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Journal articles on the topic "BaF3"
1
Kim, Julie, Sofya Rodov, Jacqueline Barrientos, Ravitharan Krishnadasan, and K. Gary J. Vanasse. "Bcl2 Associated Induction of the Suppressor of Cytokine Signaling-3 (SOCS3) Gene Involves Activation of the p44/42 MAPK Pathway." Blood 106, no. 11 (November 16, 2005): 2286. http://dx.doi.org/10.1182/blood.v106.11.2286.2286.
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Abstract SOCS3 has been shown to be an essential regulator of IL-6 signaling in hepatocytes and macrophages, as well as a negative regulator of G-CSF signaling in myeloid cells, and SOCS3 expression appears to be STAT3-dependent. However, the underlying cellular pathways which regulate SOCS3 expression in B cells remain to be clearly defined. We previously showed that polyclonal CD19+ B cells isolated from Bcl2 overexpressing Eμ-Bcl2 transgenic mice overexpress SOCS3 protein and that exogenous expression of Bcl2 in hematopoietic and fibroblast cell lines induces SOCS3 protein expression. We also found that a distinct subset of follicular lymphomas (FL) exhibit combined overexpression of Bcl2 and SOCS3. We hypothesized that Bcl2-mediated induction of SOCS3 in B cells may occur indirectly via deregulation of Bcl2-associated cell signaling pathways. In the current study, IL-3-dependent BaF3 pro-B cells were stably transduced with either a 717bp human Bcl2α cDNA (BaF3/Bcl2) or vector only control (Baf3Δ). Cell lines were initially grown in the presence of IL-3, with IL-3 removed 48 hours prior to protein measurements. Western analysis using Bcl2 antisera revealed high level Bcl2 expression in transduced cells (BaF3/Bcl2) and absence of Bcl2 in BaF3Δ control cells. When probed with SOCS3 antisera, BaF3/Bcl2 cells exhibited marked overexpression of SOCS3 protein whereas BaF3Δ control cells did not express SOCS3. To assess whether Bcl2-associated induction of SOCS3 is STAT3-dependent, we measured phospho-STAT3 levels relative to STAT3 in BaF3/Bcl2 cells. Interestingly, when probed with phospho-STAT3 and STAT3 antisera, BaF3/Bcl2 and BaF3Δ cells did not reveal phospho-STAT3 protein but revealed equivalent STAT3 protein levels. Since we had previously noted overexpression of p44/42 Map kinase (MAPK) in CD19+ B cells from Eμ-Bcl2 transgenic mice relative to littermate controls, we next wanted to determine whether p44/42MAPK signaling played a role in Bcl2-mediated SOCS3 induction. Western analysis using p44/42MAPK antisera revealed overexpression of p44/42MAPK in BaF3/Bcl2 cells relative to BaF3Δ control cells. BaF3/Bcl2 and BaF3Δ cells were then grown in the presence or absence of a specific p44/42MAPK pathway inhibitor (MEK 1/2 inhibitor U0126), and whole cell lysates were analyzed for SOCS3 expression by Western analysis. When probed with SOCS3 antisera, BaF3/Bcl2 cells selectively grown in the presence of the p44/42MAPK inhibitor revealed complete abrogation of SOCS3 protein expression while those grown in the absence of inhibitor continued to harbor SOCS3 protein. As expected, ERK1/2 protein levels were selectively decreased in response to treatment with the p44/42MAPK inhibitor, indicating specific inhibition of the p44/42MAPK pathway. Bcl2 protein levels in BaF3/Bcl2 cells remained unchanged in the presence or absence of the p44/42MAPK inhibitor. As controls, inhibitors of p38MAPK (SB203580), AKT (Triciribine), and PI3K (LY294002) were evaluated and none were found to affect SOCS3 protein levels in BaF3/Bcl2 cells. These data indicate that Bcl2-associated induction of SOCS3 in B cells involves activation of the p44/42MAPK cell signaling pathway and is independent of STAT3 activation. These studies illustrate a novel and previously unappreciated Bcl2-associated signaling pathway involving SOCS3 induction in B cells that may play an important role in B cell biology and in Bcl2-associated hematologic malignancies.
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ROCH, Anne-Marie, Gerard QUASH, Yvonne MICHAL, Jacqueline CHANTEPIE, Bernard CHANTEGREL, Christian DESHAYES, Alain DOUTHEAU, and Jacqueline MARVEL. "Altered methional homoeostasis is associated with decreased apoptosis in BAF3 bcl2 murine lymphoid cells." Biochemical Journal 313, no. 3 (February 1, 1996): 973–81. http://dx.doi.org/10.1042/bj3130973.
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Methional is a potent inducer of apoptosis in an interleukin 3-dependent murine lymphoid cell line BAF3 b0 when it is added to the culture medium. In these cells transfected with the bcl2 gene, BAF3 bcl2, the apoptotic-inducing activity of methional is dramatically reduced. The addition of disulfiram (an inhibitor of aldehyde dehydrogenase) in order to reduce methional oxidation brought about an increase in apoptosis in BAF3 b0 but not in BAF3 bcl2 cells. In contrast, the addition of quercetin (an inhibitor of aldehyde reductase) in an attempt to diminish methional reduction increased apoptosis in both BAF3 b0 and BAF3 bcl2 cells. The extent of DNA fragmentation in BAF3 bcl2 cells approached that in BAF3 b0 cells in the presence of quercetin and exogenous methional, suggesting a defect in methional biosynthesis in BAF3 bcl2 cells. Direct evidence for this was obtained by measuring labelled methional in cells incubated with the sodium salt of [U-14C]4-methylthio-2-oxobutanoic acid (MTOB), the precursor of methional. The 80% decrease in labelled methional in BAF3 bcl2 compared with BAF3 b0 cells was accompanied by a concomitant rise in the transamination of [14C]MTOB to [14C]methionine in BAF3 bcl2 cells. Inhibition of the transaminase, however, by a synthetic transition-state-type compound, pyridoxal-L-methionine ethyl ester, induced apoptosis in BAF3 b0 but not in BAF3 bcl2 cells, confirming that the defect in BAF3 bcl2 cells was not in the transaminase itself but rather in the oxidative decarboxylation step MTOB →methional. In addition, no evidence was obtained for the synthesis of [14C]malondialdehyde from [14C]methional in BAF3 bcl2 cells. As these cells show no deficiency in their content of reactive oxygen species compared with that of BAF3 b0 cells, they may possess some other defect in the β-hydroxylase enzyme system itself.
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Shibayama, Hirohiko, Naoyuki Anzai, Stephen E. Braun, Seiji Fukuda, Charlie Mantel, and Hal E. Broxmeyer. "H-Ras Is Involved in the Inside-out Signaling Pathway of Interleukin-3–Induced Integrin Activation." Blood 93, no. 5 (March 1, 1999): 1540–48. http://dx.doi.org/10.1182/blood.v93.5.1540.
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Abstract The proto-oncogene product, p21ras, has been implicated in the cellular mechanism of adhesion, although its precise role has been controversial. Numerous cytokines and growth-factors activate Ras, which is an important component of their growth-promoting signaling pathways. On the other hand, the role of Ras in cytokine-induced adhesion has not been elucidated. We therefore investigated the function of H-Ras in the inside-out signaling pathway of interleukin-3 (IL-3)–induced integrin activation in the murine Baf3 cell line after transfection of cells with either constitutively active, dominant-negative, or wild-type H-Ras cDNAs. Adhesion of Baf3 cells to fibronectin was induced by IL-3 in a dose-dependent manner via very late antigen-4 (VLA-4; 4β1 integrins) and VLA-5 (5β1 integrins) activation. On the other hand, IL-4 did not induce the adhesion of Baf3 cells to fibronectin, although IL-4 did stimulate the cell proliferation of Baf3 cells. Constitutively active H-Ras–transfected Baf3 cells adhered to fibronectin without IL-3 stimulation through VLA-4 and VLA-5, whereas dominant-negative H-Ras–transfected Baf3 cells showed significantly less adhesion induced by IL-3 compared with wild-type and constitutively active H-Ras–transfected Baf3 cells. Anti-β1 integrin antibody (clone; 9EG7), which is known to change integrin conformation and activate integrins, induced the adhesion of dominant-negative H-Ras–transfected Baf3 cells as much as the other types of H-Ras–transfected Baf3 cells. 8-Br-cAMP, Dibutyryl-cAMP, Ras-Raf-1 pathway inhibitors, and PD98059, a MAPK kinase inhibitor, suppressed proliferation and phosphorylation of MAPK detected by Western blotting with anti–phospho-MAPK antibody, but not adhesion of any type of H-Ras–transfected Baf3 cells, whereas U-73122, a phospholipase C (PLC) inhibitor, suppressed adhesion of these cells completely. These data indicate that H-Ras and PLC, but not Raf-1, MAPK kinase, or the MAPK pathway, are involved in the inside-out signaling pathway of IL-3–induced VLA-4 and VLA-5 activation in Baf3 cells.
