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Статті в журналах з теми "ELA2":
1
Rosenberg, Philip S., Steven Stein, Elin Rodger, Audrey Anna Bolyard, Mary Ann Bonilla, Yigal Dror, George Kannourakis, et al. "Genotype-Phenotype Associations in Patients with Severe Congenital Neutropenia." Blood 108, no. 11 (November 16, 2006): 502. http://dx.doi.org/10.1182/blood.v108.11.502.502.
Анотація:
Abstract BACKGROUND: G-CSF therapy has reduced sepsis mortality in patients with severe congenital neutropenia (SCN), revealing a syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML). The MDS/AML risk appears to be higher in SCN patients who are less-responsive to therapy; however, the genetic determinants of susceptibility remain to be elucidated. METHODS: We studied 82 North American and Australian patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. These patients had prospective follow-up, sufficient banked DNA for genotyping, and validated clinical data. RESULTS: Fifty-two patients (63%) were positive for germline mutations in neutrophil elastase (ELA2); the remaining 30 patients (37%) had no detectable mutations. Prior to G-CSF therapy, blood cell counts were significantly different between ELA2 positive and negative patients. Compared with ELA2 positive patients, ELA2 negative patients had significantly higher median absolute neutrophil count (ANC) values (158 versus 53 cells/uL, P=0.02), significantly lower monocyte and eosinophil counts (P<0.001), and significantly lower platelet counts (P=0.002). ELA2 negative patients were maintained on significantly lower doses of G-CSF (5.2 versus 9.9 ug/kg/day, P=0.02), consistent with higher baseline ANC values. However, ELA2 negative patients were significantly less responsive to G-CSF therapy. Compared with ELA2 positive patients, on therapy, ELA2 negative patients had significantly smaller median increases in ANC values (1200 versus 2700 cells/uL, P=0.02); the difference remained significant after controlling for individual G-CSF dose (P=0.04). ELA2 negative patients had 5 MDS/AML events in 132 person-years, versus 8 MDS/AML events in 373 person-years among ELA2 positive patients. Using the Cox proportional hazards model, the hazard of MDS/AML was 3.1-fold higher in ELA2 negative patients compared with ELA2 positive patients. This association was of borderline statistical significance (P=0.08). No patient in either group died of sepsis. We found 34 distinct mutations in 52 ELA2 positive patients. The mutation sites were not clustered in the 8 ELA2 positive patients who developed MDS/AML. We found no associations of phenotype or outcome with specific ELA2 mutations; however, the numbers were limited. CONCLUSIONS: SCN patients without mutations in ELA2 constitute a clinically distinct subgroup. ELA2 negative patients are significantly less responsive to G-CSF therapy than ELA2 positive patients, and they may be at substantially higher risk of leukemia. Additional studies are needed to confirm the latter association and identify the causative gene or genes.
2
Murakami, Mark, Jill Woloszynek, Jun Xia, Fulu Liu, and Daniel Link. "Induction of the Unfolded Protein Response but Normal Basal Granulopoiesis in Mice Expressing G192X ELA2." Blood 112, no. 11 (November 16, 2008): 314. http://dx.doi.org/10.1182/blood.v112.11.314.314.
Анотація:
Abstract Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis characterized by chronic neutropenia, a block in granulocytic differentiation at the promyelocyte/myelocyte stage, and a marked propensity to develop acute myeloid leukemia. Most cases of SCN are associated with germline heterozygous mutations of ELA2, encoding neutrophil elastase (NE). To date, 59 different, mostly missense, mutations of ELA2 have been reported. A unifying mechanism by which all of the different ELA2 mutants disrupt granulopoiesis is lacking. We and others previously proposed a model in which the ELA2 mutations result in NE protein misfolding, induction of the unfolded protein response (UPR), and ultimately apoptosis of granulocytic precursors. Testing this (and other) models has been limited by the rarity of SCN and difficulty in obtaining clinical samples for testing. Herein, we report the preliminary description of a novel transgenic mouse line that expresses G192X Ela2, reproducing the G193X ELA2 mutation found in some patients with SCN. The G192X mutation was introduced into the murine Ela2 locus by homologous recombination in embryonic stem cells. Heterozygous or homozygous G192 Ela2 “knock-in” mice were healthy with no apparent developmental defect. While expression of Ela2 mRNA was normal, no mature NE protein was detected in the neutrophils of homozygous G192X Ela2 mice. However, in granulocytic precursors (mainly promyelocytes/myelocytes) a small amount of heavily glycosylated mutant NE protein was detected. Together, these observations suggest that G192X NE protein is retained in the endoplasmic reticulum (ER) and rapidly degraded. Consistent with ER stress and induction of the UPR, a significant increase in BiP/GRP78 and ATF6 mRNA expression in mutant granulocytic precursors were observed. Surprisingly, G192X Ela2 mice have normal basal granulopoiesis. The number of circulating neutrophils, granulocytic differentiation in the bone marrow, and number and cytokine responsiveness of myeloid progenitors were comparable to wild type mice. In summary, the G192X Ela2 mice appear to reproduce the NE protein misfolding and UPR activation observed in human SCN granulocytic precursors. However, expression of G192X Ela2 is not sufficient to disrupt basal granulopoiesis in mice. Studies of stress granulopoiesis are underway.
3
Skokowa, Julia, John Paul Fobiwe, Lan Dan, Basant Kumar Thakur, and Karl Welte. "Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1." Blood 114, no. 14 (October 1, 2009): 3044–51. http://dx.doi.org/10.1182/blood-2008-11-188755.
Анотація:
Abstract Severe congenital neutropenia (CN) is a heterogeneous disorder of myelopoiesis which follows an autosomal dominant or autosomal recessive pattern of inheritance. Genetic analyses indicate mutations in the ELA2 gene in most patients. We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPα. In patients with CN, the expression of LEF-1 and C/EBPα was abrogated in myeloid progenitors leading to maturation arrest of granulopoiesis. In the present study we demonstrated that ELA2 mRNA expression in myeloid progenitors and plasma protein levels of neutrophil elastase (NE) were markedly reduced in patients with CN harboring mutations in either ELA2 or HAX-1 genes. The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPα, documenting the role of LEF1 in the diminished ELA2 expression. We found that transduction of hematopoietic cells with LEF-1 cDNA resulted in the up-regulation of ELA2/NE synthesis, whereas inhibition of LEF-1 by shRNA led to a marked reduction in the levels of ELA2/NE. LEF-1 rescue of CD34+ cells isolated from 2 patients with CN resulted in granulocytic differentiation of the cells which was in line with increased levels of functionally active ELA2/NE.
4
Nanua, Suparna, Jun Xia, Mark Murakami, Jill Woloszynek, and Daniel C. Link. "Loss of PERK Signaling Results in Impaired Granulopoiesis in Transgenic Mice Expressing Mutant Ela2." Blood 114, no. 22 (November 20, 2009): 551. http://dx.doi.org/10.1182/blood.v114.22.551.551.
