga, Benson; Hui, Ada; Maa, Yuh-Fun

    2018-01-01

    Processing equipment involving grinding of two solid surfaces has been demonstrated to induce subvisible particle formation in monoclonal antibody drug product manufacturing processes. This study elucidated potential stress types associated with grinding action to identify the stress mechanism responsible for subvisible particle formation. Several potential stress types can be associated with the grinding action, including interfacial stresses (air-liquid and liquid-solid), hydraulic/mechanical shear stress, cavitation, nucleation of stressed protein molecules, and localized thermal stress. More than one stress type can synergically affect monoclonal antibody product quality, making it challenging to determine the primary mode of stress. Our strategy was to assess and rule out some stress types through platform knowledge, rational judgments, or via small-scale models, for example, rheometer/rotator-stator homogenizer for hydraulic/mechanical shear stress, sonicator for cavitation, etc. These models may not provide direct evidence but can offer rational correlations. Cavitation, as demonstrated by sonication, proved to be quite detrimental to monoclonal antibody molecules in forming not just subvisible particles but also soluble high-molecular-weight species as well as low-molecular-weight species. This outcome was not consistent with that of grinding monoclonal antibodies between the impeller and the drive unit of a bottom-mounted mixer or between the piston and the housing of a rotary piston pump, both of which formed only subvisible particles without obvious high-molecular-weight species and low-molecular-weight species. In addition, a p -nitrophenol model suggested that cavitation in the bottom-mounted mixer is barely detectable. We attributed the grinding-induced, localized thermal effect to be the primary stress to subvisible particle formation based on a high-temperature, spray-drying model. The heat effect of spray drying also caused subvisible particles, in

  11. Identification of the homing molecules that escort pluripotent stem cells-derived hematopoietic stem cells to their niches and human activated T-cells to inflammatory sites.

    KAUST Repository

    Ali, Amal

    2017-12-01

    Hematopoietic cells exploit the multistep paradigm of cell migration to ultimately enable them to perform their function. This process is dictated by the ability of adhesion molecules on the circulating hematopoietic cells to find their counter-receptors on endothelial cells. Of those molecules, the selectin family and their respective ligands induce the initial transient interactions between circulating cells and the opposing endothelium. In this thesis, I focused on studying E-selectin mediated cellular migration in two hematopoietic cell types, namely human hematopoietic stem and progenitor cells (HSPCs) and human T-lymphocytes. HSPCs derived from pluripotent sources theoretically offers a novel, unlimited source for hematopoietic stem cell transplantation therapy. In vitro pluripotent stem cell derived- hematopoietic stem/progenitor cells (ES/iPS-HSPCs) behave much like somatic HSPCs in that they exhibit clonal expansion and multilineage hematopoietic capacity. However, unlike somatic sources, ES/iPS-HSPCs do not give rise to effective hematopoietic repopulation, which may be due to insufficient HSPCs homing to the bone marrow. HSPCs exploit E- and P-selectin to home and engraft into bone marrow niches. Thus, one of my objectives in this thesis was to study the expression of E-selectin ligands associated with ES/iPS-HSPCs. I showed that ES/iPS-HSPCs lack functional E-selectin ligand(s). In an effort to enhance the interaction between Eselectin and ES/iPS-HSPCs, we decorated the cell surface with sialyl-Lewis x (sLex) using the ex-vivo glycan engineering technology. However, this decoration did not improve the engraftment capacity of ES/iPS-HSPCs, in vivo. Induction of E-selectin expression during inflammation is key to recruitment of immune cells and therefore I also focused on analyzing the expression of E-selectin ligands on activated human T-cells. I identified several novel glycoproteins that may function as E-selectin ligands. Specifically, I compared the

  12. Direct evaluation of radiation damage in human hematopoietic progenitor cells in vivo

    International Nuclear Information System (INIS)

    Kyoizumi, Seishi; McCune, J.M.; Namikawa, Reiko

    1994-01-01

    We have developed techniques by which normal functional elements of human bone marrow can be implanted into immunodeficient C.B-17 scid/scid (SCID) mice. Afterward, long-term multilineage human hematopoiesis is sustained in vivo. We evaluated the effect of irradiation on the function of human bone marrow with this in vivo model. After whole-body X irradiation of the engrafted animals, it was determined that the D 0 value of human committed progenitor cells within the human marrow was 1.00 ± 0.09 (SEM) Gy for granulocyte-macrophage colony-forming units (CFU-GM) and 0.74 ± 0.12 Gy for erythroidburst-forming units (BFU-E). The effects of irradiation on the hematopoietic elements were reduced when the radioprotective agent WR-2721 was administered prior to irradiation. After low-dose irradiation, recovery of human granulocyte colony-stimulating factor (G-CSF). This small animal model may prove amenable for the analysis of the risk of the exposure of humans to irradiation as well as for the development of new modalities for the prevention and treatment of radiation-induced hematopoietic damage. 41 refs., 5 figs., 1 tab

  13. Transmembrane Inhibitor of RICTOR/mTORC2 in Hematopoietic Progenitors

    Directory of Open Access Journals (Sweden)

    Dongjun Lee

    2014-11-01

    Full Text Available Central to cellular proliferative, survival, and metabolic responses is the serine/threonine kinase mTOR, which is activated in many human cancers. mTOR is present in distinct complexes that are either modulated by AKT (mTORC1 or are upstream and regulatory of it (mTORC2. Governance of mTORC2 activity is poorly understood. Here, we report a transmembrane molecule in hematopoietic progenitor cells that physically interacts with and inhibits RICTOR, an essential component of mTORC2. Upstream of mTORC2 (UT2 negatively regulates mTORC2 enzymatic activity, reducing AKTS473, PKCα, and NDRG1 phosphorylation and increasing FOXO transcriptional activity in an mTORC2-dependent manner. Modulating UT2 levels altered animal survival in a T cell acute lymphoid leukemia (T-ALL model that is known to be mTORC2 sensitive. These studies identify an inhibitory component upstream of mTORC2 in hematopoietic cells that can reduce mortality from NOTCH-induced T-ALL. A transmembrane inhibitor of mTORC2 may provide an attractive target to affect this critical cell regulatory pathway.

  14. Polycomb repressive complex 2 (PRC2 restricts hematopoietic stem cell activity.

    Directory of Open Access Journals (Sweden)

    Ian J Majewski

    2008-04-01

    Full Text Available Polycomb group proteins are transcriptional repressors that play a central role in the establishment and maintenance of gene expression patterns during development. Using mice with an N-ethyl-N-nitrosourea (ENU-induced mutation in Suppressor of Zeste 12 (Suz12, a core component of Polycomb Repressive Complex 2 (PRC2, we show here that loss of Suz12 function enhances hematopoietic stem cell (HSC activity. In addition to these effects on a wild-type genetic background, mutations in Suz12 are sufficient to ameliorate the stem cell defect and thrombocytopenia present in mice that lack the thrombopoietin receptor (c-Mpl. To investigate the molecular targets of the PRC2 complex in the HSC compartment, we examined changes in global patterns of gene expression in cells deficient in Suz12. We identified a distinct set of genes that are regulated by Suz12 in hematopoietic cells, including eight genes that appear to be highly responsive to PRC2 function within this compartment. These data suggest that PRC2 is required to maintain a specific gene expression pattern in hematopoiesis that is indispensable to normal stem cell function.

  15. CRISPR/Cas9 system and its applications in human hematopoietic cells.

    Science.gov (United States)

    Hu, Xiaotang

    2016-11-01

    Since 2012, the CRISPR-Cas9 system has been quickly and successfully tested in a broad range of organisms and cells including hematopoietic cells. The application of CRISPR-Cas9 in human hematopoietic cells mainly involves the genes responsible for HIV infection, β-thalassemia and sickle cell disease (SCD). The successful disruption of CCR5 and CXCR4 genes in T cells by CRISPR-Cas9 promotes the prospect of the technology in the functional cure of HIV. More recently, eliminating CCR5 and CXCR4 in induced pluripotent stem cells (iPSCs) derived from patients and targeting the HIV genome have been successfully carried out in several laboratories. The outcome from these approaches bring us closer to the goal of eradicating HIV infection. For hemoglobinopathies the ability to produce iPSC-derived from patients with the correction of hemoglobin (HBB) mutations by CRISPR-Cas9 has been tested in a number of laboratories. These corrected iPSCs also show the potential to differentiate into mature erythrocytes expressing high-level and normal HBB. In light of the initial success of CRESPR-Cas9 in target mutated gene(s) in the iPSCs, a combination of genomic editing and autogenetic stem cell transplantation would be the best strategy for root treatment of the diseases, which could replace traditional allogeneic stem cell transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Protective effects of HemoHIM on immune and hematopoietic systems against γ-irradiation.

    Science.gov (United States)

    Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee; Yee, Sung-Tae; Kim, Sung-Ho

    2014-02-01

    We examined the effect of HemoHIM on the protective efficacy of hematopoietic stem cells and on the recovery of immune cells against sublethal doses of ionizing radiation. Two-month-old mice were exposed to γ-rays at a dose of 8, 6.5, or 5 Gy for a30-day survival study, endogenous spleen colony formation, or other experiments, respectively. HemoHIM was injected intraperitoneally before and after irradiation. Our results showed that HemoHIM significantly decreased the mortality of sublethally irradiated mice. The HemoHIM administration decreased the apoptosis of bone marrow cells in irradiated mice. On the other hand, HemoHIM increased the formation of endogenous spleen colony in irradiated mice. In irradiated mice, the recovery of total leukocytes in the peripheral blood and lymphocytes in the spleen were enhanced significantly by HemoHIM. Moreover, the function of B cells, T cells, and NK cells regenerated in irradiated mice were significantly improved by the administration of HemoHIM. HemoHIM showed an ideal radioprotector for protecting hematopoietic stem cells and for accelerating the recovery of immune cells. We propose HemoHIM as a beneficial supplement drug during radiotherapy to alleviate adverse radiation-induced effects for cancer patients. Copyright © 2013 John Wiley & Sons, Ltd.

  17. Tfe3 expression is closely associated to macrophage terminal differentiation of human hematopoietic myeloid precursors

    International Nuclear Information System (INIS)

    Zanocco-Marani, Tommaso; Vignudelli, Tatiana; Gemelli, Claudia; Pirondi, Sara; Testa, Anna; Montanari, Monica; Parenti, Sandra; Tenedini, Elena; Grande, Alexis; Ferrari, Sergio

    2006-01-01

    The MItf-Tfe family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors encodes four family members: MItf, Tfe3, TfeB and TfeC. In vitro, each protein of the family binds DNA in a homo- or heterodimeric form with other family members. Tfe3 is involved in chromosomal translocations recurrent in different tumors and it has been demonstrated, by in vivo studies, that it plays, redundantly with MItf, an important role in the process of osteoclast formation, in particular during the transition from mono-nucleated to multi-nucleated osteoclasts. Since mono-nucleated osteoclasts derive from macrophages we investigated whether Tfe3 might play a role upstream during hematopoietic differentiation. Here we show that Tfe3 is able to induce mono-macrophagic differentiation of U937 cells, in association with a decrease of cell proliferation and an increase of apoptosis. We also show that Tfe3 does not act physiologically during commitment of CD34+ hematopoietic stem cells (HSCs), since it is not able to direct HSCs toward a specific lineage as observed by clonogenic assay, but is a strong actor of terminal differentiation since it allows human primary myeloblasts' maturation toward the macrophage lineage

  18. The hematopoietic transcription factor PU.1 regulates RANK gene expression in myeloid progenitors

    International Nuclear Information System (INIS)

    Kwon, Oh Hyung; Lee, Chong-Kil; Lee, Young Ik; Paik, Sang-Gi; Lee, Hyun-Jun

    2005-01-01

    Osteoclasts are bone resorbing cells of hematopoietic origin. The hematopoietic transcription factor PU.1 is critical for osteoclastogenesis; however, the molecular mechanisms of PU.1-regulated osteoclastogenesis have not been explored. Here, we present evidence that the receptor activator of nuclear factor κB (RANK) gene that has been shown to be crucial for osteoclastogenesis is a transcriptional target of PU.1. The PU.1 -/- progenitor cells failed to express the RANK gene and reconstitution of PU.1 in these cells induced RANK expression. Treatment of the PU.1 reconstituted cells with M-CSF and RANKL further augmented the RANK gene expression. To explore the regulatory mechanism of the RANK gene expression by PU.1, we have cloned the human RANK promoter. Transient transfection assays have revealed that the 2.2-kb RANK promoter was functional in a monocyte line RAW264.7, whereas co-transfection of PU.1 transactivated the RANK promoter in HeLa cells. Taken together, these results suggest that PU.1 regulates the RANK gene transcription and this may represent one of the key roles of PU.1 in osteoclast differentiation

  19. Auto-mobilized adult hematopoietic stem cells advance neovasculature in diabetic retinopathy of mice

    Institute of Scientific and Technical Information of China (English)

    TIAN Bei; LI Xiao-xin; SHEN Li; ZHAO Min; YU Wen-zhen

    2010-01-01

    Background Hematopoietic stem cells (HSCs) can be used to deliver functionally active angiostatic molecules to the retinal vasculature by targeting active astrocytes and may be useful in targeting pre-angiogenic retinal lesions. We sought to determine whether HSC mobilization can ameliorate early diabetic retinopathy in mice.Methods Mice were devided into four groups: normal mice control group, normal mice HSC-mobilized group, diabetic mice control group and diabetic mice HSC mobilized group. Murine stem cell growth factor (murine SCF) and recombined human granulocyte colony stimulating factor (rhG-csf) were administered to the mice with diabetes and without diabetes for continuous 5 days to induce autologous HSCs mobilization, and subcutaneous injection of physiological saline was used as control. Immunohistochemical double staining was conducted with anti-mouse rat CD31 monoclonal antibody and anti-BrdU rat antibody.Results Marked HSCs clearly increased after SCF plus G-csf-mobilization. Non-mobilized diabetic mice showed more HSCs than normal mice (P=0.032), and peripheral blood significantly increased in both diabetic and normal mice (P=0.000).Diabetic mice showed more CD31 positive capillary vessels (P=0.000) and accelerated endothelial cell regeneration. Only diabetic HSC-mobilized mice expressed both BrdU and CD31 antigens in the endothelial cells of new capillaries.Conclusion Auto-mobilized adult hematopoietic stem cells advance neovasculature in diabetic retinopathy of mice.

  20. SCA-1 Expression Level Identifies Quiescent Hematopoietic Stem and Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Mina N.F. Morcos

    2017-06-01

    Full Text Available Blood cell generation depends on continuous cellular output by the sequential hierarchy of hematopoietic stem cell (HSC and progenitor populations that all contain quiescent and actively cycling cells. Hematopoietic stem and progenitor cells (HSPCs express the surface molecule Stem cell antigen 1 (SCA-1/LY6A. Using histone 2B-red fluorescent fusion protein label retention and cell-cycle reporter mice, we demonstrate that high SCA-1 expression (SCA-1hi identifies not only quiescent HSCs but quiescent cells on all hierarchical levels within the lineage−SCA-1+KIT+ (LSK population. Each transplanted SCA-1hi HSPC population also displayed self-renewal potential superior to that of the respective SCA-1lo population. SCA-1 expression is inducible by type I interferon (IFN. We show, however, that quiescence and high self-renewal capacity of cells with brighter SCA-1 expression at steady state were independent of type I IFN signaling. We conclude that SCA-1 expression levels can be used to prospectively isolate functionally heterogeneous HSPC subpopulations.

