Academic literature on the topic 'Inhibitory factor 1'
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Journal articles on the topic "Inhibitory factor 1"
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Shi, Qizhen, Erin L. Kuether, Jocelyn A. Schroeder, Crystal L. Perry, Scot A. Fahs, and Robert R. Montgomery. "Factor VIII Inhibitors: Von Willebrand Factor Makes A Difference In Vitro and In Vivo." Blood 116, no. 21 (November 19, 2010): 709. http://dx.doi.org/10.1182/blood.v116.21.709.709.
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Abstract Abstract 709 The important association between von Willebrand factor (VWF) and factor VIII (FVIII) has been investigated for decades, but the effect of VWF on FVIII inhibitors is still controversial. Studies have demonstrated that some anti-FVIII inhibitory antibodies inhibit VWF-FVIII interaction, while others rely on the presence of VWF to inhibit FVIII activities. The influence of VWF on the Bethesda assay, which is routinely used in the clinic to determine the titer of FVIII-neutralizing inhibitors, is still uncertain because the plasma from hemophilia A patients with inhibitors contains normal levels of VWF. To explore the effect of VWF on the reactivity of FVIII inhibitors, we immunized VWF and FVIII double knockout (VWFnullFVIIInull) mice with recombinant human B-domain deleted FVIII (rhFVIII) to induce anti-FVIII inhibitory antibody development. Inhibitory plasma was collected and the titer of inhibitors was determined by Bethesda assay. Murine plasma-derived VWF (from FVIIInull mice) or recombinant human VWF (rhVWF) was used to study the influence of VWF on inhibitor inactivation of FVIII activity (FVIII:C). The remaining FVIII:C after inactivation was determined by chromogenic assay. When inhibitory plasma was incubated with rhFVIII in the presence of 1 U/ml VWF, the residual FVIII activity recovered was higher than in the absence of VWF, resulting in 6.82 ± 1.12 (n = 27) fold lower apparent inhibitor titers. This protective effect is VWF dose dependent. The source of VWF (plasma-derived murine VWF vs. rhVWF) did not affect its protection of FVIII from inhibitor inactivation and VWF does not affect FVIII:C measured in the chromogenic assay in the absence of inhibitors. Interestingly, we found that inhibitor inactivation of FVIII:C in the absence of VWF occurred much faster than in its presence. When the usual 2 hr. incubation at 37°C was omitted from the Bethesda assay, adding rhVWF to rFVIII before mixing with inhibitory plasma resulted in 67.29 ± 20.18 (n = 5) fold lower apparent inhibitor titers than without added VWF. In contrast, if VWF was added to inhibitory plasma first and then mixed with rhFVIII, the inhibitor titers were only 11.04 ± 3.56 (n = 5) fold lower than without added VWF. These results indicate that rhFVIII present in a preformed VWF-FVIII complex is protected from inhibitory antibody inactivation. Conversely, when VWF and inhibitory plasma are added to rhFVIII at the same time, the VWF and inhibitors appear to compete to bind to rhFVIII. Inhibitor titers were lower than in the absence of VWF, but the protective effect is not as efficient as when VWF and rhFVIII were already associated with one another before encountering inhibitors. To confirm the protective effect of VWF on FVIII from inhibitor inactivation, we infused FVIIInull or VWFnullFVIIInull mice with inhibitory plasma and rhFVIII followed by a tail clip survival test. When rhFVIII was infused into FVIIInull mice to 2% followed by inhibitory plasma infusion, all mice with inhibitor titer of 2.5 BU/ml (n = 4) survived tail clipping, and 2 of 4 survived with either 25 BU/ml or 250 BU/ml. If inhibitory plasma was infused first followed by rhFVIII infusion, then only 2 of 6 mice with inhibitor titers of 2.5 BU/ml survived tail clip challenge and none survived with 25 BU/ml and 250 BU/ml. In the first set of mice the infused FVIII was able to form a protective complex with endogenous VWF before encountering inhibitors, while in the second set FVIII is exposed to VWF and pre-infused inhibitory antibodies at the same time, a competitive binding that appears to reduce VWF's protective effect. In contrast, when rhFVIII was infused into VWFnullFVIIInull mice followed by inhibitory plasma infusion, no animals (n = 4 for each group) survived tail clipping with inhibitor titers of 2.5 BU/ml or higher. In summary, our studies demonstrate that VWF exerts a protective effect, reducing inhibitor inactivation of FVIII, both in vitro and in vivo. While the role of VWF in stabilizing plasma FVIII in a milieu rich in proteases has been appreciated for decades, our results indicate that treatment utilizing products containing a complex of FVIII with VWF may be especially beneficial in hemophilia A patients with inhibitors. Disclosures: No relevant conflicts of interest to declare.
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Kreisberg, R., M. S. Detrick, A. P. Osmand, and R. N. Moore. "Cytokine mediation of the suppressive effect of ferritin on colony-stimulating factor-1-dependent monocytopoiesis." Journal of Immunology 150, no. 11 (June 1, 1993): 5094–103. http://dx.doi.org/10.4049/jimmunol.150.11.5094.
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Abstract Peptide-specific IgG from a rabbit immunized with an alanine-lysine-proline-arginine ((ALA1)-tuftsin) containing 14-mer "ferritin" peptide neutralized rat liver ferritin inhibition of in vitro CSF-1-dependent monocytopoiesis. Antiferritin IgG similarly neutralized the inhibitory effect of ferritin but did not neutralize peptide inhibition of the in vitro myelopoietic response. No cross-reactivity between the respective antibodies and Ag was detected either by Western immunoblot or by competitive ELISA. Depletion of adherent cells before marrow cell culture significantly reduced the inhibitory effect of ferritin but did not influence peptide inhibition of CSF-1-stimulated colony formation. Adherent marrow cells and P388D1 cells treated with both CSF-1 and ferritin, but not either alone, produced inhibitory supernatant culture media that were neutralized by antipeptide but not antiferritin IgG. High resolution molecular sieve chromatography of the inhibitory adherent marrow cell and P388D1 supernatants resolved two peaks of 50 to 60 kDa and approximately 30 kDa in each. The inhibitory activity in all four peaks was neutralized by antipeptide but not antiferritin IgG. The ferritin/CSF inhibitors were not further characterized although identity with IL-6, IL-8, TNF-alpha, transforming growth factor-beta, and IFN-alpha/beta could be eliminated. The results indicate that ferritin inhibition of CSF-1-dependent monocytopoiesis is mediated by an endogenously produced inhibitor, or inhibitors, that shares antigenic similarity with the (ALA1)-tuftsin-containing 14-mer peptide and that adherent marrow cells, most likely monocytes or macrophages, produce the endogenous inhibitors in response to both CSF-1 and ferritin.
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Mihelič, Marko, and Dušan Turk. "Two decades of thyroglobulin type-1 domain research." Biological Chemistry 388, no. 11 (November 1, 2007): 1123–30. http://dx.doi.org/10.1515/bc.2007.155.
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Abstract Thyroglobulin type-1 repeats are primarily found in thyroglobulin and several other functionally unrelated proteins. Because a few of them exhibit inhibitory activity against cysteine proteases they were named thyropins (thyroglobulin type-1 domain protease inhibitors). In contrast to cystatins, the best-characterized group of papain-like protease inhibitors, they exhibit greater selectivity in their interactions with target proteases. Interestingly, a few members inhibit aspartic protease cathepsin D and metalloproteases. In contrast to the inhibitory fragment of the major histocompatibility complex class II-associated p41 form of invariant chain, whose structural integrity appears mandatory for its inhibitory properties, short polypeptides derived from insulin-like growth factor-binding proteins exhibit the same activity as the structure of the whole fragment. Taken together, the results indicate that the thyroglobulin type-1 repeat is a structural motif occasionally employed as an inhibitor of proteases.
