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Статті в журналах з теми "MEIS Inhibitors":
1
Kocabas, F., S. N. Eren, M. Uslu, and M. Y. Yuksel. "P69Identification of cardiogenic and hematopoietic MEIS Inhibitors." Cardiovascular Research 114, suppl_1 (April 1, 2018): S18—S19. http://dx.doi.org/10.1093/cvr/cvy060.033.
2
GİRGİN, Birkan, Medine KARADAĞ-ALPASLAN, and Fatih KOCABAŞ. "Oncogenic and tumor suppressor function of MEIS and associated factors." TURKISH JOURNAL OF BIOLOGY 44, no. 6 (December 14, 2020): 328–55. http://dx.doi.org/10.3906/biy-2006-25.
Анотація:
MEIS proteins are historically associated with tumorigenesis, metastasis, and invasion in cancer. MEIS and associated PBX-HOX proteins may act as tumor suppressors or oncogenes in different cellular settings. Their expressions tend to be misregulated in various cancers. Bioinformatic analyses have suggested their upregulation in leukemia/lymphoma, thymoma, pancreas, glioma, and glioblastoma, and downregulation in cervical, uterine, rectum, and colon cancers. However, every cancer type includes, at least, a subtype with high MEIS expression. In addition, studies have highlighted that MEIS proteins and associated factors may function as diagnostic or therapeutic biomarkers for various diseases. Herein, MEIS proteins and associated factors in tumorigenesis are discussed with recent discoveries in addition to how they could be modulated by noncoding RNAs or newly developed small-molecule MEIS inhibitors.
3
Barbosa, Karina, Anagha Deshpande, Ping Xiang, Bo-Rui Chen, Adam Brown, Neil Robertson, Younguk Sun, et al. "High-Density Domain-Focused CRISPR Screens Reveal Epigenetic Regulators of Hox/Meis Gene Expression in Acute Myeloid Leukemia." Blood 136, Supplement 1 (November 5, 2020): 2–3. http://dx.doi.org/10.1182/blood-2020-141412.
Анотація:
The aberrant and constitutive activation of the HOXA cluster genes and the their-co-factor MEIS1 (HOX/MEIS) is a recurrent feature in several types of myeloid and lymphoid leukemias. Aberrant HOX/MEIS expression has been shown to drive limitless leukemia stem cell self-renewal and is therefore an attractive target for therapy in acute myeloid leukemia (AML). However, since HOX/MEIS genes encode DNA-binding transcription factors, small molecules targeting these proteins directly are lacking. Furthermore, targeting the HOX/MEIS network is complicated by the fact that these genes are coordinately regulated and have redundant functions in sustaining leukemic self-renewal. One way of therapeutically targeting aberrant HOX/MEIS transcription is the identification and pharmacologic inhibition of upstream chromatin regulators that coordinately modulate their expression. In order to identify such chromatin regulators, we made use of an endogenous GFP reporter knocked-in to the MEIS1 locus in the high HOX/MEIS-expressing U937 human AML cell line. Using this system, we first performed a high-throughput flow-cytometry-based small-molecule inhibitor screen with a library of 261 compounds targeting epigenetic regulators. In our screen, the most potent hits that reproducibly showed >50% MEIS1-GFP inhibition were small molecules that targeted DOT1L, the histone methyltransferase. DOT1L inhibitors have already been well-characterized as HOX/MEIS regulators and most epigenetic regulators are not targeted by existing compound libraries. Therefore, we decided to use a genetic screening approach to more extensively interrogate the landscape of epigenetic regulators of HOX/MEIS expression in AML. For this, we designed a custom computational pipeline and built a CRISPR library of 10,000 sgRNAs targeting functionally conserved protein domains of all catalogued chromatin modulatory proteins (> 600 proteins - 5 sgRNAs per conserved domain). This list of epigenetic regulators included histone modifying enzymes, chromatin readers, nucleosome remodelers, adaptor proteins and proteins involved in DNA and RNA modifications, as well as other transcriptional regulators. Using this comprehensive, domain-focused CRISPR library, we conducted a phenotypic enrichment screen. Specifically, we used flow cytometry to purify the top 20% GFP-MEIS1 (high) and bottom 20% GFP-MEIS1 (low) expressing cells and identified sgRNAs that were enriched particularly in the GFP-MEIS1 -low vs -high fraction using next generation sequencing. Given the extent and complexity of the CRISPR library, our approach uncovered members of six distinct chromatin modifying complexes as MEIS1 regulators (MAGeCKFlute pipeline, 2 SD > mean) and we could validate > 10 of these hits as bonafide regulators of MEIS1 as well as HOXA genes. We also demonstrated their essentiality for the proliferation of HOX-driven AML cells using arrayed sgRNA competition assays. These validated hits included several known as well as novel chromatin readers and writers amenable to small-molecule targeting. We focused our attention on the KAT7/JADE3 complex and the casein kinase 2 (CK2) family that we validated as potent and selective regulators of HOX/MEIS expression in AML cells. Our studies demonstrated that genetic depletion of components of the KAT7 complex or of the CK2 family could reverse HOX/MEIS activation in human AML cells, leading to a progressive loss of proliferative potential. Importantly, the use of the clinical-grade CK2 inhibitor CX4945 (Silmitasertib) caused a concentration-dependent down-regulation of HOX/MEIS expression in models of HOX-driven AML, leading to significant anti-leukemia effects. Our study provides a framework for the multiplexed identification of actionable dependencies targeting therapeutically recalcitrant oncogenic networks in cancer. Specifically for AML, since Silmitasertib is in Phase 2 trials for treatment of other cancers, our studies may solve the long-standing problem of targeting leukemia stem cells in AML potentially overcoming therapy refractoriness in this devastating disease. Disclosures No relevant conflicts of interest to declare.
4
Bisaillon, Richard, Eva Schmidt, Anne-Sophie Guenier, and Guy Sauvageau. "Identification of MEIS-PBX inhibitors as potential anti-leukemic agents using a high-throughput bret-based assay." Experimental Hematology 41, no. 8 (August 2013): S51. http://dx.doi.org/10.1016/j.exphem.2013.05.201.
5
Castellet, Helena, Guillermo Ramil López, Ana Garrido, Alícia Artigas-Baleri, Marta Pratcorona, Olga Salamero, Albert Cortés-Bullich, et al. "Ubtf tandem Duplications Define a Novel Subtype of Acute Myeloid Leukemia Associated with Younger Age, WT1 Mutations and HOXA9 Marked Overexpression." Blood 142, Supplement 1 (November 28, 2023): 6045. http://dx.doi.org/10.1182/blood-2023-186064.
Анотація:
Background Upstream Binding Transcription Factor ( UBTF) gene plays an important role in ribosomal RNA transcription. UBTF tandem duplications (TD) have been recently described as a recurrent genetic lesion in acute myeloid leukemia (AML). UBTF-TDs appear to be mutually exclusive with other class-defining lesions in AML and display a unique comutational signature. UBTF-mutated AML affects predominantly younger patients and is associated with trisomy 8, internal tandem duplication of FLT3 ( FLT3-ITD), mutations in WT1 and poor prognosis. Moreover, HOX and MEIS genes seem to be overexpressed in AML with UBTF-TD similarly to NPM1-mutated ( NPM1m) or KMT2A-rearragend ( KMT2Ar) AML, suggesting potential sensitivity to menin inhibitors. In this study we sought to characterize UBTF-TDs in our AML cohort. Methods We studied 456 adult patients (median age 54 years; range 18-70) diagnosed with de novo AML and included in AML-12 protocol from CETLAM group. All patients from the 2012-2017 period (n=403) were consecutively studied and we also selected 53 cases of WT1-mutated AML from the 2017-2020 period, given the strong association with UBTF-TD. Screening for UBTF-TD was performed on bone marrow (BM) or peripheral blood (PB) genomic DNA samples. Exon 13 of UBTF gene was amplified and analysed by Polymerase chain reaction (PCR) and subsequent fragment length analysis by capillary electrophoresis. Mutated samples were confirmed through Sanger sequencing. Further, RNA from 9 UBTF-TD cases was available and HOXA9 and MEIS1 gene expression analysis was performed by Real-Time Polymerase Chain Reaction (RT-qPCR). Clinical and biological data were obtained from CETLAM registry. Results UBTF-TD was found in 13 patients from our cohort whose characteristics are detailed in Table 1. UBTF-TDs range from 45 base pairs (bp) to 365 bp, being the 48 bp the most recurring size. As described, although small UBTF-TDs are in frame insertions, the largest ones are not multiple of 3. Notably, most UBTF-TDs presented small insertions and deletions among the duplication. Presence of UBTF-TD was associated with younger age (36 vs 55 years; p<0.001) and BM dysplastic changes (80% of U BTFMUT). UBTF-TD was particularly frequent (8.9% of all cases) in patients below 40 years, compared to other lesions as CEBPA mutations (1.1%). Eleven (85%) U BTFMUT patients presented intermediate cytogenetics, being trisomy 8 (5), normal karyotype (3) and 9q deletion (2) the most recurrent findings. Two cases of adverse karyotype with MECOM-rearrangements were found. As previously described, there was a strong association between UBTF-TD and of FLT3-ITD (38.5%). Other recurrent genetic lesions in AML like NPM1 and CEBPA mutations or core-binding factor (CBF) rearrangements were exclusive of UBTF wild type patients. Further, we found that UBTFMUT leukemias showed marked overexpression of HOXA9 compared with other AML subtypes (22.1-fold vs 5.0-fold; p<0.001; Fig. 1) and similar to NPM1m AML (22.3-fold). On the other hand, MEIS expression did not differ significantly among groups. Conclusions In our cohort of adult AML patients, UBTF-TDs are found in 1.8% of cases and are especially frequent in younger individuals in absence of other class-defining genetic lesions. The presence of UBTF-TD is strongly associated with cytomorphological dysplasia and co-occurrence of FLT3-ITD and WT1 mutations, while NPM1 and CEBPA mutations and CBF rearrangements appear to be mutually exclusive. HOXA9 upregulation could be a leukemogenic event in UBTF-TD AML, as described in NPM1-m and KMT2A-r AML, suggesting potential utility of menin inhibitors in this subset of patients. Screening for UBTF-TD is going to be incorporated in our molecular diagnostic panel for new AML cases.