Анотація:
Abstract Abstract 551 Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis characterized by chronic neutropenia, a block in granulocytic differentiation at the promyelocyte/myelocyte stage, and a marked propensity to develop acute myeloid leukemia. Approximately 50% of cases of SCN are associated with germline heterozygous mutations of ELA2, encoding neutrophil elastase (NE). To date, 59 different, mostly missense, mutations of ELA2 have been reported. A unifying mechanism by which all of the different ELA2 mutants disrupt granulopoiesis is lacking. We and others previously proposed a model in which the ELA2 mutations result in NE protein misfolding, induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and ultimately apoptosis of granulocytic precursors. Testing this (and other) models has been limited by the rarity of SCN and difficulty in obtaining clinical samples for testing. We previously reported preliminary findings of a novel transgenic mouse expressing a truncation mutation of Ela2 (G193X) reproducing a similar mutation found in some patients with SCN (2008 ASH abstract #314). We showed that the G193X Ela2 allele produced the expected truncated protein that was rapidly degraded. Surprisingly, basal and stress granulopoiesis were normal. We hypothesized that reduced expression of Ela2 in murine compared with human granulocytic precursors resulted in less delivery of misfolded mutant NE protein to the ER, attenuating UPR activation and preserving granulopoiesis in G193X Ela2 mice. Consistent with this hypothesis, only modest evidence of UPR activation was observed in G193X Ela2 granulocytic precursors, and these cells displayed increased sensitivity to chemical inducers of ER stress compared with wildtype granulocytic precursors. The UPR model of disease pathogenesis predicts that inhibition of the cellular pathways that handle misfolded proteins may sensitize G193X Ela2 cells to ER stress and result in impaired granulocytic differentiation. To test this prediction, we crossed G193X Ela2 mice with mice lacking protein kinase RNA (PKR)-like ER kinase (PERK); PERK is one of three major ER-resident proteins that sense ER stress and activate the UPR. Of note, homozygous loss-of-function mutations of PERK (EIF2AK3) are responsible for Wolcott-Rallison syndrome, which is characterized by infantile diabetes and neutropenia in approximately 50% of cases. Since PERK deficiency is embryonic lethal, we transplanted fetal liver cells from PERK-/-, PERK-/- × G193X Ela2, and wild type embryos into irradiated recipients. Complete donor engraftment was observed in all cohorts. Basal granulopoiesis was normal in mice reconstituted with PERK-/- cells. However, in the PERK-/- × G193X Ela2 chimeras, though blood neutrophil counts were normal, a significant reduction in bone marrow neutrophils was observed [6.01 × 106/femur ± 0.92 (PERK-/-) versus 3.14 × 106 ± 0.88 (PERK-/- × G193X Ela2); p < 0.001]. These data show that loss of PERK signaling combined with G193X Ela2 expression results in impaired granulopoiesis, providing new evidence in support of the UPR model of disease pathogenesis. Disclosures: No relevant conflicts of interest to declare.
5
Alatrash, Gheath, Luis M. Vence, Wendy Woodward, Naoto T. Ueno, and Jeffrey J. Molldrem. "Leukemia-Associated Primary Granule Proteins (PGPs) Elastase-2 and Proteinase-3 Are Aberrantly Expressed in Solid Tumors: A Potential Therapeutic Target for PR1-Directed Immunotherapy." Blood 112, no. 11 (November 16, 2008): 5440. http://dx.doi.org/10.1182/blood.v112.11.5440.5440.
Анотація:
Abstract Neutrophil elastase (ELA2) and proteinase-3 (PRTN3) are the source proteins for the nonomeric HLA-A2-restricted peptide PR1 (VLQELNVTV), a recognized leukemia-associated antigen (LAA). In myeloid leukemia, high expression of ELA2 and PRTN3 has been correlated with improved clinical outcomes following hematopoietic stem cell transplant (HSCT). Vaccination with PR-1 peptide showed efficacy in myeloid leukemia and myelodysplastic syndrome, and was associated with immunologic response (≥ 2 fold increase in PR1-specific cytotoxic T lymphocytes (PR1-CTL)) and long-lasting clinical remissions. PR1-CTLwere shown to mediate immunity elicited by PR-1 vaccine, as they preferentially recognize and kill myeloid leukemia cells. Since ELA2 and PRTN3 have been reported in breast cancer biopsies, we hypothesized that ELA2 and PRTN3 may be mislocalized in solid tumors, leading to MHC-I presentation, therefore providing a therapeutic target for PR1 vaccine. To study the subcellular localization of ELA2 and PRTN3, the cytoplasmic, nuclear, membrane, and golgi/ER fractions were obtained from inflammatory breast cancer (IBC) (MDA-IBC1 and SUM149) and melanoma (526, 624, 888 and 926) cell lines. ELA2 was preferentially expressed in the cytoplasmic fraction in the IBC cell line SUM149, while PRTN3 was expressed in the membrane and cytoskeletal fractions of the IBC cell line MDA-IBC1. In the melanoma cell lines, ELA2 was expressed in the cytoplasmic fractions, while PRTN3 was noted in the nuclear, cytoplasmic and cytoskeletal fractions. Furthermore, the HLA-A2+ melanoma cell line 888 was susceptible to lysis by PR1-CTL (approximately 30% lysis; Effector:Target ratio=1:2). Together, these results demonstrate that ELA2 and PRTN3 are aberrantly localized in non-hematopoietic cell lines, and that this can be associated with susceptibility to PR1- CTL lysis. In particular, PR1 is a potential immunotherapeutic target for patients with melanoma and breast cancer.
6
Zeidler, Cornelia, Jean Donadieu, Audrey Anna Bolyard, Peter Vandenberghe, Gusal Pracht, Blandine Beaupain, Ludwig Hoy, et al. "Update On the Risk of Leukemia in Genetic Subgroups of Congenital Neutropenia (CN): Comparison of Patients with Known Gene Mutations (ELA2, HAX1, WASP, G6PC3, p14)." Blood 114, no. 22 (November 20, 2009): 3597. http://dx.doi.org/10.1182/blood.v114.22.3597.3597.
Анотація:
Abstract Abstract 3597 Poster Board III-534 An increased risk for malignant transformation (MDS or leukemia) is well documented in patients with congenital neutropenia (CN). In this study we assessed the incidence of leukemic transformation and potential risk factors for leukemic transformation in CN patients with known gene mutations, e.g. ELA2, HAX1, G6PC3, p14, WAS or no identified mutation, respectively, by combining all available data from the European and US Branches of the Severe Chronic Neutropenia Registry (SCNIR) and the French Neutropenia Registry (FR). Data from mutational analysis were available for 407 patients. Mutations were identified in 259 CN patients, of whom 209 patients revealed ELA2 mutations, 20 HAX1 mutations, 18 WAS, 8 G6PC3 and 4 p14 mutations. In addition, in 57 patients neither ELA2 nor HAX 1 mutation were detectable and in another 91 patients ELA2 mutations could be excluded, but further genetic evaluation is not yet completed. Secondary malignancies occurred in 50 of the 407 CN patients. The distribution by genetic subtype is shown in the table below: CN subtype by gene mutation Total patient number (n) MDS/Leukemia (n/%) ELA2-CN 209 31 (14. 8%) HAX1-CN 20 4 (20%) ELA2 neg + HAX1 neg 57 6 (10.5%) ELA2 neg/ HAX1 not tested 91 5 (5.5%) WAS 18 4 (22.2%) G6PC3 8 0 p14 4 0 Total 407 50 (12.3%) All subgroups benefit from G-CSF treatment. Median G-CSF maintenance doses required during the years prior to leukemic transformation compared by genetic subtype is shown in the following table 2: CN subtype by gene mutation Without leukemia (n) Median G-CSF dose (μg/kg/d) With leukemia (n) Median G-CSF dose (μg/kg/d) ELA2-CN 75 5.0 15 15 HAX1-CN 15 5.0 4 13.4 ELA2-/HAX1- 36 7.2 4 10.5 WAS 15 2.6 4 3.0 G6PC3 8 3.9 0 na p14 4 5.1 0 na Conclusion Patients with severe congenital neutropenia who have mutations in ELA2, HAX1, or WAS and also those with no recognized mutation are at risk of secondary leukemia. So far, progression to MDS leukemia has not yet been described in the small number G6PC3 or p14 CN cases in our database. ELA2-CN or HAX1-CN patients requiring higher doses of G-CSF are at greater risk. Mutational analysis is helpful to identify the genetic cause of severe congenital neutropenia but does not serve to identify patients at risk of leukemic transformation. Disclosures: No relevant conflicts of interest to declare.