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Buzzelli, Mark D., Murali Nagarajan, John F. Radtka, Margaret L. Shumate, Maithili Navaratnarajah, Charles H. Lang, and Robert N. Cooney. "Nuclear Factor-κB Mediates the Inhibitory Effects of Tumor Necrosis Factor-α on Growth Hormone-Inducible Gene Expression in Liver." Endocrinology 149, no. 12 (August 21, 2008): 6378–88. http://dx.doi.org/10.1210/en.2007-1574.
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TNF inhibits serine protease inhibitor 2.1 (Spi 2.1) and IGF-I gene expression by GH in CWSV-1 hepatocytes. The current study describes construction of a GH-inducible IGF-I promoter construct and investigates mechanisms by which TNF and nuclear factor-κB (NFκB) inhibit GH-inducible gene expression. CWSV-1 cells were transfected with GH-inducible Spi 2.1 or IGF-I promoter luciferase constructs, incubated with TNF signaling inhibitors (fumonisin B1 for sphingomyelinase and SP600125 for c-Jun N-terminal kinase), treated with or without TNF, and then stimulated with recombinant human GH. The 5- to 6-fold induction of Spi 2.1 and IGF-I promoter activity by GH was inhibited by TNF. Neither fumonisin B1 nor SP600125 prevented the inhibitory effects of TNF on GH-inducible promoter activity. Dominant-negative inhibitor-κBα (IκBα) expression vectors (IκBαS/A or IκBαTrunc), p65 and p50 expression vectors, and p65 deletion constructs were used to investigate the NFκB pathway. IκBαS/A and IκBαTrunc ameliorated the inhibitory effects of TNF on GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection of CWSV-1 cells with expression vectors for p65 alone or p50 and p65 together inhibited GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection with a C-terminal p65 deletion (1–450) enhanced GH-inducible promoter activity, whereas the N-terminal deletion (31–551) was inhibitory for IGF-I but not Spi 2.1. Cycloheximide did not antagonize the inhibitory effects of TNF on GH-inducible IGF-I expression. We conclude the inhibitory effects of TNF on GH-inducible promoter activity are mediated by NFκB, especially p65, by a mechanism that does not require protein synthesis.
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Pehlivan, Melek, Ceyda Caliskan, Zeynep Yuce, and Hakkı Ogun Sercan. "Forced expression of Wnt antagonists sFRP1 and WIF1 sensitizes chronic myeloid leukemia cells to tyrosine kinase inhibitors." Tumor Biology 39, no. 5 (May 2017): 101042831770165. http://dx.doi.org/10.1177/1010428317701654.
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Chronic myeloid leukemia is a clonal myeloproliferative disorder that arises from the neoplastic transformation of the hematopoietic stem cell, in which the Wnt/β-catenin signaling pathway has been demonstrated to play an important role in disease progression. However, the role of Wnt signaling antagonists in therapy resistance and disease progression has not been fully investigated. We aimed to study the effects of Wnt/β-catenin pathway antagonists—secreted frizzled-related protein 1 and Wnt inhibitory factor 1—on resistance toward tyrosine kinase inhibitors in chronic myeloid leukemia. Response to tyrosine kinase inhibitors was analyzed in secreted frizzled-related protein 1 and Wnt inhibitory factor 1 stably transfected K562 cells. Experiments were repeated using a tetracycline-inducible expression system, confirming previous results. In addition, response to tyrosine kinase inhibitor treatment was also analyzed using the secreted frizzled-related protein 1 expressing, BCR-ABL positive MEG01 cell line, in the presence and absence of a secreted frizzled-related protein 1 inhibitor. Our data suggests that total cellular β-catenin levels decrease in the presence of secreted frizzled-related protein 1 and Wnt inhibitory factor 1, and a significant increase in cell death after tyrosine kinase inhibitor treatment is observed. On the contrary, when secreted frizzled-related protein 1 is suppressed, total β-catenin levels increase in the cell and the cells become resistant to tyrosine kinase inhibitors. We suggest that Wnt antagonists carry the potential to be exploited in designing new agents and strategies for the advanced and resistant forms of chronic myeloid leukemia.
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Zozulya, N. I., V. M. Chernov, I. S. Tarasova, and A. G. Rumyantsev. "Unsolved issues of providing medical care to patients with hemophilia with inhibitors in Russia." Russian Journal of Pediatric Hematology and Oncology 6, no. 2 (April 24, 2019): 48–53. http://dx.doi.org/10.21682/2311-1267-2019-6-2-48-53.
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The implementation of the state program “7 highcost nosologies” and the active work of Russian hematologists have significantly improved the specialized care for children and adults with Hemophilia. Russian hemophilia patient registry as of 10.25.2018 contained information about 7433 patients, of whom with hemophilia A – 6525 people. About 400 people were diagnosed with hemophilia with inhibitors. The inhibitor predominantly appeared at child and young age (up to 20 years). There is a high supply of coagulation factors concentrates for the treatment of hemophilia in the Russian Federation – 8.1 IU of coagulation factor VIII per capita in 2018, which corresponds to the graduation “full integration into society” according to the scale proposed by the World Hemophilia Federation. Due to the sufficient availability of coagulation factors, it is possible to conduct elimination of inhibitors by immune tolerance induction. Treatment with antiinhibitor coagulant complex and eptacog alfa (activated) requires a good venous access and is not always effective. Treatment results remain unsatisfactory in 67 % of adult patients with severe hemophilia with low inhibitor titer due to the number of bleeding per year exceeds 4. Unsatisfactory treatment results are noted in more than 1/ 3 patients with a high inhibitor titer, despite the ongoing prophylaxis with bypassing agents. Currently, clinical studies of fundamentally new drugs for hemophilia treatment, including the inhibitory form, are ongoing. One such drug is emicizumab, which is a bispecific humanized monoclonal antibody that bridges activated factor IX and factor X to restore the function of missing activated factor VIII Emicizumab is not neutralized by inhibitors to FVIII, which allows it to be successfully used in the inhibitory form of hemophilia A. The results of HAVEN 1 and HAVEN 2 studies showed the advantages of using emicizumab in prophylactic regimen in children and adults with the inhibitory form of hemophilia A compared with bypassing agents.
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E, Jingwen, Ye Liu, Shanshan Guan, Zhijian Luo, Fei Han, Weiwei Han, Song Wang, and Hao Zhang. "How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRL858R/T790M/C797S Inhibitors: A Molecular Dynamics Simulation Study." Molecules 25, no. 4 (February 18, 2020): 895. http://dx.doi.org/10.3390/molecules25040895.
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Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity.
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Batsuli, Glaivy, Courtney Cox, John F. Healey, Pete Lollar, and Shannon L. Meeks. "Anti-Factor VIII C1 Domain Antibodies Are Present in the Plasmas of Patients with Hemophilia and Inhibitors." Blood 124, no. 21 (December 6, 2014): 1482. http://dx.doi.org/10.1182/blood.v124.21.1482.1482.