  1. ROBO4-Mediated Vascular Integrity Regulates the Directionality of Hematopoietic Stem Cell Trafficking

    Directory of Open Access Journals (Sweden)

    Stephanie Smith-Berdan

    2015-02-01

    Full Text Available Despite the use of hematopoietic stem cells (HSCs in clinical therapy for over half a century, the mechanisms that regulate HSC trafficking, engraftment, and life-long persistence after transplantation are unclear. Here, we show that the vascular endothelium regulates HSC trafficking into and out of bone marrow (BM niches. Surprisingly, we found that instead of acting as barriers to cellular entry, vascular endothelial cells, via the guidance molecule ROBO4, actively promote HSC translocation across vessel walls into the BM space. In contrast, we found that the vasculature inhibits the reverse process, as induced vascular permeability led to a rapid increase in HSCs in the blood stream. Thus, the vascular endothelium reinforces HSC localization to BM niches both by promoting HSC extravasation from blood-to-BM and by forming vascular barriers that prevent BM-to-blood escape. Our results uncouple the mechanisms that regulate the directionality of HSC trafficking and show that the vasculature can be targeted to improve hematopoietic transplantation therapies.

  2. MYSM1 Is Essential for Maintaining Hematopoietic Stem Cell (HSC) Quiescence and Survival.

    Science.gov (United States)

    Huo, Yi; Li, Bing-Yi; Lin, Zhi-Feng; Wang, Wei; Jiang, Xiao-Xia; Chen, Xu; Xi, Wen-Jin; Yang, An-Gang; Chen, Si-Yi; Wang, Tao

    2018-04-25

    BACKGROUND Histone H2A deubiquitinase MYSM1 has recently been shown to be essential for hematopoiesis and hematopoietic stem cell (HSC) function in both mice and humans. However, conventional MYSM1 knockouts cause partial embryonic lethality and growth retardation, and it is difficult to convincingly remove the effects of environmental factors on HSC differentiation and function. MATERIAL AND METHODS MYSM1 conditional knockout (cKO) mice were efficiently induced by using the Vav1-cre transgenic system. The Vav-Cre MYSM1 cKO mice were then analyzed to verify the intrinsic role of MYSM1 in hematopoietic cells. RESULTS MYSM1 cKO mice were viable and were born at normal litter sizes. At steady state, we observed a defect in hematopoiesis, including reduced bone marrow cellularity and abnormal HSC function. MYSM1 deletion drives HSCs from quiescence into rapid cycling, and MYSM1-deficient HSCs display impaired engraftment. In particular, the immature cycling cKO HSCs have elevated reactive oxygen species (ROS) levels and are prone to apoptosis, resulting in the exhaustion of the stem cell pool during stress response to 5-FU. CONCLUSIONS Our study using MYSM1 cKO mice confirms the important role of MYSM1 in maintaining HSC quiescence and survival.

  3. In utero hematopoietic stem cell transfer: current status and future strategies.

    Science.gov (United States)

    Surbek, D V; Gratwohl, A; Holzgreve, W

    1999-07-01

    Successful prenatal treatment of severe immunodeficiencies by allogeneic hematopoietic stem cell transplantation in utero has been reported. Though other diseases like hemoglobinopathies or storage diseases are potentially amenable to this novel therapeutic approach, no success has yet been achieved in recipients without severe immunodeficiency. Graft rejection by the developing fetus and/or lack of selective, competitive advantage of donor versus host stem cells preventing stable engraftment seem to be the major obstacles. Several strategies to overcome these hurdles are being explored in preclinical settings, including timing and repeated dosing of stem cell administration to the fetus, ex vivo modification of the transplant, using different fetal compartments as targets for early stem cell transfer, or inducing microchimerism for postnatal transplantation from the same donor. In addition, the exact definition of the basic concept of early fetal immunologic naivete and the understanding of the molecular basics of migration and homing in fetal hematopoiesis system seem mandatory for a successful approach. Gene therapy using ex vivo transduced autologous cord blood cells or direct gene targeting in utero are other potential means to correct hematopoietic and immunologic single gene disorders in utero, though this approach is still away from the stage of clinical trials.

  4. The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.

    Science.gov (United States)

    Singbrant, Sofie; Wall, Meaghan; Moody, Jennifer; Karlsson, Göran; Chalk, Alistair M; Liddicoat, Brian; Russell, Megan R; Walkley, Carl R; Karlsson, Stefan

    2014-04-01

    The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.

  5. Impact of environmentally induced fluctuations on quantum mechanically mixed electronic and vibrational pigment states in photosynthetic energy transfer and 2D electronic spectra

    Energy Technology Data Exchange (ETDEWEB)

    Fujihashi, Yuta; Ishizaki, Akihito, E-mail: ishizaki@ims.ac.jp [Institute for Molecular Science, National Institutes of Natural Sciences, Okazaki 444-8585 (Japan); Fleming, Graham R. [Department of Chemistry, University of California, Berkeley and Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 (United States)

    2015-06-07

    Recently, nuclear vibrational contribution signatures in two-dimensional (2D) electronic spectroscopy have attracted considerable interest, in particular as regards interpretation of the oscillatory transients observed in light-harvesting complexes. These transients have dephasing times that persist for much longer than theoretically predicted electronic coherence lifetime. As a plausible explanation for this long-lived spectral beating in 2D electronic spectra, quantum-mechanically mixed electronic and vibrational states (vibronic excitons) were proposed by Christensson et al. [J. Phys. Chem. B 116, 7449 (2012)] and have since been explored. In this work, we address a dimer which produces little beating of electronic origin in the absence of vibronic contributions, and examine the impact of protein-induced fluctuations upon electronic-vibrational quantum mixtures by calculating the electronic energy transfer dynamics and 2D electronic spectra in a numerically accurate manner. It is found that, at cryogenic temperatures, the electronic-vibrational quantum mixtures are rather robust, even under the influence of the fluctuations and despite the small Huang-Rhys factors of the Franck-Condon active vibrational modes. This results in long-lasting beating behavior of vibrational origin in the 2D electronic spectra. At physiological temperatures, however, the fluctuations eradicate the mixing, and hence, the beating in the 2D spectra disappears. Further, it is demonstrated that such electronic-vibrational quantum mixtures do not necessarily play a significant role in electronic energy transfer dynamics, despite contributing to the enhancement of long-lived quantum beating in 2D electronic spectra, contrary to speculations in recent publications.

  6. Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors

    Science.gov (United States)

    Kermani, Pouneh; Rafii, Dahlia; Jin, David K.; Whitlock, Paul; Schaffer, Wendy; Chiang, Anne; Vincent, Loic; Friedrich, Matthias; Shido, Koji; Hackett, Neil R.; Crystal, Ronald G.; Rafii, Shahin; Hempstead, Barbara L.

    2005-01-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) is required for the maintenance of cardiac vessel wall stability during embryonic development through direct angiogenic actions on endothelial cells expressing the tropomysin receptor kinase B (TrkB). However, the role of BDNF and a related neurotrophin ligand, neurotrophin-4 (NT-4), in the regulation of revascularization of the adult tissues is unknown. To study the potential angiogenic capacity of BDNF in mediating the neovascularization of ischemic and non-ischemic adult mouse tissues, we utilized a hindlimb ischemia and a subcutaneous Matrigel model. Recruitment of endothelial cells and promotion of channel formation within the Matrigel plug by BDNF and NT-4 was comparable to that induced by VEGF-A. The introduction of BDNF into non-ischemic ears or ischemic limbs induced neoangiogenesis, with a 2-fold increase in the capillary density. Remarkably, treatment with BDNF progressively increased blood flow in the ischemic limb over 21 days, similar to treatment with VEGF-A. The mechanism by which BDNF enhances capillary formation is mediated in part through local activation of the TrkB receptor and also by recruitment of Sca-1+CD11b+ pro-angiogenic hematopoietic cells. BDNF induces a potent direct chemokinetic action on subsets of marrow-derived Sca-1+ hematopoietic cells co-expressing TrkB. These studies suggest that local regional delivery of BDNF may provide a novel mechanism for inducing neoangiogenesis through both direct actions on local TrkB-expressing endothelial cells in skeletal muscle and recruitment of specific subsets of TrkB+ bone marrow–derived hematopoietic cells to provide peri-endothelial support for the newly formed vessels. PMID:15765148

  7. Mixed Inhibition of Adenosine Deaminase Activity by 1,3-Dinitrobenzene: A Model for Understanding Cell-Selective Neurotoxicity in Chemically-Induced Energy Deprivation Syndromes in Brain

    Science.gov (United States)

    Wang, Yipei; Liu, Xin; Schneider, Brandon; Zverina, Elaina A.; Russ, Kristen; Wijeyesakere, Sanjeeva J.; Fierke, Carol A.; Richardson, Rudy J.; Philbert, Martin A.

    2012-01-01

    Astrocytes are acutely sensitive to 1,3-dinitrobenzene (1,3-DNB) while adjacent neurons are relatively unaffected, consistent with other chemically-induced energy deprivation syndromes. Previous studies have investigated the role of astrocytes in protecting neurons from hypoxia and chemical injury via adenosine release. Adenosine is considered neuroprotective, but it is rapidly removed by extracellular deaminases such as adenosine deaminase (ADA). The present study tested the hypothesis that ADA is inhibited by 1,3-DNB as a substrate mimic, thereby preventing adenosine catabolism. ADA was inhibited by 1,3-DNB with an IC50 of 284μM, Hill slope, n = 4.8 ± 0.4. Native gel electrophoresis showed that 1,3-DNB did not denature ADA. Furthermore, adding Triton X-100 (0.01–0.05%, wt/vol), Nonidet P-40 (0.0015–0.0036%, wt/vol), or bovine serum albumin (0.05 mg/ml or changing [ADA] (0.2 and 2nM) did not substantially alter the 1,3-DNB IC50 value. Likewise, dynamic light scattering showed no particle formation over a (1,3-DNB) range of 149–1043μM. Kinetics revealed mixed inhibition with 1,3-DNB binding to ADA (KI = 520 ± 100μM, n = 1 ± 0.6) and the ADA-adenosine complex (KIS = 262 ± 7μM, n = 6 ± 0.6, indicating positive cooperativity). In accord with the kinetics, docking predicted binding of 1,3-DNB to the active site and three peripheral sites. In addition, exposure of DI TNC-1 astrocytes to 10–500μM 1,3-DNB produced concentration-dependent increases in extracellular adenosine at 24 h. Overall, the results demonstrate that 1,3-DNB is a mixed inhibitor of ADA and may thus lead to increases in extracellular adenosine. The finding may provide insights to guide future work on chemically-induced energy deprivation. PMID:22106038

  8. Reexamination of the role of hematopoietic organs on the ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-08-04

    Aug 4, 2009 ... Sciences, 300 Fenglin Rd. Shanghai 200032, P.R. China. ... Key words: Hematopoietic organ, wing disc, hemocytes, surgical operation, silkworm, ... They were reared on artificial diet at 25°C under a 16 h ..... The image was.

  9. Mismatch repair deficient hematopoietic stem cells are preleukemic stem cells.

    Directory of Open Access Journals (Sweden)

    Yulan Qing

    Full Text Available Whereas transformation events in hematopoietic malignancies may occur at different developmental stages, the initial mutation originates in hematopoietic stem cells (HSCs, creating a preleukemic stem cell (PLSC. Subsequent mutations at either stem cell or progenitor cell levels transform the PLSC into lymphoma/leukemia initiating cells (LIC. Thymic lymphomas have been thought to develop from developing thymocytes. T cell progenitors are generated from HSCs in the bone marrow (BM, but maturation and proliferation of T cells as well as T-lymphomagenesis depends on both regulatory mechanisms and microenvironment within the thymus. We studied PLSC linked to thymic lymphomas. In this study, we use MSH2-/- mice as a model to investigate the existence of PLSC and the evolution of PLSC to LIC. Following BM transplantation, we found that MSH2-/- BM cells from young mice are able to fully reconstitute multiple hematopoietic lineages of lethally irradiated wild-type recipients. However, all recipients developed thymic lymphomas within three and four months post transplantation. Transplantation of different fractions of BM cells or thymocytes from young health MSH2-/- mice showed that an HSC enriched fraction always reconstituted hematopoiesis followed by lymphoma development. In addition, lymphomas did not occur in thymectomized recipients of MSH2-/- BM. These results suggest that HSCs with DNA repair defects such as MSH2-/- are PLSCs because they retain hematopoietic function, but also carry an obligate lymphomagenic potential within their T-cell progeny that is dependent on the thymic microenvironment.

  10. Polycomb group proteins in hematopoietic stem cell aging and malignancies

    NARCIS (Netherlands)

    Klauke, Karin; de Haan, Gerald

    Protection of the transcriptional "stemness" network is important to maintain a healthy hematopoietic stem cells (HSCs) compartment during the lifetime of the organism. Recent evidence shows that fundamental changes in the epigenetic status of HSCs might be one of the driving forces behind many

  11. Hematopoietic stem cell aging and self-renewal

    NARCIS (Netherlands)

    Dykstra, Brad; de Haan, Gerald

    A functional decline of the immune system occurs during organismal aging that is attributable, in large part, to changes in the hematopoietic stem cell (HSC) compartment. In the mouse, several hallmark age-dependent changes in the HSC compartment have been identified, including an increase in HSC

  12. Childhood Hematopoietic Cell Transplantation (PDQ®)—Health Professional Version

    Science.gov (United States)

    Hematopoietic cell transplantation involves the infusion of blood stem cells (peripheral/umbilical cord blood, bone marrow) into a patient to reconstitute the blood system. Get detailed information about autologous and allogeneic transplant, including cell selection, HLA matching, and preparative regimens, and the acute complications and late effects of treatment in this summary for clinicians.

  13. Placenta as a source of hematopoietic stem cells

    NARCIS (Netherlands)

    E.A. Dzierzak (Elaine); C. Robin (Catherine)

    2010-01-01

    textabstractThe placenta is a large, highly vascularised hematopoietic tissue that functions during the embryonic and foetal development of eutherian mammals. Although recognised as the interface tissue important in the exchange of oxygen, nutrients and waste products between the foetus and mother,

  14. Sexual function 1-year after allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Noerskov, K. H.; Schjødt, I.; Syrjala, K. L.

    2016-01-01

    Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is associated with short and long-term toxicities that can result in alterations in sexual functioning. The aims of this prospective evaluation were to determine: (1) associations between HSCT and increased sexual dysfunction...

  15. Longitudinal Assessment of Hematopoietic Stem Cell Transplantation and Hyposalivation

    DEFF Research Database (Denmark)

    Laaksonen, Matti; Ramseier, Adrian; Rovó, Alicia

    2011-01-01

    Hyposalivation is a common adverse effect of anti-neoplastic therapy of head and neck cancer, causing impaired quality of life and predisposition to oral infections. However, data on the effects of hematopoietic stem cell transplantation (HSCT) on salivary secretion are scarce. The present study...

  16. Depression and anxiety following hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Kuba, K; Esser, P; Mehnert, A

    2017-01-01

    In this prospective multicenter study, we investigated the course of depression and anxiety during hematopoietic stem cell transplantation (HSCT) until 5 years after transplantation adjusting for medical information. Patients were consulted before HSCT (n=239), at 3 months (n=150), 12 months (n=102...