6
Breitinger, Constanze, Emanuel Maethner, Maria-Paz Garcia-Cuellar, Alexandra Schambony, Kirsten Schilling, Klaus D. Fischer, and Robert K. Slany. "Hox Genes Regulate Rac1 Activity Through Control of Vav2 expression." Blood 118, no. 21 (November 18, 2011): 60. http://dx.doi.org/10.1182/blood.v118.21.60.60.
Анотація:
Abstract Abstract 60 Next to their function in embryogenesis the clustered Hox-homeobox genes are also master regulators of hematopoietic differentiation and development. Perturbed HOX expression can be found in a significant percentage of acute leukemia. Recently we have shown that several members of the HOXA cluster transform primary hematopoietic cells and induce leukemia in vivo [1]. In an attempt to define Hox downstream targets important for leukemogenesis we determined the gene expression pattern in hematopoietic precursor cells transformed by conditional HOXA1 and HOXA9 derivatives. Interestingly, amongst the several hundred genes controlled by each HOX protein individually we could identify a significant overlap of genes that responded to both. This group included c-Myb that has been shown before to be important for Hox-mediated leukemogenesis indicating that this approach is able to identify a candidate set of genes important for transformation by HOX proteins. Within this collection the gene for the guanine exchange factor Vav2 caught our interest because it had been originally identified in a screen for bona fide oncogenes. Moreover it is known that Vav2 controls activity of the small Rho-type GTPase Rac1 that in turn is an important mediator of (leukemic) stem cell mobility and engraftment. ChIP experiments confirmed HOXA9 binding in the putative vav2 promoter region. In addition a luciferase reporter placed under control of the vav2 promoter showed Hox-responsive behavior indicating that vav2 is a direct Hox-target. Concomitant with vav2-levels also Rac1 activity was under strict control of Hox factors. This was true also for HOX+Meis double transformed cells. To investigate the importance of vav2 for Hox-mediated leukemogenesis hematopoietic cells from vav2 knock-out mice were investigated in detail. vav2−/−cells could be transformed by HOXA9 (+Meis) in vitro with identical efficiency as their wild-type counterparts. Colony formation in replating assays, the capability to induce outgrowth of permanent myeloid precursor lines and the differentiation state of these lines did not differ significantly amongst the wt and vav2−/− samples. However, no active Rac1 could be detected in vav2−/− cell lines transformed by HOXA9. Importantly, retroviral re-expression of vav2 could rescue part of this defect. Obviously, Vav2 constitutes the major GEF controlling Rac1 activity in myeloid precursors despite the presence of the homologous proteins Vav1 and Vav3. Because Rac1 has been implicated in surface receptor recycling and in stem-cell homing we checked the level of the SDF1 “homing-cytokine” receptor CxCR4 (CD184) on Hox-transformed wt and vav2−/−cells and could confirm a complete absence of CD184 on the latter. Again reintroduction of vav2 rescued part of this phenotype. Transplantation experiments are underway and preliminary results indicate that loss of vav2 is accompanied by an impaired ability for extramedullary hemopoiesis, an import determinant of leukemia aggressiveness. Our results explain how Hox genes that are highly expressed in stem- and precursor cells can regulate the important process of stem cell homing. Rac1 inhibitors are known and these substances have been tested [2] in mice with special success on MLL fusion induced leukemias that are a paradigma for Hox-induced leukemogenesis. Therefore our results do not only provide the molecular framework for this observation but they are also able to identify a potential patient collective that may benefit from pharmacological Rac1 inhibition. Disclosures: No relevant conflicts of interest to declare.
7
Jarocha, Danuta Jadwiga, Paul Gadue, Wei Tong, Robert C. Newton, and Mortimer Poncz. "Janus Kinase (Jak) 1 Inhibition Affects Both Megakaryopoiesis and Thrombopoiesis." Blood 132, Supplement 1 (November 29, 2018): 2559. http://dx.doi.org/10.1182/blood-2018-99-115407.
Анотація:
Abstract JAK inhibitors are being developed to treat inflammatory, myeloproliferative and neoplastic disorders. Murine and human studies have demonstrated an essential role for JAK2 in the proliferation of hematopoietic stem/progenitor cells (HSPC) and multiple hematopoietic lineages, including erythrocytes and megakaryocytes, while Jak1 murine studies have shown a role in HSPC proliferation and myelopoiesis, but not in megakaryopoiesis. Patients enrolled in clinical studies of INCB052793, which selectively binds to JAK1, have shown thrombocytopenia occurring within 2 weeks. The aim of this study was to elucidate the basis for thrombocytopenia associated with this JAK1 inhibitor, in comparison to INCB026115, which inhibits JAK2 more so than Jak1 (Jak2/1). Knowing the precise mechanism by which Jak inhibitors induce thrombocytopenia may lead to therapeutic strategies limiting side effects, while preserving intended clinical application. We tested a broad concentration range of each of these Jak1 and Jak2/1 inhibitors from IC50 (40 and 30nM, respectively) to IC90 (400 and 300nM) to 10xIC90 (4 and 3 µM) on mobilized progenitor-derived CD34+ cells incubated 12-14 days under semisolid and under liquid conditions, focusing on effects on megakaryocyte (Meg) and platelet production. At IC90, the Jak1-selective inhibitor limited large Meg colony number to 47±8% of untreated control in semisolid growth conditions. Under similar concentrations in liquid growth conditions, the number of Megs seen was 45±8% of the untreated controls, but with a 139±17% higher level of ≥8N Megs. Agonist response of mature Megs to thrombin was not compromised. Total number of healthy, in vitro-released, platelet-like particles (PLPs) collected from Jak1-exposed cultures at Day 12 was reduced to 57±14% of the control, and similar to the decrease in Meg yield. At a similar level of inhibition, the Jak2/1 inhibitor was more robust at inhibiting megakaryopoiesis. At IC90, the Jak2/1 inhibitor fully inhibited development of large Meg colonies and reduced the number of small colonies to 43±14% of untreated control. Under liquid growth conditions, the number of Megs seen at Day 12 was 20±9% of the untreated controls, but with 132±28% higher % of ≥8N Megs. Agonist response of mature Megs was not compromised. Total number of healthy PLPs collected at Day 12 was insignificantly different despite much lower Meg yield. More detailed Jak2/1 inhibitor cultures analysis revealed enhanced Meg apoptosis by 209±61% at Day 7, and accelerated maturation as indicated by a 2-fold and 3-fold mpl receptor level at Days 7 and 11 and 321±217% higher number of Megs >2N at Day 7. As opposite to what might be expected, thrombopoiesis appeared not to be impaired by the Jak2/1 inhibitor. Inhibitor-treated Megs released similar or higher number of platelets per Meg as untreated controls upon their infusion into immunocompromized NSG mice, with similar high levels of young, thiazole orange-positive, low apoptotic, Annexin-V+ platelets. Baseline released platelet CD62p expression and PAC1 binding prior to agonist exposure were similar and increased to the same extent after thrombin (0.1-10U/ml) stimulation. In contrast, Jak1 inhibitor-treated Megs had ~50% lower number of released human platelets upon infusion into NSG mice although the released platelets were healthy and responsive to agonists. In summary, our results shed significant insight into the mechanisms of Jak1 inhibitor-associated thrombocytopenia observed in patients. We show that thrombocytopenia post the Jak2/1 inhibitor INCB026115 is due to impaired megakaryopoiesis with intact thrombopoiesis and functional, released platelets. In contrast, thrombocytopenia post the Jak1 inhibitor INCB052793 is a result of combined impairment of both megakaryopoiesis and thrombopoiesis, although the released platelets appear intact. The exact pathways blocked by the Jak1 inhibitor important for thrombopoiesis remain to be defined. Also, as liver hepatocytes together with bone marrow stromal cells are a source of thrombopoietin (TPO), and Jak1 and Jak2 are known to be involved in regulation of TPO production, studies to check the influence of Jak inhibitors on TPO production from both hepatocytes and marrow stromal cells are needed to fully understand the influence of Jak inhibitors on megakaryopoiesis/thrombopoiesis. Disclosures Jarocha: Incyte Corporation: Consultancy, Research Funding. Gadue:Incyte Corporation: Consultancy, Research Funding. Tong:Incyte Corporation: Consultancy, Research Funding. Newton:Incyte Research Institute: Employment, Equity Ownership. Poncz:Incyte Corporation: Consultancy, Research Funding.
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Haneline, Laura S., Khadijeh R. Bijangi-Vishehsaraei, Adam Werne, Kristina Wilson McKenzie, Susanna Davis, Hidenori Ichijo та Mohammad R. Saadatzadeh. "TNF-α Hypersensitivity of Fanconi Anemia Type C Deficient Cells Is Dependent on the Apoptosis Signal-Regulating Kinase 1 Signaling Pathway." Blood 104, № 11 (16 листопада 2004): 724. http://dx.doi.org/10.1182/blood.v104.11.724.724.
Анотація:
Abstract Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow (BM) aplasia. Previous studies from our lab and others suggest that enhanced oxidant- and inhibitory cytokine-mediated apoptosis of hematopoietic stem/progenitor cells are important mechanisms in the pathogenesis of BM failure in FA. Recently, we showed that oxidant-induced apoptosis in Fancc −/− murine embryonic fibroblasts (MEFs) was mediated through hyperactivation of the redox-dependent protein, apoptosis signal-regulating kinase 1 (ASK1, Saadatzadeh et al, JBC 2004). Here, we tested whether alterations in ASK1 signaling also participate in the pro-apoptotic phenotype of primary Fancc −/− MEFs and progenitors in response to the inhibitory cytokine, TNF-α. To determine whether Fancc −/− MEFs exhibit altered ASK1 signaling after TNF-α treatment, we examined ASK1 activity using in vitro kinase assays. These studies demonstrated a 2–3 fold increase in TNF-α-induced ASK1 activity in Fancc −/− MEFs compared to WT (n=5). Consistent with ASK1 hyperactivation, we observed an increase in activation of the downstream stress kinases, c-jun N-terminal kinase and p38, in Fancc −/− MEFs compared to WT (n=5). Utilizing a dominant negative ASK1 cDNA to decrease ASK1 activity, we determined that TNF-α-induced apoptosis in Fancc −/− MEFs was ASK1 dependent (n=3, p<0.05). In addition, TNF-α-induced apoptosis in Fancc −/− MEFs was completely blocked by both antioxidants (selenomethionine and N-acetylcysteine, n=3, p<0.001) and the p38 inhibitor SB 203580 (n=6, p<0.001). To examine whether ASK1 has a critical role in the hypersensitivity of Fancc −/− progenitors to TNF-α-induced apoptosis, we crossed ASK1 knockout mice with Fancc mice to generate the following four experimental genotypes; WT, Fancc +/+;ASK1 −/−, Fancc −/−;ASK1 +/+, and Fancc −/−;ASK1 −/−. BM cellularity and progenitors/femur were similar between all genotypes (n=3). Interestingly, TNF-α hypersensitivity of Fancc −/− progenitors was restored to WT levels when ASK1 was deleted (n=3, p<0.05), suggesting that TNF-α-induced hypersensitivity of Fancc −/− progenitors is mediated through ASK1, similar to Fancc −/− MEFs. In addition, TNF-α-induced apoptosis in Fancc −/− progenitors was restored to WT levels after culturing with the p38 inhibitor SB 203580 (n=6, p<0.005). Since ASK1 activity is directly regulated by the cellular redox state, these data support the idea that aberrant redox regulation may be involved in the observed pro-apoptotic phenotype of Fancc −/− cells after exposure to inhibitory cytokines such as TNF-α. Collectively, these data suggest that inhibiting the ASK1 apoptotic pathway in Fancc −/− cells via antioxidants or small molecule inhibitors may protect Fancc −/− hematopoeitic stem/progenitors from an apoptotic fate and delay BM failure.