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Abstract Hemophilia A is an X-linked disorder characterized by a deficiency or absence of blood coagulation protein factor VIII (fVIII). Treatment involves replacement of fVIII through infusions for acute bleeding episodes or prevention of bleeding events. Approximately 30% of individuals with severe hemophilia A will develop antibodies to fVIII. Many studies have characterized the antigenic properties of the C2 and A2 domains as these domains are considered the predominant immunogenic domains of the fVIII protein. However, there is increasing evidence that the C1 domain contributes to fVIII function and immune response to fVIII. Our laboratory has produced and purified a murine IgG2ak anti-human C1 domain monoclonal antibody (MAb), designated 2A9. In this study, we characterized the functional properties of MAb 2A9 using standard coagulation testing including its anti-fVIII inhibitor titer by Bethesda assay and its ability to inhibit fVIII binding to von Willebrand factor (VWF) by competition ELISA. In the Bethesda assay, 2A9 has an inhibitor titer of 97 BU/mg and is a type II inhibitor. In addition, MAb 2A9 inhibits fVIII binding to VWF in an ELISA assay with a 50% inhibitory concentration (IC50) of 1 µg/ml. This is in comparison to the potent high-titer inhibitory anti-C2 MAb I89 (IC50 0.02 µg/ml) and a control non-inhibitory anti-A2 MAb ID4 (IC50 > 10 µg/ml). We tested 11 plasma samples from patients with congenital hemophilia with inhibitors in the Emory IRB-approved inhibitor bank. The plasma samples have inhibitory titers ranging from 1 - 188 BU/ml with a median inhibitory titer of 54 BU/ml and mean inhibitory titer 59 BU/ml. The plasmas were tested for the presence of antibodies that compete with anti-C1 domain MAb 2A9 using competition ELISA with fVIII as the antigen. Biotinylated MAb 2A9 was serially diluted and the concentration of antibody required to produce an absorbance at 405 nm of 0.3 was compared between control severe hemophilia A plasma and inhibitor plasma samples. Inhibitor plasma samples that reduced the ELISA titer of MAb 2A9 were considered a competitive inhibitor. Of the 11 inhibitor plasma samples, 4 were found to compete with MAb 2A9. Our study demonstrates that anti-C1 domain antibodies are present in the plasma of patients with hemophilia A and inhibitors. Given the increasing evidence that the C1 domain is important in fVIII function it is likely that these anti-C1 antibodies are clinically relevant. Therefore, domains other than A2 and C2 need to be included in future studies of fVIII B cell epitopes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Kawai, Misato, Tomohiro Osanai, Makoto Tanaka, Koji Magota, Hirofumi Tomita, and Ken Okumura. "Mitochondrial Inhibitory Factor Protein 1 Functions as an Endogenous Inhibitor for Coupling Factor 6." Journal of Cellular Biochemistry 117, no. 7 (January 15, 2016): 1680–87. http://dx.doi.org/10.1002/jcb.25461.
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Tenan, Mirna, Giulia Fulci, Michele Albertoni, Annie-Claire Diserens, Marie-France Hamou, Michèle El Atifi-Borel, Jean-Jacques Feige, Michael S. Pepper, and Erwin G. Van Meir. "Thrombospondin-1 Is Downregulated by Anoxia and Suppresses Tumorigenicity of Human Glioblastoma Cells." Journal of Experimental Medicine 191, no. 10 (May 15, 2000): 1789–98. http://dx.doi.org/10.1084/jem.191.10.1789.
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Angiogenesis, the sprouting of new capillaries from preexisting blood vessels, results from a disruption of the balance between stimulatory and inhibitory factors. Here, we show that anoxia reduces expression of thrombospondin-1 (TSP-1), a natural inhibitor of angiogenesis, in glioblastoma cells. This suggests that reduced oxygen tension can promote angiogenesis not only by stimulating the production of inducers, such as vascular endothelial growth factor, but also by reducing the production of inhibitors. This downregulation may significantly contribute to glioblastoma development, since we show that an increase in TSP-1 expression is sufficient to strongly suppress glioblastoma cell tumorigenicity in vivo.
Dissertations / Theses on the topic "Inhibitory factor 1"
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Ho, Sze-hang, and 何思恆. "Differential expression of Wnt inhibitors Dickkopf-1 (Dkk-1) and Wnt inhibitory factor-1 (Wif1) in the regulation of urorectal development." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/207999.
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In mammals, the external genitalia, urinary tract and anorectal tract are developed from a common embryonic primordium, the urorectum. Cloaca is the hollow space inside the urorectum that connects the hindgut and the urogenital sinus. During the urorectal development, the external genitalia is formed from the outgrowth of genital tubercle (GT) protruding from the urorectum, while the future urinary tract and anorectal tract are formed by the partition of cloaca during cloacal septation. GT outgrowth and cloacal septation are important developmental events for the formation of genitourinary and anorectal system. In human, dysregulation of these developmental events results in congenital anorectal malformations (ARM).
Wnt signaling is one of the key signaling pathways that regulates urorectal development. The activity of Wnt signaling is initiated by the binding of Wnt ligands to cell surface receptors, which can be antagonized by secretory Wnt inhibitors. Dickkopf1 (Dkk1) and Wnt inhibitory factor 1 (Wif1) are secretory Wnt inhibitors implicated in urorectal development. However, the functions of other secretory Wnt inhibitors during urorectal developments remain to be elucidated.
In this study, expression analyses showed that Dkk1, Dickkopf2 (Dkk2), Dickkopf4 (Dkk4), Secreted Frizzled-related Protein 1 (Sfrp1) and Wif1 were expressed in the developing urorectum. The dynamic, overlapping and restricted expression patterns of these Wnt inhibitors were closely associated with the GT outgrowth and the cloacal septation events, implying that these Wnt inhibitors functioned in a coordinated manner in defining the field of Wnt signaling activities in the developing urorectum.
Wif1 knockout mice (〖Wif1〗^(-/-)) was used as the model to investigate the functions of and the interplay between secretory Wnt inhibitors in urorectal development. GT outgrowth and cloacal septation defects were observed in 〖Wif1〗^(-/-) embryos. Most of the 〖Wif1〗^(-/-) embryos displayed varying degrees of GT outgrowth defects, while septation defects were only occasionally observed. This suggested that GT outgrowth and cloacal septation were regulated by Wif1 via different regulatory mechanisms.
In the urorectum of 〖Wif1〗^(-/-) embryos, Dkk1 was significantly upregulated in the peri-cloacal mesenchyme. Further expression analysis suggested that Dkk1 was sufficient to rescue cloacal septation defects but not GT outgrowth defects in 〖Wif1〗^(-/-)embryos. In the 〖Wif1〗^(-/-) embryos with severe GT outgrowth defects, the Fgf8-expressing distal urethral epithelium, the signaling center in the urorectum, was absent, suggesting that the GT outgrowth defects could be contributed by the loss of dUE-expressing signals such as Fgf8.
This study demonstrated the importance of secretory Wnt inhibitors in the GT outgrowth and cloacal septation and suggested that secretory Wnt inhibitors played partially overlapping roles in urorectal development. A rescue mechanism for cloacal septation performed by Dkk1 upon Wif1 deletion was proposed. Such auto-regulatory mechanism within the Wnt signaling pathway indicated that Wnt inhibitors play essential regulatory roles in the urorectal development and a balanced Wnt signaling activity modulated by Wnt inhibitors is crucial to the development of urorectum.published_or_final_version
Surgery
Master
Master of Philosophy
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Montero, Rosa Maria. "Chemokines and macrophage migration inhibitory factor in diabetic nephropathy." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29851.
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Introduction: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the Western world. Aim: To determine whether macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1) or CC chemokine ligand 18 (CCL18) have a causative role in the development of renal inflammation and fibrosis in DN and are useful biomarkers of disease progression. Methods: Urine and plasma samples were collected from 115 DM and 116 Non-DM at baseline, previously analysed for MCP-1 and CCL18 ELISA by Dr Qureshi. I measured MIF in these samples and collected 107 DM and 114 Non-DM data points (GFR, ACR/UPCR and clinical parameters) at >18 months and >3 years. MIF, MCP-1 and CCL18 urine, plasma and serum analysis was performed in 42 DM and 60 Non-DM at >3 years follow up. Intrinsic renal cells were cultured and stimulated with diabetic conditions. These cytokines and fibronectin were measured in tubuloepithelial cells and podocytes. Results: Baseline plasma CCL18 and MIF predicted a decline in GFR in DM at >18 months but not at >3 years. Cytokine production varies over time with significant correlations at baseline that are not maintained. Cytokines correlate differently with GFR, ACR/UPCR in DM versus Non-DM proteinuric renal diseases. Plasma and serum cytokine levels correlated significantly with no correlation between these and urinary levels. All intrinsic renal cells were able to produce MIF, MCP-1 and CCL18 following stimulation. The interaction of these cytokines and their effects on fibronectin vary in diabetic conditions and following recombinant cytokine stimulation. The diabetic environment appears to orchestrate cytokine signals according to cell type. Conclusion: These results suggest cytokines may play a key role in the pathogenesis and or progression of DN. The clinical study suggests cytokines may predict progression; however, larger studies are needed with samples taken at different time points.