  17. Lung function after allogeneic hematopoietic stem cell transplantation in children

    DEFF Research Database (Denmark)

    Uhlving, Hilde Hylland; Larsen Bang, Cæcilie; Christensen, Ib Jarle

    2013-01-01

    Reduction in pulmonary function (PF) has been reported in up to 85% of pediatric patients during the first year after hematopoietic stem cell transplantation (HSCT). Our understanding of the etiology for this decrease in lung function is, however, sparse. The aim of this study was to describe PF...

  18. Two hemocyte lineages exist in silkworm larval hematopoietic organ.

    Directory of Open Access Journals (Sweden)

    Yuichi Nakahara

    Full Text Available BACKGROUND: Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. METHODOLOGY/PRINCIPAL FINDINGS: To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. CONCLUSIONS/SIGNIFICANCE: From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori.

  19. Two hemocyte lineages exist in silkworm larval hematopoietic organ.

    Science.gov (United States)

    Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

    2010-07-28

    Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori.

  20. Dynamic changes in mouse hematopoietic stem cell numbers during aging

    NARCIS (Netherlands)

    de Haan, G; Van Zant, G

    1999-01-01

    To address the fundamental question of whether or not stem cell populations age, we performed quantitative measurements of the cycling status and frequency of hematopoietic stem cells in long-lived C57BL/6 (B6) and short-lived DBA/2 (DBA) mice at different developmental and aging stages. The

  1. Lifelong dietary intervention does not affect hematopoietic stem cell function

    NARCIS (Netherlands)

    Lazare, Seka; Ausema, Albertina; Reijne, Aaffien C; van Dijk, Gertjan; van Os, Ronald; de Haan, Gerald

    Hematopoietic stem cells (HSCs) undergo a profound functional decline during normal aging. Because caloric or dietary restriction has been shown to delay multiple aspects of the aging process in many species, we explored the consequences of lifelong caloric restriction, or conversely, lifelong

  2. Bone marrow transplantations to study gene function in hematopoietic cells

    NARCIS (Netherlands)

    de Winther, Menno P. J.; Heeringa, Peter

    2011-01-01

    Immune cells are derived from hematopoietic stem cells in the bone marrow. Experimental replacement of bone marrow offers the unique possibility to replace immune cells, to study gene function in mouse models of disease. Over the past decades, this technique has been used extensively to study, for

  3. On traveling-wave field-effect flow control for simultaneous induced-charge electroosmotic pumping and mixing in microfluidics: physical perspectives and theoretical analysis

    Science.gov (United States)

    Liu, Weiyu; Ren, Yukun; Tao, Ye; Li, Yanbo; Wu, Qisheng

    2018-05-01

    Since its first proposition at the end of the last century (Schasfoort et al 1999 Science 286 942-5), field-effect flow control at micrometer dimensions has attracted tremendous attention from the microfluidic community. Most previous research on this subject has mainly focused on enhancing the electroosmotic pump flow rate by introducing an additional in-phase counterionic charge across the diffusing screening cloud with external gate electrodes of static DC voltages. However, there is a flaw, namely that AC fields, which suppress undesirable electrochemical reactions, result in zero time-averaged flow. Starting from this point, we present herein a brand new approach to traveling-wave field-effect electroosmosis control from a theoretical point of view, in the context of a smart manipulation tool for the stratified liquid content of miniaturization systems. In the configuration of a traveling-wave flow field-effect transistor (TW-FFET), the field-induced out-of-phase Debye screening charge within the thin double layer originates from the forward propagation of a traveling potential wave along a discrete arrangement of external gating electrode arrays, which interacts actively with the horizontal standing-wave electric field imposed across the source-drain terminal. Since the voltage waves and induced free charge are all sinusoidal functions of the observation time, the net ICEO flow component can survive in a broad frequency range. Due to the action of the background AC electric field on the inhomogeneous counterionic charge induced at the solution/sidewall interface, asymmetric ICEO vortex patterns appear above the traveling-wave gate arrays, giving rise to simultaneous induced-charge electroosmotic pumping and mixing of fluidic samples. A mathematical model is then developed to numerically investigate the feasibility of TW-FFETs in electrokinetic microflow manipulation. A prototyping paradigm of fully electrokinetics-driven microfabricated fluidic networks in a

  4. Ionizing radiation effects on the KG1A primitive hematopoietic cell line

    International Nuclear Information System (INIS)

    Clave, Emmanuel; Carosella, Edgardo D.; Gluckman, Eliane; Dubray, Bernard; Socie, Gerard

    1996-01-01

    Purpose: Better understanding of radiation-induced effects on the hematopoietic system is important in both the context of therapeutic intervention and accidental exposure. However, direct study of these effects on the hematopoietic stem cell pool is hampered by the small number of accessible cells. We, thus, studied radiation-induced effects on the KG1a stem cell line. Methods and Materials: We confirmed and extended the immunophenotype of KG1a with monoclonal antibodies, established a radiation survival curve, and quantified mRNAs by Northern blotting 30 min after 1, 2, and 3 Gy of ionizing radiation (IR) and followed for up to 48 h after a 3 Gy dose. Cell cycle status and apoptosis were assessed by fluorescent-activated cell sorter (FACS) analysis, cell morphology, and DNA fragmentation. Results: KG1a was found to be CD34+, CD7+, Thy1 low, CD38 low, lineage negative (neg), C-KITneg and HLA-DRneg, a phenotype consistent with a primitive hematopoietic origin. This immunophenotype was not altered by x-ray irradiation. The D 0 value was 1.75 Gy. We showed a time-dependent variation of c-jun mRNA expression with an early and transient dose-dependent induction followed by a second increase at 24 and 48 h: a biphasic dose-dependent variation of bcl-2 expression 30 min after irradiation with a reduction of mRNA level at 1 Gy, and a normalization at higher doses and stable levels of mRNA for c-fos, c-myc, G-CSF, GM-CSF, IL-6, TNF-α, TGF-β, and MIP-1α genes. Cell cycle analysis showed the absence of G1/S phase arrest, a point consistent with the absence of detection of P53 mRNA by Northern blot analysis. The dose-dependent G2/M phase arrest was not followed by significant apoptotic cell death. Conclusion: Taken together, this data indicates that radiation-induced cell death of KG1a, a cell line that has a relatively high D 0 value, does not seem to be the result of the apoptotic pathway but occurs subsequent to a G2/M phase arrest

  5. Symptoms after hospital discharge following hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Gamze Oguz

    2014-01-01

    Full Text Available Aims: The purposes of this study were to assess the symptoms of hematopoietic stem cell transplant patients after hospital discharge, and to determine the needs of transplant patients for symptom management. Materials and Methods: The study adopted a descriptive design. The study sample comprised of 66 hematopoietic stem cell transplant patients. The study was conducted in Istanbul. Data were collected using Patient Information Form and Memorial Symptom Assessment Scale (MSAS. Results: The frequency of psychological symptoms in hematopoietic stem cell transplant patients after discharge period (PSYCH subscale score 2.11 (standard deviation (SD = 0.69, range: 0.93-3.80 was higher in hematopoietic stem cell transplant patients than frequency of physical symptoms (PHYS subscale score: 1.59 (SD = 0.49, range: 1.00-3.38. Symptom distress caused by psychological and physical symptoms were at moderate level (Mean = 1.91, SD = 0.60, range: 0.95-3.63 and most distressing symptoms were problems with sexual interest or activity, difficulty sleeping, and diarrhea. Patients who did not have an additional chronic disease obtained higher MSAS scores. University graduates obtained higher Global Distress Index (GDI subscale and total MSAS scores with comparison to primary school graduates. Total MSAS, MSAS-PHYS subscale, and MSAS-PSYCH subscale scores were higher in patients with low level of income (P < 0.05. The patients (98.5% reported to receive education about symptom management after hospital discharge. Conclusions: Hematopoietic stem cell transplant patients continue to experience many distressing physical or psychological symptoms after discharge and need to be supported and educated for the symptom management.

  6. Development of model for analysing respective collections of intended hematopoietic stem cells and harvests of unintended mature cells in apheresis for autologous hematopoietic stem cell collection.

    Science.gov (United States)

    Hequet, O; Le, Q H; Rodriguez, J; Dubost, P; Revesz, D; Clerc, A; Rigal, D; Salles, G; Coiffier, B

    2014-04-01

    Hematopoietic stem cells (HSCs) required to perform peripheral hematopoietic autologous stem cell transplantation (APBSCT) can be collected by processing several blood volumes (BVs) in leukapheresis sessions. However, this may cause granulocyte harvest in graft and decrease in patient's platelet blood level. Both consequences may induce disturbances in patient. One apheresis team's current purpose is to improve HSC collection by increasing HSC collection and prevent increase in granulocyte and platelet harvests. Before improving HSC collection it seemed important to know more about the way to harvest these types of cells. The purpose of our study was to develop a simple model for analysing respective collections of intended CD34+ cells among HSC (designated here as HSC) and harvests of unintended platelets or granulocytes among mature cells (designated here as mature cells) considering the number of BVs processed and factors likely to influence cell collection or harvest. For this, we processed 1, 2 and 3 BVs in 59 leukapheresis sessions and analysed corresponding collections and harvests with a referent device (COBE Spectra). First we analysed the amounts of HSC collected and mature cells harvested and second the evolution of the respective shares of HSC and mature cells collected or harvested throughout the BV processes. HSC collections and mature cell harvests increased globally (pcollections and harvests, which showed that only pre-leukapheresis blood levels (CD34+cells and platelets) influenced both cell collections and harvests (CD34+cells and platelets) (pcollections and mature unintended cells harvests (pcollections or unintended mature cell harvests were pre-leukapheresis blood cell levels. Our model was meant to assist apheresis teams in analysing shares of HSC collected and mature cells harvested with new devices or with new types of HSC mobilization. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, and adult hematopoietic tissues

    NARCIS (Netherlands)

    Jokubaitis, Vanta J.; Sinka, Lidia; Driessen, Rebecca; Whitty, Genevieve; Haylock, David N.; Bertoncello, Ivan; Smith, Ian; Peault, Bruno; Tavian, Manuela; Simmons, Paul J.

    2008-01-01

    Previous studies revealed that mAb BB9 reacts with a subset of CD34(+) human BM cells with hematopoietic stem cell (HSC) characteristics. Here we map B89 expression throughout hernatopoietic development and show that the earliest definitive HSCs that arise at the ventral wall of the aorta and

  8. A case report of mixed acinar-endocrine carcinoma of the pancreas treated with S-1 chemotherapy: Does it work or induce endocrine differentiation?

    Science.gov (United States)

    Yokode, Masataka; Itai, Ryosuke; Yamashita, Yukimasa; Zen, Yoh

    2017-11-01

    Acinar cell carcinomas (ACCs) and mixed acinar-endocrine carcinomas (MAECs) of the pancreas are rare, accounting for only 1% of pancreatic tumors. Although both typically present at an advanced stage, chemotherapeutic regimes have not yet been standardized. A 65-year-old man presented with a large mass in the pancreatic tail with multiple liver metastases. He was initially treated with gemcitabine for suspected ductal carcinoma of the pancreas, but no response was observed. S-1, administered as second-line chemotherapy, showed an approximately 38% reduction in the size of the primary tumor and metastatic deposits with therapeutic effects being maintained for 12 months. When the tumor progressed again, he underwent a percutaneous liver biopsy, which led to the diagnosis of MAEC. Combination therapy with cisplatin and etoposide targeting the endocrine component was administered, and this was based on the endocrine component potentially being less sensitive to S-1 than the ACC element. However, therapy was stopped due to the development of neutropenia, and the patient is currently receiving best supportive care. Given the previous studies suggested that S-1 is more effective for ACCs than gemcitabine, MAECs may also respond to S-1 chemotherapy, similar to ACCs. Another potential interpretation is that S-1 was effective when the condition was ACC, and eventually showed decreased effectiveness when the condition shifted to MAEC. Future studies are needed to conclude whether S-1 chemotherapy truly works against MAECs or induces endocrine differentiation in ACCs as a part of the drug-resistance process.

  9. Sub-Doppler spectroscopy of thioformaldehyde: Excited state perturbations and evidence for rotation-induced vibrational mixing in the ground state

    International Nuclear Information System (INIS)

    Clouthier, D.J.; Huang, G.; Adam, A.G.; Merer, A.J.

    1994-01-01

    High-resolution intracavity dye laser spectroscopy has been used to obtain sub-Doppler spectra of transitions to 350 rotational levels in the 4 1 0 band of the A 1 A 2 --X 1 A 1 electronic transition of thioformaldehyde. Ground state combination differences from the sub-Doppler spectra, combined with microwave and infrared data, have been used to improve the ground state rotational and centrifugal distortion constants of H 2 CS. The upper state shows a remarkable number of perturbations. The largest of these are caused by nearby triplet levels, with matrix elements of 0.05--0.15 cm -1 . A particularly clear singlet--triplet avoided crossing in K a ' = 7 has been shown to be caused by interaction with the F 1 component of the 3 1 6 2 vibrational level of the a 3 A 2 state. At least 53% of the S 1 levels show evidence of very small perturbations by high rovibronic levels of the ground state. The number of such perturbations is small at low J, but increases rapidly beyond J=5 such that 40%--80% of the observed S 1 levels of any given J are perturbed by ground state levels. Model calculations show that the density and J dependence of the number of perturbed levels can be explained if there is extensive rotation-induced mixing of the vibrational levels in the ground state

  10. Inactivation of the forkhead transcription factor FoxO3 is essential for PKB-mediated survival of hematopoietic progenitor cells by kit ligand

    DEFF Research Database (Denmark)

    Engström, Maria; Karlsson, Richard; Jönsson, Jan-Ingvar

    2003-01-01

    OBJECTIVE: Kit ligand (KL) is a major survival factor for hematopoietic stem cells. Although anti-apoptotic bcl-2 family members are expressed in these cells, the survival effects by KL appear to involve other mechanisms. Survival signals can also be elicited by the activation of phosphatidylinos......OBJECTIVE: Kit ligand (KL) is a major survival factor for hematopoietic stem cells. Although anti-apoptotic bcl-2 family members are expressed in these cells, the survival effects by KL appear to involve other mechanisms. Survival signals can also be elicited by the activation......, immunofluorescence, and subcellular fractionation, we analyzed the effects of KL on PKB and different forkhead family members in two factor-dependent cell lines, FDCP-mix and FDC-P1, as well as primary mouse bone marrow-derived Lin(-) progenitors. Forced overexpression of triple mutated form of FoxO3 by retroviral...

  11. Mixing Ventilation

    DEFF Research Database (Denmark)

    Kandzia, Claudia; Kosonen, Risto; Melikov, Arsen Krikor

    In this guidebook most of the known and used in practice methods for achieving mixing air distribution are discussed. Mixing ventilation has been applied to many different spaces providing fresh air and thermal comfort to the occupants. Today, a design engineer can choose from large selection...

  12. [Results of hematopoietic stem cell transplantation in hemoglobinopathies: thalassemia major and sickle cell disease].