9
Wang, Wei, Peng Li, Annette Schettino, Zhe Peng, and Maureen McLeod. "Characterization of Functional Regions in the Schizosaccharomyces pombe mei3 Developmental Activator." Genetics 150, no. 3 (November 1, 1998): 1007–18. http://dx.doi.org/10.1093/genetics/150.3.1007.
Анотація:
Abstract The Schizosaccharomyces pombe mei3+ gene is expressed only in diploid cells undergoing meiosis. Ectopic expression of mei3+ in haploid cells causes meiotic catastrophe. Mei3 is an inhibitor of Ran1/Pat1 kinase and contains a nine-amino-acid motif, Mei3-RKDIII, that resembles two regions in the Ste11 substrate for Ran1/Pat1. Substitution of serine for Arg-81 within Mei3-RKDIII transforms the inhibitor into a substrate for Ran1/Pat1. Thus, it is likely that Mei3-RKDIII defines a pseudosubstrate sequence. In this study, we constructed a series of mei3 deletion mutations and assayed each for activity. This analysis indicates that the carboxy-terminal domain of Mei3 is sufficient for function in vivo. Alanine-scanning mutagenesis identifies critical residues within the inhibitory domain. Two mutations, SM1 and SM8, fail to cause meiotic catastrophe. The SM1 mutation contains alterations of amino acid residues in Mei3-RKDIII. Recombinant SM1 protein exhibits reduced ability to inhibit Ran1/Pat1 kinase in vitro and interacts inefficiently with the kinase in a two-hybrid assay. The SM8 protein binds to Ran1/Pat1 in a two-hybrid assay but fails to inhibit Ran1/Pat1 substrate phosphorylation in vitro. These findings provide evidence that Mei3-RKDIII defines a Ran1/Pat1-binding site that is necessary but not sufficient for inhibition of the kinase. Using fusions to green fluorescent protein, the cellular localization of Ran1 and Mei3 was examined in living cells. Ran1 is concentrated in the nucleus. Mei3 is also enriched in the nucleus and, consistent with the genetic and biochemical results, the inhibitory domain of Mei3 is sufficient for nuclear localization.
10
KAYA, Mustafa Oğuzhan. "Out-of-mind Inhibitors Of Human Serum Paraoxonase 1 (PON1): An In Vitro study." Middle East Journal of Science 3, no. 1 (August 26, 2017): 59–77. http://dx.doi.org/10.23884/mejs.2017.3.1.07.
Дисертації з теми "MEIS Inhibitors":
1
Mammadova, Aynura. "The role of MEIS inhibitors in cardiac regeneration and protection." Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAJ006.
Анотація:
Le gène homeobox de type TALE MEIS1 a été identifié comme un facteur critique dans le contrôle de l'arrêt du cycle cellulaire des cardiomyocytes et pouvant ainsi représenter une cible thérapeutique attrayante. Nos dernières recherches ont révélé le potentiel de la suppression de MEIS1 dans la promotion de la régénération des cardiomyocytes. Des expériences effectuées avec des cardiomyocytes néonataux ont montré que deux petites molécules innovantes, MEISi-1 et MEISi-2, ont amélioré la prolifération (cellules Ph3+TnnT) et la cytokinèse (cellules AuroraB+TnnT) de ces cellules. La suppression de l'activité de MEIS1 a entraîné une diminution de l'expression de ces gènes cibles et des inhibiteurs des kinases dépendantes des cyclines. De plus, cette recherche s'est également intéressée à la différentiation de cellules souches pluripotentes induites humaines (hiPSCs) en cardiomyocytes pour examiner l'impact de la suppression de MEIS1, sans modification de leur viabilité. Fait intéressant, un traitement à court et à long terme avec MEISi des hiPSCs a conduit à une élévation significative de l'expression des gènes spécifiques cardiaques essentiels, influençant notablement le mésoderme cardiaque et les cellules progénitrices, et positionnant les inhibiteurs de MEIS1 comme des modulateurs cruciaux de l'expression génique cardiaque. Nos résultats indiquent que les inhibiteurs de MEIS peuvent offrir une protection contre les effets cardiotoxiques aigus de la doxorubicine (DOX) chez les rats Wistar, comme en témoigne la structure préservée du tissu cardiaque et les niveaux inchangés de fibrose ou de collagène. Les analyses qPCR ont en outre confirmé la surexpression des gènes des progéniteurs cardiaques et un équilibre dans l'expression génique anti-apoptotique et liée aux ROS, suggérant un rôle protecteur des inhibiteurs de MEIS contre les dommages induits par la DOX sans influencer la fibrose. Ces résultats soulignent le potentiel thérapeutique des inhibiteurs de MEIS en cardiologie régénérative, suggérant leur utilité dans l'amélioration du renouvellement des cardiomyocytes et offrant une protection contre la cardiotoxicitéThe TALE-type homeobox gene MEIS1 has been identified as a critical factor in controlling the cell cycle arrest of cardiomyocytes, presenting itself as an attractive target for therapy. Our latest investigations have revealed the potential of MEIS1 suppression to promote the regeneration of cardiomyocytes. Further experiments with neonatal cardiomyocytes showed that two innovative small molecules, MEISi-1 and MEISi-2, enhanced the proliferation (Ph3+TnnT cells) and cytokinesis (AuroraB+TnnT cells) of these cells. Suppressing MEIS1 activity resulted in the diminished expression of its target genes and the inhibitors of cyclin-dependent kinases. Additionally, this research extended to cultivating human induced pluripotent stem cells (hiPSCs) into cardiomyocytes to examine the impact of MEIS1 suppression, which notably did not compromise their viability. Intriguingly, short-term and long-term treatment with MEISi in hiPSCs led to significant elevation in essential cardiac-specific gene expression, notably influencing cardiac mesoderm and progenitor cells, and positioning MEIS1 inhibitors as crucial modulators of cardiac gene expression. Our findings indicate that MEIS inhibitors can provide protection against the acute cardiotoxic effects of doxorubicin (DOX) in Wistar rats, as evidenced by the maintained structure of cardiac tissue and unchanged levels of fibrosis or collagen. qPCR analyses further confirmed the upregulation of cardiac progenitor genes and a balance in anti-apoptotic and ROS-related gene expression, hinting at the protective role of MEIS inhibitors against DOX-induced damage without influencing fibrosis. These results highlight the therapeutic potential of MEIS inhibitors in regenerative cardiology, suggesting their utility in enhancing cardiomyocyte renewal and offering protection against cardiotoxicity
2
Aouadi, Wahiba. "Les méthyltransférases de la coiffe du MERS-CoV : étude fonctionnelle et recherches d'inhibiteurs." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0145/document.
Анотація:
Mon travail de thèse s’est focalisé sur l’étude fonctionnelle de deux méthyltransférases (MTases) de la structure coiffe des ARNs, les protéines nsp14 et nsp16, chez le coronavirus responsable du syndrome respiratoire du Moyen-Orient (MERS-CoV). Notre étude a démonté un processus de méthylation séquentiel. La coiffe est d’abord méthylée en position N7 par nsp14 formant la coiffe-0 (7mGpppN). La coiffe-0 est ensuite méthylée en position 2’OH du premier nucléotide de l’ARN par nsp16 stimulée par nsp10 formant une coiffe 1 (7mGpppN2’Om). De plus, nos résultats suggèrent un mécanisme de régulation allostérique de l’activité de nsp16 par nsp10. Nos résultats indiquent que l’interaction nsp10/nsp16 est régulée par la variation de concentration du SAM et/ou de SAH. Le SAM présent à une concentration physiologique, environ 100 µM dans les cellules, favorise l’assemblage du complexe nsp10/nsp16. La faible concentration intracellulaire du SAH produit accélère la dissociation du complexe nsp10/nsp16 permettant le « turnover » de la réaction enzymatique. Par ailleurs, nous avons cartographié les résidus essentiels au recrutement de l’ARN par nsp16. Les méthylations étudiées jouent un rôle important dans la réplication virale. Nous avons donc criblé des inhibiteurs des deux MTases nsp14 et nsp10/nsp16 respectivement à partir des chimiothèques « Prestwick » et « 2P2I3D ». En résumé, mon travail de thèse a décortiqué les bases moléculaires de méthylation de la coiffe chez le MERS-CoV et a permis d’identifier des inhibiteurs de MTases représentant un point de départ crucial pour le développement d’antiviraux contre les CoVMy PhD work focused on the functional study of two cap RNA methyltransferases (MTases), nsp14 and nsp16, of the Middle-East respiratory syndrome coronavirus (MERS-CoV). Our study demonstrates a sequential methylation process. The cap is first methylated at the N7 position by nsp14 forming a cap-0 (7mGpppN). It is next methylated at the 2’OH position of the first transcribed nucleotide by nsp16 stimulated by nsp10 forming a cap-1 (7mGpppN2’Om). Furthermore, our results suggest an allosteric regulation mechanism of the nsp16 activity by nsp10. Moreover, our results indicate that the nsp10/nsp16 interaction is regulated by the variation of SAM and/or SAH concentration. SAM present at physiologic concentration, around 100µM in cells, enhances the assembly of nsp10/nsp16. The weak intracellular concentration of SAH by-product speeds up the dissociation of nsp10/nsp16 allowing the enzymatic reaction turnover. In addition, we have mapped the essential residues for the recruitment of the RNA by nsp16. The methylations studied in this work play an important role for viral replication. We have therefore screened inhibitors of nsp14 and nsp10/nsp16 MTases respectively from chemical libraries « Prestwick » and « 2P2I3D ». In summary, my PhD work deciphers the molecular bases of cap RNA methylation of MERS-CoV and identifies MTase inhibitors that represent a crucial starting point for the development of antivirals against CoV
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Gomes, Roger Almeida. "Estudo de aminoÃcidos sulfurados como inibidores de corrosÃo do aÃo carbono em meio aquoso de cloreto." Universidade Federal do CearÃ, 2008. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=3502.