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Davis, Stephanie. "Leukemia Inhibitory Factor as a Neuroprotective Agent against Focal Cerebral Ischemia." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6218.
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Previous publications from this laboratory demonstrated that administration of leukemia inhibitory factor (LIF) (125 µg/kg) to young, male Sprague-Dawley rats at 6, 24, and 48 h after middle cerebral artery occlusion (MCAO) reduced infract volume, improved sensimotor skills, and alleviated damage to white matter at 72 h after the injury. In vitro studies using cultured oligodendrocytes (OLs) showed that LIF (200 ng/ml) also protects against 24 h of oxygen-glucose deprivation through activation of Akt signaling and upregulation of the antioxidant enzymes peroxiredoxin IV and metallothionein III. Other groups have demonstrated that LIF reduces neurodegeneration in animal models of disease, but the neuroprotective mechanisms of LIF during permanent ischemia have not yet been examined. The overall hypothesis to be tested in this project is whether LIF exerts similar protective mechanisms against neurons during ischemia through increased antioxidant enzyme expression in neurons.
In the first set of experiments, superoxide dismutase (SOD) activity was significantly increased in the ipsilateral hemisphere of LIF-treated rats compared to rats that received PBS treatment at 72 h after MCAO. Western blot and immunohistochemical analysis revealed that SOD3 was upregulated in brain tissue and induced specifically in cortical neurons tissue at this time point. Neurons that expressed high levels of SOD3 at 72 h after MCAO also showed high levels of phosphorylated Akt (Ser473). LIF (200 ng/ml) reduced necrotic and apoptotic cell death against 24 h of OGD as measured by lactate dehydrogenase (LDH) release and caspase-3 activation. Quantitative real-time PCR analysis showed that LIF treatment upregulated SOD3 gene expression in vitro during OGD. Treatment with 10 µM Akt Inhibitor IV and transfection with SOD3 siRNA counteracted the neuroprotective effects of LIF in vitro, showing that upregulation of SOD3 and activation of Akt signaling are necessary for LIF-mediated neuroprotection.
Several transcription factors that regulated Akt-inducible genes were previously identified by this lab, including myeloid zinc finger-1 (MZF-1) and specificity protein-1 (Sp1). The goal of the second set of experiments was to determine whether LIF exerted protective actions through MZF-1 and Sp1. According to analysis with Genomatix, MZF-1 and Sp1 have multiple binding sites in the promoter for the rat SOD3 gene. Western blot analysis showed that there was a trend towards increased MZF-1 protein expression in the brains of LIF-treated rats that approached significance. Immunohistochemical analysis and quantitative real-time PCR showed a significant in vitro upregulation in MZF-1 expression among LIF-treated neurons compared to PBS-treated neurons. Sp1 gene expression was not changed by LIF treatment, but there was a trend towards increased protein expression. In addition, there was a significant correlation between Sp1 and MZF-1 among brain samples from LIF-treated rats but not PBS-treated or sham rats at 72 h after MCAO. Immunohistochemical analysis revealed that Sp1 and MZF-1 co-localized with neuronal nuclei and SOD3 at 72 h after MCAO. Neurons that were transfected with MZF-1 or Sp1 siRNA following isolation did not show a significant decrease in LDH release after 24 h OGD that was observed among neurons transfected with scrambled siRNA. These data demonstrate that Sp1 and MZF-1 are involved with the neuroprotective signaling of LIF under ischemia.
This laboratory has demonstrated that LIF activates transcription of protective genes and increases the activity of transcription factors through modulation of intracellular signaling. However, the upstream signaling mechanisms of LIF during ischemia had not previously been investigated. Previous investigators found that the LIF-specific subunit of the heterodimeric LIF receptor (LIFR) is induced by CNS injury. Western blot analysis was used to determine whether LIFR was induced in the brain and the spleen, which plays a role in the peripheral immune response, after MCAO. According to these results, LIF treatment significantly upregulates LIF in the brain compared to PBS treatment or sham injury at 72 h after MCAO. Genomatix analysis of the LIFR promoter region revealed a binding site for Sp1, which is one of the transcription factors responsible for neuroprotection by LIF. At this same time point, splenic LIFR expression is significantly reduced after MCAO compared to sham injury. LIF treatment did not significantly increase LIFR expression, but did significantly increase spleen size compared to PBS treatment at 72 h after MCAO. Although there was a trend towards increased LIFR expression in the spleen from 24 h to 72 h after MCAO, this increase was not statistically significant. However, there was a significant positive correlation between spleen weight and LIFR expression among rats euthanized 24-72 h after MCAO/sham injury. In addition, there was a significant negative correlation between LIFR expression in the brain and the spleen weight, thus showing that LIFR is upregulated following the splenic response.
According to findings from other groups, JAK1 has been shown to associate with the heterodimeric LIF receptor (LIFR/gp130) and directly activate PI3K/Akt signaling. To test whether JAK1 contributes neuroprotection during ischemia, cultured neurons were treated with several concentrations (2.5-50 nM) of GLPG0634, a JAK1-specific inhibitor prior to 24 h of OGD. With the exception of the 2.5 nM concentration, all concentrations of GLPG0634 significantly decreased LDH release compared to DMSO treatment, with the 5 nM concentration having the most potent effect on reducing cytotoxicity. However, the 5 nM concentration had no significant did not significantly reduce LDH release compared to DMSO treatment under 24 h of normoxic conditions. These results indicate that JAK1 activity is primarily detrimental to neurons during ischemia. Although it is possible that LIF signaling activates JAK1, it is unlikely that JAK1 is responsible for LIF-mediated neuroprotection during ischemia.
The results of these experiments allowed us to determine several molecular mechanisms for LIF-mediated neuroprotection. LIF, which binds to its heterodimeric receptor, activates Akt signaling during ischemia. The transcription factors Sp1 and MZF-1, which are located downstream of Akt, bind to the promoter of the SOD3 gene. In addition, Sp1 also regulates the LIFR gene. SOD3 upregulation increases total SOD activity, which decreases apoptotic and necrotic cell death during apoptosis. Due to its ability to promote antioxidant expression and survival signaling in multiple neural cell types, LIF shows promise as a novel treatment for permanent focal cerebral ischemia.
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Chandok, Ravi. "Inhibitory effects on human immunodeficiency virus type-1 by insulin-like growth factor-1." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0002/MQ37103.pdf.
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Russell, Kirsty. "The role of macrophage migration inhibitory factor in airways disease." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/23917.
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Chronic obstructive pulmonary disease (COPD) and severe asthma are progressive chronic inflammatory diseases of the airways. Both diseases are characterised by airflow limitation and share some pulmonary symptoms. However they have distinct inflammatory cell signatures and differ in response to corticosteroid (CS) treatment. Most asthmatic patients control their disease with CS, with a few showing a relative CS resistance; however COPD patients show little or no improvement with CS and are CS insensitive. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory mediator whose function is yet to be fully elucidated. MIF has been shown to counter-act the immunosuppressive action of CS. MIF is elevated in chronic diseases such as asthma and atherosclerosis. The role of MIF in COPD has not been investigated and its role in asthma is not fully understood. MIF inhibition attenuated ozone-induced airway inflammation and lung function in vivo but did not affect CS sensitivity. MIF expression did not vary between stable COPD patients and controls. Pro-inflammatory effects of MIF were investigated in THP-1 monocytes and primary cells. There was no clear role for MIF in LPS-induced inflammation. MIF modulated the transactivation functions of CS in THP-1 cells. Finally I took an unbiased approach to generate new hypotheses for MIF function using proteomic and transcriptomic techniques. The RIG-I-like pathway was identified by proteomics as a novel target pathway and was investigated in THP-1 cells and human BAL macrophage samples following viral infection. The role of MIF in airway inflammation remains unclear and results demonstrated here show MIF function does not necessarily translate from mouse to humans. MIF does not seem to have a role in the inflammation of stable disease. The proteomic data suggests that the association between viral infection, MIF and CS in regulating CS sensitivity in COPD and severe asthma should be investigated.