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Shibayama, Hirohiko, Naoyuki Anzai, Stephen E. Braun, Seiji Fukuda, Charlie Mantel, and Hal E. Broxmeyer. "H-Ras Is Involved in the Inside-out Signaling Pathway of Interleukin-3–Induced Integrin Activation." Blood 93, no. 5 (March 1, 1999): 1540–48. http://dx.doi.org/10.1182/blood.v93.5.1540.405k10_1540_1548.
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The proto-oncogene product, p21ras, has been implicated in the cellular mechanism of adhesion, although its precise role has been controversial. Numerous cytokines and growth-factors activate Ras, which is an important component of their growth-promoting signaling pathways. On the other hand, the role of Ras in cytokine-induced adhesion has not been elucidated. We therefore investigated the function of H-Ras in the inside-out signaling pathway of interleukin-3 (IL-3)–induced integrin activation in the murine Baf3 cell line after transfection of cells with either constitutively active, dominant-negative, or wild-type H-Ras cDNAs. Adhesion of Baf3 cells to fibronectin was induced by IL-3 in a dose-dependent manner via very late antigen-4 (VLA-4; 4β1 integrins) and VLA-5 (5β1 integrins) activation. On the other hand, IL-4 did not induce the adhesion of Baf3 cells to fibronectin, although IL-4 did stimulate the cell proliferation of Baf3 cells. Constitutively active H-Ras–transfected Baf3 cells adhered to fibronectin without IL-3 stimulation through VLA-4 and VLA-5, whereas dominant-negative H-Ras–transfected Baf3 cells showed significantly less adhesion induced by IL-3 compared with wild-type and constitutively active H-Ras–transfected Baf3 cells. Anti-β1 integrin antibody (clone; 9EG7), which is known to change integrin conformation and activate integrins, induced the adhesion of dominant-negative H-Ras–transfected Baf3 cells as much as the other types of H-Ras–transfected Baf3 cells. 8-Br-cAMP, Dibutyryl-cAMP, Ras-Raf-1 pathway inhibitors, and PD98059, a MAPK kinase inhibitor, suppressed proliferation and phosphorylation of MAPK detected by Western blotting with anti–phospho-MAPK antibody, but not adhesion of any type of H-Ras–transfected Baf3 cells, whereas U-73122, a phospholipase C (PLC) inhibitor, suppressed adhesion of these cells completely. These data indicate that H-Ras and PLC, but not Raf-1, MAPK kinase, or the MAPK pathway, are involved in the inside-out signaling pathway of IL-3–induced VLA-4 and VLA-5 activation in Baf3 cells.
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Barrientos, Jacqueline C., Sofya Rodov, Arthur W. Zieske, and K. Gary J. Vanasse. "The Suppressor of Cytokine Signaling-3 Gene Is Overexpressed in Human De Novo Follicular Lymphomas and Promotes IL-3-Independent Proliferation of the BaF3 Pro-B Cell Line." Blood 104, no. 11 (November 16, 2004): 1107. http://dx.doi.org/10.1182/blood.v104.11.1107.1107.
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Abstract The recent generation of mice lacking functional SOCS3 in hepatocytes, macrophages, and neutrophils reveals SOCS3 to be an essential regulator of IL-6 signaling via mediation of gp130-related cellular complexes, as well as a negative regulator of G-CSF signaling in myeloid cells. Although SOCS3 would appear to be a critical physiologic regulator of inflammatory responses, its possible role in hematologic malignancies and the underlying mechanisms which regulate its expression in B cells remain to be clearly defined. We previously showed that CD19+ B cells isolated from Eμ-Bcl-2 transgenic mice express high levels of SOCS3 in addition to overexpression of Bcl-2. Moreover, hematopoietic cell lines transduced to stably overexpress Bcl-2 exhibited marked induction of SOCS3 compared to controls, suggesting Bcl-2-associated pathways may play a role in the induction of SOCS3. In the current study, we describe SOCS3 overexpression limited to neoplastic follicular lymphoma (FL) cells in Bcl-2-associated human de novo FL and show that overexpression of SOCS3 is capable of stimulating cytokine-independent cellular proliferation of the BaF3 pro-B cell line. We measured SOCS3 protein levels by immunohistochemistry in paraffin-embedded biopsies from twelve patients diagnosed with de novo, untreated histologic grade I or II FL which harbored t(14;18) and Bcl-2 overexpression. In 9/12 de novo FL cases examined, immunostaining with two distinct antibodies to SOCS3 revealed marked overexpression of SOCS3 protein that, within the follicular center cell region, was limited to neoplastic FL cells and co-localized with Bcl-2 primarily in the nucleus of positive cells. In contrast, SOCS3 protein was not detected by immunostaining in germinal center follicular B cells from benign hyperplastic tonsil tissue. To further evaluate the role of SOCS3 in B cell biology, the IL-3-dependent BaF3 pro-B cell line was stably transduced with either a retroviral expression construct containing a 675bp human SOCS3 cDNA (BaF3SOCS3) or with vector only control (BaF3Δ). Whereas no SOCS3 protein was detected in control cells, high level expression of SOCS3 in transduced BaF3SOCS3 cells was confirmed by Western analysis using SOCS3 anti-sera. Furthermore, Bcl-2 protein was not detected in either BaF3SOCS3 or control cell lines. 2 x 105 BaF3SOCS3, BaF3Δ, and non-transduced BaF3 cell lines were initially grown in the presence 10% fetal bovine serum (FBS) and 5% WEHI 3B cell-conditioned medium as a source of IL-3. IL-3 was then removed by washing with DMEM/10% FBS. Cell viability was then measured by recording absorbance at 490nm using incorporation of the MTS tetrazolium compound. Interestingly, BaF3SOCS3 cells overexpressing SOCS3 did not undergo apoptosis but were able to proliferate in the absence of IL-3, with percent viable cells approaching 400% at > 96 hours, which represented the final time-point measured. In contrast, BaF3Δ and non-transduced BaF3 cells underwent apoptotic cell death between 8 and 36 hours in response to IL-3 withdrawal. Thus, SOCS3 overexpression confers IL-3-independent cell proliferation to the BaF3 cell line. These data indicate that unlike its negative regulatory effect on G-CSF signaling in myeloid cells, overexpression of SOCS3 in B cells may promote B cell proliferation rather than growth suppression and may play an important role in the pathogenesis of de novo FL in humans.
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Kakumitsu, Haruko, Kazuya Shimoda, Takashi Haro, Kotaro Shide, Takashi Kumano, Seido Oku, Kenjirou Kamezaki, Akihiko Numata, Katsuto Takenaka, and Mine Harada. "Tyrosine Kinase 2 (Tyk2) Interacts with and Phosphorylates Siva-1, and Auguments the Apoptotic Effect Induced by Siva-1." Blood 108, no. 11 (November 16, 2006): 1726. http://dx.doi.org/10.1182/blood.v108.11.1726.1726.