Анотація:
CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorO presente trabalho tem como objetivo estudar os efeitos de inibiÃÃo de dois aminoÃcidos sulfurados (cisteÃna e metionina) como inibidores de corrosÃo do aÃo carbono 1010 em meio de cloreto. Foram utilizadas medidas gravimÃtricas e tÃcnicas eletroquÃmicas, tais como polarizaÃÃo potenciodinÃmica e espectroscopia de impedÃncia eletroquÃmica. Foram investigados parÃmetros que possam influenciar no desempenho dos aminoÃcidos, tais como concentraÃÃo (10-2 â 10-5 M), pH (1 e 7), temperatura (5 â 60ÂC) e adiÃÃo de aditivos (molibdato, tungstato e silicato). Um estudo do processo de adsorÃÃo tambÃm foi feito, sendo que a partir dele foram obtidos parÃmetros termodinÃmicos e cinÃticos. Adicionalmente, a caracterizaÃÃo morfolÃgica da superfÃcie do substrato foi feita por meio da microscopia eletrÃnica de varredura verificando a evoluÃÃo dos produtos de corrosÃo com o tempo de imersÃo. Os resultados mostraram que o pH à um fator importante no desempenho anticorrosivo dos aminoÃcidos devido as suas caracterÃsticas. As medidas de impedÃncia mostraram que ocorre somente um processo de transferÃncia de carga na interface eletrodo / soluÃÃo, sendo que a eficiÃncia aumenta com o tempo devido ao aumento de molÃculas adsorvidas. O processo de adsorÃÃo dos aminoÃcidos na superfÃcie do metal à exotÃrmico e espontÃneo. As micrografias mostraram que na presenÃa de aminoÃcidos o processo de corrosÃo do aÃo à retardado. Foi verificado que a cisteÃna forma um complexo solÃvel com o metal enquanto que a metionina nÃo apresentou esse fenÃmeno durante o mesmo perÃodo de tempo. Os compostos inorgÃnicos nÃo proporcionam um efeito sinÃrgico aos aminoÃcidos, ou seja, nÃo houve um aumento do desempenho dos mesmos.
This work aims to study the inhibitionÂs effects of two sulfur amino acids (cysteine and methionine) as corrosion inhibitors of carbon steel 1010 in chloride medium. The study was carried out by gravimetric and electrochemical techniques, such as potentiodynamic polarization and electrochemical impedance spectroscopy. Parameters that might influence the performance of amino acids, such as concentration (10-2 - 10-5 M), pH (1 and 7), temperature (5 - 60 Â C) and addition of additives (molybdate, tungstate and silicate) were investigated. A study of the adsorption was also made, and that from it were obtained thermodynamic and kinetic parameters. Additionally, the surface morphology of the substrate was assessed by scanning electron microscopy to check the progress of the corrosion products with time of immersion. The results showed that the pH is an important factor in the performance of amino acids because the anticorrosion characteristics. The impedance measures showed that occurs only a charge transfer process at the interface electrode / solution, and the efficiency increases with time due to the increase of adsorbed molecules. The process of adsorption of amino acids on the metalÂs surface is exothermic and spontaneous. The micrographs showed that in the presence of amino acids the corrosion process of steel is retarded. It was found that the cysteine forms a soluble complex with the metal while methionine did not present this phenomenon during the same period. The inorganic compounds do not provide a synergistic effect on amino acids, i.e., there werenÂt an increase in the performance of them.
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Sierra, Aristizábal Ruth Verónica 1983. "Produção de leveduras oleaginosas em meio de cultura contendo hidrolisado de bagaço de cana-de-açúcar." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/266600.
Анотація:
Orientadores: Telma Teixeira Franco, Cecilia Sulzbacher CarusoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Química
Made available in DSpace on 2018-08-22T22:39:37Z (GMT). No. of bitstreams: 1 SierraAristizabal_RuthVeronica_M.pdf: 1527858 bytes, checksum: 19be6c21b6ac83bc742a54aa2002ae6a (MD5) Previous issue date: 2013
Resumo: Material lignocelulósico, como bagaço de cana de açúcar, é matéria prima potencial para produção de biocombustíveis de segunda geração. Hidrolisado hemicelulósico (H-H) rico em xilose pode ser fermentado por leveduras oleaginosas para a produção de lipídeos. Nesse sentido, o objetivo deste trabalho foi adaptar a Lipomyces starkeyi DSM 70296 em meios de cultivo contendo H-H de bagaço de cana-de-açúcar. O H-H com 12 g/L de xilose, 2 g/L de glicose, 10 g/L de ácido acético, 0,7 g/L de furfural e 1,3 g/L de HMF foi obtido após sete etapas de sequenciais de extração de bagaço previamente explodido a vapor. A levedura foi adaptada por engenharia evolutiva em meio de cultivo contendo concentrações crescentes de H-H. Como resultado, obteve-se a levedura adaptada ao meio de cultivo contendo 30% de H-H, a qual apresentou maior produtividade celular (113,90 mg/L/h) e concentração celular (9,79 g/L) em relação à cepa não adaptada (73,54 mg/L/h e 5,21 g/L, respectivamente). Fermentações em biorreator em meio sintético e contendo 30% de H-H apresentaram velocidades especificas máximas de crescimento (?max) de 0,117 e 0,122 h-1, respectivamente. Através de planejamento experimental 23 foram determinados os efeitos do ácido acético, furfural e hidroximetilfurfural (HMF) no crescimento e produção de lipídeos da levedura. Resultados indicaram que o ácido acético apresentou efeito significativo sobre os parâmetros cinéticos aumentando a duração da fase lag até em 34 horas, além da redução da produtividade celular (Px) e da velocidade de consumo de substrato (rs). Adicionalmente foram verificados efeitos sinérgicos positivos entre ácido acético conjuntamente com furfural e HMF. Testes indicaram a possibilidade de altos níveis de inibição dos produtos gerados pela degradação da lignina em concentrações acima de 7,32 g/L
Abstract: Lignocellulosic materials, such sugar cane bagasse, as reported as potential feedstocks for production of second generation biofuels, through hemicellulose hydrolysates (H-H) extraction rich in xylose and the subsequent fermentation with oleaginous yeast for lipids production. In this regard, the objective of this study was to adapt the Lipomyces starkeyi DSM 70296 in culture media containing H-H of sugar cane bagasse. The H-H with 12 g/L of xylose, 2 g/L of glucose, 10 g/L acetic acid, 0.7 g/L of furfural and 1.3 g/L of HMF was obtained after seven sequential extraction steps of bagasse previously pretreated by steam explosion. The yeast was adapted by evolutionary engineering in culture medium containing increasing concentrations of H-H. As result, there was obtained the yeast adapted to culture medium containing 30% of H-H, which showed higher cell productivity (113.90 mg/L/h) and cell concentration (9.79 g/L) compared to not adapted strain (73.54 mg/L/h and 5.21 g/L, respectively). Fermentation in Bioreactor in synthetic medium and containing 30% of H-H medium showed maximum specific growth rate (?max) of 0.117 and 0.122 h-1, respectively. Through experimental design 23 was determined the effects of acetic acid, furfural and hydroxymethylfurfural (HMF) on growth and yield lipid yeast. As result, there was obtained that acetic acid had significant effect on kinetic parameters by increasing the duration of lag phase up to 34 hours, besides reduction of cell productivity (Px) and rate of substrate consumption (rs). Additionally positive synergistic effects were observed when acetic acid is found in culture media with furfural and HMF. Preliminary tests indicate the possibility of high levels of inhibition of products generated by lignin degradation at concentrations above 7.32 g/L
Mestrado
Engenharia de Processos
Mestra em Engenharia Química
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Costa, Thiago Santangelo. "Obtenção do copolímero de acrilonitrila e vinil-tetrazol e sua aplicação como inibidor de corrosão para meio ácido." Universidade do Estado do Rio de Janeiro, 2007. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=2803.
Анотація:
Polímeros heterocíclicos abrangem uma grande variedade de materiais, desde simples polímeros lineares sintetizados a partir de monômeros do tipo heterocíclicos vinílicos até polímeros altamente funcionalizados e reticulados. Neste trabalho realizou-se a modificação química da poliacrilonitrila com a incorporação de grupos tetrazol em diferentes teores (1%, 2,5%, 5% e 10%). Os copolímeros de acrilonitrila e vinil-tetrazol obtidos foram caracterizados por FTIR e o seu comportamento térmico analisado por DSC e TGA. Os polímeros heterocíclicos foram avaliados como inibidores de corrosão para aço-carbono em meio ácido obtendo-se bons resultados e alcançando, em alguns casos, uma eficiência de inibição média superior a 70%Heterocyclic polymers enclose a great variety of materials, since simple linear polymers synthesized from monomers of vinyl heterocyclics to polymers highly functionalized and crosslinked. In this work was carried out the chemical modified of polyacrilonitrile with incorporation of tetrazole groups in different quantities (1%, 2,5%, 5% and 10%). The acrilonitrile and vinyl-tetrazole copolymers were characterized by FTIR and its thermal behavior analyzed by DSC and TGA. The heterocyclic polymers were evaluated as corrosion inhibitor to carbon steel in acidic medium. It was obtained good results and in some cases inhibitor efficient average higher than 70% were reached
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Cunha, Maico Taras da. "Estudo comparativo dos inibidores benzotriazol e tolitriazol na oxidação de materiais ferrosos em meio de ácido sulfúrico." Universidade de São Paulo, 2003. http://www.teses.usp.br/teses/disponiveis/46/46132/tde-02022018-104217/.