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Ng, Chun-laam, and 吳圳嵐. "Wnt inhibitory factor 1 (Wif-1) coordinates Shh and Wnt signaling activities in urorectal development." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48329629.
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In vertebrates, the urogenital sinus and the hindgut are connected at a hollow region called cloaca. A midline mesenchymal structure known as urorectal septum (urs) descends from the ventral body wall to separate the urogenital sinus from the hindgut before the formation of an anal opening. Subsequent cloaca membrane regression at the ventral midline of the genital tubercle (GT) is crucial for the formation of an anal opening. These two events are important during cloaca septation in urorectal development.
Mice with defective Shh or Wnt signaling displayed similar urorectal defects such as GT agenesis, un-partitioned cloaca (persistent cloaca) and proximal urethral opening that are attributable to increased cell apoptosis. Furthermore, Shh and Wnt signal transduction coordinate with each other and regulate cell survival of the developing urorectum. However, the molecular mechanisms by which these two signaling pathways coordinate in urorectal development remain unclear.
We previously identified Wnt inhibitory factor1 (Wif1) from Affymetrix array analysis for genes/pathways that is implicated in urorectal development. Wif1 is a secreted protein that binds directly to Wnt ligands preventing Wnts from binding to receptors. This leads to -catenin degradation and thereby inhibits their activities. It is known that Wif1 binds to Wnt3a and Wnt5a with high affinity and deletion of Wnt3a, Wnt5a and -catenin in mice caused GT agenesis, persistent cloaca and proximal hypospadias. Using ETU-induced anorectal malformations model, I found out that Wif1 is ectopically expressed in the un-tubularized and un-septated urorectum. Wif1 is mainly expressed at the fusing endoderm that associates with programmed cell death during cloaca septation. Exogenous addition of Wif1 protein in urorectum culture also caused cloaca membrane disintegration, and proximal urethral opening that may be due to aberrant apoptosis.
Shh and Wif1 are differentially expressed at the cloaca endoderm. In normal mice, Shh is highly expressed at the cloaca endoderm except those Wif1-expressing endodermal cells. Blockage of Shh pathway by cyclopamine in urorectum culture induced ectopic expression of Wif1, concomitant with genital tubercle hypoplasia and un-septated cloaca. More importantly, deletion of Shh in mice hastened Wif1 expression at the cloaca membrane endoderm and elicited increased cell death in the
Wif1 expressing endoderm. Wif1-/- embryos display urorectal defects including delayed genital outgrowth and proximal hypospadias. Therefore, disruption of spatiotemporal expression of Wif1 could lead to defective Wnt signaling and contributes to abnormal urorectal development in Shh-/- mutant.
Current study revealed that Wif1 is involved in urorectal development and is implicated in urorectal defects. It may function as a pro-apoptotic factor to regulate endodermal cell death which is essential for the septation process. Its specific expression is restricted at the midline cloaca endoderm by Shh signaling to inhibit local Wnt--catenin activities during cloaca septation. I proposed novel hypothetical models to explain (1) the significance of the tempo-spatial expression of Wif1; (2) the significance of cell death; and (3) the molecular mechanism that Shh signaling regulates Wnt signaling activities through Wif1 in urorectal development.published_or_final_version
Surgery
Doctoral
Doctor of Philosophy
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Cavalli, Eugenio. "Role for Macrophage Migration Inhibitory Factor in Multiple Sclerosis." Doctoral thesis, Università di Catania, 2017. http://hdl.handle.net/10761/3800.
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Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays an important role in the pathogenesis of numerous inflammatory and autoimmune disorders. As such, it is an attractive therapeutic target for the treatment of these disorders. . Several data suggest a key role of MIF in the pathogenesis of Multiple Sclerosis (MS). In mice with EAE, an animal model of MS, MIF was found to be upregulated in the affected tissue . Immunoneutralization or genetic depletion of MIF reduced the severity of the disease by impairing the migration of autoreactive T cells to the CNS and downregulating the inflammatory cytokine production and the inhibition of MIF actions by usage of neutralizing anti-MIF antibodies has also proven therapeutically effective. However, more potent and specific inhibitors targeting MIF or its downstream effects are needed for the development of novel pharmaceutical therapies for MIF- associated diseases, such as MS.
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Lerouley, Orane. "Étude du rôle métabolique du peptide inhibiteur de l'ATP synthase IF1, en conditions physiologique et pathologique." Electronic Thesis or Diss., Bordeaux, 2024. https://theses.hal.science/tel-04887979.
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La F1F0 ATP-synthase est une machinerie multi-protéique permettant la transduction de l'énergie d'un gradient électrochimique en énergie chimique sous forme d’ATP. Ce complexe protéique est enchâssé dans la membrane interne mitochondriale de par son domaine Fo, lui-même physiquement associé à un secteur catalytique intra-mitochondrial, le domaine F1. Cette enzyme mitochondriale joue un rôle primordial dans le métabolisme énergétique. L'ATP synthase de levure, comme celle du mammifère, sont des enzymes réversibles dont l’activité hydrolytique est régulée par un inhibiteur endogène : IF1. Un deuxième peptide inhibiteur, STF1, a été identifié, uniquement chez la levure. L’inhibition de l’ATP synthase par IF1/STF1 est dépendante du pH, par conséquent ces inhibiteurs sont inactifs dans des conditions physiologiques où la mitochondrie est polarisée, mais sont actifs dans des conditions pathologiques de dépolarisation. Pour autant, l’importance métabolique et physiopathologique d’IF1/STF1 a été remise en question par les modèles levures et murins démontrant que la perte de cet inhibiteur n’a quasiment aucune incidence sur le métabolisme ou la physiologie de ces organismes. Mon travail de thèse a permis d’étudier des mécanismes d’action de cet inhibiteur sur l’ATP synthase associés ou non à des stress énergétiques affectant l’état de polarisation mitochondrial. Mon travail a permis de mettre en évidence un nouveau mécanisme d’action d’IF1/STF1 dans la stabilité et la maintenance du sous-assemblage de l’ATP synthase, le F1 libre (domaine soluble F1 non associé au domaine F0). La présence de ce domaine catalytique déconnecté de la force protomotrice, constitue une réelle menace énergétique. En effet, la toxicité énergétique potentielle du F1 libre est donc soit inhibée par l’action directe d’IF1/STF1, soit prévenue en absence d’IF1/STF1 par l’instabilité et la disparition physique de ce sous-complexe. Mes travaux de thèses ont de plus permis de définir que l’action d’IF1/STF1 était particulièrement cruciale dans des conditions métaboliques dites glyco-oxydatives spécifiquement observées en milieu glycérol. Dans ces conditions, la prolifération cellulaire et la maintenance du potentiel phosphate sont placés sous la co-dépendance de l’ATP synthase et des phosphorylations par le substrat des kinases glycolytiquesF1Fo ATP synthase is a multi-protein machinery that converts the energy of an electrochemical gradient into chemical energy in the form of ATP. This protein complex is anchored in the mitochondrial inner membrane by its Fo sector, which is itself physically associated with an intra-mitochondrial F1 catalytic sector. This mitochondrial enzyme plays a key role in energy metabolism. Yeast and mammalian ATP synthase, are reversible enzymes and this hydrolytic activity is regulated by an endogenous inhibitor: IF1. In yeast, another inhibitor peptide, STF1, has been identified. Inhibition of ATP synthase by IF1/STF1 is pH-dependent, so these inhibitors are inactive under physiological conditions where mitochondrial are polarised, but IF1/STF1 are particularly active under pathological conditions of depolarisation. Intriguingly, the metabolic and pathophysiological importance of IF1/STF1 has been challenged by yeast and mouse models showing that the loss of this inhibitor has almost no detectable impact on the metabolism or physiology of these organisms. My thesis work investigated the mechanisms of action of these inhibitors on ATP synthase, associated or not with energy stresses affecting the mitochondrial polarization state. My work has highlighted a new mechanism of action for IF1 by demonstrating that it controls the stability and maintenance of the ATP synthase sub-assembly, the free F1 (soluble F1 sector not associated with the F0 sector). The presence of this catalytic sector, disconnected from the proton motor force, represents a serious energetic threat. The potential energetic toxicity of free F1 is annihilated through two mechanisms: (i) the direct canonical inhibition of IF1/STF1, or (ii) the instability and physical disappearance of free F1 in absence of IF1/STF1. My thesis work also defined that the action of IF1/STF1 was particularly crucial under mitochondrial depolarization stress conditions in glyco-oxidative metabolism observed in glycerol medium. Under these conditions, the phosphate potential is co-dependent on ATP synthase and substrate phosphorylation of glycolytic kinases, and cell proliferation under depolarisation stress relies on IF1/STF1 activity
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Leduc, Katy. "Influence du facteur gestationnel leukemia inhibitory factor sur la différenciation cellulaire d'un modèle de trophoblaste humain." Thèse, Université du Québec à Trois-Rivières, 2011. http://depot-e.uqtr.ca/2696/1/030294663.pdf.