7
Ono, Yoko, Sijie Lu, Anna Sergeeva, Changqing Wang, Eric Wieder, and Jeffrey J. Molldrem. "PR1 Leukemia-Associated Antigen Is Cross-Presented by B Cells from Soluble Serum Proteases." Blood 106, no. 11 (November 16, 2005): 2397. http://dx.doi.org/10.1182/blood.v106.11.2397.2397.
Анотація:
Abstract PR1 (VLQELNVTV) is an HLA-A*0201-binding leukemia-associated peptide epitope within proteinase 3 (PRTN3) and neutrophil elastase (ELA2), and PR1-specific CD8+ cytotoxic T lymphocytes (PR1-CTL) contribute to cytogenetic remission in some patients with chronic myelogenous leukemia. It is not understood how immunity is induced to the PR1 self-antigen in leukemia patients. Normally, myeloid dendritic cells (mDC) take up exogenous antigen and peptides are cross-presented on MHC-I to induce CTL immunity. However, in myeloid leukemia patients, mDC do not function normally and they are reduced in number. On the other hand, B cells, and potentially plasmacytoid DC (pDC), are uninvolved in the malignant process but they have been implicated in tolerance induction. Indeed, PRTN3 and ELA2 are present in serum and cross-presentation of soluble antigens can lead to cross-tolerance. To investigate whether B cells can cross-present PRTN3 or ELA2, both genes were first cloned from normal bone marrow and individually cloned into the human B cell line HMy.CIR-A2 cell (previously transfected with HLA-A*0201), which doesn’t normally express the proteins. Transfectant-induced proliferation of 25-day old PR1-CTL cell lines, measured by BrDU incorporation, was used to assess sustained PR1 antigen presentation. PRTN3- and ELA2-transfected HMy.CIR-A2 cells induced HLA-A2-restricted PR1-specific CTL proliferation compared to control sham transfectants with/without HLA-A*0201. PR1 presentation was proteasome-dependent and involved transport from the ER to the cell surface since PR1-CL proliferation was abrogated by treating the transfectants with lactacystin and Brefeldin A, respectively. Western blotting (WB) of cell supernatants showed that transfected HMy.CIR-A2 cells also secreted PRTN3 and ELA2. Furthermore, endocytosis of ELA2 by HMy.CIR-A2 and normal CD19+ B cells occurred within 30 minutes, by intracellular FACS staining. Early endocytosis of ELA2 was partly mediated by binding to LOX-1, a class E scavenger receptor on B cells and DC, since poly (I) and anti-LOX-1 antibody blocked uptake, but did not involve the scavenger receptors SR-A, CD91, or CD36 (no expression by FACS analysis). Confocal microscopy demonstrated that soluble ELA2 co-localized primarily to LAMP-2+ vesicles and to a lesser extent to cytoplasm of CD19+ B cells after 2 hours co-incubation. In contrast, freshly isolated mDC (CD11c+ CD14-) expressed ELA2 exclusively in lysosomes, shown by LAMP-2 co-localization. Like B cells, freshly isolated pDC did not express ELA2 transcripts (by RT-PCR) or protein (by WB), and confocal microscopy confirmed endocytosis of soluble ELA2 with similar lysosome + cytoplasm localization. Finally, cross-presentation of soluble ELA2 by HMy.CIR-A2 cells to PR1-CTL could be blocked by pre-treating B cells with lactacystin. In summary, soluble ELA2 and PRTN3 are taken up by normal B cells and ELA2 by pDC, in part via the LOX-1 scavenger receptor, and are localized primarily to lysosomes and to cytoplasm to a lesser extent. We previously showed that both proteins bind to ubiquitin and to the chaperone protein gp96 in protein-pulsed B cells, and the proteasome is required for PR1 processing. Thus, this is the first evidence that soluble tumor antigens can be cross-presented by B cells using the “phagosome-to-lysosome” pathway, and it suggests how immunity to the PR1 antigen could occur in leukemia patients.
8
Ishiyama, Ken, Yukio Kondo, Eric D. Wieder, Sijie Lu, and Jeffrey J. Molldrem. "Aberrantly Expressed Neutrophil Elastase (ELA2) Cleaves Cyclin E (CCNE) in the Nucleus and Cytoplasm of Acute Lymphocytic Leukemia Yielding Novel Leukemia-Associated Antigens." Blood 108, no. 11 (November 16, 2006): 4429. http://dx.doi.org/10.1182/blood.v108.11.4429.4429.
Анотація:
Abstract We have shown that donor-derived cytotoxic T lymphocytes (CTL) are specific for two HLA-A2-restricted peptides derived from CCNE (CCNE1144–152, ILLDWLMEV and CCNE2144–152, ILLDWLLEV) specifically lyse lymphoid and myeloid leukemia cells that aberrantly express CCNE. The CCNE protein is overexpressed in AML, ALL, and CML, and in solid tumors such as breast, lung, and gastric cancers. Furthermore, five low molecular weight forms (LMWFs) of CCNE, which are constitutively active to promote cell division, are found only in malignant cells, though it is not known how LMWFs are formed in leukemia. We hypothesized that the cleavage of CCNE into LMWFs occurs by enzymatic cleavage from aberrantly expressed ELA2 in leukemia, which renders the leukemia susceptible to killing by ELA2- and CCNE-specific CTL. Whole cell lysates from U937, HL60, and bone marrow from patients with B-ALL, but not from PBMC or bone marrow cells from healthy donors or ALL patients in remission, showed high expression of CCNE and LMWF by western blot (WB). Recombinant ELA2 added to B cell-derived whole cell lysates increased LMWFs, and the leukocyte elastase inhibitor Elafin prevented this cleavage. Subcellular fractions studied by coimmunoprecipitation showed that ELA2 was bound to CCNE in the nucleus, cytoplasm, and membrane-bound organelles of B-ALL, but not in normal cells. Because nuclear expression of CCNE increases during normal cell division, we studied healthy donor PBMC stimulated with anti-CD3 and anti-CD28 and found no expression of ELA2 or CCNE LMWFs by WB. We conclude that ELA2, normally expressed only in myeloid cells, is also expressed in some ALL blasts, and this data explains how CCNE LMWFs are formed in leukemia. Our findings also suggest how ELA2-mediated cleavage of the PML-RARα fusion product, required for leukemic transformation, could occur when ELA2 is aberrantly expressed in the nucleus. Finally, this work implies that overexpression of CCNE and the LMWFs that contain the immunogenic peptides could increase susceptibility of leukemia cells to CCNE-CTL lysis.
9
Alatrash, Gheath, Yoko Ono, Sijie Lu, Anna Sergeeva, Changqing Wang, Eric Wieder, and Jeffrey J. Molldrem. "Aberrant Subcellular Localization of Azurophil Granule Proteins in Myeloid Leukemia Favors Peptide Antigen Presentation on MHC-I and Susceptibility to Killing by Cytotoxic T Lymphocytes." Blood 110, no. 11 (November 16, 2007): 4900. http://dx.doi.org/10.1182/blood.v110.11.4900.4900.