Анотація:
Foi feito um estudo comparativo da ação inibidora dos compostos benzotriazol (BTAH) e tolitriazol (TTAH) sobre a oxidação de metais ferrosos e sobre a reação H+/H2, sobre ferro, em meios de ácido sulfúrico. Foram estudados, como metais ferrosos, o ferro puro (99,9% de pureza), em meio de H2SO4 0,5molL-1, o aço carbono 1008, em H2SO4 0,5mol L-1e o aço inoxidável 304, em meio de H2SO4 4,5 mol L-1. Foram empregadas, como técnicas, medidas de potencial de circuito aberto em função do tempo, ensaios gravimétricos, curvas de polarização potenciostáticas, voltametria linear com eletrodo parado e com eletrodo de disco rotativo, cronoamperometria, espectroscopia por impedância eletroquímica, espectroscopia Raman e microscopia eletrônica de varredura (MEV). Os compostos BTAH e TTAH atuaram como inibidores para os três materiais ferrosos estudados. No caso do aço carbono 1008 e do aço inoxidável 304, os efeitos dos dois inibidores se comparam e, para uma concentração igual a 1,0 x 10-2 mol L-1 apresentam uma eficiência máxima de 98%, verificada por técnicas estacionárias e não estacionárias. O TTAH, em mais baixa concentração, se mostrou melhor inibidor para o aço carbono, enquanto para o aço inoxidável 304 foi tão bom inibidor quanto o BTAH. Análise das superfícies por MEV mostrou que os inibidores não impedem a dissolução das inclusões presentes nos aços estudados, permitindo o ataque localizado no entorno das mesmas, no caso do aço 304. Os compostos BTAH e TTAH se mostraram inibidores menos efetivos para o ferro, com eficiências comparáveis e iguais a 60% na concentração mais elevada estudada, 1,0 x 10-2 mol L-1 . O estudo da oxidação do ferro, na região de Tafel, empregando impedância eletroquímica, mostrou que o BTAH e o TTAH atuam de forma comparável, formando um complexo com o intermediário Fe (II) adsorvido. Ensaios por espectroscopia Raman in situ revelaram que há formação de complexos de ferro com o BTAH e TTAH. Os resultados de impedância eletroquímica, juntamente com os de espectroscopia Raman do complexo Fe(II)BTA sólido levaram à conclusão de que o filme inibidor sobre ferro é o próprio complexo Fe(II)BTA. Estudos de polarização catódica sobre ferro, em meio desaerado, mostraram que tanto o BTAH quanto o TTAH inibem a reação H+/H2, através da formação de um filme que obedece à isoterma de adsorção de Langmuir. Valores de ΔGº de adsorção sugerem que a adsorção é de natureza química, o que foi confirmado por espectroscopia Raman. Estudos empregando voltametria de baixa velocidade de varredura, com eletrodo de disco rotativo, mostraram que a ação inibidora é favorecida pelo maior transporte de massa à superfície do eletrodo de ferro. Os resultados de impedância permitiram sugerir dois diferentes mecanismos para a ação dos inibidores sobre o processo de oxidação do ferro em meio de ácido sulfúrico.A comparative study of the inhibitor behavior of benzotriazol (BTAH) and tolitriazol (TTAH) over the oxidation of ferrous metals and over the reaction H+/H2, over iron in sulfuric acid media has been performed. The ferrous metals studied were pure Iron (99.9% purity) and carbon steel 1008, both in 0.5 mol.L-1 H2SO4 and 304 stainless steel in 4.5 mol.L-1 H2SO4. The techniques employed were, open circuit potential vs. time, gravimetry, potentiostatic polarization curves, linear voltammetry with both stationary and rotating disk electrodes, chronoamperometry, electrochemical impedance spectroscopy, Raman spectroscopy and scanning electron microscopy (SEM). BTAH and TTAH have shown to act as inhibitors for the three studied ferrous metals. The inhibiting effect of these compounds was analogous for both carbon steel 1008 and 304 stainless steel. Furthermore stationary and non-stationary techniques have shown that both inhibitors exhibited the maximum of efficiency (98%) in 1.0 x 10-2 mol.L-1. For the lowest studied concentration, TTAH exhibited a better inhibiting effect over the carbon steel, while for the 304 stainless steel TTAH and BTAH presented the same inhibiting efficiency. SEM Analysis of the surfaces showed that the inhibitors do not avoid the dissolution of the inclusions that exist in the studied steels, instead, for 304 stainless steel they permit a localized attack on the contour of the inclusions. Both BTAH and TTAH have shown a less effective inhibitory effect for iron with 60% of efficiency for the highest studied concentration (1.0 x 10-2 mol.L-1). The study of the oxidation of iron performed on the Tafel region by electrochemical impedance spectroscopy showed that both BTAH and TTAH act similarly, forming a complex with the adsorbed intermediary Fe(II). Raman spectroscopy measurements performed in situ indicated the formation of iron complexes with BTAH and TTAH. The analysis of the results obtained for the complex Fe(II)BTA with both electrochemical impedance spectroscopy and Raman spectroscopy techniques revealed that this complex forms the inhibitor film. Cathodic polarization studies performed for iron in dearated media showed that both BTAH and TTAH forma film that obeys to the Langmuir adsorption isotherm on the iron surface which inhibits the H+/H2 reaction. Furthermore ΔGº adsorption values suggest that the adsorption is chemical in nature which was confirmed by Raman spectroscopy. Low rate voltammetry studies performed with rotating disk electrode, showed that the inhibitory effect is favored by the mass transport towards the iron electrode surface. From the impedance spectroscopy results two different mechanisms could be proposed to the inhibitor effect over the process of iron oxidation in sulfuric acid media.
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Costa, Jeremias de Freitas. "Avaliação de aminoácidos como inibidores de corrosão para cobre em meio de água do mar artificial." Universidade do Estado do Rio de Janeiro, 2013. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=8914.
Анотація:
Inibidores de corrosão são substâncias que quando adicionadas a um meio agressivo, diminuem ou previnem a reação de oxidação de um metal com este meio e/ou as reações de redução de espécies presentes no meio. Para a inibição da corrosão de cobre e suas ligas em meios ácidos ou neutros, o inibidor mais empregado é o benzotriazol (BTAH), o qual forma complexos com os íons Cu (I) e Cu (II) na superfície do metal, diminuindo o processo corrosivo. A preocupação com a preservação ambiental e a toxicidade de inibidores de corrosão vem sendo discutida na literatura. Vários estudos têm-se intensificado usando aminoácidos, como proposta para substituição ao BTAH, considerado tóxico. Entre os aminoácidos estudados, dois apresentavam enxofre em suas moléculas (cisteína e metionina) e um outro sem heteroátomo na cadeira lateral (glicina). As concentrações variaram entre 10-2 a 10-4 mol/L e pH da solução entre 7,2 e 8,4. Foram realizadas medidas gravimétricas (ensaios de imersão total) e técnicas eletroquímicas, tais como polarização potenciodinâmica e espectroscopia de impedância eletroquímica. A caracterização morfológica da superfície do substrato após os ensaios de imersão total (743 horas) foi feita por meio de microscopia eletrônica de varredura (MEV), espectroscopia de raios X por dispersão de energia (EDS ou EDX) e difração de raios X (DRX). Embora os resultados com aminoácidos tenham sido sempre muito inferiores àqueles obtidos na presença de BTAH, comportamentos semelhantes em função da concentração dos aminoácidos puderam ser observados pelos diagramas de Nyquist. Contudo, com exceção dos resultados verificados para o meio contendo cisteína 10-2 mol/L, todas as eficiências de inibição para os meios contendo aminoácidos, obtidas pelos ensaios de imersão total, foram negativas, mostrando que o tempo de exposição também pode ser relevante para o desempenho destes inibidores. Entre todos os aminoácidos testados, os meios contendo glicina apresentaram os piores desempenhos anticorrosivos, inclusive acelerando o processo de dissolução anódica do cobre. Esse resultado pode estar relacionado à faixa de pH das soluções testadas e à solubilidade dos complexos de cobre formados com os aminoácidos, mostrando que uma faixa ótima de pH também deve ser assegurada para aprimorar a ação destes aminoácidos como inibidores de corrosãoCorrosion inhibitors are substances that, when added to an aggressive medium reduce or prevent the oxidation reaction of a metal with such medium and / or the reduction reactions of specimens present in the medium. For inhibiting the corrosion of copper and copper alloys in acidic or neutral media, the most widely used inhibitor is benzotriazole (BTAH), which forms complexes with the Cu (I) and Cu (II) ions on the metal surface, decreasing the corrosive process. The concern for environmental preservation and the toxicity of corrosion inhibitors have been discussed in the literature. Several studies havebeen intensified using amino acids as a proposal to replace the BTAH, which is considered toxic. Among the amino acids studied, two presented sulfur in their molecules (cysteine and methionine) and another without heteroatom in the side chair (glycine). The concentrations ranged from 10-2 to 10-4mol/L and the pH of the solution variedbetween 7,2 and 8,4. Gravimetric measurements (total immersion tests) and electrochemical techniques, such as potentiodynamic polarization and electrochemical impedance spectroscopy, were performed. The morphological characterization of the substrate surface after the immersion tests (743 hours) was made by means of scanning electron microscopy (SEM), X-rays spectroscopy energy dispersive (EDS or EDX) and X-rays diffraction (XRD ).This effect was probably due to the increased concentration of molecules adsorbed on the metal surface. Although the results with amino acids were always lower than those obtained in the presence of BTAH, similar behaviorsas a function of the amino acid concentration could be observed for the Nyquist diagrams. However, except for the results observed for the cysteine medium containing 10-2mol/L, all the inhibition efficiencies of the media containing amino acids, obtained by total immersion tests, were negative, showing that exposure time may also be relevant to the performance of these inhibitors. Among all amino acids tested, the medium containing glycine showed the worst corrosion performance, accelerating the process of anodic dissolution of copper. This result may be related to the pH range of tested solutions and to the solubility of the copper complexes formed with amino acids, showing that an optimal range of pH must also be provided to enhance the action of these amino acids as corrosion inhibitors
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Weißbach, Rebekka [Verfasser], Elmar [Akademischer Betreuer] Wahle, Ralph [Akademischer Betreuer] Golbik, and Gregor [Akademischer Betreuer] Meiß. "Identifizierung eines spezifischen Protein-Inhibitors für die Endonuklease G in Drosophila melanogaster / Rebekka Weißbach. Betreuer: Elmar Wahle ; Ralph Golbik ; Gregor Meiß." Halle, Saale : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2009. http://d-nb.info/1025055551/34.