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Subang, Maria Cristina. "The regulation of ciliary neurotrophic factor, leukemia inhibitory factor and monocyte chemoattractant protein-1 in injured peripheral nervous tissue." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0034/NQ64675.pdf.
Full textBooks on the topic "Inhibitory factor 1"
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Harris, James, and Eric F. Morand, eds. Macrophage Migration Inhibitory Factor. New York, NY: Springer US, 2020. http://dx.doi.org/10.1007/978-1-4939-9936-1.
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Aledort, Louis M., Leon W. Hoyer, Jeanne M. Lusher, Howard M. Reisner, and Gilbert C. White, eds. Inhibitors to Coagulation Factors. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4613-0331-2.
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Phuong, My Tran. "Anthrapyrazole cysteinyl peptides as inhibitors of AP-1 transcription factor binding". Leicester: De Montfort University, 1998.
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Fleischmann, Roy. Signalling pathway inhibitors. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0081.
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Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and SyK pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Tofacitinib is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2 while baricitinib (formerly INCB028050) predominantly inhibits JAK1/2. Many of the proinflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Fostamatinib disodium is an orally available inhibitor of spleen tyrosine kinase (SyK), which is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling may interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib has been investigated in multiple phase 2 and phase 3 trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα) and in patients who have failed TNFα inhibitors. The efficacy of fostamatinib and baricitinib has been investigated in phase 2 trials; both are in large phase 3 clinical programmes. Each of these medications has demonstrated efficacy; their safety profile has been shown to be different from each other and from currently approved biological agents. This chapter discusses what is currently known and understood about their efficacy and safety.
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Nielsen, David A., Dmitri Proudnikov, and Mary Jeanne Kreek. The Genetics of Impulsivity. Edited by Jon E. Grant and Marc N. Potenza. Oxford University Press, 2012. http://dx.doi.org/10.1093/oxfordhb/9780195389715.013.0080.
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Impulsivity is a complex trait that varies across healthy individuals, although when excessive, it is generally regarded as dysfunctional. Impulsive behavior may lead to initiation of drug addiction that interferes with inhibitory controls, which may in turn result in facilitation of the individual’s impulsive acts. Although environmental factors play a considerable role in impulsive behavior, a body of evidence collected in twin studies suggests that about 45% of the variance in impulsivity is accounted for by genetic factors. Genetic variants studied in association with impulsivity include those fortryptophan hydroxylase 1 and 2 (TPH1 and TPH2), the serotonintransporter (SERT), serotonin receptors, and genes of the monoamine metabolism pathway (e.g., monoamine oxidase A, MAOA). Other systems may also play a role in these behaviors, such as the dopaminergic system (the dopamine receptors DRD2, DRD3, and DRD4, and the dopamine transporter, DAT), the catecholaminergic system (catechol-O-methyltransferase, COMT), and the GABAergic system (GABAreceptor subunit alpha-1, GABRA1; GABA receptor subunit alpha-6, GABRA6; and GABA receptor subunit beta-1, GABRB1). Taking into account involvement of the hypothalamic-pituitary-adrenal (HPA) axis, the number of candidate genes implicated in impulsivity may be increased significantly and, therefore, may go far beyond those of serotonergic and dopaminergic systems. For a number of years, our group has conducted studies of the association of genes involved in the modulation of the stress-responsive HPA axis and several neurotransmitter systems, all involved in the pathophysiology of anxiety and depressive disorders, impulse control and compulsive disorders, with drug addiction. These genes include those of the opioid system: the mu- and kappa-opioid receptors (OPRM1 and OPRK1) and the nociceptin/orphaninFQ receptor (OPRL1); the serotonergic system: TPH1 and TPH2 and the serotonin receptor 1B (5THR1B); the catecholamine system: COMT; the HPA axis: themelanocortin receptor type 2 (MC2R or adrenocorticotropic hormone, ACTHR); and the cannabinoid system: the cannabinoid receptor type 1 (CNR1). In this chapter we will focus on these findings.
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Ralston, Stuart H. Paget’s disease of bone. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0144.
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Paget's disease of bone (PDB) affects up to 1% of people of European origin aged 55 years and above. It is characterized by focal abnormalities of bone remodelling which disrupt normal bone architecture, leading to expansion and reduced mechanical strength of affected bones. This can lead to various complications including deformity, fracture, nerve compression syndromes, and osteoarthritis, although many patients are asymptomatic. Genetic factors play a key role in the pathogenesis of PDB. This seems to be mediated by a combination of rare genetic variants which cause familial forms of the disease and common variants which increase susceptibility to environmental triggers. Environmental factors which have been suggested to predispose to PDB include viral infections, calcium and vitamin D deficiency, and excessive mechanical loading of affected bones. The diagnosis can be made by the characteristic changes seen on radiographs, but isotope bone scans are helpful in defining disease extent. Serum alkaline phosphatase levels can be used as a measure of disease activity. Inhibitors of bone resorption are the mainstay of medical management for PDB and bisphosphonates are regarded as the treatment of choice. Bisphosphonates are highly effective at reducing bone turnover in PDB and have been found to heal osteolytic lesions, and normalize bone histology. Although bisphosphonates can improving bone pain caused by elevated bone turnover, most patients require additional therapy to deal with symptoms associated with disease complications. It is currently unclear whether bisphosphonate therapy is effective at preventing complications of PDB.
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Ralston, Stuart H. Paget’s disease of bone. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199642489.003.0144_update_001.
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Paget’s disease of bone (PDB) affects up to 1% of people of European origin aged 55 years and above. It is characterized by focal abnormalities of bone remodelling which disrupt normal bone architecture, leading to expansion and reduced mechanical strength of affected bones. This can lead to various complications including deformity, fracture, nerve compression syndromes, and osteoarthritis, although many patients are asymptomatic. Genetic factors play a key role in the pathogenesis of PDB. This seems to be mediated by a combination of rare genetic variants which cause familial forms of the disease and common variants which increase susceptibility to environmental triggers. Environmental factors which have been suggested to predispose to PDB include viral infections, calcium and vitamin D deficiency, and excessive mechanical loading of affected bones. The diagnosis can be made by the characteristic changes seen on radiographs, but isotope bone scans are helpful in defining disease extent. Serum alkaline phosphatase levels can be used as a measure of disease activity. Inhibitors of bone resorption are the mainstay of medical management for PDB and bisphosphonates are regarded as the treatment of choice. Bisphosphonates are highly effective at reducing bone turnover in PDB and have been found to heal osteolytic lesions, and normalize bone histology. Although bisphosphonates can improving bone pain caused by elevated bone turnover, most patients require additional therapy to deal with symptoms associated with disease complications. It is currently unclear whether bisphosphonate therapy is effective at preventing complications of PDB.