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Abstract Jak-Stat pathway is essential to transduce cytokine signalings. We previously reported that tyrosine kinase 2 (Tyk2), one of the Jak kinases, was essential but Stat1 was dispensable in IFN-alpha-induced B lymphocyte apoptosis. This indicates the existence of other signaling molecules besides Stat1 downstream of activated Tyk2. Therefore, in order to find Tyk2-activated signaling molecules which transduce IFN-alpha signal and induce B lymphocyte apoptosis, we performed a yeast two-hybrid screen for proteins that interact with Tyk2, and identified Siva-1, which had been originally cloned as a CD27 binding protein. Siva-1 has a death domain (DD) homology region and induces apoptosis in various cells through binding CD27, which belongs to the tumor necrosis factor receptor (TNFR) family. We found that Tyk2 interacts with and phosphorylates Siva-1. Two regions of Siva-1, the N-terminus and the middle portion of the protein containing a death domain homology region, contributed to binding to Tyk2, and two tyrosines of Siva-1, Tyr53 and Tyr162, were phosphorylated by Tyk2. Because Siva-1 is so far thought to be a proapoptotic protein, we assessed whether Tyk2 had any effects on Siva-1-mediated apoptosis through the Tyk2-Siva-1 interaction. First, we established BaF3 cell (IL-3 dependent murine proB cell) lines stably expressing either wild-type Tyk2 (BaF3/WT Tyk2) or constitutively activated Tyk2 which Valine678 was replaced by Phenylalanine (BaF3/V678F Tyk2). In BaF3/V678F Tyk2 cells, Tyk2 and Stats are constitutively activated, and they grow in the absence of IL-3. We transiently transfected either GFP-Siva-1 or control GFP vector into BaF3/parent cells, BaF3/WT Tyk2 cells or BaF3/V678F Tyk2 cells. Thirty-six hours after transfection, we measured annexin V positive cells by flow cytometry on GFP-positive cells. Approximately 24% of both BaF3/parent cells and BaF3/WT Tyk2 cells transfected with GFP-Siva-1 fell into apoptosis, whereas only less than 7% of the cells transfected control vector showed apoptosis. The frequency of this Siva-1-induced apoptosis was increased in BaF3/V678F Tyk2 cells (over 43% vs <10% of expressing control vector), suggesting that activated Tyk2 augmented the apoptotic function of Siva-1. In conclusion, we show that Tyk2 associates with and phosphorylates Siva-1 and that this Tyk2-Siva-1 interaction enhances the apoptotic effect induced by Siva-1. This indicates that Siva-1 might be a probable key molecule downstream of Tyk2 which is activated in response to IFN-alpha.
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Kimura, Shinya, Hidekazu Segawa, Junya Kuroda, Takeshi Yuasa, and Taira Maekawa. "CNS-9, a Novel Specific Inhibitor of ABL Tyrosine Kinase Overcomes Resistance Mechanism of Imatinib." Blood 104, no. 11 (November 16, 2004): 761. http://dx.doi.org/10.1182/blood.v104.11.761.761.
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Abstract Imatinib mesylate (also known as STI-571 and Gleevec) has drastically changed the treatment of Philadelphia chromosome positive (Ph+) leukemias. However, the resistance to imatinib has frequently been reported, particularly in patients with advanced-stage disease. A novel orally bioavailable inhibitor of the ABL tyrosine kinase (TK) named CNS-9 was developed from the 2-(phenylamino)pyrimidine class to overcome resistance mechanisms of imatinib. Inhibition of TK phosphorylation (IC50) on wild type (wt) BCR/ABL in 293T cell line by CNS-9 was 22nM, which was 2-log more potent than imatinib. Importantly, CNS-9 inhibited TK phosphorylation of E255K mutant BCR/ABL with IC50 of 98nM, while imatinib could not inhibit it with clinically relevant concentration. The T315I mutant BCR/ABL protein was resistant to CNS-9 and imatinib. CNS-9 also inhibited TK phosphorylation of platelet-derived growth factor receptor (PDGFR) or c-Kit pathways at the very similar observed IC50s when compared with imatinib, in spite of significant higher potency against ABL. The ability of CNS-9 in vitro to inhibit 101 TK molecules was assayed by KinaseProfilerTM (Upstate), showing also more specific inhibitory activity against ABL than imatinib. The growth of BCR/ABL-positive cell lines K562, KU812, BaF3 harboring wt BCR/ABL (BaF3/wt) and E255K (BaF3/E255K) was inhibited by CNS-9 with IC50 of 5, 3, 17, and 110nM, respectively (Table 1). Generally, CNS-9 was 20 to 30-fold more potent on the growth inhibition than imatinib in these same cell lines. We next investigated the in vivo effect on the leukemic growth inhibition of CNS-9. Nude mice were injected subcutaneously with 3x107 KU812 (wt BCR/ABL) on Day 0. CNS-9 or imatinib were orally administrated twice a day from Day 7 to Day 18. The dosages of CNS-9 and imatinib, which inhibited completely tumor growth were 20mg/kg/day and 200mg/kg/day, respectively, indicating that CNS-9 is 10-fold potent than imatinib in vivo. To examine the in vivo effect of CNS-9 against mutant BCR/ABL, BaF3/wt, BaF3/E255K or BaF3/T315I were engrafted to nude mice and treated with CNS-9 or imatinib. CNS-9 was also 10-fold potent than imatinib against BaF3/wt. Intriguingly, mice harboring BaF3/wt or BaF3/E255K showed significantly prolonged survival when treated with CNS-9. Consistent with in vitro assay, CNS-9 had no effect on T315I, and imatinib was not effective against both E255K and T315I. In conclusion, CNS-9 is substantially more inhibitory and more specifically than imatinib toward BCR/ABL-dependent cell growth both in vitro and in vivo Moreover, CNS-9 may be effective for leukemia patients whose leukemic cells harbor E255K mutant. The efficacy and safety of CNS-9 for Ph+ leukemias should be verified in early phase clinical trials. The IC50s values of leukemic cell lines for CNS-9 and imatinib CNS-9 (nM) imatinib (nM) K562 p210 wt BCR/ABL 5 130 KU812 p210 wt BCR/ABL 3 67 U937 BCR/ABL (−) >1000 >1000 BaF3 p190 wt BCR/ABL 17 360 BaF3 p190 E255K BCR/ABL 110 >1000 BaF3 p190 T315I BCR/ABL >1000 >1000
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Berg, Stephanie, Manuel O. Diaz, Sucha Nand, and Jiwang Zhang. "Germline Mutations Predispose to Familial Myeloproliferative Neoplasms." Blood 134, Supplement_1 (November 13, 2019): 2969. http://dx.doi.org/10.1182/blood-2019-124805.