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Vespa, Alfredo Sahade. "Avaliação de inibidores de corrosão em meios agressivos que simulam os de produção de petróleo." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/3/3137/tde-20062017-132713/.
Анотація:
Através de técnicas eletroquímicas (espectroscopia de impedância eletroquímica, resistência à polarização linear e curvas de polarização potenciodinâmica), gravimétrica e analítica, compostos orgânicos foram estudados para avaliar suas possibilidades de emprego como inibidores de corrosão. Poliglicerol hiper-ramificado puro, modificado com dicloro-fosfato, funcionalizado com grupo tiol, funcionalizado com grupo sulfeto e com grupo sulfonato de potássio - foram os compostos sintetizados e testados. Além desses, compostos comerciais, um contendo a função fosfinato e outro a função imidazolina quaternária foram testados com o mesmo intuito. Isotermas de adsorção foram ajustadas aos dados obtidos para imidazolina quaternária. Para simular condições próximas às encontradas na produção de petróleo, água do mar sintética acidificada com ácido clorídrico até pH 3 foi o meio utilizado, tendo o aço carbono 1020 empregado como substrato metálico. O Poliglicerol hiper-ramificado gerou resultados eletroquímicos e gravimétricos que mostraram que em concentrações de até 600 ppm desse composto o processo corrosivo é incentivado ao invés de ser desacelerado, indicando que tal composto não deve ser usado como inibidor de corrosão. O Poliglicerol hiper-ramificado modificado com dicloro-fosfato apresentou resultados insatisfatórios para as condições testadas tanto nos ensaios eletroquímicos como nos gravimétricos. Nas concentrações de 200, 400 e 600 ppm desse composto, a concentração intermediária é a única que diminui ligeiramente a taxa de corrosão, e para as demais concentrações a corrosão é incentivada. Os ensaios eletroquímicos das outras três moléculas obtidas por funcionalização do poliglicerol hiper-ramificado com grupos tiol, sulfonato e sulfeto indicaram aumento da deterioração do substrato. Os resultados de impedância eletroquímica indicaram que o composto à base de fosfinato e na concentração de 2000 ppm e maiores tempos de imersão resultaram em melhores resultados protetores. O ajuste dos dados às isotermas de adsorção para a imidazolina quaternária apresentou melhores resultados para o modelo de Flory-Huggins, porém, os elevados valores de coeficiente de determinação R2 das isotermas de Langmuir e Temkin também permitem dizer que tais modelos de adsorção são seguidos.Organic compounds were studied by lectrochemical (electrochemical impedance spectroscopy, linear polarization resistance and potenciodynamic polarization curves), analytical and gravimetric techniques, to analyze the possibilities of their use as corrosion inhibitors. Hyper branched polyglycerol only and modified with dichloro-phosphate, functionalized with thiol group, functionalized with sulfide and also with sulphonate group were synthesized and tested as corrosion inhibitors. Furthermore, commercial compounds, one based on phosphinate and a quaternary imidazoline were tested with the same objective. Adsorption isotherms were adjusted to the data obtained for quaternary imidazoline. To simulate the conditions close to those found in petroleum production, synthetic sea water acidified with hydrochloric acid up to pH 3 was the medium used, with 1020 carbon steel used as a metal substrate. The hyper branched polyglycerol generated electrochemical and gravimetric results which showed that, in concentrations up to 600 ppm of this compound, the corrosive process is favored rather than decelerated, indicating that this compound should not be used as a corrosion inhibitor. The hyper branched polyglycerol modified with dichloro-phosphate presented unsatisfactory results for the tested conditions for both electrochemical and gravimetric measurements. At concentrations of 200, 400 and 600 ppm of this compound, the intermediate concentration is the only one that slightly decreases the corrosion rate, and for the other concentrations corrosion is favored. The electrochemical measurements for the other three molecules obtained by functionalization of the hyper branched polyglycerol with thiol, sulphonate and sulfide groups indicated an increase on the substrate deterioration. The electrochemical impedance results showed that the compound based on phosphinate at 2000 ppm concentration and for higher immersion times resulted in better protective results. The adjustment of the data of the adsorption isotherms for quaternary imidazoline presented better results for the Flory-Huggins model. However, the high values of correlation factor R2 of Langmuir and Temkin isotherms show that these adsorption models are also followed.
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Machado, Pedro Alves. "Estudo da atuação e sinergismo de inibidores de corrosão para o aço inoxidável austenítico 304 em meio de ácido peracético comercial 0,2%." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/46/46136/tde-30092014-110547/.
Анотація:
O ser humano tem uma grande necessidade de se proteger de fontes de contaminação microbianas. Para tal, ao longo da história, diversos meios foram empregados, desde lavagem com água corrente até as mais modernas substâncias esterilizantes. Entre essas, o ácido peracético (APA) é o mais seguro, sob o ponto de vista ambiental, além de não ser cancerígeno ou tóxico para o corpo humano. O maior empecilho para a aplicação do APA em certas superfícies é seu caráter fortemente oxidante, que pode causar danos em materiais metálicos. Para que tal aplicação seja viável, é necessária a aplicação de inibidores de corrosão que reduzam os danos que o APA possa causar. Para tanto, foram estudadas sete substâncias empregadas comercialmente como inibidores de corrosão para aço inoxidável 304 em meio de ácido peracético a temperatura ambiente: benzotriazol (BTAH), molibdato de sódio, tungstato de sódio, fosfato monossódico, fosfato dissódico, hexametafosfato de sódio e dodecilsulfato de sódio (SDS) e, posteriormente, sinergismos entre os mesmos. Seus desempenhos foram estudados por diferentes técnicas eletroquímicas: potencial de circuito aberto, polarização linear potenciodinâmica, cronoamperometria, espectroscopia de impedância eletroquímica. A superfície do aço foi estudada por microscopia eletrônica de varredura (MEV). As técnicas eletroquímicas demonstraram que o aço 304 encontra-se passivado em meio de ácido peracético 0,2%. Sua resistência à corrosão pode ser significativamente aumentada com o emprego de BTAH, e de sua mistura com SDS, chegando a uma eficiência inibidora de 70%. Os outros inibidores ou pares de inibidores estudados apresentaram eficiências mais baixas. Ensaios microbiológicos foram realizados com o objetivo de se determinar se os inibidores de corrosão poderiam interferir no desempenho do APA como esterilizante. Os resultados obtidos comprovaram que a presença dos inibidores de corrosão BTAH e SDS não interfere sobre a ação esterilizante do APA.The humanity has a great need to protect itself from microbial contamination. For that, through the history, several ways were employed, since running water washing until the most modern sterilizing substances. Between those, the peracetic acid (PAA) is the safest, under an environmentalist view, besides not being carcinogenic nor toxic to the human body. The great trouble to the application of PAA in some surfaces is its high oxidative property, which can cause damage to metallic materials. Therefore the application of corrosion inhibitor is necessary to reduces the damage that PAA might cause. For that, seven substances commercially applied as corrosion inhibitors for the 304 stainless steel in peracetic acid media were studied: benzotriazole (BTAH), sodium molybdate, sodium tungstate, monosodic phosphate, disodic phosphate, sodium hexametaphophate and sodium dodecilsulphate, as well as the synergism between them. Their per formances were studied through several electrochemical techniques: open circuit potential, linear polarization, chronoamperometry and electrochemical impedance spectroscopy. The steel surfaces were studied through scanning electronic microscopy (SEM). The electrochemical techniques showed that the 304 stainless steel presents passive behavior in 0.2% PAA media. Its corrosion resistance can be significantly improved through the application of BTAH alone, and in combination with SDS, achieving 70% of inhibitor efficiency. The other inhibitors and mixtures studied presented lower efficiency. Microbiological studies were performed aiming to define if the corrosion inhibitor could interfere with the PAA sterilizing performance. The results proved that the presence of BTAH and SDS corrosion inhibitors did not interfere with the sterilizing properties of PAA.
Частини книг з теми "MEIS Inhibitors":
1
Sharif, Saima, Saira Rafaqat, and Shagufta Naz. "Biomarkers of Metabolic Syndrome in Cardiomyopathy: A Leading Cause of Heart Failure." In New Insights on Cardiomyopathy [Working Title]. IntechOpen, 2023. http://dx.doi.org/10.5772/intechopen.109381.
Анотація:
Cardiomyopathy is a disease of the heart muscle, which makes the muscles harder to pump blood to the rest of the body leading to heart failure. The main types of cardiomyopathies include dilated cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, arrhythmogenic right ventricular dysplasia, restrictive cardiomyopathy, and Takotsubo cardiomyopathy. On the other hand, Metabolic syndrome (MetS) is the clustering of different medical conditions, which requires at least three of the five following diseases. These diseases are high blood sugar, high blood pressure, high serum triglycerides, low serum high-density lipoprotein, and central obesity. The risk of developing type 2 diabetes and cardiovascular disease associated with metabolic syndrome. In MetS, many different biomarkers are used in the early detection and risk stratification of MetS patients. It includes adiponectin, leptin, interleukin 6, tumor necrosis factor-alpha, uric acid, interleukin 10, ghrelin, adiponectin, paraoxonase, oxidized low-density lipoprotein, and plasminogen activator inhibitor-1. This chapter provides an overview and focuses on the basic role of major biomarkers of metabolic syndrome in the pathogenesis of different types of cardiomyopathies, which mainly highlights recent pathophysiological aspects in the development and progress of cardiomyopathy which is the leading cause of heart failure. In conclusion, biomarkers of metabolic syndrome play a significant role in the development and progress of cardiomyopathy which is the leading cause of heart failure.
2
Kapoor, Mayank, Prasan Kumar Panda, and Vivek Mohanty. "Pharmacotherapy for COVID-19: A Ray of Hope." In Fighting the COVID-19 Pandemic [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.97012.
Анотація:
Most viral infections have limited treatment options available and the same holds for COVID-19, its causative agent being the SARS-CoV-2 virus. Drugs used in the past against Severe Acute Respiratory Syndrome (SARS) or Middle East Respiratory Syndrome (MERS) viruses, which belong to the same family of viruses as the novel Coronavirus included ribavirin, interferon (alfa and beta), lopinavir-ritonavir combination, and corticosteroids. There remains controversy regarding their efficacy to date, except for the last one. Hence, large-scale multicentric trials are being conducted involving multiple drugs. Chloroquine and hydroxy-chloroquine were initially taking the race ahead but have now been rejected. Remdesivir was a promising candidate, for which the FDA had issued an emergency use authorization, but now is not recommended by the WHO. Convalescent plasma therapy had promising results in the early severe viremia phase, but the PLACID trial made an obscure end. Only corticosteroids have shown demonstrable benefits in improving mortality rates among severe COVID-19 cases. Many new modalities like monoclonal antibodies and tyrosine kinase inhibitors are discussed. In this chapter, we review the therapeutic drugs under investigation for the COVID-19 treatment, their mode of action, degree of effectiveness, and recommendations by different centers regarding their use in current settings.