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Gnudi, Luigi, Giorgio Gentile, and Piero Ruggenenti. The patient with diabetes mellitus. Edited by Giuseppe Remuzzi. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0149_update_001.
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About one third of patients with type 1 diabetes develop diabetic nephropathy long-term (usually not before at least 10 years of diabetes), though this proportion is falling as standards of care have risen. Nephropathy is strongly associated with other microvascular complications of diabetes, so that some degree of retinopathy is to be expected, and evidence of neuropathy is common. Patients with type 2 diabetes are equally susceptible, but this is an older group in which vascular disease and other pathologies are also more likely. The rise in type 2 diabetes accounts for diabetes being the most common recorded cause of end stage renal disease (ESRD) in the developed world.Diabetic nephropathy is characterized by a progression through hyperfiltration, microalbuminuria, hypertension, overt proteinuria, nephrotic syndrome, loss of GFR, to ESRD. Risk factors for developing it include genetic factors (though no major single gene effects have been identified), and quality of glycaemic control.The risk of progression can at early stages be reduced by improved glycaemic control, and control of hypertension also slows progression. However angiotensin converting enzyme inhibitors or receptor blockers (ACEi, ARB) are the standard of care for patients with microalbuminuria or overt proteinuria, as they have been shown to reduce the risk of renal endpoints. Combination therapy with both ACEi and ARB together has been associated with a high risk of AKI, hyperkalaemia and other adverse effects so is not generally recommended. Other promising agents in combination are under investigation but none adequately proven at this stage.Patients who reach ESRD have reduced survival on all modalities compared to age-matched patients with other diagnoses. Best rehabilitation and survival for those who are suitable is through renal transplantation, though combined pancreas-renal transplantation may offer still better outcomes for selected patients.
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Ferro, Charles J., and Khai Ping Ng. Recommendations for management of high renal risk chronic kidney disease. Edited by David J. Goldsmith. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0099.
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Poorer renal function is associated with increasing morbidity and mortality. In the wider population this is mainly as a consequence of cardiovascular disease. Renal patients are more likely to progress to end-stage renal disease, but also have high cardiovascular risk. Aiming to reduce both progression of renal impairment and cardiovascular disease are not contradictory. Focusing on the management of high-risk patients with proteinuria and reduced glomerular filtration rates, it is recommended that blood pressure should be kept below 140/90, or 130/80 if proteinuria is > 1 g/24 h (protein:creatinine ratio (PCR) >100 mg/mmol or 0.9 g/g). These targets may be modified according to age and other factors. Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor antagonists should form part of the therapy for patients with proteinuria > 0.5 g/24 h (PCR > 50 mg/mmol or 0.45 g/g). Use of ACEIs or angiotensin receptor blockers in patients with lower levels of proteinuria may be indicated in some patient groups even in the absence of hypertension, notably in diabetic nephropathy. Evidence that other agents that reduce proteinuria bring additional benefits is weak at present. The best studies of ‘dual-blockade’ with various combinations of ACEIs, ARBs, and renin inhibitors have shown additional hazard with little evidence of additional benefit. Hyperlipidaemia—regardless of lipid levels, statin therapy is indicated in secondary cardiovascular prevention, and in primary prevention where cardiovascular risk is high, noting that current risk estimation tools do not adequately account for the increased risk of patients with CKD. There is not substantial evidence that lipid lowering therapy impacts on average rates of loss of GFR in progressive CKD. Non-drug lifestyle interventions to reduce cardiovascular risk, including stopping smoking, are important for all. Acidosis—in more advanced CKD it is justified to treat acidosis with oral sodium bicarbonate. Diet—sodium restriction to < 100 mmol/day (6 g/day) and avoidance of excessive dietary protein are justified in early to moderate CKD. Recommendations to limit levels of protein to 0.8 g/kg body weight are suggested by some, but additional protective effects of this are likely to be slight in patients who are otherwise well managed. Low-protein diets may carry some risk. Lower-protein diets may however be used to prevent symptoms in advanced CKD not treated by dialysis.
Book chapters on the topic "Inhibitory factor 1"
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Hoffmann, Adrian, Leon Christian Zwißler, Omar El Bounkari, and Jürgen Bernhagen. "Studying the Pro-Migratory Effects of MIF." In Macrophage Migration Inhibitory Factor, 1–18. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_1.
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Abidi, Jawad H., James Harris, and Nadia S. Deen. "Co-Immunoprecipitation of Macrophage Migration Inhibitory Factor." In Macrophage Migration Inhibitory Factor, 115–22. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_10.
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Graham, Amanda, and Warren B. Nothnick. "Concurrent Immunohistochemical Localization and Western Blot Analysis of the MIF Receptor, CD74, in Formalin-Fixed, Paraffin-Embedded Tissue." In Macrophage Migration Inhibitory Factor, 123–34. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_11.
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Gu, Ran. "Methods to Determine the Effects of MIF on In Vitro Osteoclastogenesis Using Murine Bone Marrow-Derived Cells and Human Peripheral Blood Mononuclear Cells." In Macrophage Migration Inhibitory Factor, 135–45. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_12.
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Deen, Nadia S., Jacinta P. Lee, and James Harris. "Inducing and Inhibiting Autophagy to Investigate Its Interactions with MIF." In Macrophage Migration Inhibitory Factor, 147–58. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_13.
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Pinar, Anita A., and James Harris. "Assays for Measuring the Role of MIF in NLRP3 Inflammasome Activation." In Macrophage Migration Inhibitory Factor, 159–72. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_14.
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Zamani, Shahrzad, Eric F. Morand, and Jacqueline K. Flynn. "Assays for Inducing and Measuring Cell Death to Detect Macrophage Migration Inhibitory Factor (MIF) Release." In Macrophage Migration Inhibitory Factor, 173–83. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_15.
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Aitken, Elizabeth H. "Assessing the Role of MIF in Plasmodium spp. Infections Using Ex Vivo Models." In Macrophage Migration Inhibitory Factor, 185–92. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_16.
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Vujičić, Milica, Sanja Despotović, Tamara Saksida, and Ivana Stojanović. "The Effect of Macrophage Migration Inhibitory Factor on Intestinal Permeability: FITC-Dextran Serum Measurement and Transmission Electron Microscopy." In Macrophage Migration Inhibitory Factor, 193–201. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_17.
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Allam, Venkata Sita Rama Raju, and Maria B. Sukkar. "Investigating MIF in Mouse Models of Severe Corticosteroid-Resistant Neutrophilic Asthma." In Macrophage Migration Inhibitory Factor, 203–12. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_18.
Full textConference papers on the topic "Inhibitory factor 1"
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Babaer, Duaa A., and Xiaofei Wang. "Abstract 4604: Activities ofin vitroprepared recombinant wnt inhibitory factor-1 (Wif-1)." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4604.
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Furmaniak-Kazmierczak, E., J. Jagielski, and T. Wilusz. "THE EFECT OF CMTI-I INHIBITOR ON HUMAN BLOOD CLOTTING SYSTEM." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644327.
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Polipeptyde inhibitors for different serine proteases have been isolated from a variety of plants. Among them there are the inhibitors from squash seeds of molecular weight about 3 300 /1/. The experiments were carried out to determine the effect of one of the squash inhibitors /CMTI-I/ on human blood clotting system. The 0.1 ml of inhibitor /O,8-100 ug/ was added to 0,1 ml of normal intact plasma and incubated 0,5, 15, 30 and 60 minutes at 37°C. It was found that partial tromboplastin time /PTT/ and activated partial thromboplastin time /APTT/ were prolonged. CMTI-I did not show a progressive mode of action upon prolonged time of incubation. There was no effect of CMTI-I on prothrombin time /PT/, thrombin time /TT/ and Stypven-cephalin time /ScT/. The influence of CMTI-I on APTT of factor-XII and factor-XI deficient plasmas as well as on a plasma without factor-XII and factor-XI /exhausted plasma/ was studied. The APTTs of the factor-XII and factor-XI deficient plasmas were prolonged while the APTT of the "exhausted plasma" was unchanged. The performed experiments shown that CMTI-I inhibitor blocks the clot-promoting activity of contact activated plasma. This inhibitory action is stronger in the case of factor XI than of factor XII.1. Wieczorek M., et al., 1985, Biochem. Biophys. Res. Commun. 126:646-652.