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Background: Myeloproliferative neoplasms (MPNs), commonly polycythemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythemia (ET), are a group of malignant hematologic disorders characterized by proliferation and accumulation of terminally differentiated blood cells of erythroid, myeloid and megakaryocytic origin (Cazzola, Blood 2014).Somatic driver mutations, frequently JAK2V617F, MPLW515L/K or mutant CALR in sporadic MPNs affect signaling by the thrombopoietin (THPO) and/or the erythropoietin (EPO) receptor (Pickman, PLoS 2016). MPL is the receptor of THPO and JAK2 is the key downstream mediator of THPO/MPL signaling (Nangalia NEJM 2013). In familial MPNs (families with more than 1 member developing a MPN) a germline mutation predisposes to disease development. These mutations can reveal pathways or processes involved in the pathogenesis of the disease, independent of, or cooperating with, the somatic driver mutations (Rumi, JCO 2007). We identified 3 putative predisposing germline mutations in 1 family, 3 affected generations developed MPN (PMF, ET and PV): RBSN frameshift,JAK2R340Q & PRKAA2Q425P missense variants. RBSN encodes Rabenosyn-5 protein (RBSN) which plays a role in early growth-factor receptor clathrin-dependent endocytosis (Nielsen, J Cell Biol 2000) (Fig.1).We discovered that wild type (WT) Rabenosyn-5 regulates cell surface MPL levels in hematopoietic progenitor cells and predict that MPL levels on the cell surface are negatively associated with WT Rabenosyn-5 levels. We hypothesize that the RBSN mutation predisposes to MPN development in this family, leading to abnormal activation of THPO signaling by reducing MPL turnover. Methods: Peripheral blood DNA from patient samples were analyzed for potential putative mutations using Agilent SureSelect Human ALL Exon V5+UTRs exome capture kit followed by parallel sequencing with Illumina HiSeq 2000. In vitro studies involved using the BaF3 system and CRISPR-Cas9 gene editing technique. We generated BaF3-MPL (BaF3 cells transduced with human CD4-MPL fusion) cell lines that rely on IL3 or human THPO cytokines for growth & proliferation (Fig.2&3). We transduced RBSN into the BaF3-MPL cell lines and produced RBSN heterozygous (HT) and homozygous (HM) mutants. We first generated LentiCRISPRV2GFP-mRBSN vector by inserting RBSN specific guide RNA into the LentiCRISPRV2GFP vector and generated lentivirus expressing both Cas9 and guide RNA by co-transfecting 293T cells with LentiCRISPRV2GFP vector and viral packaging vectors. The final virus was used to infect BaF3-MPL cells. Transduced cells were purified by FACS to select GFP+ cells and individual cells were grown in culture. RBSN gene mutations were examined using PCR and sequenced accordingly. To study whether the RBSN mutation alters the surface MPL levels, we stained BaF3-MPL, HT-RBSN-BaF3 and HM-RBSN-BaF3 cells with APC-CD4 antibody and the surface levels of MPL were detected by FACS by comparing the mean fluorescence intensity (MFI) of APC. Results: We identified several colonies with either HT-RBSN-BaF3 or HM-RBSN-BaF3. The guide RNA we designed specifically targeted the 12th exon of the RBSN gene which best recapitulates the mutations observed in our patients, thus, the frameshift mutations in HT-RBSN-BaF3 and HM-RBSN-BaF3 cell lines we predict will make truncated forms of RBSN which will be verified by Western Blotting for future experiments. Surface levels of MPL in the HT-RBSN-BaF3 and HM-RBSN-BaF3 cells are greater than that in BaF3-MPL cells, suggesting RBSN negatively regulates THPO-MPL signaling by regulating the cell surface MPL levels (Fig. 4). Conclusions: RBSN is a regulator of receptor trafficking, which mediates the fusion of the endocytosed receptor to the early endosome and then lysosome for degradation. We propose that genetic inactivation of RBSN might prevent the endocytosed MPL from endosome-degradation and enhance the reuse of MPL by recycling. Future experiments are planned to include in vivo studies to study whether inactivation of RBSN promoted MPN-like disease development into NSG mice and transducing our established cell lines to label individual cell compartments to study THPO-stimulated signaling. Our findings, if confirmed, will further clarify aspects of familial and somatic MPN pathogenesis and may inform efforts to devise new therapeutic and diagnostic strategies for this disease complex. Disclosures No relevant conflicts of interest to declare.
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Yamamoto, Yukiya, Sachiko Iba, Akihiro Abe, and Nobuhiko Emi. "Elongation of MPL Transmembrane Domain Is a Novel Activating-Mutation in Essential Thrombocythemia." Blood 126, no. 23 (December 3, 2015): 1628. http://dx.doi.org/10.1182/blood.v126.23.1628.1628.
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Abstract Essential thrombocythemia (ET) is a clonal disease of hematopoietic stem cell. Somatic gene mutations including JAK2 or CALR are hallmark of diagnosis and molecular targets for developing novel therapies. However, non-mutated ET cases within JAK2 and CALR still exist. The third mutated gene of ET is MPL, which is known as encoding thrombopoietin receptor. MPL W515 and S505 are hot spot for missense mutations leading to constitutive active MPL signaling. These missense mutations are located within transmembrane or juxtamembrane domain of MPL. Here, we present a novel activating-mutation of MPL in an ET patient. The patient was a 54-year-old woman with occasional headache. A full blood count showed a hemoglobin level of 12.2 g/dL, a white blood cell count of 11.2 x 103/mL and a platelet count of 164 x 104/mL. A bone marrow sample was hypercellular, containing increased megakaryocytes. Chromosomal analysis showed normal karyotype. Further genetic analysis did not detect JAK2 V617F or CALR mutation. Finally, we directly sequenced MPL exon 10. The result showed MPL c.1496-1497AT>TGGGCCTCAGCTGGGCG (Figure 1). This mutation has been considered as an in-frame mutation, indicating MPL p.H499LGLSWA (reference: NP_005364). The amino acids insertion in transmembrane domain of MPL belongs to hydrophobic family, suggesting that MPL H499 mutation (H499ins) might construct stable structure. To investigate whether MPL H499ins is functionally active, we established stable BaF3/MPL H499ins cell lines. In contrast to BaF3/MPL wild-type, BaF3/MPL H499ins cells proliferate without WEHI3-conditioned medium as well as BaF3/MPL W515L or S505N. Western blot analysis showed BaF3/MPL H499ins cells constitutionally activate downstream signaling including JAK-STAT, MAPK and AKT. Furthermore, we established stable BaF3 cell lines with MPL H499 LGLSWALGLSWA (H499 insx2), MPL H499del and others. In contrast to BaF3/H499del, H499L, H499LG and H499insx3, BaF3/MPL H499insx2 cells proliferate without WEHI3-conditioned medium. This result suggests that elongation of MPL transmembrane domain is a novel oncogenic mechanism leading to constitutive active MPL signaling. Phosphorylation of MPL Y626 has significant role to transduce MPL signaling. To explore if constitutive activation of MPL H499ins depends on phosphorylation of MPL Y626, we established stable BaF3 cell lines with MPL H499insY626F. The BaF3 cells could not proliferate without WEHI3-conditioned medium. This result clearly shows phosphorylation of MPL Y626 has a pivotal role for constitutive activation of MPL H499ins. Finally, we examined potential effect to inhibit constitutive MPL signaling with JAK1/2 inhibitor, Ruxolitinib. In contrast to K562, growth of BaF3/MPL H499ins cells were inhibited with Ruxolitinib at half maximal effective concentration 113 nM as well as MPL W515L or S505N (Figure 2). In summary, elongation of MPL transmembrane domain is a novel oncogenic mechanism in ET patients. Ruxolitinib is also a potent inhibitor against MPL activating mutations as well as JAK2 V617F-associated myeloproliferative neoplasm. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
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Persico, Justin, Imawati Budjahardo, and Kenneth Kaushansky. "The Homodimeric Hematopoietic Cytokine Receptor C-Mpl Requires Cross Phosphorylation in Order to Signal Cell Proliferation." Blood 112, no. 11 (November 16, 2008): 3734. http://dx.doi.org/10.1182/blood.v112.11.3734.3734.