    Science.gov (United States)

    Hladun, R; Elorza, I; Olivé, T; Dapena, J L; Llort, A; Sánchez de Toledo, J; Díaz de Heredia, C

    2013-08-01

    The prevalence of hemoglobinopathies in Spain is increasing as a result of immigration. Thalassemia major presents with chronic hemolytic anemia that requires regular red blood cell transfusions within the first year of life. Patients with sickle cell disease suffer from chronic anemia, vasculopathy and progressive damage in almost any organ. There is decreased life expectancy in both conditions. Allogeneic hematopoietic stem cell transplantation represents the only potentially curative option. Seventeen patients (fourteen thalassemia major, and three sickle cell disease) underwent allogeneic hematopoietic stem cell transplantations. In the thalassemia group, nine donors were HLA-geno-identical siblings, two were partially matched related donors (one HLA allele mismatch), and three unrelated donors. All three patients with sickle cell disease were transplanted from HLA-geno-identical siblings. The source of stem cells was bone marrow in sixteen cases. Median patient age at transplant was six years (range: 1-16) in the thalassemia group, and twelve years (range: 8-15) in the sickle cell disease group. The graft was successful in all patients. Secondary graft rejection was observed in two thalassemia patients rendering them dependent on blood transfusions. Complete chimerism was observed in thirteen patients and, although mixed chimerism occurred in two, with all of them showing normal hemoglobin levels after transplantation and not requiring further transfusion support. Patients affected by sickle cell disease did not present with new vaso-occlusive crises, and stabilization of pulmonary and neurological function was observed. Chronic graft-versus-host disease was detected in three patients affected by thalassemia, and hypogonadotrophic hypogonadism in five patients. We conclude that for thalassemia major and sickle cell disease, allogenic hematopoietic stem cell transplantation from HLA-geno-identical siblings offers a high probability of complication-free survival

  13. IRS-1: essential for insulin- and IL-4-stimulated mitogenesis in hematopoietic cells.

    Science.gov (United States)

    Wang, L M; Myers, M G; Sun, X J; Aaronson, S A; White, M; Pierce, J H

    1993-09-17

    Although several interleukin-3 (IL-3)-dependent cell lines proliferate in response to IL-4 or insulin, the 32D line does not. Insulin and IL-4 sensitivity was restored to 32D cells by expression of IRS-1, the principal substrate of the insulin receptor. Although 32D cells possessed receptors for both factors, they lacked the IRS-1--related protein, 4PS, which becomes phosphorylated by tyrosine in insulin- or IL-4--responsive lines after stimulation. These results indicate that factors that bind unrelated receptors can use similar mitogenic signaling pathways in hematopoietic cells and that 4PS and IRS-1 are functionally similar proteins that are essential for insulin- and IL-4--induced proliferation.

  14. Successful Hematopoietic Stem Cell Transplantation Following a Cyclophosphamide-Containing Preparative Regimen with Concomitant Phenobarbital Administration

    Directory of Open Access Journals (Sweden)

    Catherine Weber

    2012-01-01

    Full Text Available Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG, and total body irradiation (TBI followed by an allogeneic hematopoietic stem cell transplant (HSCT for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

  15. Successful hematopoietic stem cell transplantation following a cyclophosphamide-containing preparative regimen with concomitant phenobarbital administration.

    Science.gov (United States)

    Weber, Catherine; Kasberg, Heather; Copelan, Edward

    2012-01-01

    Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

  16. Oxidative Stress, Bone Marrow Failure, and Genome Instability in Hematopoietic Stem Cells

    Directory of Open Access Journals (Sweden)

    Christine Richardson

    2015-01-01

    Full Text Available Reactive oxygen species (ROS can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.

  17. Stimulation and inhibition of erythropoiesis in donors and hematopoietic effect in irradiated recipient

    Energy Technology Data Exchange (ETDEWEB)

    Ninkov, V; Piletic, O; Stepanovic, D [Institut za Nuklearne Nauke Boris Kidric, Vinca (Yugoslavia); Belgrade Univ. (Yugoslavia). Inst. of Histology)

    1976-03-01

    Regeneration dynamics in bone marrow and spleen was studied in rats after irradiation of 800 R and transfusion of bone marrow cells from donors treated in different ways. Priority of the microenvironment of the recipient or of the information obtained in cell donors with respect to further hematopoietic cell differentiation was studied in irradiated recipients. Rats irradiated with 800 R were used as recipients in the experiments. The donors of marrow cells were the rats with stimulated or inhibited erythropoiesis. Stimulation of erythropoiesis was induced by bleeding and experimental polycythemia was provoked by packed erythrocytes. According to our results, it can be concluded that the processes of postirradiation hematopoiesis after transplantation of the bone marrow cells depend on the number and proliferative state of both donors and recipient stem cells, and microenvironment, not excluding the information introduced with the donor cell transplant.

  18. Ratiometric, single-dye, pH-sensitive inhibited laser-induced fluorescence for the characterization of mixing and mass transfer

    Science.gov (United States)

    Lacassagne, Tom; Simoëns, Serge; El Hajem, Mahmoud; Champagne, Jean-Yves

    2018-01-01

    Inhibited planar laser-induced fluorescence (I-PLIF) techniques are widely used for heat and mass transfer studies in fluid mechanics. They allow the visualization of instantaneous two-dimensional field of a passive or reactive scalar, providing that this scalar acts as an inhibitor to the fluorescence of a specific molecule, and that this molecule is homogeneously mixed in the fluid at a known concentration. Local scalar values are deduced from fluorescence recordings thanks to preliminary calibration procedure. When confronted with non-optically thin systems, however, the knowledge of the excitation intensity distribution in the region of interest is also required, and this information is most of the time hard to obtain. To overcome that problem, two-color ratiometric PLIF techniques ( {I}^ {r}-PLIF) have been developed. In these methods, the ratio of two different fluorescence wavelengths triggered by the same excitation is used as an indicator of the scalar value. Such techniques have been used for temperature measurements in several studies but never, to the author's knowledge, for pH tracking and acid-base mixing, despite the frequent use of the one-color version in mass transfer studies. In the present work, a ratiometric pH-sensitive-inhibited PLIF technique ( {I}_ {pH}^ {r}-PLIF) using fluorescein sodium as a single dye and applicable to complex geometries and flows is developed. Theoretical considerations show that the ratio of the two-color fluorescence intensities should only depend on the dye's spectral quantum yield, itself pH-dependent. A detailed spectrofluorimetric study of fluorescein reveals that this ratio strictly increases with the pH for two well-chosen spectral bands (fluorescence colors). A similar trend is found when using sCmos cameras equipped with optical filters to record fluorescence signals. The method is then experimented on a test flow, a turbulent acidic jet injected in an initially pH-neutral volume of fluid. The results obtained

  19. Exercise increases the frequency of circulating hematopoietic progenitor cells, but reduces hematopoietic colony-forming capacity.

    Science.gov (United States)

    Kroepfl, Julia Maria; Pekovits, Karin; Stelzer, Ingeborg; Fuchs, Robert; Zelzer, Sieglinde; Hofmann, Peter; Sedlmayr, Peter; Dohr, Gottfried; Wallner-Liebmann, Sandra; Domej, Wolfgang; Mueller, Wolfram

    2012-11-01

    Circulating hematopoietic progenitor cells (CPCs) may be triggered by physical exercise and/or normobaric hypoxia from the bone marrow. The aim of the study was to investigate the influence of physical exercise and normobaric hypoxia on CPC number and functionality in the peripheral blood as well as the involvement of oxidative stress parameters as possibly active agents. Ten healthy male subjects (25.3±4.4 years) underwent a standardized cycle incremental exercise test protocol (40 W+20 W/min) under either normoxic (FiO2 ∼0.21) or hypoxic conditions (FiO2exercise. The number of CPCs in the peripheral blood was analyzed by flow cytometry (CD34/CD45-positive cells). The functionality of cells present was addressed by secondary colony-forming unit-granulocyte macrophage (CFU-GM) assays. To determine a possible correlation between the mobilization of CPCs and reactive oxygen species, parameters for oxidative stress such as malondialdehyde (MDA) and myeloperoxidase (MPO) were obtained. Data showed a significant increase of CPC release under normoxic as well as hypoxic conditions after 10 min of recovery (Pexercise (Pexercise, possibly due to the influence of increased oxidative stress levels.

  20. Neutrino mixing, flavor states and dark energy

    International Nuclear Information System (INIS)

    Blasone, M.; Capolupo, A.; Capozziello, S.; Vitiello, G.

    2008-01-01

    We shortly summarize the quantum field theory formalism for the neutrino mixing and report on recent results showing that the vacuum condensate induced by neutrino mixing can be interpreted as a dark energy component of the Universe

  1. Meis1 Is Required for Adult Mouse Erythropoiesis, Megakaryopoiesis and Hematopoietic Stem Cell Expansion.

    Directory of Open Access Journals (Sweden)

    Michelle Erin Miller

    Full Text Available Meis1 is recognized as an important transcriptional regulator in hematopoietic development and is strongly implicated in the pathogenesis of leukemia, both as a Hox transcription factor co-factor and independently. Despite the emerging recognition of Meis1's importance in the context of both normal and leukemic hematopoiesis, there is not yet a full understanding of Meis1's functions and the relevant pathways and genes mediating its functions. Recently, several conditional mouse models for Meis1 have been established. These models highlight a critical role for Meis1 in adult mouse hematopoietic stem cells (HSCs and implicate reactive oxygen species (ROS as a mediator of Meis1 function in this compartment. There are, however, several reported differences between these studies in terms of downstream progenitor populations impacted and effectors of function. In this study, we describe further characterization of a conditional knockout model based on mice carrying a loxP-flanked exon 8 of Meis1 which we crossed onto the inducible Cre localization/expression strains, B6;129-Gt(ROSA26Sor(tm1(Cre/ERTNat/J or B6.Cg-Tg(Mx1-Cre1Cgn/J. Findings obtained from these two inducible Meis1 knockout models confirm and extend previous reports of the essential role of Meis1 in adult HSC maintenance and expansion and provide new evidence that highlights key roles of Meis1 in both megakaryopoiesis and erythropoiesis. Gene expression analyses point to a number of candidate genes involved in Meis1's role in hematopoiesis. Our data additionally support recent evidence of a role of Meis1 in ROS regulation.

  2. Failure in activation of the canonical NF-κB pathway by human T-cell leukemia virus type 1 Tax in non-hematopoietic cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Mizukoshi, Terumi; Komori, Hideyuki; Mizuguchi, Mariko [Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Abdelaziz, Hussein [Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura (Egypt); Hara, Toshifumi [Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Higuchi, Masaya [Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Japan); Tanaka, Yuetsu [Department of Immunology, Graduate School and Faculty of Medicine, Ryukyu University, Okinawa (Japan); Ohara, Yoshiro [Department of Microbiology, Kanazawa Medical University, Ishikawa (Japan); Funato, Noriko [Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Fujii, Masahiro [Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Japan); Nakamura, Masataka, E-mail: naka.gene@tmd.ac.jp [Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan)

    2013-09-01

    Human T-cell leukemia virus type 1 (HTLV-1) Tax (Tax1) plays crucial roles in leukemogenesis in part through activation of NF-κB. In this study, we demonstrated that Tax1 activated an NF-κB binding (gpκB) site of the gp34/OX40 ligand gene in a cell type-dependent manner. Our examination showed that the gpκΒ site and authentic NF-κB (IgκB) site were activated by Tax1 in hematopoietic cell lines. Non-hematopoietic cell lines including hepatoma and fibroblast cell lines were not permissive to Tax1-mediated activation of the gpκB site, while the IgκB site was activated in those cells in association with binding of RelB. However RelA binding was not observed in the gpκB and IgκB sites. Our results suggest that HTLV-1 Tax1 fails to activate the canonical pathway of NF-κB in non-hematopoietic cell lines. Cell type-dependent activation of NF-κB by Tax1 could be associated with pathogenesis by HTLV-1 infection. - Highlights: • HTLV-1 Tax1 does not activate RelA of NF-κB in non-hematopoietic cell lines. • Tax1 activates the NF-κB non-canonical pathway in non-hematopoietic cell lines. • Tax1 does not induce RelA nuclear translocation in those cell lines, unlike TNFα. • The OX40L promoter κB site is activated by ectopic, but not endogenous, RelA.

  3. Molecular functions of the LIM-homeobox transcription factor Lhx2 in hematopoietic progenitor cells derived from mouse embryonic stem cells.

    Science.gov (United States)

    Kitajima, Kenji; Kawaguchi, Manami; Iacovino, Michelina; Kyba, Michael; Hara, Takahiko

    2013-12-01

    We previously demonstrated that hematopoietic stem cell (HSC)-like cells are robustly expanded from mouse embryonic stem cells (ESCs) by enforced expression of Lhx2, a LIM-homeobox domain (LIM-HD) transcription factor. In this study, we analyzed the functions of Lhx2 in that process using an ESC line harboring an inducible Lhx2 gene cassette. When ESCs are cultured on OP9 stromal cells, hematopoietic progenitor cells (HPCs) are differentiated and these HPCs are prone to undergo rapid differentiation into mature hematopoietic cells. Lhx2 inhibited differentiation of HPCs into mature hematopoietic cells and this effect would lead to accumulation of HSC-like cells. LIM-HD factors interact with LIM domain binding (Ldb) protein and this interaction abrogates binding of LIM-only (Lmo) protein to Ldb. We found that one of Lmo protein, Lmo2, was unstable due to dissociation of Lmo2 from Ldb1 in the presence of Lhx2. This effect of Lhx2 on the amount of Lmo2 contributed into accumulation of HSC-like cells, since enforced expression of Lmo2 into HSC-like cells inhibited their self-renewal. Expression of Gata3 and Tal1/Scl was increased in HSC-like cells and enforced expression of Lmo2 reduced expression of Gata3 but not Tal1/Scl. Enforced expression of Gata3 into HPCs inhibited mature hematopoietic cell differentiation, whereas Gata3-knockdown abrogated the Lhx2-mediated expansion of HPCs. We propose that multiple transcription factors/cofactors are involved in the Lhx2-mediated expansion of HSC-like cells from ESCs. Lhx2 appears to fine-tune the balance between self-renewal and differentiation of HSC-like cells. © AlphaMed Press.

  4. Vascular Endothelial Growth Factor and Angiopoietin-1 Stimulate Postnatal Hematopoiesis by Recruitment of Vasculogenic and Hematopoietic Stem Cells

    Science.gov (United States)

    Hattori, Koichi; Dias, Sergio; Heissig, Beate; Hackett, Neil R.; Lyden, David; Tateno, Masatoshi; Hicklin, Daniel J.; Zhu, Zhenping; Witte, Larry; Crystal, Ronald G.; Moore, Malcolm A.S.; Rafii, Shahin

    2001-01-01

    Tyrosine kinase receptors for angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) are expressed not only by endothelial cells but also by subsets of hematopoietic stem cells (HSCs). To further define their role in the regulation of postnatal hematopoiesis and vasculogenesis, VEGF and Ang-1 plasma levels were elevated by injecting recombinant protein or adenoviral vectors expressing soluble VEGF165, matrix-bound VEGF189, or Ang-1 into mice. VEGF165, but not VEGF189, induced a rapid mobilization of HSCs and VEGF receptor (VEGFR)2+ circulating endothelial precursor cells (CEPs). In contrast, Ang-1 induced delayed mobilization of CEPs and HSCs. Combined sustained elevation of Ang-1 and VEGF165 was associated with an induction of hematopoiesis and increased marrow cellularity followed by proliferation of capillaries and expansion of sinusoidal space. Concomitant to this vascular remodeling, there was a transient depletion of hematopoietic activity in the marrow, which was compensated by an increase in mobilization and recruitment of HSCs and CEPs to the spleen resulting in splenomegaly. Neutralizing monoclonal antibody to VEGFR2 completely inhibited VEGF165, but not Ang-1–induced mobilization and splenomegaly. These data suggest that temporal and regional activation of VEGF/VEGFR2 and Ang-1/Tie-2 signaling pathways are critical for mobilization and recruitment of HSCs and CEPs and may play a role in the physiology of postnatal angiogenesis and hematopoiesis. PMID:11342585

  5. Mixing in a Microfluid Device

    DEFF Research Database (Denmark)

    Hjorth, Poul G.; Deryabin, Mikhail

    Mixing of fluids in microchannels cannot rely on turbulence since the flow takes place at extremly low Reynolds numbers. Various active and passive devices have been developed to induce mixing in microfluid flow devices. We describe here a model of an active mixer where a transverse periodic flow...