Анотація:
Abstract The recognition of leukemia-associated antigens (LAA) by immune cells is essential for generating anti-leukemia responses. Whether elicited by vaccine or hematopoietic stem cell transplantation (HSCT), anti-leukemia immunity requires that cytotoxic T lymphocytes (CTL) recognize and mount an effective response against leukemia cells. PR1 is a nonomeric HLA-A2-restricted peptide (VLQELNVTV) derived from the myeloid-restricted serine proteases neutrophil elastase (ELA2) and proteinase-3 (PRTN3), recognized azurophil granule proteins. PR1-specific cytotoxic T lymphocytes (PR1-CTL) have been shown to preferentially recognize and kill myeloid leukemia cells. We hypothesized that aberrant protein expression in target leukemia cells predisposes to CTL killing. To determine the subcellular localization of ELA2 and PRTN3 in leukemia and in healthy donor (HD) neutrophils, high-speed ultracentrifugation of leukapheresed cells from patients with AML and CML in blast crises yielded 4 fractions: cytoplasmic, nuclear, membrane and golgi/endoplasmic reticulum (ER). Western blot analyses identified higher levels of ELA2 and PRTN3 in cytoplasmic, nuclear, and golgi/ER fractions in leukemia, compared to HD granulocytes. Confocal microscopy of leukapheresed myeloid blasts and HD granulocytes confirmed these findings. We further hypothesized that cross-presentation of PR1 is necessary for priming anti-leukemia immunity. Confocal microscopy of the human B-cell line HMy.CIR-A2, co-incubated with either purified or recombinant ELA2 and PRTN3 demonstrated co-localization of both proteins with LAMP-2, a marker of lysosomes and early endosomes, and small distribution in cytoplasm after 2 hours. Uptake of ELA2 and PRTN3 by HMy.CIR-A2 cells was additionally confirmed by Western blots. Priming of naive PR1-CTL by co-culture of HD lymphocytes with PRTN3 or ELA2-transfected HMy.CIR-A2 cells was confirmed by cell proliferation assays using BrDU. This could be abrogated by addition of lactacystin and cyclohexamide to cell culture. Together, these results demonstrate that ELA2 and PRTN3 are aberrantly localized preferentially in gogli/ER and cytoplasmic fractions in leukemia, rather than azurophil granules, which are often absent or deficient in myeloid leukemia. Similar forced subcellular localization of these proteins in B cells leads to their susceptibility to PR1-CTL killing. Therefore, we conclude that the natural mistrafficking of PRTN3 and ELA2 in myeloid leukemia is necessary to render cells susceptible to CTL attack and that cross-presentation of ELA2 and PRTN3 contributes to priming of a PR1-CTL response.
10
Skokowa, Julia, John-Paul Fobiwe, Dan Lan, Manuela Germeshausen, and Karl Welte. "Defective Expression of Neutrophil Serine Proteases in Myeloid Progenitors of Congenital Neutropenia Patients Carrying Either ELA2 or HAX1 Mutations." Blood 110, no. 11 (November 16, 2007): 3299. http://dx.doi.org/10.1182/blood.v110.11.3299.3299.
Анотація:
Abstract Severe congenital neutropenia (CN) is a heterogeneous disorder of myelopoiesis with two major types of inheritance: autosomal dominant CN defined by mutations in ELA2 gene encoding neutrophil elastase (NE) (Horwitz M., et al., Nat Genet.1999;23:433) and autosomal recessive CN (including Kostmann syndrome) carrying HAX-1 mutations (Klein C., et al., Nat Genet.2007;39:86), both characterized by a maturation arrest of granulopoiesis at the level of promyelocytes. In the present study we aimed to evaluate the expression profile of genes specifically expressed in the CD33+ bone marrow promyelocytes of both patient groups harbouring ELA2 or HAX1 mutations. In healthy individuals mRNA expression levels of neutrophil serine proteases (neutrophil elastase (ELA2), cathepsin G, cathepsin D, proteinase 3 and azurocidin) as well as of myeloperoxidase (MPO) and defensins reached highest levels in the azurophil granules at the promyelocytic stage of neutrophil differentiation (Borregaard N., et al., Curr Opin Hematol.2001;8:23). We found downregulation of mRNA expression levels of ELA2 (8.9 fold), cathepsin G (7.6 fold), cathepsin D (11.2 fold), proteinase 3 (9.2 fold) and defensin B1 (6.5 fold) in both groups of CN patients (with ELA2 or HAX1 mutations), in comparison to G-CSF-treated patients with idiopathic neutropenia (IN) and G-CSF-treated healthy controls. In contrast, there were no difference in mRNA expression levels of azurocidin and only slight decrease in the expression of MPO mRNA in CN patients. Additionally, we found significantly reduced protein levels of neutrophil elastase (NE) in plasma of CN patients irrespective of “ELA2 or HAX1” inheritance, in comparison to cyclic neutropenia (CyN) patients, IN patients and G-CSF-treated healthy controls. Taken together, both ELA2 and HAX1 mutations are associated with defective expression of neutrophil serine proteases such as NE, cathepsin G, cathepsin D, proteinase 3 as well as of defensin B1 in CD33+ myeloid progenitor cells of CN patients, suggesting a common pathway for both patient groups. Intriguingly, ELA2 expression is directly regulated by LEF-1, suggesting that abrogated LEF-1 expression in CN promyelocytes (Skokowa J., et al., Nat. Med.2006;12:1191) may be responsible for defective serine proteases expression in both groups, since all are regulated by a similar mechanism.
Дисертації з теми "ELA2":
1
Shkotova, Viktoriia. "Návrh systému sběru a vyhodnocovaní událostí v provozu u DOA organizace." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2021. http://www.nusl.cz/ntk/nusl-449716.
Анотація:
The diploma thesis focuses on the issue of the system of collection and evaluation of operational events at the DOA organization. It specifies the basic legislative requirements and regulations in the field of reporting incidents of an aircraft technical. For the analysis of the given topic, Czech companies were contacted, which could share their own experience in the framework of security management using a proactive method. Based on the summary of findings, the system of event collection and processing was designed. The system could be used by organizations dealing with the design of aircraft category ELA2
2
Fobiwe, John Paul Ndeh [Verfasser], and Karl [Akademischer Betreuer] Welte. "Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1 / John Paul Ndeh Fobiwe. Abteilung für Molekulare Hämatopoese der Medizinischen Hochschule Hannover. Betreuer: Karl Welte." Hannover : Bibliothek der Medizinischen Hochschule Hannover, 2010. http://d-nb.info/1008925098/34.
3
Silva, Camila Diane. "(C)elas e elas." reponame:Repositório Institucional da UFSC, 2015. https://repositorio.ufsc.br/xmlui/handle/123456789/160724.
Анотація:
Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Filosofia e Ciências Humanas, Programa de Pós-Graduação em História, Florianópolis, 2015.Made available in DSpace on 2016-04-19T04:13:37Z (GMT). No. of bitstreams: 1 337972.pdf: 2556549 bytes, checksum: 7630d0501a11cdef14d47a2d0ef071e4 (MD5) Previous issue date: 2015
A presente dissertação tem como objetivo problematizar as experiências afetivas e/ou sexuais entre mulheres na Ala Feminina do Presídio Regional de Joinville e perceber como estas experiências podem desconstruir normativas de gênero e sexualidades. Além disso, tem a intenção de analisar como os discursos sobre gênero e sexualidades foram tratados nesta instituição prisional, apontando para permanências e rupturas. As fontes utilizadas foram entrevistas orais realizadas no ano de 2013, que contaram com o aporte da Metodologia de História Oral e a análise de Livros de Ocorrência da Ala Feminina que compreendiam os anos de 2003-2010. Para as análises do Livro de Ocorrências utilizei a análise do discurso como ferramenta. Além destas fontes, recortes de jornais da cidade foram utilizados de modo a complementar a pesquisa. Através das análises das fontes foi possível evidenciar o presídio como um local a possibilitar que muitas mulheres se permitissem a outras experiências em relação ao gênero e sexualidade; já que houve a possibilidade, destas se distanciarem de normas impostas culturalmente. Para algumas das entrevistadas foi, no presídio, longe das cobranças sociais que estas se permitiram romper com a posição de dona de casa e mãe, se relacionar afetivamente e/ou sexualmente com outras mulheres, adotar padrões estéticos masculinos que outrora se sentiram impelidas a negar devido ao preconceito que sofriam em seu cotidiano, entre outras rupturas, que estas atribuem ao fato de estarem vivendo em um ?mundo de mulheres?. Problematizar estas experiências desencadeadas neste espaço prisional pode representar uma fissura na constituição de saberes e verdades que regulam as relações de gênero e a sexualidade. Nesse sentido vejo a importância deste trabalho ao oferecer novos subsídios para compreensão do gênero e da sexualidade, bem como contribuir com temáticas pouco exploradas pela história como a homossexualidade de mulheres.