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Abstract Objectives: The three primary regulators of hematopoiesis, erythropoietin, granulocyte colony-stimulating factor and thrombopoietin, bind to homodimeric members of the cytokine receptor superfamily and utilize Janus Kinase (JAK) 2 to initiate signaling. Recently, mutations in JAK2, particularly JAK2V617F, were found to contribute to the pathogenesis of the myeloproliferative disorders. In vitro studies have determined that only homodimeric cytokine receptors can support JAK2-mediated cytokine hypersensitivity. As part of a strategy to identify novel approaches to inhibit mutant JAK2 function we tested whether the homodimeric receptors initiate signaling by JAK2 mediated receptor trans-phosphorylation, and whether JAK2V617F escapes this requirement. Methods: We introduced the engineered receptor Myr/FKBPF36V/c-Mplcyto into hematopoietic cell lines containing either wild-type JAK2 or JAK2V617F, a receptor designed to adopt either a monomeric or dimeric state depending on the absence or presence, respectively, of the chemical dimerizer AP20187. To evaluate the effects of receptor dimerization on the growth of wild-type and V617F mutant JAK2 cell lines we measured reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). If either of the cell lines were able to support cell proliferation in absence of receptor dimerization it would indicate that signaling is initiated by ipsilateral receptor phosphorylation, as opposed to the trans-phosphorylation employed by subfamilies of heterodimeric receptors, such as that for IL-2. Results: The Myr/FKBPF36V/c-Mplcyto receptor construct was subcloned into a retroviral vector, transduced into Baf3, Baf3/JAK2 and Baf3/JAK2V617F cells and spontaneous, IL-3- and AP20187-induced cell proliferation was assessed. Equal expression of the receptor construct in each cell line was confirmed by western blotting. Both Baf3/JAK2- and Baf3/JAK2V617F-derived cell lines transduced with wild type c-Mpl served as controls, and quantitative western blotting was used to verify that equal levels of the two receptor constructs were introduced into the cell lines. Growth factor dependence was confirmed in the control cell lines with both thrombopoietin and IL-3 and was confirmed with IL-3 in the experimental cell lines. There was an increased sensitivity to growth factors in the control cell line containing the JAK2 V617F mutant, consistent with a myeloproliferative phenotype. When Myr/FKBPF36V/Mplcyto was introduced into either Baf3/JAK2 or Baf3/JAK2V617F cells, the cells remained dependent on either IL-3 or AP20187, although maximal rates of cell growth were significantly greater in the Baf3/JAK2V617F/Myr/FKBPF36V/Mplcyto cells than in Baf3/JAK2/Myr/FKBPF36V/Mplcyto cells. The maximal rate of growth of Baf3/JAK2V617F/Myr/FKBPF36V/Mplcyto cells also significantly exceeded that of the Baf3 parental cell line. Furthermore, we found that in the absence of chemically induced dimerization neither Myr/FKBPF36V/c-Mplcyto/JAK2 nor Myr/FKBPF36V/c-Mplcyto JAK2V617F cells proliferated. Conclusions: These results argue that JAK2 induces signaling by trans-phosphorylation of the cytoplasmic domains of c-Mpl and that the kinase hyperactivity displayed by JAK2V617F cannot overcome this requirement. Therefore it may be possible to alter or inhibit trans-phosphorylation and attenuate JAK2V617F-mediated myeloproliferation.
Dissertations / Theses on the topic "BaF3"
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Engelmann, Ines. "Änderung der Stoffwechselaktivität von BaF3-Zellen durch die Expression von BCR/ABL." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-163535.
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Die vorliegende Arbeit handelt von einer in vitro Untersuchung der Stoffwechselveränderun-gen durch die Expression von BCR/ABL bei BaF3-Zellen, einer murinen, IL-3-abhängigen B-Zelllinie. Die Zellen wurden in nährstoffreichem Standard- und in durch Titrationen ermittel-tem nährstoffarmem Minimalmedium auf unterschiedliche Stoffwechselaktivität in Abhän-gigkeit von BCR/ABL-Expression untersucht sowie auf die zusätzliche Beeinflussbarkeit durch IL-3. Danach wurden vergleichend zwischen den 2 Zelllinien (BaF3 und BaF3-BCR/ABL) im Minimalmedium und im Standardmedium Metabolite wie Glukose, Laktat und Aminosäuren bestimmt, wobei BaF3-BCR/ABL sowohl mit als auch ohne IL-3 kultiviert wur-de. Um den Einfluss von Nährstoffrestriktion auf die Therapie zu zeigen, wurden anschlie-ßend vergleichend in den beiden Medien die Tyrosinkinaseinhibitoren Imatinib und Nilotinib titriert.
Die Ergebnisse zeigen, dass BaF3-BCR/ABL einen Wachstumsvorteil im Minimalmedium hat, welcher im Standardmedium nicht vorliegt. Während die bereits bekannte Verstärkung der Glukoseaufnahme durch BCR/ABL im Standardmedium bestätigt wurde, konnte im Minimal-medium Gegenteiliges gezeigt werden. Zudem wurde ein Unterschied im Aminosäurestoff-wechsel zwischen BaF3 + IL-3 und BaF3-BCR/ABL + IL-3 im Minimalmedium deutlich. Die therapeutische Relevanz des gezeigten Einflusses der Nährstoffrestriktion konnte anschlie-ßend in der Tyrosinkinaseinhibitortitration dargestellt werden, da die Medikamente in Abhän-gigkeit vom Medium unterschiedliche Wirkungen zeigen.
Insgesamt bieten die Ergebnisse einen metabolischen Erklärungsansatz für das Überleben von Tumorstammzellen in nährstoffarmen Arealen des Knochenmarks unter Therapie und Raum für neue Therapieansätze.
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Engelmann, Ines [Verfasser], Thoralf [Akademischer Betreuer] Lange, and Michael [Akademischer Betreuer] Cross. "Änderung der Stoffwechselaktivität von BaF3-Zellen durch die Expression von BCR/ABL : Änderung der Stoffwechselaktivität von BaF3-Zellen durch die Expression von BCR/ABL / Ines Engelmann ; Thoralf Lange, Michael Cross." Leipzig : Universitätsbibliothek Leipzig, 2015. http://d-nb.info/1239564937/34.
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Groom, Laura R. "Synthesis and reactions of titanium-nitrogen multiple bonds." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:17286f91-a1d9-48dc-baf3-02fbbe30a314.
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This Thesis reports the synthesis and reactions of new hydrazide, alkoxyimide and benzimidamide complexes (L)Ti=NX (X = NAr2, NOtBu or C(Ar)NOtBu; L = dianionic supporting ligand or ligand set). The work is supported by DFT calculations which are used to rationalise the reaction outcomes observed and, in one case, the bonding in alkoxyimide complexes. Chapter One provides a background to hydrazide complexes, starting with their relevance to nitrogen fixation. In addition, Group 4 imide, alkylidene hydrazide and alkoxyimide complexes are also reviewed. The Chapter focuses in particular on the synthesis, structure, and stoichiometric and catalytic reactions of these complexes with unsaturated substrates. Chapter Two describes the development of the virtually unexplored 1,2-diamination reaction. The substrate scope and isolation of the vinylamine products are discussed. The protonation of the vinylimide complex Ti(N2NMe){NC(Ph)C(Me)NPh2}(py) and the overall diamination reaction itself is then explored through an in-depth experimental and computational study. Chapter Three details the synthesis of cyclopentadienyl-amidinate supported alkoxyimide complexes. The first detailed reactivity study, supported by structural and computational studies, of any alkoxyimide complex is reported. Novel reactivity at Ti=Nα and, in one instance, Nα–Oβ reductive bond cleavage is observed. Chapter Four describes the reactivity of the benzimidamide complex Cp*Ti{PhC(NiPr)2}{NC(ArF5)NOtBu} with a range of substrates including heterocumulenes, aldehydes, isonitriles and B(ArF5)3. Novel reactivity at Ti=Nα, and 3-component coupling is presented, and the experimental results supported by structural and computational studies. Chapter Five presents full experimental procedures and characterising data for the new complexes reported.
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Meyer, Stefan [Verfasser], Xiaohua [Akademischer Betreuer] Yu, Bernhard [Akademischer Betreuer] Brümmer, and Thomas [Akademischer Betreuer] Kneib. "Estimation of the Long-Run Food Price Equilibrium in Germany, the U.S. and Europe / Stefan Meyer. Gutachter: Bernhard Brümmer ; Thomas Kneib. Betreuer: Xiaohua Yu." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2013. http://nbn-resolving.de/urn:nbn:de:gbv:7-11858/00-1735-0000-0001-BAF3-7-8.
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Tan, Justin Teng-Tiong. "Mystical anthropology in Gregory of Nyssa's Homilies on the Song of Songs." Thesis, King's College London (University of London), 1995. https://kclpure.kcl.ac.uk/portal/en/theses/mystical-anthropology-in-gregory-of-nyssas-homilies-of-the-song-of-songs(98abf7a5-3380-48cd-baf3-20bbfb9ba285).html.