  6. Tumor-induced osteomalacia with elevated fibroblast growth factor 23: a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature.

    Science.gov (United States)

    Hu, Fang-Ke; Yuan, Fang; Jiang, Cheng-Ying; Lv, Da-Wei; Mao, Bei-Bei; Zhang, Qiang; Yuan, Zeng-Qiang; Wang, Yan

    2011-11-01

    Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "lomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.

  7. Rhizomucor and Scedosporium Infection Post Hematopoietic Stem-Cell Transplant

    Directory of Open Access Journals (Sweden)

    Dânia Sofia Marques

    2011-01-01

    Full Text Available Hematopoietic stem-cell transplant recipients are at increased risk of developing invasive fungal infections. This is a major cause of morbidity and mortality. We report a case of a 17-year-old male patient diagnosed with severe idiopathic acquired aplastic anemia who developed fungal pneumonitis due to Rhizomucor sp. and rhinoencephalitis due to Scedosporium apiospermum 6 and 8 months after undergoing allogeneic hematopoietic stem-cell transplant from an HLA-matched unrelated donor. Discussion highlights risk factors for invasive fungal infections (i.e., mucormycosis and scedosporiosis, its clinical features, and the factors that must be taken into account to successfully treat them (early diagnosis, correction of predisposing factors, aggressive surgical debridement, and antifungal and adjunctive therapies.

  8. Aging, Clonality and Rejuvenation of Hematopoietic Stem Cells

    Science.gov (United States)

    Akunuru, Shailaja; Geiger, Hartmut

    2016-01-01

    Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and increased production of reactive oxygen species have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as clonal selection of HSCs upon aging provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and potentially, alleviating aging-associated immune remodeling and myeloid malignancies. PMID:27380967

  9. Haemopedia: An Expression Atlas of Murine Hematopoietic Cells

    Directory of Open Access Journals (Sweden)

    Carolyn A. de Graaf

    2016-09-01

    Full Text Available Hematopoiesis is a multistage process involving the differentiation of stem and progenitor cells into distinct mature cell lineages. Here we present Haemopedia, an atlas of murine gene-expression data containing 54 hematopoietic cell types, covering all the mature lineages in hematopoiesis. We include rare cell populations such as eosinophils, mast cells, basophils, and megakaryocytes, and a broad collection of progenitor and stem cells. We show that lineage branching and maturation during hematopoiesis can be reconstructed using the expression patterns of small sets of genes. We also have identified genes with enriched expression in each of the mature blood cell lineages, many of which show conserved lineage-enriched expression in human hematopoiesis. We have created an online web portal called Haemosphere to make analyses of Haemopedia and other blood cell transcriptional datasets easier. This resource provides simple tools to interrogate gene-expression-based relationships between hematopoietic cell types and genes of interest.

  10. Protein Kinase C Enzymes in the Hematopoietic and Immune Systems.

    Science.gov (United States)

    Altman, Amnon; Kong, Kok-Fai

    2016-05-20

    The protein kinase C (PKC) family, discovered in the late 1970s, is composed of at least 10 serine/threonine kinases, divided into three groups based on their molecular architecture and cofactor requirements. PKC enzymes have been conserved throughout evolution and are expressed in virtually all cell types; they represent critical signal transducers regulating cell activation, differentiation, proliferation, death, and effector functions. PKC family members play important roles in a diverse array of hematopoietic and immune responses. This review covers the discovery and history of this enzyme family, discusses the roles of PKC enzymes in the development and effector functions of major hematopoietic and immune cell types, and points out gaps in our knowledge, which should ignite interest and further exploration, ultimately leading to better understanding of this enzyme family and, above all, its role in the many facets of the immune system.

  11. The many faces of hematopoietic stem cell heterogeneity

    Science.gov (United States)

    2016-01-01

    Not all hematopoietic stem cells (HSCs) are alike. They differ in their physical characteristics such as cell cycle status and cell surface marker phenotype, they respond to different extrinsic signals, and they have different lineage outputs following transplantation. The growing body of evidence that supports heterogeneity within HSCs, which constitute the most robust cell fraction at the foundation of the adult hematopoietic system, is currently of great interest and raises questions as to why HSC subtypes exist, how they are generated and whether HSC heterogeneity affects leukemogenesis or treatment options. This Review provides a developmental overview of HSC subtypes during embryonic, fetal and adult stages of hematopoiesis and discusses the possible origins and consequences of HSC heterogeneity. PMID:27965438

  12. Transplantation Dose Alters the Differentiation Program of Hematopoietic Stem Cells.

    Science.gov (United States)

    Brewer, Casey; Chu, Elizabeth; Chin, Mike; Lu, Rong

    2016-05-24

    Hematopoietic stem cell (HSC) transplantation is the most prevalent stem cell therapy, but it remains a risky procedure. To improve this treatment, it is important to understand how transplanted stem cells rebuild the blood and immune systems and how this process is impacted by transplantation variables such as the HSC dose. Here, we find that, in the long term following transplantation, 70%-80% of donor-HSC-derived clones do not produce all measured blood cell types. High HSC doses lead to more clones that exhibit balanced lymphocyte production, whereas low doses produce more T-cell-specialized clones. High HSC doses also produce significantly higher proportions of early-differentiating clones compared to low doses. These complex differentiation behaviors uncover the clonal-level regeneration dynamics of hematopoietic regeneration and suggest that transplantation dose can be exploited to improve stem cell therapy. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  13. FIFTY YEARS OF MELPHALAN USE IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

    Science.gov (United States)

    Bayraktar, Ulas D.; Bashir, Qaiser; Qazilbash, Muzaffar; Champlin, Richard E.; Ciurea, Stefan O.

    2015-01-01

    Melphalan remains the most widely used agent in preparative regimens for hematopoietic stem-cell transplantation. From its initial discovery more than 50 years ago, it has been gradually incorporated in the conditioning regimens for both autologous and allogeneic transplantation due to its myeloablative properties and broad antitumor effects as a DNA alkylating agent. Melphalan remains the mainstay conditioning for multiple myeloma and lymphomas; and has been used successfully in preparative regimens of a variety of other hematological and non-hematological malignancies. The addition of newer agents to conditioning like bortezomib or lenalidomide for myeloma, or clofarabine for myeloid malignancies, may improve antitumor effects for transplantation, while in combination with alemtuzumab may represent a backbone for future cellular therapy due to reliable engraftment and low toxicity profile. This review summarizes the development and the current use of this remarkable drug in hematopoietic stem-cell transplantation. PMID:22922522

  14. Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody Mediated Rejection After Vascularized Composite Allotransplantation

    Science.gov (United States)

    2017-10-01

    Award Number: W81XWH-16-1-0664 TITLE: Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody-Mediated Rejection after...Annual 3. DATES COVERED 15 Sep 2016 – 14 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Autologous Hematopoietic Stem Cell Transplantation to...sensitization, autologous hematopoietic stem cell transplantation, antibody mediated rejection, donor specific antibodies 16. SECURITY CLASSIFICATION OF

  15. Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia

    Science.gov (United States)

    Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T.; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R.; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D.; Lutz, Christoph

    2017-01-01

    In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. PMID:28550184

  16. Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia.

    Science.gov (United States)

    Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D; Lutz, Christoph

    2017-09-01

    In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. Copyright© 2017 Ferrata Storti Foundation.

  17. Coordinate expansion of murine hematopoietic and mesenchymal stem cell compartments by SHIPi.

    Science.gov (United States)

    Brooks, R; Iyer, S; Akada, H; Neelam, S; Russo, C M; Chisholm, J D; Kerr, W G

    2015-03-01

    Promoting the expansion of adult stem cell populations offers the potential to ameliorate radiation or chemotherapy-induced bone marrow failure and allows for expedited recovery for patients undergoing these therapies. Previous genetic studies suggested a pivotal role for SH2 domain-containing inositol-5-phosphatase 1 (SHIP1) in limiting the size of the hematopoietic stem cell (HSC) compartment. The aim of this study was to determine whether our recent development of small molecule SHIP1 inhibitors offers the potential for pharmacological expansion of the HSC compartment in vivo. We show here that treatment of mice with aminosteroid inhibitors of SHIP1 (SHIPi) more than doubles the size of the adult mesenchymal stem cell (MSC) compartment while simultaneously expanding the HSC pool sixfold. Consistent with its ability to target SHIP1 function in vivo, SHIPi also significantly increases plasma granulocyte colony-stimulating factor (G-CSF) levels, a growth factor that supports proliferation of HSC. Here, we show that SHIPi-induced G-CSF production mediates HSC and MSC expansion, as in vivo neutralization of G-CSF abrogates the SHIPi-induced expansion of both the HSC and MSC compartments. Due to its expansionary effect on adult stem cell compartments, SHIPi represents a potential novel strategy to improve declining stem cell function in both therapy induced and genetically derived bone marrow failure syndromes. © 2014 AlphaMed Press.

  18. Lineage-related cytotoxicity and clonogenic profile of 1,4-benzoquinone-exposed hematopoietic stem and progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Chow, Paik Wah [Biomedical Science Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Toxicology Laboratory, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur (Malaysia); Abdul Hamid, Zariyantey, E-mail: zyantey@ukm.edu.my [Biomedical Science Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Toxicology Laboratory, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur (Malaysia); Chan, Kok Meng [Environmental Health and Industrial Safety Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Toxicology Laboratory, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur (Malaysia); Inayat-Hussain, Salmaan Hussain [Environmental Health and Industrial Safety Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Rajab, Nor Fadilah [Biomedical Science Programme, School of Diagnostic & Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Abdul Muda Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan (Malaysia); Toxicology Laboratory, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur (Malaysia)

    2015-04-01

    Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are sensitive targets for benzene-induced hematotoxicity and leukemogenesis. The impact of benzene exposure on the complex microenvironment of HSCs and HPCs remains elusive. This study aims to investigate the mechanism linking benzene exposure to targeting HSCs and HPCs using phenotypic and clonogenic analyses. Mouse bone marrow (BM) cells were exposed ex vivo to the benzene metabolite, 1,4-benzoquinone (1,4-BQ), for 24 h. Expression of cellular surface antigens for HSC (Sca-1), myeloid (Gr-1, CD11b), and lymphoid (CD45, CD3e) populations were confirmed by flow cytometry. The clonogenicity of cells was studied using the colony-forming unit (CFU) assay for multilineage (CFU-GM and CFU-GEMM) and single-lineage (CFU-E, BFU-E, CFU-G, and CFU-M) progenitors. 1,4-BQ demonstrated concentration-dependent cytotoxicity in mouse BM cells. The percentage of apoptotic cells increased (p < 0.05) following 1,4-BQ exposure. Exposure to 1,4-BQ showed no significant effect on CD3e{sup +} cells but reduced the total counts of Sca-1{sup +}, CD11b{sup +}, Gr-1{sup +}, and CD45{sup +} cells at 7 and 12 μM (p < 0.05). Furthermore, the CFU assay showed reduced (p < 0.05) clonogenicity in 1,4-BQ-treated cells. 1,4-BQ induced CFU-dependent cytotoxicity by significantly inhibiting colony growth for CFU-E, BFU-E, CFU-G, and CFU-M starting at a low concentration of exposure (5 μM); whereas for the CFU-GM and CFU-GEMM, the inhibition of colony growth was remarkable only at 7 and 12 μM of 1,4-BQ, respectively. Taken together, 1,4-BQ caused lineage-related cytotoxicity in mouse HPCs, demonstrating greater toxicity in single-lineage progenitors than in those of multi-lineage. - Highlights: • We examine 1,4-BQ toxicity targeting mouse hematopoietic cell lineages. • 1,4-BQ induces concentration-dependent cytotoxicity in bone marrow (BM) cells. • 1,4-BQ shows lineage-related toxicity on hematopoietic stem and

  19. Lineage-related cytotoxicity and clonogenic profile of 1,4-benzoquinone-exposed hematopoietic stem and progenitor cells

    International Nuclear Information System (INIS)

    Chow, Paik Wah; Abdul Hamid, Zariyantey; Chan, Kok Meng; Inayat-Hussain, Salmaan Hussain; Rajab, Nor Fadilah

    2015-01-01

    Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are sensitive targets for benzene-induced hematotoxicity and leukemogenesis. The impact of benzene exposure on the complex microenvironment of HSCs and HPCs remains elusive. This study aims to investigate the mechanism linking benzene exposure to targeting HSCs and HPCs using phenotypic and clonogenic analyses. Mouse bone marrow (BM) cells were exposed ex vivo to the benzene metabolite, 1,4-benzoquinone (1,4-BQ), for 24 h. Expression of cellular surface antigens for HSC (Sca-1), myeloid (Gr-1, CD11b), and lymphoid (CD45, CD3e) populations were confirmed by flow cytometry. The clonogenicity of cells was studied using the colony-forming unit (CFU) assay for multilineage (CFU-GM and CFU-GEMM) and single-lineage (CFU-E, BFU-E, CFU-G, and CFU-M) progenitors. 1,4-BQ demonstrated concentration-dependent cytotoxicity in mouse BM cells. The percentage of apoptotic cells increased (p < 0.05) following 1,4-BQ exposure. Exposure to 1,4-BQ showed no significant effect on CD3e + cells but reduced the total counts of Sca-1 + , CD11b + , Gr-1 + , and CD45 + cells at 7 and 12 μM (p < 0.05). Furthermore, the CFU assay showed reduced (p < 0.05) clonogenicity in 1,4-BQ-treated cells. 1,4-BQ induced CFU-dependent cytotoxicity by significantly inhibiting colony growth for CFU-E, BFU-E, CFU-G, and CFU-M starting at a low concentration of exposure (5 μM); whereas for the CFU-GM and CFU-GEMM, the inhibition of colony growth was remarkable only at 7 and 12 μM of 1,4-BQ, respectively. Taken together, 1,4-BQ caused lineage-related cytotoxicity in mouse HPCs, demonstrating greater toxicity in single-lineage progenitors than in those of multi-lineage. - Highlights: • We examine 1,4-BQ toxicity targeting mouse hematopoietic cell lineages. • 1,4-BQ induces concentration-dependent cytotoxicity in bone marrow (BM) cells. • 1,4-BQ shows lineage-related toxicity on hematopoietic stem and progenitors. • 1,4-BQ

  20. Aging of hematopoietic stem cells: DNA damage and mutations?

    Science.gov (United States)

    Moehrle, Bettina M; Geiger, Hartmut

    2016-10-01

    Aging in the hematopoietic system and the stem cell niche contributes to aging-associated phenotypes of hematopoietic stem cells (HSCs), including leukemia and aging-associated immune remodeling. Among others, the DNA damage theory of aging of HSCs is well established, based on the detection of a significantly larger amount of γH2AX foci and a higher tail moment in the comet assay, both initially thought to be associated with DNA damage in aged HSCs compared with young cells, and bone marrow failure in animals devoid of DNA repair factors. Novel data on the increase in and nature of DNA mutations in the hematopoietic system with age, the quality of the DNA damage response in aged HSCs, and the nature of γH2AX foci question a direct link between DNA damage and the DNA damage response and aging of HSCs, and rather favor changes in epigenetics, splicing-factors or three-dimensional architecture of the cell as major cell intrinsic factors of HSCs aging. Aging of HSCs is also driven by a strong contribution of aging of the niche. This review discusses the DNA damage theory of HSC aging in the light of these novel mechanisms of aging of HSCs. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  1. SBR-Blood: systems biology repository for hematopoietic cells.