Abstract : This dissertation aims to problematize the afective and/or sexual experiences among women in the Female Aisle in the Regional Penitentiary of Joinville and understand how these experiences may deconstruct gender and sexuality rules. Besides, it intends to analyze how the speeches on gender and sexuality have been dealt with in this prison institution, pointing to abidance and rupture. The sources used were the oral interviews held in the year of 2013, that happened within the contribuition of the Methodology of Oral History and the analysis of the Occurrences Book of the Female Aisle that corresponded to the years 2003-2010. For the analysis of the Occurrences Book I used the analysis of the speech as a tool. Besides these sources, newspaper cuts from the city were used to complement the research. Through the analysis of the sources it was possible to point out the penitentiary as a place to enable that many women allowed themselves to have other experiences regarding their own gender and sexuality; because there was a possibility, some of these women distanced themselves from the culturally imposed rules. For some of the interviewed it was in the penitentiary, away from the social demands, that they allowed themselves to disconnect from the position of housewife and mother, relate afectively and/or sexualy with other women, adopt masculine beauty standards that once they felt they had to deny due to prejudice they suffered in their routines, among other ruptures, that they impute to the fact that they?re living in a ?women?s world?. Problematizing these experiences unfolded in this prison environment may represent a cleft in the constitution of knoledge and truths that regulate gender and sexuality. This way I set the importance of this piece of work in offering new aids to the understanding of gender and sexuality, as well as contribute with themes not yet much explored by history, like homossexuality among women.
4
Perucchi, Juliana. "Eu, tu, elas." Florianópolis, SC, 2001. http://repositorio.ufsc.br/xmlui/handle/123456789/81405.
Анотація:
Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Filosofia e Ciências Humanas. Programa de Pós-Graduação em PsicologiaMade available in DSpace on 2012-10-19T03:17:30Z (GMT). No. of bitstreams: 0Bitstream added on 2014-09-25T19:52:19Z : No. of bitstreams: 1 181653.pdf: 6758890 bytes, checksum: 17242acfbd058af05b4481d8ffa3ea83 (MD5)
A pergunta proposta nessa pesquisa lançou uma discussão: quais os sentidos que mulheres, com possibilidades de sentir diversos tipos de atração erótica ou de se relacionar fisicamente de diversas maneiras com outras mulheres, atribuem às relações sociais que estabelecem em um gueto GLS de Florianópolis? Essa questão trouxe à cena importantes categorias de análise: homoerotismo feminino, relações sociais e gueto GLS. Tais categorias foram problematizadas nessa dissertação de mestrado e contemplam os estudos sobre constituição de subjetividades, os estudos de gênero e dos modos de vida que, por sua vez, englobam e analisam teoricamente outros aspectos que se destacaram na pesquisa de campo desenvolvida no decorrer dessa investigação. O presente trabalho vai ao encontro da proposta de repensar a ciência do ponto de vista das mulheres, de dar-lhes espaço de palavra, na tentativa de desconstruir o modelo androcêntrico que tem norteado a maioria dos estudos científicos há tempos, inclusive na área da Psicologia. Assim, o estudo dos inúmeros agenciamentos de subjetivação que atravessam o sujeito cotidianamente constitui uma perspectiva de pesquisa bastante interessante, na medida em que trabalha a idéia de identidade pessoal socialmente construída e inacabada, legitimando gênero como categoria útil para se problematizar e investigar alguns aspectos fundamentais no processo de constituição do sujeito. Ao término desta pesquisa conclui-se que as relações sociais estabelecidas entre as mulheres (com outras mulheres e homens) que transitam pelo gueto, constituem e significam esse território na mesma medida em que são por ele constituídas. O gueto, enquanto espaço de construção de subjetividades, media a própria construção dessas mulheres não apenas como pessoas com possibilidades de se relacionarem afetiva e sexualmente com outras do mesmo sexo que o seu mas, sobretudo, enquanto sujeitos no mundo. O trânsito desses sujeitos no interior do gueto indica o cerceamento das condutas dessas mesmas pessoas fora dos limites desse território. Reconhecido como lugar de proteção e legitimação de comportamentos e posturas, o gueto problematiza os domínios do espaço privado e do espaço público, (re)produzindo modos de vida bastante peculiares.
5
Resende, Adriana Agostini de. "The L Word - eLas por eLas: e o universo lésbico se apresenta na TV." Universidade Federal de Minas Gerais, 2010. http://hdl.handle.net/1843/FAFI-84GNGB.
Анотація:
This thesis is geared towards portraying the lesbian universe through the analysis of five characters from the TV series The L Word. We aim to provide our readers with reasons as to why this series was such a worldwide success, obtaining fans from all four corners of the earth, including those from countries that didnt air the series. Our study will focus more specifically on the observation of the different ways its narrative is presented and speaks to its audience. To achieve this, we addresses the issue of lesbian identity in addition to discussing thestatus of television in an era in which new technologies enable the audience closer contact. Moreover, this research also briefly addresses the history and some of the possible TV series formats. With basis on The L Word series reviews and critics and by putting into practice the proposed thesis title elas por elas (them by them1), we are able to notice with precision how intensely all crew members became involved in the making of this series not only duri ng its shooting but also behind its scenes. After focusing on theories applied to each individual character, this thesis aims to identify traces of the lesbian universe depicted by the series characters thereby consequently offering its spectators, especiallythose who are lesbian, a wide range of identification options.Esta dissertação pretende analisar de que forma o universo lésbico se dá a ver a partir da análise de cinco personagens da série The L Word. Nosso objetivo é o de chegar a pistas do porquê a série conseguiu angariar fãs em todo o mundo, inclusive em países em que sequer foi exibida na televisão, observando especialmente os modos como sua narrativa se apresenta e dialoga com as telespectadoras. Para isso, o trabalho perpassa a discussão do que seria a identidade lésbica e também o debate de como está a televisão numa época em que novas tecnologias permitem uma aproximação ainda maior com o telespectador. Além disso, esta pesquisa resgata, ainda que brevemente, a história e alguns dos formatos possíveis das séries de TV. Ao recuperar o que se disse sobre The L Word e colocando em prática o que propõe o título elas por elas , percebemos com mais precisão o quanto a série envolveu toda a equipe de trabalho, mobilizando-a também para além das câmeras. Após enfocar teorias relativas à questão da personagem, a dissertação busca identificar traços do universo lésbico que se dão a ver por meio das personagens, oferecendo consequentemente um leque de opções de identificação junto às telespectadoras, especialmente às lésbicas.