Тези доповідей конференцій з теми "MEIS Inhibitors":
1
Li, Maodong, Jianfeng Xiao, Sixue Guo, Junming Zhao, and Yingtong Chen. "The Introduction of New Scale and Corrosion Inhibitor of Central Air Conditioning Circulating Cooling Water." In 2014 International Conference on Mechatronics, Electronic, Industrial and Control Engineering. Paris, France: Atlantis Press, 2014. http://dx.doi.org/10.2991/meic-14.2014.246.
2
Zaghloul, Nancy, Ahmed Awaisu, Ahmed Mahfouz, Sumaya Al Saadi, and Hazem Elewa. "Trends of use of SGLT2 inhibitors in Qatar." In Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2021. http://dx.doi.org/10.29117/quarfe.2021.0108.
Анотація:
Background: Type 2 diabetes mellitus (T2DM) represents a growing health challenge in Qatar and worldwide. T2DM is associated with a high risk of cardiovascular (CV) morbidity and mortality, and progression of renal disease. Sodium glucose co-transporter 2 inhibitors (SGLT2is) are the most recently approved class of glucose lowering medications (GLMs). To date, there is a limited knowledge about the adoption of SGLT2is by clinicians compared to other oral GLMs in Qatar and Middle East and North Africa (MENA) region. Accordingly, this proposed study aims to explore the trends in SGLT2is use compared to other oral GLMs in Qatar from 2016 to 2020. Methods: This is a descriptive, retrospective cross-sectional study where information on all oral GLMs prescriptions dispensed as in- or out-patient from 2016 to 2020 in all Hamad Medical Corporation (HMC) hospitals were collected. Outcomes included the number and relative frequency of quarterly prescriptions of different oral GLMs classes [metformin, sulfonylureas (SUs), dipeptidyl peptidase 4 inhibitors (DPP-4is), thiazolidinediones (TZDs), meglitinides (MEGs), α-glucosidase inhibitors (AGIs), and SGLT2is] from 2016 to 2020. Results: Overall, the prescription rate of GLMs increased during the last five years. SGLT2is use increased over the years after being introduced to the formulary in 2017, replacing SUs which exhibited significant decline between 2017 and 2020. There was a slight reduction in metformin use, and a slight increase in DPP-4is use. TZDs, MEGs, and AGIs prescriptions remained stable. Among SGLT2is, empagliflozin showed considerable increase on the expense of dapagliflozin which decreased significantly by the end of 2018. Conclusion: SGLT2is have been gradually replacing SUs in Qatar and the trend of their use is similar to that reported in other countries. The trend among SGLT2is suggests greater preference for empagliflozin over dapagliflozin.
3
Yue, Zhiwei David, Qiwei Wang, Tao Chen, Tawfik Ghamdi, Yi-Tsung Alex Lu, and Ashley Ariyaratna. "Optimizing Scale Inhibitor Squeeze Performance for Chalk Reservoirs: Concept, Validation, to Treatment Design." In SPE Oilfield Scale Symposium. SPE, 2024. http://dx.doi.org/10.2118/218746-ms.
Анотація:
Abstract One of the largest oilfields experienced calcite scale depositions on downhole tubing and surface equipment. The incumbent solution is a conventional precipitation-type scale inhibitor squeeze. However, the chalk reservoir features calcium-rich formation waters and strong binding affinities to the selected inhibitor. Such factors often challenge the squeeze design with brine incompatibility, water-loading, and low inhibitor return concentrations in the flowbacks, leading to higher frequency of treatments especially when higher inhibitor MECs are required. This study details four squeeze optimization approaches for chalk-type formations: 1) Screening of new inhibitor chemistries to provide equivalent inhibition performance and better high-salinity brine tolerance through static bottle and dynamical scaling loop methodologies; 2) Optimizing the main-treatment pH for carbonate formations; 3) Investigation of a newly developed flush-additive squeeze enhancement technology; and 4) Inhibitor-rock adsorption modifiers to boost the inhibitor return profile. Items 2-4 were evaluated through carefully designed dynamical core flood techniques with great data reproducibility. Through a comprehensive screening of 18 products, one scale inhibitor chemistry was identified demonstrating excellent calcite inhibition and superior brine compatibility. Furthermore, the inhibitor adsorption/desorption profiles showed that the carbonate matrix responded significantly differently to the inhibitor pH. With a normalized inhibitor MEC of 2-ppm, the core lives were 1200, 1800, and 650 PV under the same treating parameters with the main-treatment pH at 2.5, 4.5, and 7, respectively. Besides adopting the optimal pH, the treatment live was further increased to 2,800 PV using 2% squeeze enhancer in the preflush. Different from the flush-additive enhancer, the adsorption modifier was directly applied with the inhibitor. Synergistic effects were observed as the treatment lasted 2000, 2400, 2700 PV for 1%, 2%, and 5% modifier in the inhibitor package. The next steps are to conduct cost analysis among the options for an optimization, followed with formation damage evaluations using the reservoir core plugs from the formation depths. The data will be used to design the field trials. This study shows how different parameters and chemistries can be utilized to improve the inhibitor squeeze lives for chalk reservoirs. The treatment design methodology for the chemical additive application is outlined and presented.
4
Saito, Ken, Kazuto Okazaki, Kentaro Sakata, Tatsuya Ogiwara, Yoshifumi Sekine, and Fumio Uchikoba. "Pulse-Type Hardware Inhibitory Neural Networks for MEMS micro robot using CMOS technology." In 2011 International Joint Conference on Neural Networks (IJCNN 2011 - San Jose). IEEE, 2011. http://dx.doi.org/10.1109/ijcnn.2011.6033416.
5
Pan, Feng, Abdoul Kader Maiga, and Po-Hao Adam Huang. "Solvent-Based Polymer Swelling Characterization for the Development of the Nano/Micro-Particle Polymer Composite MEMS Corrosion Sensor." In ASME 2014 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2014. http://dx.doi.org/10.1115/imece2014-40145.
Анотація:
The concept of using Micro-Electro-Mechanical Systems (MEMS) for in-situ corrosion sensing and for long-term applications has been proposed and is currently under development by our research lab. This is a new type of sensing using MEMS technology and, to the knowledge of our team, has not been explored previously. The MEMS corrosion sensor is based on the oxidation of metal nano/micro-particle embedded in elastomeric polymer to form a composite sensing element. The polymer controls the diffusion into and out of the sensor while the corrosion of the metal particles inhibits electrical conduction which is used as the detection signal. The work presented here is based on part of the methods developed for the removal of native and process-induced metal oxides. A major aspect is the study of the swelling dynamics of the polymer matrix (polydimethylsiloxane, PDMS) intended for enhancing material transport of etchants into and reaction products out of the composite during oxide removal. More specifically, the characterization of the swelling of copper particles-PDMS composite samples in liquid solvent baths is presented.
6
Maiga, Abdoul Kader, and Adam Huang. "Swelling-Etching Characterization of PDMS-Copper Particle for the Development of the Nano/Micro-Particle Polymer Composite MEMS Corrosion Sensor." In ASME 2015 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2015. http://dx.doi.org/10.1115/imece2015-53705.
Анотація:
The concept of using Micro-Electro-Mechanical Systems (MEMS) for in-situ corrosion sensing and for long-term applications has been proposed and is currently under development by our research lab. This is a new type of sensing using MEMS technology and, to the knowledge of our team, has not been explored previously. The MEMS corrosion sensor is based on the oxidation of metal nano/micro-particle embedded in elastomeric polymer to form a composite sensing element. The polymer controls the diffusion into and out of the sensor while the corrosion of the metal particles inhibits electrical conduction which is used as the detection signal. The work presented here is based on the experimental wet-chemistry method developed for the removal of native and process-induced metal oxides. A major aspect is the study of the swelling dynamics of the polymer matrix (polydimethylsiloxane, PDMS) and its influence on the material transport of etchants into and reaction products out of the composite during oxide removal. The understanding of this process is important to the ultimate development of the MEMS corrosion sensor, where the swelling must be controlled sufficiently to prevent stress-induced delamination of the sensing element from the substrate. For the first time, the simultaneous swelling (toluene) and oxide removal (acetic acid) characterization of the copper particles embedded in PDMS will be published. The experimental setup consists of small disk samples of the composite (6.35mm diameter × 1mm thick) dropped into a 50mL beaker filled with the swelling agent (the amount of which is part of the parametric study). This is then followed by the addition of the etching agent after reaching the swelling time constants characterized in prior work. The full process is captured through a HD webcam set inverted underneath the beaker. The swelling and contraction process is analyzed in real-time, while post processing of the recorded video is available to verify unexpected responses. Data gather so far indicate interesting swelling recovery phenomenon that is mostly consistent with the two part kinetics of swelling and etching. However, some data also seem to suggest a third mechanism that may be explained by material stiffness changes as etching and swelling proceed simultaneously. A full set of data currently being gathered will provide more clues and aid in the development of a consistent theoretical explanation. The final goal of this series of experiment is to provide mathematical models of the observed phenomenon so they can be used to aid the development of the fabrication processes of the MEMS corrosion sensor.
7
Grøn, B., and F. Brosstad. "IMMUNO-VISUALIZATION OF FIBRINOGEN AND FIBRIN IN GELS PRDUCED BY GELATION OF PLASMA WITH ETHANOL." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643326.