    Science.gov (United States)

    Lichtenberg, Jens; Heuston, Elisabeth F; Mishra, Tejaswini; Keller, Cheryl A; Hardison, Ross C; Bodine, David M

    2016-01-04

    Extensive research into hematopoiesis (the development of blood cells) over several decades has generated large sets of expression and epigenetic profiles in multiple human and mouse blood cell types. However, there is no single location to analyze how gene regulatory processes lead to different mature blood cells. We have developed a new database framework called hematopoietic Systems Biology Repository (SBR-Blood), available online at http://sbrblood.nhgri.nih.gov, which allows user-initiated analyses for cell type correlations or gene-specific behavior during differentiation using publicly available datasets for array- and sequencing-based platforms from mouse hematopoietic cells. SBR-Blood organizes information by both cell identity and by hematopoietic lineage. The validity and usability of SBR-Blood has been established through the reproduction of workflows relevant to expression data, DNA methylation, histone modifications and transcription factor occupancy profiles. Published by Oxford University Press on behalf of Nucleic Acids Research 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  2. The transcriptional landscape of hematopoietic stem cell ontogeny

    Science.gov (United States)

    McKinney-Freeman, Shannon; Cahan, Patrick; Li, Hu; Lacadie, Scott A.; Huang, Hsuan-Ting; Curran, Matthew; Loewer, Sabine; Naveiras, Olaia; Kathrein, Katie L.; Konantz, Martina; Langdon, Erin M.; Lengerke, Claudia; Zon, Leonard I.; Collins, James J.; Daley, George Q.

    2012-01-01

    Transcriptome analysis of adult hematopoietic stem cells (HSC) and their progeny has revealed mechanisms of blood differentiation and leukemogenesis, but a similar analysis of HSC development is lacking. Here, we acquired the transcriptomes of developing HSC purified from >2500 murine embryos and adult mice. We found that embryonic hematopoietic elements clustered into three distinct transcriptional states characteristic of the definitive yolk sac, HSCs undergoing specification, and definitive HSCs. We applied a network biology-based analysis to reconstruct the gene regulatory networks of sequential stages of HSC development and functionally validated candidate transcriptional regulators of HSC ontogeny by morpholino-mediated knock-down in zebrafish embryos. Moreover, we found that HSCs from in vitro differentiated embryonic stem cells closely resemble definitive HSC, yet lack a Notch-signaling signature, likely accounting for their defective lymphopoiesis. Our analysis and web resource (http://hsc.hms.harvard.edu) will enhance efforts to identify regulators of HSC ontogeny and facilitate the engineering of hematopoietic specification. PMID:23122293

  3. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3

    Science.gov (United States)

    Rimmelé, Pauline; Liang, Raymond; Bigarella, Carolina L; Kocabas, Fatih; Xie, Jingjing; Serasinghe, Madhavika N; Chipuk, Jerry; Sadek, Hesham; Zhang, Cheng Cheng; Ghaffari, Saghi

    2015-01-01

    Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3−/− HSC that are defective in their activity. We show that Foxo3−/− HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3−/− hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3−/− HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells. PMID:26209246

  4. Cell cycle regulation of hematopoietic stem or progenitor cells.

    Science.gov (United States)

    Hao, Sha; Chen, Chen; Cheng, Tao

    2016-05-01

    The highly regulated process of blood production is achieved through the hierarchical organization of hematopoietic stem cell (HSC) subsets and their progenies, which differ in self-renewal and differentiation potential. Genetic studies in mice have demonstrated that cell cycle is tightly controlled by the complex interplay between extrinsic cues and intrinsic regulatory pathways involved in HSC self-renewal and differentiation. Deregulation of these cellular programs may transform HSCs or hematopoietic progenitor cells (HPCs) into disease-initiating stem cells, and can result in hematopoietic malignancies such as leukemia. While previous studies have shown roles for some cell cycle regulators and related signaling pathways in HSCs and HPCs, a more complete picture regarding the molecular mechanisms underlying cell cycle regulation in HSCs or HPCs is lacking. Based on accumulated studies in this field, the present review introduces the basic components of the cell cycle machinery and discusses their major cellular networks that regulate the dormancy and cell cycle progression of HSCs. Knowledge on this topic would help researchers and clinicians to better understand the pathogenesis of relevant blood disorders and to develop new strategies for therapeutic manipulation of HSCs.

  5. Herpes zoster-associated voiding dysfunction in hematopoietic malignancy patients.

    Science.gov (United States)

    Imafuku, Shinichi; Takahara, Masakazu; Uenotsuchi, Takeshi; Iwato, Koji; Furue, Masutaka

    2008-01-01

    Voiding dysfunction is a rare but important complication of lumbo-sacral herpes zoster. Although the symptoms are transient, the clinical impact on immunocompromised patients cannot be overlooked. To clarify the time course of voiding dysfunction in herpes zoster, 13 herpes zoster patients with voiding dysfunction were retrospectively analyzed. Of 13 patients, 12 had background disease, and six of these were hematopoietic malignancies; four of these patients were hematopoietic stem cell transplant (HSCT) recipients. Ten patients had sacral lesions, two had lumbar, and one had thoracic lesions. Interestingly, patients with severe rash, or with hematopoietic malignancy had later onset of urinary retention than did patients with mild skin symptoms (Mann-Whitney U analysis, P = 0.053) or with other background disease (P = 0.0082). Patients with severe skin rash also had longer durations (P = 0.035). In one case, acute urinary retention occurred as late as 19 days after the onset of skin rash. In immune compromised subjects, attention should be paid to patients with herpes zoster in the lumbo-sacral area for late onset of acute urinary retention even after the resolution of skin symptoms.

  6. TET2 deficiency inhibits mesoderm and hematopoietic differentiation in human embryonic stem cells

    DEFF Research Database (Denmark)

    Langlois, Thierry; da Costa Reis Monte Mor, Barbara; Lenglet, Gaëlle

    2014-01-01

    . Here, we show that TET2 expression is low in human embryonic stem (ES) cell lines and increases during hematopoietic differentiation. ShRNA-mediated TET2 knockdown had no effect on the pluripotency of various ES cells. However, it skewed their differentiation into neuroectoderm at the expense...... profile, including abnormal expression of neuronal genes. Intriguingly, when TET2 was knockdown in hematopoietic cells, it increased hematopoietic development. In conclusion, our work suggests that TET2 is involved in different stages of human embryonic development, including induction of the mesoderm...... and hematopoietic differentiation. Stem Cells 2014....

  7. Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII- and PI3K-dependent mechanisms synergizing in leukemogenic rearrangements.

    Science.gov (United States)

    Biechonski, Shahar; Gourevich, Dana; Rall, Melanie; Aqaqe, Nasma; Yassin, Muhammad; Zipin-Roitman, Adi; Trakhtenbrot, Luba; Olender, Leonid; Raz, Yael; Jaffa, Ariel J; Grisaru, Dan; Wiesmuller, Lisa; Elad, David; Milyavsky, Michael

    2017-02-15

    Quercetin (Que) is an abundant flavonoid in the human diet and high-concentration food supplement with reported pro- and anti-carcinogenic activities. Topoisomerase II (TopoII) inhibition and subsequent DNA damage induction by Que was implicated in the mixed lineage leukemia gene (MLL) rearrangements that can induce infant and adult leukemias. This notion raised concerns regarding possible genotoxicities of Que in hematopoietic stem and progenitor cells (HSPCs). However, molecular targets mediating Que effects on DNA repair relevant to MLL translocations have not been defined. In this study we describe novel and potentially genotoxic Que activities in suppressing non-homologous end joining and homologous recombination pathways downstream of MLL cleavage. Using pharmacological dissection of DNA-PK, ATM and PI3K signalling we defined PI3K inhibition by Que with a concomitant decrease in the abundance of key DNA repair genes to be responsible for DNA repair inhibition. Evidence for the downstream TopoII-independent mutagenic potential of Que was obtained by documenting further increased frequencies of MLL rearrangements in human HSPCs concomitantly treated with Etoposide and Que versus single treatments. Importantly, by engaging a tissue engineered placental barrier, we have established the extent of Que transplacental transfer and hence provided the evidence for Que reaching fetal HSPCs. Thus, Que exhibits genotoxic effects in human HSPCs via different mechanisms when applied continuously and at high concentrations. In light of the demonstrated Que transfer to the fetal compartment our findings are key to understanding the mechanisms underlying infant leukemia and provide molecular markers for the development of safety values. © 2016 UICC.

  8. Genetic DNA profile in urine and hair follicles from patients who have undergone allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Santurtún, Ana; Riancho, José A; Santurtún, Maite; Richard, Carlos; Colorado, M Mercedes; García Unzueta, Mayte; Zarrabeitia, María T

    2017-09-01

    Biological samples from patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) constitute a challenge for individual identification. In this study we analyzed the genetic profiles (by the amplification of 15 autosomic STRs) of HSCT patients found in different types of samples (blood, hair and urine) that may be the source of DNA in civil or criminal forensic cases. Our results show that while in hair follicles the donor component was not detected in any patient, thus being a reliable source of biological material for forensic identification, mixed chimerism was detected in urine samples from all patient, and no correlation was found between the time elapsed from the transplant and the percentage of chimerism. These results certainly have practical implications if the urine is being considered as a source of DNA for identification purposes in HSTC patients. Moreover, taking into consideration that chimerism was found not only in patients with leukocyturia (given the hematopoietic origin of leukocytes, this was expected), but also in those without observable leukocytes in the sediment, we conclude that an alternative source or sources of donor DNA must be implicated. Copyright © 2017 The Chartered Society of Forensic Sciences. Published by Elsevier B.V. All rights reserved.

  9. Hematopoietic Stem and Progenitor Cell Expansion in Contact with Mesenchymal Stromal Cells in a Hanging Drop Model Uncovers Disadvantages of 3D Culture

    Directory of Open Access Journals (Sweden)

    Olga Schmal

    2016-01-01

    Full Text Available Efficient ex vivo expansion of hematopoietic stem cells with a concomitant preservation of stemness and self-renewal potential is still an unresolved ambition. Increased numbers of methods approaching this issue using three-dimensional (3D cultures were reported. Here, we describe a simplified 3D hanging drop model for the coculture of cord blood-derived CD34+ hematopoietic stem and progenitor cells (HSPCs with bone marrow-derived mesenchymal stromal cells (MSCs. When seeded as a mixed cell suspension, MSCs segregated into tight spheroids. Despite the high expression of niche-specific extracellular matrix components by spheroid-forming MSCs, HSPCs did not migrate into the spheroids in the initial phase of coculture, indicating strong homotypic interactions of MSCs. After one week, however, HSPC attachment increased considerably, leading to spheroid collapse as demonstrated by electron microscopy and immunofluorescence staining. In terms of HSPC proliferation, the conventional 2D coculture system was superior to the hanging drop model. Furthermore, expansion of primitive hematopoietic progenitors was more favored in 2D than in 3D, as analyzed in colony-forming assays. Conclusively, our data demonstrate that MSCs, when arranged with a spread (monolayer shape, exhibit better HSPC supportive qualities than spheroid-forming MSCs. Therefore, 3D systems are not necessarily superior to traditional 2D culture in this regard.

  10. Hematopoietic Stem and Progenitor Cell Expansion in Contact with Mesenchymal Stromal Cells in a Hanging Drop Model Uncovers Disadvantages of 3D Culture.

    Science.gov (United States)

    Schmal, Olga; Seifert, Jan; Schäffer, Tilman E; Walter, Christina B; Aicher, Wilhelm K; Klein, Gerd

    2016-01-01

    Efficient ex vivo expansion of hematopoietic stem cells with a concomitant preservation of stemness and self-renewal potential is still an unresolved ambition. Increased numbers of methods approaching this issue using three-dimensional (3D) cultures were reported. Here, we describe a simplified 3D hanging drop model for the coculture of cord blood-derived CD34(+) hematopoietic stem and progenitor cells (HSPCs) with bone marrow-derived mesenchymal stromal cells (MSCs). When seeded as a mixed cell suspension, MSCs segregated into tight spheroids. Despite the high expression of niche-specific extracellular matrix components by spheroid-forming MSCs, HSPCs did not migrate into the spheroids in the initial phase of coculture, indicating strong homotypic interactions of MSCs. After one week, however, HSPC attachment increased considerably, leading to spheroid collapse as demonstrated by electron microscopy and immunofluorescence staining. In terms of HSPC proliferation, the conventional 2D coculture system was superior to the hanging drop model. Furthermore, expansion of primitive hematopoietic progenitors was more favored in 2D than in 3D, as analyzed in colony-forming assays. Conclusively, our data demonstrate that MSCs, when arranged with a spread (monolayer) shape, exhibit better HSPC supportive qualities than spheroid-forming MSCs. Therefore, 3D systems are not necessarily superior to traditional 2D culture in this regard.

  11. Multi-Wave Mixing Processes

    CERN Document Server

    Zhang, Yanpeng

    2009-01-01

    "Multi-Wave Mixing Processes - From Ultrafast Polarization Beats to Electromagnetically Induced Transparency" discusses the interactions of efficient multi-wave mixing (MWM) processes enhanced by atomic coherence in multilevel atomic systems. It covers topics in five major areas: attosecond and femtosecond polarization beats of four-wave mixing (FWM) processes; heterodyne detection of FWM, six-wave mixing (SWM) and eight-wave mixing (EWM) processes; Raman and Rayleigh enhanced polarization beats; coexistence and interactions of MWM processes via electromagnetically induced transparency(EIT); multi-dressing MWM processes. The book is intended for researchers, advanced undergraduate and graduate students in Nonlinear Optics. Dr. Yanpeng Zhang is a professor at the Key Laboratory for Physical Electronics and Devices of the Ministry of Education, Xi'an Jiaotong University. Dr. Min Xiao is a professor of Physics at University of Arkansas, Fayetteville, U.S.A.