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Schwether, Natália Diniz. "Agora é que são elas." reponame:Repositório Institucional da UFSC, 2016. https://repositorio.ufsc.br/xmlui/handle/123456789/168628.
Анотація:
Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Sócio-Econômico, Programa de Pós-Graduação em Relações Internacionais, Florianópolis, 2016.Made available in DSpace on 2016-09-27T04:00:47Z (GMT). No. of bitstreams: 1 339594.pdf: 1721326 bytes, checksum: 1a981bb23adaf18482b8c72f6f161294 (MD5) Previous issue date: 2016
Estudo acerca da incorporação feminina nas Forças Armadas de Brasil e Argentina. A organização militar fechada e fiel aos seus valores prezou ao longo dos séculos por preservar sua dinâmica e homogeneidade. As mudanças do mundo pós-Guerra Fria criaram novas condições que tornaram incontestável a necessidade de uma modernização institucional e reordenamento da atuação das forças, entre elas enfatiza-se a possibilidade de participação das mulheres. A pesquisa tem o intuito de identificar o processo que permeou a incorporação feminina na instituição, para tanto, se propõe a realizar um recorrido histórico do processo, com o auxílio das ações e resultados obtidos nos Estados Unidos, uma vez que é o país que mais antecedentes proporciona sobre a temática. Com vistas a responder o questionamento: como ocorreu o processo de incorporação das mulheres nas Forças Armadas de Brasil e Argentina? Realiza-se uma análise do contexto nacional de ambos os países, permeado pela transição democrática e a reformulação das relações civis-militares, da mesma forma que à atuação dos movimentos de mulheres e às mudanças no contexto internacional. Em suma, a pesquisa se desenvolve em bases qualitativas, por meio da análise de bibliografia pertinente, recorre-se, também, a fontes primárias como atas de reuniões e entrevista.
Abstract : Study on the incorporation of women in the armed forces of Brazil and Argentina. Over the centuries, the closed military organization faithful to their values preferred to preserve its homogeneity and dynamic. However, the changes of the Post-cold war era created new conditions that made an uncontested need for an institutional modernization and improvement on the performance of the forces, among them emphasizes the possibility of women?s participation. The research aims to identify the process that permeated the female incorporation into the institution; therefore, it proposes to perform an examination into the historic process, with the aid of the actions and results obtained in the United States, since it is the country that provides more background on the subject. In order to answer the question: how was the process of incorporation of women in the armed forces of Brazil and Argentina? Is carried out a national context analysis of both countries, permeated by the democratic transition and the recasting of civil-military relations, in the same way as the action of women's movements and changes in the international context. In short, the research is developed in qualitative basis, through the analysis of texts produced on the subject, and also resorts to primary sources such as minutes of meetings and interview.
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Guimaraes, Cristiane Viana. "Estudo retrospectivo imunoistoquímico e pesquisa por PCR em fezes e sorologia para Lawsonia Intracellularis em equinos no Estado de Minas Gerais - Brasil." Universidade Federal de Minas Gerais, 2008. http://hdl.handle.net/1843/ELAS-7JZMY8.
Анотація:
The proliferative enteropathy caused by intracellular bacteria, Lawsonia intracellularis, has been described in equine in Australia, United States, Canada and in countries of Europe, (Switzerland and Belgium). Currently, the disease has not been diagnosed in any country of Latin America. The predominance of the disease in equine is still unknown. A retrospective study was conducted using paraffin blocks of equine cases from the veterinarian schools of Universidade Federal de Minas Gerais (UFMG) and Universidade Federal de Lavras (UFLA). Also a prospective study using serology and PCR for detecting antibodies and L. intracellularis shedding in fecal samples was conducted in different equine herds in the state of Minas Gerais, Brasil. Fifty-one cases of equines with enteric disorders from the period of 1970 to 2006 from UFMG and nine cases of UFLA were compiled and selected from the period of 2000 to 2007. Histological cuts of the blocks containing fragments of intestine and stomach were prepared in signalized glass-slides, and were submitted to IHQ using the method of Streptavidin, polyclonal antibody against L. intracellularis and ACE (Amino Etil-carbazol) cromogen solution. No positive sample in IHQ was identified. For the longitudinal study, sera and fecal samples from 223 animals from 14 horse farms and veterinarian schools of UFMG a serological test using the imunoperoxidase technique in glass sheets and PCR were used. From the 223 samples serologically tested, eight equine had 1:60 titer, and were considered positive. The PCR technique in feces for bacterias DNA detection identified seven positive equine for L. intracellularis. Seropositivity and detection of bacteria in colts feces in equine population in the State of Minas Gerais, Brasil, indicates the presence of the agent and the possibility of the disease associated with the infection. This should be an alert to clinics as possible differential diagnosis of enteric disease equineA enteropatia proliferativa causada pela bactéria intracelular, Lawsonia intracellularis, tem sido relatada em eqüinos na Austrália, Estados Unidos, Canadá e em países na Europa (Suíça e Bélgica). No entanto, até o momento, a doença não foi diagnosticada em nenhum país da América Latina. A prevalência da doença em eqüinos é desconhecida. Pesquisou-se a ocorrência da enteropatia proliferativa em eqüinos no Estado de Minas Gerais, Brasil, através de estudo retrospectivo no arquivo do Setor de Patologia da Escola de Veterinária da Universidade Federal de Minas Gerais (UFMG) e da Universidade Federal de Lavras (UFLA), e através da aplicação da técnica de PCR em fezes e sorologia. O estudo retrospectivo foi realizado a partir de amostras em blocos de parafina, de 51 casos compilados de equinos com desordens entéricas provenientes na Escola de Veterinária da UFMG, no período de 1970 a 2006, e de nove casos provenientes da UFLA no período de 2000 a 2007. Cortes histológicos em lâminas silanizadas dos blocos contendo fragmentos de intestino e estômago foram submetidos a imunoistoquímica (IHQ) utilizando o método da Streptavidina Marcada, anticorpo policlonal contra L. intracellularis e solução de cromógeno de AEC (Amino Etil-carbazol). Não foi identificada nenhuma amostra positiva à IHQ. Para realização da pesquisa por PCR em fezes e sorologia foram utilizados o teste sorológico, usando a técnica de imunoperoxidase em lâminas de vidro, e a técnica de PCR em amostras fecais coletadas de 223 eqüinos provenientes de 14 haras e de eqüinos hospitalizados na escola de veterinária da UFMG. Das 223 amostras avaliadas sorologicamente, foram identificados vinte e um eqüinos com titulação de 1:60, sendo considerados positivos. À técnica de PCR em fezes para detecção de DNA da L. intracellularis identificou sete equinos positivos. Soropositividade e detecção de bactérias nas fezes de potros na população de equinos do Estado de Minas Gerais, Brasil, indica a presença do agente e a possibilidade de doença associada a infecção, sendo um alerta para os clínicos como possível diagnóstico diferencial de enterite em eqüinos
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Gilsig, Marcie-Ann. "Elam Ives, Jr. (1802-1864) : musicianeducator." Thesis, McGill University, 1985. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=65958.
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Lima, Marli Machado [UNESP]. "Entre elas: cartografias dos devires amorosos." Universidade Estadual Paulista (UNESP), 2009. http://hdl.handle.net/11449/97609.