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The Thesis is an attempt to explicate Gregory of Nyssa's mystical anthropology in one of his most mature of mystical writings, the Homilies to the Song of Songs. Gregory's mystical anthropology draws its basis from his philosophical anthropology, and explores the implication of the nature and destiny of man in terms of the concept of divinisation or the transformation of human nature by the indwelling Christ. Gregory utilises the neo-Platonic concept of the ascent of the soul to its original perfection, but transforms this concept by the biblical doctrine of Grace and Incarnation. Holding to the unbridgeable gulf between the Created and the Uncreated, Gregory proposes the abandonment of all senses and entrance into the darkness where God ist and he postulates the divinisation of human nature without end based on that unbridgeable gulf. Gregory's philosophical anthropology would be incomplete without his mystical anthropology. The divinisation of human nature does not imply an idiosyncratic idea of the soul in flight, "from the alone to the Alone". The soul, as Gregory understands it, is firmly attached to its ecclesiastical community, where it has its space-time existence in a life of imitating its Lord in his love for mankind. Its destiny is ultimately linked with the destiny of the body of Christ, the Church. Gregory's concept is then compared with Origen's, whose ideas are said to have the most influence on Gregory's. Analysis shows that there are extrapolations of Origen's theology in Gregory's, but there are obvious discontinuities. The fact of the Incarnation is stressed by both writers, but the soul in Origen seems to pass beyond faith in the Incarnation in its ascent to God into the light of the full knowledge of God; whereas Gregory places his theology on the faith of the Incarnation throughout the soul's ascent, not into increasing light, but into increasing darkness where God is. An illustration of Gregorys mystical anthropology can be detected in his other writing, the Life of Macrina, where he describes his sister using the familiar imageries from the Song of Songs i. e. virgin, bride, Thecla, refining gold and guidance to her ascetic community. Her ascent in perfection is also described in the language of the doctrine of Epektasis. Gregory seems to see in Macrina a real life paradigm for his mystical anthropology.
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Akhter, Shakil. "Basic needs analysis of participants in social forestry projects in north-west Bangladesh." Thesis, Bangor University, 2001. https://research.bangor.ac.uk/portal/en/theses/basic-needs-analysis-of-participants-in-social-forestry-projects-in-northwest-bangladesh(24d019d4-ed54-42d3-baf3-588cfb7191f8).html.
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Satisfaction of basic needs is among the priority objectives of the Bangladesh government, a priority reflected in the forestry sector. Elaborate programmes have been chalked out in both public and private sectors. This study attempts to assess performance of a public sector social forestry project in Bangladesh in terms of basic needs fulfilment of participating rural farmers. `Thana Afforestation and Nursery Development Project' is a major social forestry project in Bangladesh, covering the whole country except the Sundarbans mangrove forest and the hill forests in the east. The project has several components, major among which are agroforestry (AF) and woodlot (WL) schemes. The project started in revised form in 1991-92. This research attempts to study the consumption pattern of basic needs goods (food and non-food) of participants and the project's contribution to satisfying basic needs. Rajshahi Division comprises north west Bangladesh and supports a large area of social forestry plantations. A stratified multi-stage random design was adopted for sampling participants. Stratification was based on agro-ecological zones (AEZs), while the stages consisted of districts, villages and participants. The sample consisted of 180 participants (90 each from AF and WL) from 32 villages distributed in five districts and in five agro-ecological zones. A household questionnaire survey was administered to participants to apprehend various aspects like socio-economic profile, basic consumption needs, involvement in the project, benefits derived, and knowledge, awareness, attitude and opinions. Tree growth measures of participants' plots were also recorded to estimate expected final return, since no plot has been harvested, despite reaching the rotation age in 1998. Data analyses on socio-economic aspects of participants reveal that most males and females occur in the most economically active age class. 54% are literate with 24% having primary education. Agriculture is the main occupation (54%), while 32% have other occupations like tradespersons and professionals. Seasonal employment is dominant (57%) depending upon the nature of agriculture. Most households (42%) reported monthly income in the range Tk. 1000-2000. AF plots are mostly in the range 0.2-0.4 ha while WL plots are larger (0.4-1.0 ha). Although the project is designed for landless farmers, in reality only 17% of farmers were genuinely landless, the remainder having their own land in the range 0.02-0.11 ha. Own land of AF and WL farmers is highly unequally distributed with Gini concentration ratio (GCR) of 0.60 and 0.61 respectively. 75% of participants have cattle (2 or more head). Food consumption of participants has been studied to some depth, food being the most important basic needs item. Participants consume 1010 gms of food per head per day, rice and vegetables constituting 55% and 22% of average daily food basket. Energy and protein consumption are relatively high in the national context (2427 Kcal and 72.38 gms per head per day). They derive higher food value from all major food items except fish and fruits, which are dearer and less available items in Rajshahi (also explained by income elasticity and regression analysis results). Poverty analysis tells quite an encouraging story: poverty head count ratio (HCR) of 21.4, compared with national HCR of 47.5. AF farmers are less poor (HCR 20.76) than WL farmers (HCR 22.05). Depth of poverty is higher for WL farmers, while severity of poverty is higher for AF farmers. Income inequality of participants is less than both national and rural distributions (GCR of 0.35, compared to 0.43 and 0.38 respectively). WL farmers suffer less income inequality. Incidence of poverty is lowest in TMF zone and highest in LBT zone, although income inequality is lowest in the latter zone. Both schemes are profitable in all AEZs, with the WL scheme promising greater returns per ha and HBT zone showing the highest NPV value. Mean financial IRRs are high: 57% for AF and 48% for WL. Conversely, financial BCRs are higher for WL plots (5.32) than for AF plots (3.32). Altogether, WL plots generate higher financial revenues than AF plots over the project life (8 years). Sensitivity analyses show that both schemes are financially robust under differing site and cost conditions. Per capita per day basic needs income needed to satisfy the minimum caloric requirement, derived from both food and non-food items, has been estimated as Tk. 16.00. Basic needs outcomes of the combined analyses show that both schemes successfully fulfil the basic needs of participants and WL is more promising. LBT zone ranks first in the AF scheme, while HBT zone provides the highest per ha per year basic needs value.
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Tun, Paul Fei-Tun. "BAFF, B cells and tumour immunity." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534210.
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Bitoun, Samuel. "Mise au point de modèles animaux pour étudier la physiopathologie de la polyarthrite rhumatoïde et le rôle du méthotrexate dans la tolérisation." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS174.
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La polyarthrite rhumatoïde (PR) est une maladie auto-immune (MAI) dans laquelle des anticorps anti-peptides citrullinés (ACPA) sont un outil diagnostique très spécifique. L’un des traitements clé de la PR est le méthotrexate (MTX). En plus de son action directe sur la maladie il renforce l’effet des anti-TNF alpha (aTNF). Ceci pourrait passer par une prévention de la formation d’anticorps anti-médicaments dirigés contre les aTNF ce qui leur fait perdre leur efficacité.Nous avons développé un modèle macaque pour reproduire la maladie humaine par immunisation avec des peptides citrullinés dans le contexte d’un facteur génétique favorisant la PR : l’épitope HLA partagé. L’immunisation de macaques avec divers peptides citrullinés en utilisant un boost intra-articulaire a déclenché une réponse T et B anti-citrulline et a entraîné une mono-arthrite chronique.Le rôle du MTX sur l’immunogénicité des aTNF a été étudié sur un modèle de souris autoimmunes, les souris BAFF transgéniques (tg) qui présentent une MAI. L’utilisation du MTX juste avant l’injection d’aTNF a permis de prévenir l’immunisation contre ce médicament uniquement chez ces souris BAFFtg et pas chez des souris sauvages ou chez des macaques. Nous avons démontré que ces souris BAFFtg surexprimaient CD73, ce qui permettait une sécrétion accrue d’adénosine et de cellules B régulatrices sous l’effet du MTX. L’interaction entre BAFF et le méthotrexate a été confirmée chez l’homme dans la cohorte ABIRISK : le MTX prévient plus efficacement l’immunogénicité chez les patients avec des taux de BAFF élevés.En conclusion, nous avons mis au point deux nouveaux modèles animaux permettant de mieux comprendre la physiopathologie de la PR et d’optimiser l’utilisation des traitements biologiques qui s’étend dans tous les domaines de la médecineTitle : Development of new animal models to study the pathophysiology of RA and the role of methotrexate-induced tolerance.Keywords : Rheumatoid arthritis, shared epitope, ACPA, immunogenicity, methotrexate, TNF inhibitorsAbstract: Rheumatoid arthritis (RA) is an autoimmune disease (AID) where antibodies directed against citrullinated peptides (ACPA) are highly specific for the diagnosis. One of the key treatments of RA is methotrexate. It has an action on both the disease and reinforces the effect of second line TNF inhibitors (TNFi). MTX might act via prevention of anti-drug antibodies (ADAb) directed against TNFi that are implicated in loss of efficacy of TNFi. We have developed a macaque model to recapitulate the human disease by immunization with citrullinated peptides in the context of a genetic factor favoring RA: the shared epitope on the HLA. Immunization of macaques with citrullinated peptides and intra-articular boost cause an anti-citrulline T and B cell response and a chronic monoarthritis.The role of MTX-induced tolerance against TNFI has been studied in autoimmune BAFF transgenic (tg) mice using MTX just before treatment with TNFi we were able to prevent ADAb formation in BAFFtg mice and not wild type mice or macaques. We identified that BAFFtg mice expressed elevated CD73 leading to more adenosine and regulatory B cells as actors in MTX-induced tolerance. This MTX-BAFF interaction was further confirmed in humans in the ABIRISK cohort where MTX was more efficient to prevent ADAb formation in RA patients with elevated BAFF levels.Setting up two new animal models allows better understanding of RA pathophysiology and better use of biologics that extend to other domains of medicine
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Sutherland, Andrew Peter Robert St Vincents Clinical School UNSW. "BAFF regulation of peripheral T cell responses." Awarded by:University of New South Wales. St Vincents Clinical School, 2005. http://handle.unsw.edu.au/1959.4/22788.