  12. Chinese Herbal Formula, Modified Danggui Buxue Tang, Attenuates Apoptosis of Hematopoietic Stem Cells in Immune-Mediated Aplastic Anemia Mouse Model

    Directory of Open Access Journals (Sweden)

    Jingwei Zhou

    2017-01-01

    Full Text Available A derivative formula, DGBX, which is composed of three herbs (Radix astragali, Radix Angelicae sinensis, and Coptis chinensis Franch, is derived from a famous Chinese herbal formula, Danggui Buxue Tang (DBT (Radix astragali and Radix Angelicae sinensis. We aimed to investigate the effects of DGBX on the regulation of the balance between proliferation and apoptosis of hematopoietic stem cells (HSCs due to the aberrant immune response in a mouse model of aplastic anemia (AA. Cyclosporine (CsA, an immunosuppressor, was used as the positive control. Our results indicated that DGBX could downregulate the production of IFNγ in bone marrow cells by interfering with the binding between SLAM and SAP and the expressions of Fyn and T-bet. This herbal formula can also inhibit the activation of Fas-mediated apoptosis, interferon regulatory factor-1-induced JAK/Stat, and eukaryotic initiation factor 2 signaling pathways and thereby induce proliferation and attenuate apoptosis of HSCs. In conclusion, DGBX can relieve the immune-mediated destruction of HSCs, repair hematopoietic failure, and recover the hematopoietic function of HSCs in hematogenesis. Therefore, DGBX can be used in traditional medicine against AA as a complementary and alternative immunosuppressive therapeutic formula.

  13. Effects of ionizing radiation on the hematopoietic niche and treatment of acute radiation syndrome by gene therapy in highly-irradiated monkeys

    International Nuclear Information System (INIS)

    Garrigou, Ph.

    2011-01-01

    The hematopoietic stem cell niche represents a complex radiosensitive compartment whose protection is required for recovery from radiation-induced myelosuppression. We initially studied RI effects on endothelial and mesenchymal progenitors by an evaluating radiosensitivity and cell death. Then, we have proposed a new gene therapy strategy based on local and short term secretion of Sonic hedgehog morphogen to favour vascular niche repair and to stimulate residual hematopoietic stem and progenitor cells. We investigated the hematopoietic response of 8-Gy gamma irradiated monkeys to a single intra-osseous injection of xenogeneic multipotent mesenchymal stem cells transduced with a Shh pIRES2 plasmid. Thrombocytopenia and neutropenia duration were significantly reduced in grafted animals and clonogenics normalized from day 42. Areas under the curve of PLTs and ANCs between day 0 and day 30 were significantly higher in treated animals than in controls. Grafting Matrigel TM colonized or not with ASC in immunocompromised mice demonstrated a notable pro-angiogenic activity for Shh-ASC. Long term follow up (180-300 days) confirmed a durable recovery in the four grafted monkeys. Globally this study suggests that grafting Shh-multipotent stem cells may represent a new strategy to cure radiation-induced niche damage. (author)

  14. Mixed parentage

    DEFF Research Database (Denmark)

    Bang Appel, Helene; Singla, Rashmi

    2016-01-01

    Despite an increase in cross border intimate relationships and children of mixed parentage, there is little mention or scholarship about them in the area of childhood and migrancy in the Nordic countries. The international literature implies historical pathologisation, contestation and current...... of identity formation in the . They position themselves as having an “in-between” identity or “ just Danes” in their every day lives among friends, family, and during leisure activities. Thus a new paradigm is evolving away- from the pathologisation of mixed children, simplified one-sided categories...

  15. Mechanistic aspects of radioprotection by todralazine hydrochloride, a hematopoietic stem cell expanding agent

    International Nuclear Information System (INIS)

    Dimri, Manali; Joshi, Jaidev; Jain, Sanjoli; Ghosh, Subhajit; Srivastva, Nitisha; Prem Kumar, Indracanti; Chakrabarti, Rina

    2014-01-01

    Previously, we have reported todralazine hydrochloride, an antihypertensive drug, as a radioprotector and hematopoietic stem cell (HSC) expanding agent. The present study aims at unraveling mechanistic aspects of its radioprotective and HSC expanding potential. Zebrafish Tg (cmyb:GFP) embryos treated with 5 μM todralazine from 24-36 hours post fertilization (hpf), increased the number of HSCs (∼ 2 folds) at aorta gonad mesonephros (AGM) region. Similarly, the expression of HSC marker genes, runx1 (3.3 folds) and cMyb (1.4 folds) were also found to be increased. Further, todralazine also accelerated hematopoietic lineage production, erythropoiesis, as evaluated in chemical induced anemic model in zebrafish. Genome wide expression changes in todralazine treated embryos (from 24-36 hpf) using microarray, revealed up and down regulation of 645 and 429 genes respectively. Pathway analysis using DAVID database strongly suggested up regulation of wnt pathway (p<0.019253), which is known to involve in HSC expansion, in todralazine pre-treated embryos. NOS1, known to have its role in HSC expansion through wnt pathway, has been significantly upregulated (1.54 folds; q PCR) by todralazine treatment (from 24-36 hpf). Todralazine treatment (∼30 minutes; 20 Gy) led to a significant upregulation of antioxidant genes (SOD, catalase), DNA damage response genes (p53, p21, GADD45) and nucleotide excision repair genes (XPC, XPA, XPF, XPD) when compared to irradiated control. Immunohistochemical analysis of DNA damage marker (γH2AX) (30 minutes post irradiation), further supported radiation induced DNA damage and protection by todralazine pre-treatment. Corroborating these results, pre-irradiation treatment of todralazine reduced radiation induced apoptosis (caspase 3 assay). Overall, the results suggest that, todralazine protects zebrafish from radiation induced damages by upregulating antioxidant defense system, DNA damage recognition, DNA repair machinery and by reducing cell

  16. Single thrombopoietin dose alleviates hematopoietic stem cells intrinsic short- and long-term ionizing radiation damage. In vivo identification of anatomical cell expansion sites.

    Science.gov (United States)

    Tronik-Le Roux, Diana; Nicola, Marie-Anne; Vaigot, Pierre; Nurden, Paquita

    2015-01-01

    Hematopoietic stem cells (HSC) are essential for maintaining the integrity of complex and long-lived organisms. HSC, which are self-renewing, reconstitute the hematopoietic system through out life and facilitate long-term repopulation of myeloablated recipients. We have previously demonstrated that when mice are exposed to sublethal doses of ionizing radiation, subsets of the stem/progenitor compartment are affected. In this study we examine the role of thrombopoietin (TPO) on the regenerative capacities of HSC after irradiation and report the first demonstration of efficacy of a single injection of TPO shortly after in vivo exposure to ionizing radiation for reducing HSC injury and improving their functional outcome. Our results demonstrate that TPO treatment not only reduced the number of apoptotic cells but also induced a significant modification of their intrinsic characteristics. These findings were supported by transplantation assays with long-term HSC that were irradiated or unirradiated, TPO treated or untreated, in CD45.1/CD45.2 systems and by using luciferase-labeled HSC for direct bioluminescence imaging in living animals. Of particular importance, our data demonstrate the skull to be a highly favorable site for the TPO-induced emergence of hematopoietic cells after irradiation, suggesting a TPO-mediated relationship of primitive hematopoietic cells to an anatomical component. Together, the data presented here: provide novel findings about aspects of TPO action on stem cells, open new areas of investigation for therapeutic options in patients who are treated with radiation therapy, and show that early administration of a clinically suitable TPO-agonist counteracts the previously observed adverse effects.

  17. Mixed Movements

    DEFF Research Database (Denmark)

    Brabrand, Helle

    2010-01-01

    levels than those related to building, and this exploration is a special challenge and competence implicit artistic development work. The project Mixed Movements generates drawing-material, not primary as representation, but as a performance-based media, making the body being-in-the-media felt and appear...... as possible operational moves....

  18. Lateral Mixing

    Science.gov (United States)

    2014-09-30

    negative (right panel c) and the kinetic energy dissipation is larger than that expected from meterological forcing alone (right panel a). This is...10.1002/grl.50919. Shcherbina, A. et al., 2014, The LatMix Summer Campaign: Submesoscale Stirring in the Upper Ocean., Bull. American Meterological

  19. The role of tumor suppressor p15Ink4b in the regulation of hematopoietic progenitor cell fate

    International Nuclear Information System (INIS)

    Humeniuk, R; Rosu-Myles, M; Fares, J; Koller, R; Bies, J; Wolff, L

    2013-01-01

    Epigenetic silencing of the tumor suppressor gene p15Ink4b (CDKN2B) is a frequent event in blood disorders like acute myeloid leukemia and myelodysplastic syndromes. The molecular function of p15Ink4b in hematopoietic differentiation still remains to be elucidated. Our previous study demonstrated that loss of p15Ink4b in mice results in skewing of the differentiation pattern of the common myeloid progenitor towards the myeloid lineage. Here, we investigated a function of p15Ink4b tumor suppressor gene in driving erythroid lineage commitment in hematopoietic progenitors. It was found that p15Ink4b is expressed more highly in committed megakaryocyte–erythroid progenitors than granulocyte–macrophage progenitors. More importantly, mice lacking p15Ink4b have lower numbers of primitive red cell progenitors and a severely impaired response to 5-fluorouracil- and phenylhydrazine-induced hematopoietic stress. Introduction of p15Ink4b into multipotential progenitors produced changes at the molecular level, including activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling, increase GATA-1, erythropoietin receptor (EpoR) and decrease Pu1, GATA-2 expression. These changes rendered cells more permissive to erythroid commitment and less permissive to myeloid commitment, as demonstrated by an increase in early burst-forming unit-erythroid formation with concomitant decrease in myeloid colonies. Our results indicate that p15Ink4b functions in hematopoiesis, by maintaining proper lineage commitment of progenitors and assisting in rapid red blood cells replenishment following stress

  20. Analysis and manipulation of hematopoietic progenitor and stem cells from murine embryonic tissues

    NARCIS (Netherlands)

    A. Medvinsky (Alexander); S. Taoudi (Samir); S.C. Mendes (Sandra); E.A. Dzierzak (Elaine)

    2008-01-01

    textabstractHematopoietic development begins in several locations in the mammalian embryo: yolk sac, aorta-gonad-mesonephros region (AGM), and the chorio-allantoic placenta. Generation of the most potent cells, adult definitive hematopoietic stem cells (HSCs), occurs within the body of the mouse

  1. An in vitro model of hemogenic endothelium commitment and hematopoietic production

    NARCIS (Netherlands)

    Yvernogeau, Laurent; Gautier, Rodolphe; Khoury, Hanane; Menegatti, Sara; Schmidt, Melanie; Gilles, Jean Francois; Jaffredo, Thierry

    2016-01-01

    Adult-type hematopoietic stem and progenitor cells are formed during ontogeny from a specialized subset of endothelium, termed the hemogenic endothelium, via an endothelial-to-hematopoietic transition (EHT) that occurs in the embryonic aorta and the associated arteries. Despite efforts to generate

  2. Aging of hematopoietic stem cells : Intrinsic changes or micro-environmental effects?

    NARCIS (Netherlands)

    Woolthuis, Carolien M.; de Haan, Gerald; Huls, Gerwin

    During development hematopoietic stem cells (HSCs) expand in number and persist throughout life by undergoing self-renewing divisions. Nevertheless, the hematopoietic system does not escape the negative effects of aging, suggesting that self-renewal is not complete. A fundamental issue in stem cell

  3. Aging impairs long-term hematopoietic regeneration after autologous stem cell transplantation

    NARCIS (Netherlands)

    Woolthuis, Carolien M; Mariani, Niccoló; Verkaik-Schakel, Rikst Nynke; Brouwers-Vos, Annet Z.; Schuringa, Jan Jacob; Vellenga, Edo; de Wolf, Joost T M; Huls, Gerwin

    Most of our knowledge of the effects of aging on the hematopoietic system comes from studies in animal models. In this study, to explore potential effects of aging on human hematopoietic stem and progenitor cells (HSPCs), we evaluated CD34(+) cells derived from young (<35 years) and old (>60 years)

  4. Effects of hematopoietic growth factors on purified bone marrow progenitor cells

    NARCIS (Netherlands)

    F.J. Bot (Freek)

    1992-01-01

    textabstractWe have used highly enriched hematopoietic progenitor cells and in-vitro culture to examine the following questions: 1. The effects of recombinant lL-3 and GM-CSF on proliferation and differentiation of enriched hematopoietic progenitor cells have not been clearly defined: - how do IL~3

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

    NARCIS (Netherlands)

    T.C. Luis (Tiago)

    2010-01-01

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  7. Pharmacoeconomics of Hematopoietic Stem Cell Mobilization : An Overview of Current Evidence and Gaps in the Literature

    NARCIS (Netherlands)

    Shaughnessy, Paul; Chao, Nelson; Shapiro, Jamie; Walters, Kent; McCarty, John; Abhyankar, Sunil; Shayani, Sepideh; Helmons, Pieter; Leather, Helen; Pazzalia, Amy; Pickard, Simon

    Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have

  8. Autologous hematopoietic stem cell transplantation in classical Hodgkin's lymphoma

    Directory of Open Access Journals (Sweden)

    Afonso José Pereira Cortez

    2011-02-01

    Full Text Available BACKGROUND: Hodgkin's lymphoma has high rates of cure, but in 15% to 20% of general patients and between 35% and 40% of those in advanced stages, the disease will progress or will relapse after initial treatment. For this group, hematopoietic stem cell transplantation is considered one option of salvage therapy. OBJECTIVES: To evaluate a group of 106 patients with Hodgkin's lymphoma, who suffered relapse or who were refractory to treatment, submitted to autologous hematopoietic stem cell transplantation in a single transplant center. METHODS: A retrospective study was performed with data collected from patient charts. The analysis involved 106 classical Hodgkin's lymphoma patients who were consecutively submitted to high-dose chemotherapy followed by autologous transplants in a single institution from April 1993 to December 2006. RESULTS: The overall survival rates of this population at five and ten years were 86% and 70%, respectively. The disease-free survival was approximately 60% at five years. Four patients died of procedure-related causes but relapse of classical Hodgkin's lymphoma after transplant was the most frequent cause of death. Univariate analysis shows that sensitivity to pre-transplant treatment and hemoglobin < 10 g/dL at diagnosis had an impact on patient survival. Unlike other studies, B-type symptoms did not seem to affect overall survival. Lactic dehydrogenase and serum albumin concentrations analyzed at diagnosis did not influence patient survival either. CONCLUSION: Autologous hematopoietic stem cell transplantation is an effective treatment strategy for early and late relapse in classical Hodgkin's lymphoma for cases that were responsive to pre-transplant chemotherapy. Refractory to treatment is a sign of worse prognosis. Additionally, a hemoglobin concentration below 10 g/dL at diagnosis of Hodgkin's lymphoma has a negative impact on the survival of patients after transplant. As far as we know this relationship has not

  9. Oxidative stress in normal hematopoietic stem cells and leukemia.

    Science.gov (United States)

    Samimi, Azin; Kalantari, Heybatullah; Lorestani, Marzieh Zeinvand; Shirzad, Reza; Saki, Najmaldin

    2018-04-01

    Leukemia is developed following the abnormal proliferation of immature hematopoietic cells in the blood when hematopoietic stem cells lose the ability to turn into mature cells at different stages of maturation and differentiation. Leukemia initiating cells are specifically dependent upon the suppression of oxidative stress in the hypoglycemic bone marrow (BM) environment to be able to start their activities. Relevant literature was identified by a PubMed search (2000-2017) of English-language literature using the terms 'oxidative stress,' 'reactive oxygen species,' 'hematopoietic stem cell,' and 'leukemia.' The generation and degradation of free radicals is a main component of the metabolism in aerobic organisms. A certain level of ROS is required for proper cellular function, but values outside this range will result in oxidative stress (OS). Long-term overactivity of reactive oxygen species (ROS) has harmful effects on the function of cells and their vital macromolecules, including the transformation of proteins into autoantigens and increased degradation of protein/DNA, which eventually leads to the change in pathways involved in the development of cancer and several other disorders. According to the metabolic disorders of cancer, the relationship between OS changes, the viability of cancer cells, and their response to chemotherapeutic agents affecting this pathway are undeniable. Recently, studies have been conducted to determine the effect of herbal agents and cancer chemotherapy drugs on oxidative stress pathways. By emphasizing the role of oxidative stress on stem cells in the incidence of leukemia, this paper attempts to state and summarize this subject. © 2018 APMIS. Published by John Wiley & Sons Ltd.