Анотація:
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lima_mm_me_assis.pdf: 746567 bytes, checksum: 725bc3d4a33d18fde44ca7e965d38deb (MD5)A partir do método cartográfico, esta pesquisa apresenta os relacionamentos amorosos de mulheres lésbicas, em uma cidade de médio porte, no interior paulista. A proposta metodológica foi de fundamental importância, na medida em que permitiu o desenvolvimento de uma investigação participativa na qual o pesquisador se implica. A partir de Michel Foucault, focamonos no processo de resistência como forma dessas mulheres afirmarem suas escolhas amorosas e resistirem ao poder heteronormativo. Como foco de interesse, também privilegiamos a produção de subjetividades, os processos de singularização e “revolução molecular”– propostas desenvolvidas por Gilles Deleuze e Feliz Guattari –, que se centram nos processos de criação de novas formas de existir, ao invés das idéias de classe, submissão e opressão. Algumas questões norteiam este trabalho: O que é ser lésbica? É desejar uma mulher? É manter relações com ela? É ser amiga delas e se solidarizar com elas? Pode ser tudo isso. Elas são várias, estão em todos os lugares e se manifestam de múltiplas formas. Também amam, se relacionam e fazem sexo de infinitas maneiras diferentes.
From the cartographic method, this research presents the love relationships of lesbian women, in a city of a medium size, the São Paulo state interior. The methodological proposal was of fundamental importance, as it allowed the development of a participative inquiry in which the researcher envolves herself. From Michel Foucault, we focuse ourself in the resistance process as a form of these women to affirm ther love choices and to resist the heteronormative power. As a focus of interest, we also privilege the production of subjectivities, the processes of singularization and “molecular revolution” - proposals developed by Gilles Deleuze and Felix Guattari -, that they are centered in the processes of creation of new forms to existing, instead of the ideas of classes, submission and oppression. Some questions guide this work: What is to be a lesbian? Is it to desire a woman? Is it to have sex with her? Is it to be friendly with them and to be solidary with them? This can be everything. They are several kind of womem, are everywhere and they reveal themselves in multiple forms. They also love, they get along and they make sex in infinite different ways.
10
Lima, Marli Machado. "Entre elas : cartografias dos devires amorosos /." Assis : [s.n.], 2009. http://hdl.handle.net/11449/97609.
Анотація:
Orientador: Wiliam Siqueira PeresBanca: Anna Paula Uziel
Banca: Fernando Silva Teixeira Filho
Resumo: A partir do método cartográfico, esta pesquisa apresenta os relacionamentos amorosos de mulheres lésbicas, em uma cidade de médio porte, no interior paulista. A proposta metodológica foi de fundamental importância, na medida em que permitiu o desenvolvimento de uma investigação participativa na qual o pesquisador se implica. A partir de Michel Foucault, focamonos no processo de resistência como forma dessas mulheres afirmarem suas escolhas amorosas e resistirem ao poder heteronormativo. Como foco de interesse, também privilegiamos a produção de subjetividades, os processos de singularização e "revolução molecular"- propostas desenvolvidas por Gilles Deleuze e Feliz Guattari -, que se centram nos processos de criação de novas formas de existir, ao invés das idéias de classe, submissão e opressão. Algumas questões norteiam este trabalho: O que é ser lésbica? É desejar uma mulher? É manter relações com ela? É ser amiga delas e se solidarizar com elas? Pode ser tudo isso. Elas são várias, estão em todos os lugares e se manifestam de múltiplas formas. Também amam, se relacionam e fazem sexo de infinitas maneiras diferentes.
Abstract: From the cartographic method, this research presents the love relationships of lesbian women, in a city of a medium size, the São Paulo state interior. The methodological proposal was of fundamental importance, as it allowed the development of a participative inquiry in which the researcher envolves herself. From Michel Foucault, we focuse ourself in the resistance process as a form of these women to affirm ther love choices and to resist the heteronormative power. As a focus of interest, we also privilege the production of subjectivities, the processes of singularization and "molecular revolution" - proposals developed by Gilles Deleuze and Felix Guattari -, that they are centered in the processes of creation of new forms to existing, instead of the ideas of classes, submission and oppression. Some questions guide this work: What is to be a lesbian? Is it to desire a woman? Is it to have sex with her? Is it to be friendly with them and to be solidary with them? This can be everything. They are several kind of womem, are everywhere and they reveal themselves in multiple forms. They also love, they get along and they make sex in infinite different ways.
Mestre
Книги з теми "ELA2":
1
Leite, Ivana de Arruda. Elas. São Paulo: Callis, 2004.
2
Leite, Ivana de Arruda. Elas. São Paulo: Callis, 2004.
3
Lassry, Elad. Elad Lassry. London: White Cube, 2011.
4
Cakradhar, Gōvindarāju. Anuvadiñcaḍaṃ elā? [Hyderabad, India]: Media House Publications, 1998.
5
Ekdal, Müfid. Prenses Elâ. Cağaloğlu, İstanbul: Altın Kitaplar, 2000.
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Hamo, Yossi. Atah medaber elai? Yerushalayim: Hotsaʼat Kenaʻan, 2009.
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Rotem, Yehudit. Matai tavo elai. Or Yehudah: Kineret, 2012.
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Cakradhar, Gōvindarāju. Pracāraṃ pondaḍaṃ elā? Hyderabad: Media House Publications, 1999.
9
Shpigel, Muḳi. Dege mifrats-Elat. [Israel]: Hotsaʾat ha-Ḥevrah le-hanagat ha-ṭevaʻ, 1993.
10
Devir, Natan. Elat ha-Yehudim. Hod ha-Sharon: Asṭrolog, 2003.
Частини книг з теми "ELA2":
1
Pettis, Jeffrey B., Jo Nash, Benjamin Beit-Hallahmi, Ruth Williams, David A. Leeming, Robert S. Ellwood, Jeffrey B. Pettis, et al. "Elan Vital." In Encyclopedia of Psychology and Religion, 274. Boston, MA: Springer US, 2010. http://dx.doi.org/10.1007/978-0-387-71802-6_198.
2
Chanard, Christian. "ELAN-CorpA." In Corpus-based Studies of Lesser-described Languages, 311–32. Amsterdam: John Benjamins Publishing Company, 2015. http://dx.doi.org/10.1075/scl.68.10cha.
3
Allwardt, Ulrich. "Tauchvergnügen in Elat." In Israel, 125–26. Wiesbaden: VS Verlag für Sozialwissenschaften, 1987. http://dx.doi.org/10.1007/978-3-663-01260-3_20.
4
Moreau, Pierre-Etienne. "REM (Reduce Elan Machine): Core of the New ELAN Compiler." In Rewriting Techniques and Applications, 265–69. Berlin, Heidelberg: Springer Berlin Heidelberg, 2000. http://dx.doi.org/10.1007/10721975_19.
5
Álvarez-Mon, Javier. "Elam: Iran's First Empire." In A Companion to the Archaeology of the Ancient Near East, 740–57. Oxford, UK: Wiley-Blackwell, 2012. http://dx.doi.org/10.1002/9781444360790.ch39.
6
Danckwerts, Rainer, Dankwart Vogel, Klaus Bovermann, Walter Deuber, and Roland Stowasser. "Ausgewählte Programme in ELAN." In Elementare Methoden der Kombinatorik, 175–201. Wiesbaden: Vieweg+Teubner Verlag, 1985. http://dx.doi.org/10.1007/978-3-322-96684-1_7.
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Harrow, Jenny, Susan Lord, Jan Sacharko, Allyson Reaves, Anne Sander, Martha Chen, Michael Bisesi, et al. "Bhatt, Ela R." In International Encyclopedia of Civil Society, 63–64. New York, NY: Springer US, 2010. http://dx.doi.org/10.1007/978-0-387-93996-4_178.
8
Lazary, S., and H. Gerber. "Ela Disease Associations." In Improving Genetic Disease Resistance in Farm Animals, 134–42. Dordrecht: Springer Netherlands, 1989. http://dx.doi.org/10.1007/978-94-009-1057-7_15.