Анотація:
The Ethanol Gelation Test(=EGT) is a well-documented simple,specific and frequently used test to detect plasma soluble fibrin(Godal & Abildgaard:Gelation of soluble fibrin in plasma by ethanol.Scand.J.Haanat.3,342,1966) .If soluble fibrin present in plasma amounts to 1% or more of the plasma-f ibrinogen conc.,the admixing of 0.15 ml 50% ethanol to 0.5 ml plasma in a test tube will-(subsequent to incubation for 10 min at 20°C)-upon tilting the test tube semi-horizontally produce a characteristic,(upwardly) convex gel. Although earlier studies have confirmed the validity and specificity of EGT as a means to detect soluble fibrin,we found it of interest to see to which degree such soluble fibrin is FXIII-stabilized EGT-positive(from patients with Disseminated Intravascular Coagula-tion(DIC) and EGT-negative plasma was studied as follows: The EGT test was performed as above,and the entire content of the test tube emptied upon a nylon micro-meshed membrane.Applying slight suction underneath the nylon manbrane the fluid was removed,leaving the ethanol precipitated material which was immediately dissolved in SDS (1%)-urea(5M)-Tris-HCl (0.15M,pH8.6). After incubation at 100°C for 1 min the material was SDS-electrophoresed on flat-bed agarose(2%) Subsequent to Western-blotting onto nitrocellulose and gelatine-blocking, the fibrin(ogen)-related pattern was reacted with either: a)polyclonal antibodies to fibrinogen,b)plyclonal antibodies to FPA or c)monoclonal antibody to FPA(gift from Dr.Nieuwenhuizen, Leyden, Holland) .Then,the fibrin(ogen)related pattern was developed using peroxidase-conjugated secondary antibodies.From the specificity of the primary antibodies used,it could be deduced that:1)A substantial amount of the soluble fibrin content of DIC-plasma was present in an oligomeric form(up to 6-mers) .2)These oligomers contained fibrinogen, i.e. thus representing FXIII-1 inked fibrinogen/fibrin hybride molecules .3) Even normal plasma contained some detectable oli-gomers(up to 3-mers) .4) Col lecting blood with all appropriate thrombin- and FXIII-inhibitors did not change the patterns obtained and described above.It may be concluded that soluble fibrin occurs mainly in a FXIII-stabilized,oligomeric form which contains fibrinogen Due to the nature of the polymerization process,the fibrinogen moiety of these hybride molecules must be end-located representing a physiological means to inhibit further polymer growth.
8
Holloway, D. S., L. Summaria, R. C. Wohl, and J. A. Caprini. "MODIFICATION OF GLUTAMIC AND ASPARTIC ACID RESIDUES OF PLASMINOGEN INHIBITS ITS ABILITY TO FORM AN ACTIVE PLASMINOGEN-STREPTOKINASE COMPLEX." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643600.
Анотація:
Plasminogen binds to streptokinase in a 1:1 molar complex that has activity as a plasminogen activator. This function of plasminogen, as a cofactor for streptokinase conversion of plasminogen to plasmin, was studied after treatment of Glu-, Lys-, and Mini-plasminogens with 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide (EDC). Amino acid analysis showed that both aspartic and glutamic acid residues were modified by EDC. Activity of the complex formed between streptokinase and the modified plasminogen was measured using the cfhromogenic substrate H-D-Val-Leu-Lys-pNA. Plasminogen, 2.8 uM, was incubated with 40 mM EDC in 50 mM MES buffer, pH 6.0, at 25°C. At various times while reacting plasminogen with the EDC, aliquots were removed for assay. Plasminogen function was assayed by mixing with a slight molar excess of streptokinase for 1 min at 37 C, followed by reaction with 0.1 M substrate, and absorbancy monitored at 405 nm. Modifications of 20% of the glutamic and aspartic acid residues occurred after treatment of plasminogen with EDC. This resulted in 80 to 90% inhibition of activation in all three types of plasminogen. Glu- and Lys-plasminogens reacted more quickly with the EDC than did Mini-plasminogen, with 50% inhibition occurring after 16 ± 5, 16 ± 4, and 67 ± 13 min reaction time with EDC for Glu-, Lys-, and Mini-plasminogens, respectively. Maximum inhibition of activation occurred within 1 hr reaction with EDC for Glu- and Lys-plasminogens but required 2.5 hr for Mini-plasminogen. The time courses for activation inhibition and the modification of the glutamic and aspartic acids of treated Mini-plasminogen were compared. A significant decrease in activation occurred (52%) concomitant with modification of only one or two glutamic acids, followed on further reaction with EDC by more loss of activatability as more glutamic and aspartic acids were modified. The inability of plasminogen to form an active plasminogen-streptokinase complex after modification with EDC indicates that glutamic and aspartic acid residues are involved in the binding site of plasminogen for streptokinase.
9
SCHLEGEL, N., J. MOAKE, C. LOIRAT, M. F. HURTAUD, S. LEVY-TOLEDANO, and H. MATHIEU. "CHILDHOOD HEMOLYTIC UREMIC SYNDROME (HUS) : VON WILLEBRAND FACTOR (vWF) AND PLATELET AGGREGATING ACTIVITY (PAA) STUDIES." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643475.
Анотація:
It has been suggested that a vWF High Molecular Weight Multi-mers (HMWM) decrease or a PAA were involved in the pathogenesis of HUS. We have studied 8 children (6 girls,_2 boys; 7 months-8_1/2 years old) with HUS : plasma creatinine /μmol/l; mean(range)/=306 (105-524), hemoglobin (g/100ml)-7(6.3-7.8), schistocytes (%)=8(1-18), platelets (x103/mm3)-57(10-115). The vWF was studied quantitatively (antigen ; vWF RAg assay) and qualitatively (multimeric pattern : immunoblotting and autoradiography). PAA studied by incubating the patient's platelet poor plasma (RPR) with washed normal platelets (aggregometer, % light transmission) and confirmed by Thromboxane B2 (TXB2) assay and [14C] Serotonine release study. The PAA was characterized by studying the in vitro effect of several platelet aggregation inhibitors, Immunoglobulins (Igs) and Fresh Frozen Plasma (FFP) on the platelet aggregation.An increase of vWF RAg (%) was observed in 6 cases : mean:330, and possibly related with renal failure. A vWF HMWM decrease was found in 3 patients : 2/3 with associated infection(E.Coli, Pneumococcus), 1/3 with severe hemolysis. Two of these 3 patients had a favourable renal outcome and 1 a severe course (chronic hemodialysis, Arterial Thrombotic MicroAngiopathy at renal histology).An important PAA was evidenced only in 1 patient : post bone-marrow graft HUS during neuroblastoma(NB),arterial hypertension and chronic renal failure. This PAA was Ca++, TXB2 and cAMP dependent; it was moderately inhibited in vitro by Igs and FFP, but persisted after 5 days of Igs infusion (0.3g/Kg/day). Treatment with aspirin and dipyridamole (10mg/Kg/day each) suppressed the patient platelet auto-aggregation although the PAA persisted (follow up:10months). The PAA did not seem to be related with the NB (absence of GD2 ganglioside, specific marker of NB); it could be related with anti platelet antibodies. The coexistence of the two abnormalities could not be demonstrated in our patients.In conclusion, a vWF HMWM decrease was found in 3 out of 8 children patients with HUS. Its presence was not correlated with the severity of the disease. We could demonstrate the presence of PAA during childhood HUS in only 1 post bone-marrow graft case. The PAA characterization is useful for therapeutic decisions and contributes to a better pathogenetic understanding.
10
Anno, Kotaro, George J. Moridis, and Thomas A. Blasingame. "JFTS+H: A Julia-Based Parallel Simulator for the Description of the Coupled flow, Thermal and Geochemical Processes in Hydrate-Bearing Geologic Media." In SPE Reservoir Simulation Conference. SPE, 2021. http://dx.doi.org/10.2118/203953-ms.
Анотація:
Abstract The objectives of this study are to develop (a) the Julia Flow and Transport Simulator (JFTS), a serial and parallel, high performance non-isothermal, multi-phase, multi-component general simulator of flow and transport through porous/fractured media, and (b) an associated module that describes quantitatively the Equation-of-State (EOS) of the complete H2O+CH4 system by covering all combinations of phase coexistence that are possible in geologic media and including all the regions of the phase diagram that involve CH4-hydrates. The resulting simulator (hereafter referred to as the JFTS+H code) can describe all possible scenarios of hydrate occurrence, dissociation and formation/evolution and is to be used for the investigation of problems of (a) gas production from natural CH4-hydrate accumulations in geologic media, as well as for (b) the analysis of any laboratory experiments involving CH4-hydrates. As indicated by the JFTS name, this simulator is written in the Julia programming language and its parallelization is based on the Message Passing Interface (MPI) approach. The JFTS+H simulator is a fully-implicit, Jacobian-based compositional simulator that describes the accumulation, flow and transport of heat, and up to four mass components (H2O, CH4, CH4-hydrate and a water-soluble inhibitor) distributed among four possible phases (aqueous, gas, hydrate, and ice) in complex 3D geologic systems. The dissociation and formation of CH4-hydrates can be described using either an equilibrium or a kinetic model. The automatic derivate capability of Julia greatly simplifies and enhances the Jacobian computations. The MPI Interface (Blaise, 2019) is implemented in all components of the code, and the METIS library (Karypis, 2013) is used for the domain decomposition needed for the effective parallelization of the solution of the Jacobian matrix equation that is accomplished using the LIS library (Nishida, 2010) of parallel Conjugate Gradient solvers for large systems of simultaneous linear equations. The JFTS+H code can model the fluid flow, thermal and geochemical processes associated with the formation and dissociation of CH4-hydrates in geological media, either in laboratory or in natural hydrate accumulations. This code can simulate any combination of the three possible gas hydrate dissociation methods (depressurization, thermal stimulation, and inhibitor effects), and computes all associated parameters describing the system behavior. The JFTS+H results show very good agreement with solutions of standard reference problems, and of large 2D and 3D problems obtained from another well-established and widely used numerical simulator. The code exploits the speed, computational efficiency and low memory requirements of the Julia programming language. The parallel architecture of JFTS+H addresses the persistent problem of very large computational demands in serial hydrate simulations by using multiple processors to reduce the overall execution time and achieve scalable speedups. The code minimizes communications between processors and maximizes computations within the same computational node, which has important consequences (especially when coupled with the automatic derivative capabilities of Julia) on performance in the development of the Jacobian matrix. An optimal LIS solver is recommended for this type of problem after evaluating different options. This approach provides both speedup and computational efficiency results when different numbers of processors are called in the solution process. This work is believed to be the first application of Julia (a new, highly efficient language designed for demanding scientific computations) to create a simulator for flow and transport in porous media. JFTS+H is a fast, robust parallel simulator that uses the most recent scientific advances to account for all known processes in a dynamic hydrate system and works seamlessly on any computational platform (from laptop computers to workstations, to clusters and supercomputers with thousands of processors).