  10. The Hematopoietic Stem Cell Therapy for Exploration of Space

    Science.gov (United States)

    Roach, Allana Nicole; Brezo, Jelena

    2002-01-01

    Astronauts experience severe/invasive disorders caused by space environments. These include hematological/cardiac abnormalities, bone and muscle losses, immunodeficiency, neurological disorders and cancer. While the cause of these symptoms are not yet fully delineated, one possible explanation could be the inhibition of hematopoietic stem cell (HSC) growth and hematopoiesis in space. HSCs differentiate into all types of blood cells, and growing evidence indicates that the HSCs also have the ability to transdifferentiate to various tissues, including muscle, skin, liver, neuronal cells and possibly bone. Therefore, a hypothesis was advanced in this laboratory that the hematopoietic stem cell-based therapy, herein called the hematopoietic stem cell therapy (HSCT), could mitigate some of the disorders described above. Due to the magnitude of this project our laboratory has subdivided it into 3 sections: a) HSCT for space anemia; b) HSCT for muscle and bone losses; and c) HSCT for immunodeficiency. Toward developing the HSCT protocol for space anemia, the HSC transplantation procedure was established using a mouse model of beta thalassemia. In addition, the NASA Rotating Wall Vessel (RWV) culture system was used to grow HSCs in space condition. To investigate the HSCT for muscle loss and bone loss, donor HSCs were genetically marked either by transfecting the beta-galactosidase-containing plasmid, pCMV.SPORT-beta-gal or by preparing from b-galactosidase transgenic mice. The transdifferentiation of HSCs to muscle is traced by the reporter gene expression in the hindlimb suspended mice with some positive outcome, as studied by the X-gal staining procedure. The possible structural contribution of HSCs against muscle loss is being investigated histochemically.

  11. Gene transfer to pre-hematopoietic and committed hematopoietic precursors in the early mouse Yolk Sac: a comparative study between in situ electroporation and retroviral transduction

    Directory of Open Access Journals (Sweden)

    Lécluse Yann

    2007-07-01

    Full Text Available Abstract Background Hematopoietic development in vertebrate embryos results from the sequential contribution of two pools of precursors independently generated. While intra-embryonic precursors harbour the features of hematopoietic stem cells (HSC, precursors formed earlier in the yolk sac (YS display limited differentiation and self-renewal potentials. The mechanisms leading to the generation of the precursors in both sites are still largely unknown, as are the molecular basis underlying their different potential. A possible approach to assess the role of candidate genes is to transfer or modulate their expression/activity in both sites. We thus designed and compared transduction protocols to target either native extra-embryonic precursors, or hematopoietic precursors. Results One transduction protocol involves transient modification of gene expression through in situ electroporation of the prospective blood islands, which allows the evolution of transfected mesodermal cells in their "normal" environment, upon organ culture. Following in situ electroporation of a GFP reporter construct into the YS cavity of embryos at post-streak (mesodermal/pre-hematopoietic precursors or early somite (hematopoietic precursors stages, high GFP expression levels as well as a good preservation of cell viability is observed in YS explants. Moreover, the erythro-myeloid progeny typical of the YS arises from GFP+ mesodermal cells or hematopoietic precursors, even if the number of targeted precursors is low. The second approach, based on retroviral transduction allows a very efficient transduction of large precursor numbers, but may only be used to target 8 dpc YS hematopoietic precursors. Again, transduced cells generate a progeny quantitatively and qualitatively similar to that of control YS. Conclusion We thus provide two protocols whose combination may allow a thorough study of both early and late events of hematopoietic development in the murine YS. In situ

  12. Selection of genetically modified hematopoietic cells in vitro and in vivo using alkylating agent lysomustine.

    Science.gov (United States)

    Rozov, F N; Grinenko, T S; Levit, G L; Krasnov, V P; Belyavsky, A V

    2010-09-15

    Efficient gene transfer into hematopoietic stem cells is vital for the success of gene therapy of hematopoietic and immune system disorders. An in vivo selection system based on a mutant form of the O(6)-methylguanine-DNA-methyltransferase gene (MGMTm) is considered one of the more promising strategies for expansion of hematopoietic cells transduced with viral vectors. Here we demonstrate that MGMTm-expressing cells can be efficiently selected using lysomustine, a nitrosourea derivative of lysine. K562 and murine bone marrow cells expressing MGMTm are protected from the cytotoxic action of lysomustine in vitro. We also show in a murine model that MGMTm-transduced hematopoietic cells can be expanded in vivo on transplantation into sublethally irradiated recipients followed by lysomustine treatment. These results indicate that lysomustine can be used as a potent novel chemoselection drug applicable for gene therapy of hematopoietic and immune system disorders. 2010 Elsevier Inc. All rights reserved.

  13. Explanation of application standards of hematopoietic stimulating factors in the treatment of acute radiation sickness

    International Nuclear Information System (INIS)

    Xing Zhiwei; Jiang Enhai; Wang Guilin; Luo Qingliang

    2012-01-01

    Occupational standard of the Ministry of health-Application Standards of Hematopoietic Stimulating Factors in the Treatment of Acute Radiation Sickness has been completed as a draft standard. Based on the wide study and analysis of related animal experimental literature about hematopoietic stimulating factor in the treatment of acute radiation sickness and domestic and foreign clinical reports about application of hematopoietic stimulating factor in radiation accidents in the past decade, the standard was enacted according to the suggestions of International Atomic Energy Agency and the United States Strategic National Stockpile Radiation Working Group and European countries about the application of hematopoietic stimulating factor. It is mainly used for nuclear accident emergency and the treatment of the bone marrow form of acute radiation sickness caused by radiation accidents. It also applies to other hematopoietic failure diseases. In order to implement this standard correctly, the relevant contents of the standard were interpreted in this article. (authors)

  14. Effects of medium-induced ρ-ω meson mixing on the equation of state in isospin-asymmetric nuclear matter

    International Nuclear Information System (INIS)

    Jiang Weizhou; Li Baoan

    2009-01-01

    We reexamine effects of the ρ-ω meson mixing mediated by nucleon polarizations on the symmetry energy in isospin-asymmetric nuclear matter. Taking into account the rearrangement term neglected in previous studies by others, we evaluate the ρ-ω mixing angle in a novel way within the relativistic mean-field models with and without chiral limits. It is found that the symmetry energy is significantly softened at high densities contrary to the finding in earlier studies. As the first step of going beyond the lowest-order calculations, we also solve the Dyson equation for the ρ-ω mixing. In this case, it is found that the symmetry energy is not only significantly softened by the ρ-ωmixing at suprasaturation densities, similar to the lowest-order ρ-ω mixing, but interestingly also softened at subsaturation densities. In addition, the softening of the symmetry energy at subsaturation densities can be partly suppressed by the nonlinear self-interaction of the σ meson.

  15. Validation of Effective Models for Simulation of Thermal Stratification and Mixing Induced by Steam Injection into a Large Pool of Water

    Directory of Open Access Journals (Sweden)

    Hua Li

    2014-01-01

    Full Text Available The Effective Heat Source (EHS and Effective Momentum Source (EMS models have been proposed to predict the development of thermal stratification and mixing during a steam injection into a large pool of water. These effective models are implemented in GOTHIC software and validated against the POOLEX STB-20 and STB-21 tests and the PPOOLEX MIX-01 test. First, the EHS model is validated against STB-20 test which shows the development of thermal stratification. Different numerical schemes and grid resolutions have been tested. A 48×114 grid with second order scheme is sufficient to capture the vertical temperature distribution in the pool. Next, the EHS and EMS models are validated against STB-21 test. Effective momentum is estimated based on the water level oscillations in the blowdown pipe. An effective momentum selected within the experimental measurement uncertainty can reproduce the mixing details. Finally, the EHS-EMS models are validated against MIX-01 test which has improved space and time resolution of temperature measurements inside the blowdown pipe. Excellent agreement in averaged pool temperature and water level in the pool between the experiment and simulation has been achieved. The development of thermal stratification in the pool is also well captured in the simulation as well as the thermal behavior of the pool during the mixing phase.

  16. Hematopoietic growth factors for the treatment of myelodysplastic syndromes

    DEFF Research Database (Denmark)

    Hansen, P B; Penkowa, M; Johnsen, H E

    1998-01-01

    with milder forms of MDS combined with low prestudy endogenous S-Epo levels. The possible synergistic effect of combining rhEpo with rhG-CSF or rhGM-CSF has been studied with erythropoietic response rates of about 40%. The safety of the cytokine administration seems acceptable with no significant stimulation...... of leukemic myelopoiesis and subsequent progression into overt acute myeloid leukemia. In conclusion, combinations of hematopoietic growth factors may be of clinical benefit in some patients with MDS. However, due to the cost and unpredictable clinical outcome there is a need for extended laboratory research...

  17. The Hematopoietic Stem Cell Therapy for Exploration of Deep Space

    Science.gov (United States)

    Ohi, Seigo; Roach, Allana-Nicole; Fitzgerald, Wendy; Riley, Danny A.; Gonda, Steven R.

    2003-01-01

    It is hypothesized that the hematopoietic stem cell therapy (HSCT) might countermeasure various space-caused disorders so as to maintain astronauts' homeostasis. If this were achievable, the HSCT could promote human exploration of deep space. Using animal models of disorders (hindlimb suspension unloading system and beta-thalassemia), the HSCT was tested for muscle loss, immunodeficiency and space anemia. The results indicate feasibility of HSCT for these disorders. To facilitate the HSCT in space, growth of HSCs were optimized in the NASA Rotating Wall Vessel (RWV) culture systems, including Hydrodynamic Focusing Bioreactor (HFB).

  18. Next-generation sequencing and FISH studies reveal the appearance of gene mutations and chromosomal abnormalities in hematopoietic progenitors in chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Miguel Quijada-Álamo

    2017-04-01

    genetic alterations in CLL was derived, suggesting that most of the genetic events appear on the hematopoietic progenitors, although these mutations could induce the beginning of tumoral cell expansion at different stage of B cell differentiation. Conclusions Our study showed the presence of both gene mutations and chromosomal abnormalities in early hematopoietic progenitor cells from CLL patients.

  19. Parity mixing

    International Nuclear Information System (INIS)

    Adelberger, E.G.

    1975-01-01

    The field of parity mixing in light nuclei bears upon one of the exciting and active problems of physics--the nature of the fundamental weak interaction. It is also a subject where polarization techniques play a very important role. Weak interaction theory is first reviewed to motivate the parity mixing experiments. Two very attractive systems are discussed where the nuclear physics is so beautifully simple that the experimental observation of tiny effects directly measures parity violating (PV) nuclear matrix elements which are quite sensitive to the form of the basic weak interaction. Since the measurement of very small analyzing powers and polarizations may be of general interest to this conference, some discussion is devoted to experimental techniques

  20. Gene expression profile in bone marrow and hematopoietic stem cells in mice exposed to inhaled benzene

    International Nuclear Information System (INIS)

    Faiola, Brenda; Fuller, Elizabeth S.; Wong, Victoria A.; Recio, Leslie

    2004-01-01

    Acute myeloid leukemia and chronic lymphocytic leukemia are associated with benzene exposure. In mice, benzene induces chromosomal breaks as a primary mode of genotoxicity in the bone marrow (BM). Benzene-induced DNA lesions can lead to changes in hematopoietic stem cells (HSC) that give rise to leukemic clones. To gain insight into the mechanism of benzene-induced leukemia, we investigated the DNA damage repair and response pathways in total bone marrow and bone marrow fractions enriched for HSC from male 129/SvJ mice exposed to benzene by inhalation. Mice exposed to 100 ppm benzene for 6 h per day, 5 days per week for 2 week showed significant hematotoxicity and genotoxicity compared to air-exposed control mice. Benzene exposure did not alter the level of apoptosis in BM or the percentage of HSC in BM. RNA isolated from total BM cells and the enriched HSC fractions from benzene-exposed and air-exposed mice was used for microarray analysis and quantitative real-time RT-PCR. Interestingly, mRNA levels of DNA repair genes representing distinct repair pathways were largely unaffected by benzene exposure, whereas altered mRNA expression of various apoptosis, cell cycle, and growth control genes was observed in samples from benzene-exposed mice. Differences in gene expression profiles were observed between total BM and HSC. Notably, p21 mRNA was highly induced in BM but was not altered in HSC following benzene exposure. The gene expression pattern suggests that HSC isolated immediately following a 2 weeks exposure to 100 ppm benzene were not actively proliferating. Understanding the toxicogenomic profile of the specific target cell population involved in the development of benzene-associated diseases may lead to a better understanding of the mechanism of benzene-induced leukemia and may identify important interindividual and tissue susceptibility factors

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

    Science.gov (United States)

    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. Copyright© Ferrata Storti Foundation.

  2. Bone Shaft Revascularization After Marrow Ablation Is Dramatically Accelerated in BSP-/- Mice, Along With Faster Hematopoietic Recolonization.

    Science.gov (United States)

    Bouleftour, Wafa; Granito, Renata Neves; Vanden-Bossche, Arnaud; Sabido, Odile; Roche, Bernard; Thomas, Mireille; Linossier, Marie Thérèse; Aubin, Jane E; Lafage-Proust, Marie-Hélène; Vico, Laurence; Malaval, Luc

    2017-09-01

    The bone organ integrates the activity of bone tissue, bone marrow, and blood vessels and the factors ensuring this coordination remain ill defined. Bone sialoprotein (BSP) is with osteopontin (OPN) a member of the small integrin binding ligand N-linked glycoprotein (SIBLING) family, involved in bone formation, hematopoiesis and angiogenesis. In rodents, bone marrow ablation induces a rapid formation of medullary bone which peaks by ∼8 days (d8) and is blunted in BSP-/- mice. We investigated the coordinate hematopoietic and vascular recolonization of the bone shaft after marrow ablation of 2 month old BSP+/+ and BSP-/- mice. At d3, the ablated area in BSP-/- femurs showed higher vessel density (×4) and vascular volume (×7) than BSP+/+. Vessel numbers in the shaft of ablated BSP+/+ mice reached BSP-/- values only by d8, but with a vascular volume which was twice the value in BSP-/-, reflecting smaller vessel size in ablated mutants. At d6, a much higher number of Lin - (×3) as well as LSK (Lin - IL-7Rα - Sca-1 hi c-Kit hi , ×2) and hematopoieti