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The activation and effector function of CD4+ T cells are critical points of regulation during an antigen specific T cell response. Dysregulation of these processes can lead to the development of human diseases, encompassing both immunodeficiency and autoimmunity. Members of the TNF superfamily have recently emerged as important regulators of T cell responses, with their overexpression causing autoimmune inflammation in animal models. As overproduction of the novel TNF superfamily ligand BAFF is associated with several autoimmune conditions, we sought to examine the potential role of BAFF as a regulator of T cell activation and effector function. We initially demonstrated BAFF costimulation of T cell activation in vitro. Generation of specific monoclonal antibodies identified BAFF-R as the only BAFF receptor present on T cells, and showed that it was expressed in an activation-dependent and subset-specific manner. Impaired BAFF costimulation in BAFF-R deficient mice indicated that BAFF-R was crucial for mediating BAFF effects in T cells. Analysis of T cell responses in vivo revealed that BAFF transgenic mice have increased T cell priming and recall responses to protein antigens, and showed a corresponding increase in the DTH model of Th1 cell-dependent inflammation. In addition, Th2-dependent allergic airway responses are suppressed in BAFF transgenic mice. Crossing to a B cell deficient background revealed that the proinflammatory effects of BAFF on T cell priming and DTH rely on the presence of B cells, while the suppressive effects during allergic airway inflammation are B cell independent. These data demonstrated that BAFF regulated the outcome of T cell responses in vivo and identified BAFF dependent crosstalk between T and B cells. Stimulation of B cells with BAFF induced the upregulation of MHC class II and ICOS-L both in vitro and in vivo. Induction of these cell surface molecules was associated with an increased capacity to induce T cell proliferation, however this effect was independent of ICOS-L expression. Thus it was demonstrated that BAFF regulated T cell activation and effector function both directly, via stimulation of BAFF-R, and indirectly, by altering the function of B cells. These data suggest that BAFF dependent alterations in T cell function may be an additional causative factor in the association between elevated BAFF levels and the generation of autoimmunity.
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Myers, Valerie. "The Role of BAG3 in the Failing Heart." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/490584.
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Biomedical SciencesPh.D.
Heart disease has been the leading cause of death in the United States for more than 90 years. The leading cause of death in individuals aged 65 and older has remained diseases of the heart from 1950 to the current time. According to the CDC, once diagnosed with heart disease, individuals have an approximately 50% chance of dying within 5 years, regardless of race. Mortality related to heart disease increased dramatically from the start of the 1900s to 1921, but subsequently experienced a steady decline from the mid-1960’s to 2000. However, when the decrease in heart disease is examined at the level of race it is clear that the decrease is not equally shared. While the leading cause of death among both Caucasian American men and women and African American men and women remains heart disease, the decrease in incidence of coronary heart disease among African American men was only half of the decrease in incidence among Caucasian American men. Genetic variants in BAG3 (Bcl-2 associated athanogene 3), a highly evolutionarily conserved gene that has recently emerged as a major dilated cardiomyopathy locus, are prevalent in isolated populations. This led us to hypothesize that variants in BAG3 might contribute to the increased prevalence of IDC in individuals of African ancestry. Expressed predominantly in the heart, the skeletal muscle and in many cancers, BAG3 has pleotropic effects in the heart. It inhibits apoptosis by binding to Bcl-2, facilitates protein quality control by binding to both large and small heat shock proteins, mediates adrenergic responsiveness by coupling the β-adrenergic receptor and the L-type Ca2+ channel, and maintains the integrity of the sarcomere by anchoring actin filaments to the Z disc. However, a paucity of subjects of African ancestry have been included in cohorts of probands with familial dilated cardiomyopathy whose exomes or genomes have been sequenced. Based on our previous observations and reports from other groups we postulated: 1) that mice with haplo-insufficiency of BAG3 will re-capitulate disease seen in humans and serve as a model for studying the pathogenesis of BAG3. 2) The prevalence or identification of specific BAG3 variants will differ by race and/or ethnicity. 3) SNVs of BAG3 may contribute to disease progression and thereby be pathogenic. Our study points out that we cannot understand population-based differences without enhancing the diversity of populations included in genomic studies. Similarly, in the era of big data, efforts must be undertaken to assess the genetic profile of both probands and their family members as without the ability to measure segregation, penetrance and plasticity we can only ascribe associations to functional genetic variants.
Temple University--Theses
Books on the topic "BaF3"
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OZKAYA, GUROL. KASABA BAF VE HATIRLAYABİLDİKLERİM. KUZEY KIBRIS: RÜSTEM KİTABEVİ VE YAYINCILIK ŞTİ., 2005.
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Prophets with honour: A documentary history of Lekhotla la Bafo. Johannesburg: Ravan Press, 1988.
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Edgar, Robert. Prophets with honour: A documentary history of Lekhotla la Bafo. Johannesburg: Ravan Press, 1987.
Find full textBook chapters on the topic "BaF3"
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Bulkan, Özlem, Burak Yalamaz, and M. Namık Cagatay. "A sedimentological pattern of a coastal transitional environment: from the Eastern Mediterranean Sea shoreline through the Lake Bafa." In Proceedings e report, 385–91. Florence: Firenze University Press, 2020. http://dx.doi.org/10.36253/978-88-5518-147-1.38.
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This study represents the lithological correlation of multi-cores taken from the various parts of the current Lake Bafa basin, BAF35, - 37 - 39 - 41, - 42, - 46. Concerning the main depositional characteristics, we reconstructed fundamental characteristics of local abrupt and gradual environmental fluctuations. The gradual changes reflect four main environmental phases are lacustrine stage (last 0.8 ky), lagoon stage (0.8–1.75 ky BP), marine-river interaction stage (1.75–2.7 ky BP) and the earliest marine-dominated stage (>2.7 ky BP).
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Posypaiko, V. I., and E. A. Alekseeva. "BaF2." In Phase Equilibria in Binary Halides, 34–45. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-9024-4_14.
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Wittlinger, Jürgen. "BAFA." In Photovoltaikanlagen im Steuerrecht, 45. Wiesbaden: Gabler Verlag, 2012. http://dx.doi.org/10.1007/978-3-8349-3741-4_9.
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Saidak, Zuzana, Zakaria Ezzoukhry, Jean-Claude Maziere, Antoine Galmiche, Ken-Ichi Takemaru, Xingwang Chen, Feng-Qian Li, et al. "BAF." In Encyclopedia of Signaling Molecules, 185. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_100105.