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Kirchner, Hélèene, and Pierre-Etienne Moreau. "Non-deterministic Computations in ELAN." In Recent Trends in Algebraic Development Techniques, 168–83. Berlin, Heidelberg: Springer Berlin Heidelberg, 1999. http://dx.doi.org/10.1007/3-540-48483-3_12.
10
Moser, Michael. "The ELAN performance analysis environment." In CONPAR 90 — VAPP IV, 188–99. Berlin, Heidelberg: Springer Berlin Heidelberg, 1990. http://dx.doi.org/10.1007/3-540-53065-7_99.
Тези доповідей конференцій з теми "ELA2":
1
Thao, Tran Phuong, and Kazumasa Omote. "ELAR." In ACSAC '16: 2016 Annual Computer Security Applications Conference. New York, NY, USA: ACM, 2016. http://dx.doi.org/10.1145/2991079.2991082.
2
Lemus, Renato. "ELAF posters." In LATIN-AMERICAN SCHOOL OF PHYSICS MARCOS MOSHINSKY ELAF: Nonlinear Dynamics in Hamiltonian Systems. AIP Publishing LLC, 2014. http://dx.doi.org/10.1063/1.4861697.
3
Azevedo e Souza, Ana Cecilia de, Enio Frota da Silveira, José Carlos Nogueira, Marco Antonio Chaer do Nascimento, and Danilo de Paiva Almeida. "Collision Processes of Ion, Positron, Electron and Photon Beams with Matter." In ELAF 91. WORLD SCIENTIFIC, 1992. http://dx.doi.org/10.1142/9789814538053.
4
Oldenburg, G. "Honeywill-Elac Bottom Chart." In OCEANS '87. IEEE, 1987. http://dx.doi.org/10.1109/oceans.1987.1160728.
5
Vaccarella, Peter W., James C. Jensen, and Albert A. Adams. "Lotus Elan - An RTM Composite Success." In International Congress & Exposition. 400 Commonwealth Drive, Warrendale, PA, United States: SAE International, 1991. http://dx.doi.org/10.4271/910441.
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Xie, Lingjing, and Xuesong Zhang. "Parallel Acceleration of ELAS on ARM." In 2019 5th International Conference on Control, Automation and Robotics (ICCAR). IEEE, 2019. http://dx.doi.org/10.1109/iccar.2019.8813705.
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"IT-ELA 2020 TOC." In 2020 1st. Information Technology To Enhance e-learning and Other Application (IT-ELA). IEEE, 2020. http://dx.doi.org/10.1109/it-ela50150.2020.9253071.
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"IT-ELA 2020 Index." In 2020 1st. Information Technology To Enhance e-learning and Other Application (IT-ELA). IEEE, 2020. http://dx.doi.org/10.1109/it-ela50150.2020.9253093.
9
Vieira, Igor Rodrigues, Leonardo da Silva Sousa, Vinícius Rafael Lobo de Mendonça, Cássio Leonardo Rodrigues, and Auri Marcelo Rizzo Vincenzi. "Dívida Técnica: um estudo de caso com produtos de código aberto." In Simpósio Brasileiro de Qualidade de Software. Sociedade Brasileira de Computação - SBC, 2013. http://dx.doi.org/10.5753/sbqs.2013.15290.
Анотація:
Este artigo avalia a metáfora da dívida técnica em produtos de código aberto, considerando seu estado sobre esses produtos, no intuito de demonstrar a possibilidade de utilização dessa abordagem para o gerenciamento e avaliação da qualidade. Este trabalho está relacionado com a avaliação de recentes versões de um conjunto de quarenta projetos da Comunidade de Software Livre, escolhidos arbitrariamente. Esses projetos são submetidos à avaliação da plataforma Sonar, a qual possibilita coletar métricas estáticas e dinâmicas, entre elas a Dívida Técnica. Os resultados obtidos são utilizados para avaliar as características da dívida técnica sobre esse conjunto de projetos, além de verificar se ela está em um nível aceitável.
10
Macias, Manuel E., and Israel Mendez. "eLab - Remote electronics lab in real time." In 2007 37th annual frontiers in education conference - global engineering: knowledge without borders, opportunities without passports. IEEE, 2007. http://dx.doi.org/10.1109/fie.2007.4418154.
Звіти організацій з теми "ELA2":
1
Bickford, Mark. Event Logic Assistant (Elan). Fort Belvoir, VA: Defense Technical Information Center, July 2008. http://dx.doi.org/10.21236/ada487443.
2
Wong, C., and L. Collins. TECHNICAL EQUIVALENCE BETWEEN PERKIN-ELMER DRCe AND ELAN 6000 FOR THE ANALYSIS OF 238U IN URINE BIOASSAY SAMPLES. Office of Scientific and Technical Information (OSTI), September 2007. http://dx.doi.org/10.2172/924967.
3
Cho, J., C. Madden, and J. Bennett. Documents Requested for CA ELAP Accreditation (Document Master List, Personnel, Training Records, Internal Audits, Management Review, NCR example, MDL Studies). Office of Scientific and Technical Information (OSTI), August 2021. http://dx.doi.org/10.2172/1814679.
4
Rui, Taniele, and Mauricio Fiore, eds. Working Paper Series: Comunidades Terapêuticas no Brasil. Drugs, Security and Democracy Program, Social Science Research Council, June 2021. http://dx.doi.org/10.35650/ssrc.2082.d.2021.
Анотація:
Espalhadas pelo Brasil e atingindo força política inédita, as comunidades terapêuticas são tão inescapáveis do debate sobre políticas de drogas quanto complexas em sua definição. Embora não sejam uma criação brasileira, elas operam nesse país há algumas décadas, sendo que sua disseminação se intensificou nos anos 1990. Em 2011, elas foram incorporadas oficialmente à Rede de Atenção Psicossocial (RAPS) brasileira. Desde então, as comunidades terapêuticas estão no centro de debates públicos sobre sua regulamentação; sobre como devem – ou mesmo se devem – ser caracterizadas no sistema de saúde; sobre o nível de supervisão a que devem ser submetidas; sobre suas fontes de financiamento, particularmente se devem ou não ter acesso a financiamento público; e, mais importante, sobre a qualidade dos serviços que oferecem e as várias denuncias de violações de direito existentes. No entanto, um debate público bem informado só pode florescer se as informações disponíveis forem baseadas em evidências. O programa Drugs, Security and Democracy to SSRC preocupa com a relevância dos projetos de pesquisa que apoia e o debate em torno das comunidades terapêuticas no Brasil aponta para uma clara necessidade de pesquisas imparciais que abordem diferentes aspectos transversais deste tópico em suas várias dimensões: jurídica, regulatória, sanitária e de observância dos direitos humanos, entre outros. É nesse contexto que publicamos esta working paper series sobre comunidades terapêuticas no Brasil. Os oito artigos que compõem esta série oferecem uma visão multidisciplinar sobre o tema, expandindo e aprofundando a literatura existente e oferecendo contribuições contundentes para uma análise substantiva das comunidades terapêuticas como instrumentos de politica pública. Embora possam ser lidos separadamente, é como conjunto que a força dos oito artigos que compõem esta série se torna mais evidente. Mesmo que ofereçam perspectivas diversas, são trabalhos complementares— e já essenciais— na delineação e compreensão do fenômeno das comunidades terapêuticas no Brasil.
5
Port Moresby - Lot 10 Ogoa Street - Land purchased for construction of Manager's residence, view from this land of Ela Beach - July 1960. Reserve Bank of Australia, March 2021. http://dx.doi.org/10.47688/rba_archives_pn-004194.