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Myles, Arpita, Jean L. Scholz, and Michael P. Cancro. "BAFF/BLyS Family." In Encyclopedia of Signaling Molecules, 523–31. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_101556.
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Warnatz, Klaus. "Baff-Receptor Deficiency." In Encyclopedia of Medical Immunology, 1–2. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4614-9209-2_29-1.
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Smulski, Cristian R., Patricia Odermatt, and Hermann Eibel. "BAFF Receptor Deficiency." In Humoral Primary Immunodeficiencies, 131–47. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-91785-6_11.
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Ahmed, Martin J. "Bildungsdifferentielle Fertilität – BAFR." In Deutschlands zukünftige Bildungsstruktur, 171–204. Wiesbaden: Springer Fachmedien Wiesbaden, 2015. http://dx.doi.org/10.1007/978-3-658-09337-2_7.
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Myles, Arpita, Jean L. Scholz, and Michael P. Cancro. "BAFF/BLyS Family." In Encyclopedia of Signaling Molecules, 1–10. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4614-6438-9_101556-1.
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Warnatz, Klaus. "Baff-Receptor Deficiency." In Encyclopedia of Medical Immunology, 47–49. New York, NY: Springer New York, 2020. http://dx.doi.org/10.1007/978-1-4614-8678-7_29.
Full textConference papers on the topic "BaF3"
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Racu, Andrei, Marius Stef, Irina Nicoara, Daniel Vizman, and Gabriel Buse. "Photoluminescence and Judd-Ofelt analysis of ErF3–doped BaF3 crystals." In RAD Conference. RAD Centre, 2021. http://dx.doi.org/10.21175/rad.abstr.book.2021.15.4.
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Alfano, Gianvincenzo, Sergio Greco, Francesco Parisi, and Irina Trubitsyna. "Defining the Semantics of Abstract Argumentation Frameworks through Logic Programs and Partial Stable Models (Extended Abstract)." In Thirtieth International Joint Conference on Artificial Intelligence {IJCAI-21}. California: International Joint Conferences on Artificial Intelligence Organization, 2021. http://dx.doi.org/10.24963/ijcai.2021/641.
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Extensions of Dung’s Argumentation Framework (AF) include the class of Recursive Bipolar AFs (Rec-BAFs), i.e. AFs with recursive attacks and supports. We show that a Rec-BAF \Delta can be translated into a logic program P_\Delta so that the extensions of \Delta under different semantics coincide with subsets of the partial stable models of P_\Delta.
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Serikov, Arkady. "Shielding Analyses for Gamma Spectrometer GAMMACELL in Experiments on Neutron Generator." In 12th International Conference on Nuclear Engineering. ASMEDC, 2004. http://dx.doi.org/10.1115/icone12-49196.
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The paper is devoted to computational analysis of shielding properties of spectrometer GAMMACELL irradiated by neutrons from 14.1 MeV Neutron Generator (NG). The shielding is required to protect the BaF2 crystals of the gamma spectrometer GAMMACELL from background thermal neutrons, scattered from the walls and equipment in experimental room. GAMMACELL is a scintillation spectrometer of full gamma particles absorption. It consists of 9 BaF2 crystals; each of them has 40×40×100 mm3 dimensions and is viewed by photomultiplier tube. Neutrons also cause flashes in BaF2 crystals and give spurious pulses. The ultimate aim of the work is to simulate the severe radiation load on spectrometer GAMMACELL and to find proper radiation shield to fulfill the most favorable operating conditions for the GAMMACELL. The neutrons were generated with energy 14.1 MeV form the source on titanium–tritium target on a copper substrate. Accelerator tube makes deuteron current with spot 4 mm diameter on the target. Between the neutron source and GAMMACELL crystals collimator is placed in order to separate neutron current with particular energy and angle. The collimator is pointed to the central BaF2 crystal, counter is turned on only in case when gammas hit it. The other 8 periphery BaF2 crystals are intended for registration of Compton and annihilation gamma radiation which scattered from central crystal. The periphery crystals must be covered by lateral shielding case for protection form background radiation. It is supposed that on the basis of shielding analyses provided and data obtained in this work the real experiment on the Neutron Generator (NG) will be performed. But the experiment on NG will be not at the final destination for the results application obtained in this work, diagnostics of plasma in fusion tokamak-type reactor by means of GAMMACELL gamma spectrometry is planned. Plasma diagnostics by gamma emission from nuclear reactions on particles accelerated upon high energy during Deuterium-Tritium nuclear fusion. Resonances and thresholds in nuclear reactions reveal the value of particle energy based on registered gamma energy in GAMMACELL. High-penetrating capability of gamma quantum gives an opportunity to examine the plasma on all full depth.
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Arnfred, Jonas T., Viet Dung Nguyen, and Stefan Winkler. "BAFT: Binary affine feature transform." In 2017 IEEE International Conference on Image Processing (ICIP). IEEE, 2017. http://dx.doi.org/10.1109/icip.2017.8296797.
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Cirlan, Florina, Gabriel Buse, and Irina Nicoara. "Dislocations in YbF3 doped BaF2 crystals." In TIM 2013 PHYSICS CONFERENCE. AIP Publishing LLC, 2014. http://dx.doi.org/10.1063/1.4903022.
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Grabow, Jens-Uwe, William Ballard, Alexander Preston, Graceson Aufderheide, and Richard Mawhorter. "ROTATIONAL SPECTROSCOPY OF BaF." In 2020 International Symposium on Molecular Spectroscopy. Urbana, Illinois: University of Illinois at Urbana-Champaign, 2020. http://dx.doi.org/10.15278/isms.2020.th05.
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Zhang, Yulan, Jiandong Yang, Jinliang Feng, and Yongliang Li. "BaF 2 crystal machining." In Photonics China '98, edited by Qiming Xin and Robert E. Parks. SPIE, 1998. http://dx.doi.org/10.1117/12.318304.
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Shin, Jungpil, Toshiki Okuyama, and Keunsoo Yun. "Sensory calligraphy learning system using Yongzi-Bafa." In 2013 8th International Forum on Strategic Technology (IFOST). IEEE, 2013. http://dx.doi.org/10.1109/ifost.2013.6616869.
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Lü, Cui-Juan, and Chun-Wang Ma. "n + BaF2 REACTION STUDIED BY TALYS1.4 TOOLKIT." In 15th National Conference on Nuclear Structure in China. WORLD SCIENTIFIC, 2016. http://dx.doi.org/10.1142/9789813109636_0014.
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Heerdegen, Wolfgang. "ATR investigations of BaF2 and PbF2 films." In Luebeck - DL tentative, edited by Herbert M. Heise, Ernst H. Korte, and Heinz W. Siesler. SPIE, 1992. http://dx.doi.org/10.1117/12.56442.
Full textReports on the topic "BaF3"
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Jordan, Tyler. Development of an ultra-fast BaF2-based detector. Office of Scientific and Technical Information (OSTI), November 2020. http://dx.doi.org/10.2172/1726114.
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Gardner C., L. Ahrens, J. W. Glenn, J. A. Kozak, and J. F. Ryan. Booster Fault Study for the BAF Penetration Site. Office of Scientific and Technical Information (OSTI), January 2000. http://dx.doi.org/10.2172/1132453.
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Jordan, Tyler Alexander. Development of an ultra-fast BaF₂-based detector. Office of Scientific and Technical Information (OSTI), April 2020. http://dx.doi.org/10.2172/1615640.
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Kendzie, John E. Correlating Meteorological, Satellite, and Ground Sampling Data to Determine Source of PM2.5 at Bagram Airfield (BAF), Afghanistan. Fort Belvoir, VA: Defense Technical Information Center, June 2015. http://dx.doi.org/10.21236/ad1012710.
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Kim, Min Gyu. Structural and magnetic properties of transition metal substituted BaFe2As2 compounds studied by x-ray and neutron scattering. Office of Scientific and Technical Information (OSTI), January 2012. http://dx.doi.org/10.2172/1082966.
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