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Ramachandran, Ilangovan, David Obeso, Antonio Reis, and Lurdes Queimado. "Abstract 5625: Wnt inhibitory factor 1 is a potent growth inhibitory agent for salivary gland tumor cells." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-5625.
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Ramachandran, Ilangovan, Satish Ramalingam, Gopalan Natarajan, Wilbur K. Mills, Shrikant Anant, Antonio M. C. Reis, and Lurdes Queimado. "Abstract 3055: Wnt inhibitory factor 1 inhibits cervical cancer cell growthin vitro." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-3055.
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Womble, J. T., V. Mcquade, H. Kim, M. D. Ihrie, R. M. Tighe, L. G. Que, M. Sauler, and J. L. Ingram. "Glucagon Like Peptide-1 Receptor Signaling Suppresses Pulmonary Macrophage Migration Inhibitory Factor and CD74 Expression." In American Thoracic Society 2023 International Conference, May 19-24, 2023 - Washington, DC. American Thoracic Society, 2023. http://dx.doi.org/10.1164/ajrccm-conference.2023.207.1_meetingabstracts.a3012.
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Ofosu, F. A., G. J. Modi, M. R. Buchanan, J. Hirsh, and M. A. Blajchman. "HEPARIN IS NOT AN EFFICIENT INHIBITOR OF THE FACTOR Xa-DEPENDENT ACTIVATION OF FACTOR V AND FACTOR VIII." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642931.
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We have previously proposed that the steps in coagulation most sensitive to inhibition by heparin are the thrombin-dependent activation of factor V and factor VIII. This observation was based on the demonstration that therapeutic concentrations of heparin or 1μM of the thrombin specific inhibitor, phe-pro-arg CH2Cl (PPACK) completely inhibited the activation of prothrombin when contact-activated plasma (CAP) was recalcified for up to 1 min. Under similar conditions, heparin and PPACK only partially inhibited the activation of factor X. Moreover, the addition of thrombin (lOnM) to CAP 1 min before that of heparin or PPACK reversed their inhibitory effects. We now provide further support for our hypothesis by showing that when the activity of thrombin is suppressed by heparin or PPACK, efficient activation of radiolabelled prothrombin occurs only when the factor Xa then present activates factor V and factor VIII. We compared the effects of HEP of PPACK on the following four systems for initiating the activation of prothrombin: (1) CAP; (2) CAP + lOnM thrombin; (3) CAP + InM Xa and (4) unactivated plasma + InM Xa + InM Va + coagulant phospholipids. In each system, the enzymes were added 1 min before the heparin or PPACK. In the absence of heparin or PPACK, all four systems generated the same amount of thrombin activity in 45s. Complete inhibition of prothrombin activation by heparin and PPACK was observed only in system 1 which did not contain exogenous thrombin or factor Xa. No inhibition by heparin or PPACK was observed when thrombin or factor Xa was added to CAP in systems (2) and (3). Only partial inhibition was observed in system (4) which contained exogenous prothrombi-nase complex. Factor Xa thus provides an effective by-pass mechanism for the activation of factor VIII and factor V in plasma containing therapeutic concentrations of heparin. Our data provide further evidence that the heparin-antithrombin III system is not effective in inactivating factor Xa. These results support the hypothesis that in unactivated normal plasma, the primary anticoagulant effect of heparin is the inhibition of the thrombin-dependent activation of factor V and factor VIII.
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Tymecka, Dagmara, Patrycja Redkiewicz, Piotr F. J. Lipinski, and Aleksandra Misicka. "Inhibitory activity and proteolytic stability in human serum of peptide inhibitors of the Vascular Endothelial Growth Factor A165/Neuropilin-1 complex." In 37th European Peptide Symposium, 1112. The European Peptide Society, 2024. http://dx.doi.org/10.17952/37eps.2024.p1112.
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Vassallo, Irene, Wanyu Lambiv, Mauro Delorenzi, Tal Shay, Annie-Claire Diserens, Anjan Misra, Burt Feuerstein, et al. "Abstract 2117: The Wnt inhibitory factor 1 (WIF-1) has tumor suppressing functions in glioblastoma potentially by inducing cellular senescence." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2117.
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Lang, T., J. Lee, A. Pinar, H. Fan, A. Mansell, E. Morand, and J. Harris. "344 Linking macrophage migration inhibitory factor and nlrp3 in the pathogenesis of il-1 dependent inflammatory disorders." In LUPUS 2017 & ACA 2017, (12th International Congress on SLE &, 7th Asian Congress on Autoimmunity). Lupus Foundation of America, 2017. http://dx.doi.org/10.1136/lupus-2017-000215.344.
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Ramachandran, Ilangovan, Vengatesh Ganapathy, and Lurdes Queimado. "Abstract 5274: Wnt inhibitory factor 1 reduces the growth and migration of human adenoid cystic carcinoma cells." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-5274.
Full textReports on the topic "Inhibitory factor 1"
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Beavers, Gui, and Sridhar. PR-186-073508-R01 Environmental and Stress Factors that Produce SCC in Existing Ethanol Facilities. Chantilly, Virginia: Pipeline Research Council International, Inc. (PRCI), February 2011. http://dx.doi.org/10.55274/r0010441.
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The potential exists for stress corrosion cracking (SCC) of carbon steel pipelines transporting fuel grade ethanol (FGE) and FGE- gasoline blends. The objective of SCC 4-3 Phase 2 was determine if inhibitors are effective in preventing SCC growth under more realistic field conditions than those found in the slow strain rate (SSR) tests performed previously. The results of the research demonstrated that: 1. Un-notched SSR test results generally correlated well with the results of the crack growth tests using precracked CT specimens, although the latter test technique was somewhat more aggressive. 2. The notched SSR test technique was so aggressive that it was not useful for screening SCC inhibitors. 3. E-50, prepared with a simulated FGE was consistently more potent as a cracking agent than SFGE. 4. Some commercial inhibitors were effective in inhibiting ethanol SCC under many of the test conditions. 5. The commercial inhibitors, in general, were less effective in E-50 than in SFGE. 6. Ammonium hydroxide, at a relatively low concentration, was by far the most effective inhibitor evaluated. 7. For one commercial inhibitor, a higher concentration was needed to inhibit SCC in one lot of corn based FGE than in SFGE. 8. Water inhibited, but did not completely arrest, SCC in the crack growth tests in SFGE. 9. Sustained crack growth was observed in SFGE in which no chloride was added. 10. Evidence of loss of inhibition, at low concentrations, was observed in an inhibition scheme for batching of FGE with gasoline in which a high initial dose, followed by a low maintenance dose was used.
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Sisler, Edward C., Raphael Goren, and Akiva Apelbaum. Controlling Ethylene Responses in Horticultural Crops at the Receptor Level. United States Department of Agriculture, October 2001. http://dx.doi.org/10.32747/2001.7580668.bard.
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Ethylene is a plant hormone that controls many plant responses, such as growth, senescence, ripening, abscission and seed germination. Recently, 1-methy- cyclopropene (1-MCP), was shown to bind to ethylene receptor for a certain period of time and prevent ethylene action. The objectives of this research were to synthesize analogues of 1-MCP and test their potency to block the ethylene receptor and inhibit ethylene action. During the course of this project, procedures for synthesis and shipment of the cyclopropene compounds were developed as well assay procedures for each compound were worked out. Thirteen new compounds were synthesized. All of them are structural analogues of 1-MCP, with substitution in the 1-position and a side chain containing 2 to 10 carbons. After preliminary studies, nine promising compounds were selected for in-depth study. The potency of the compounds to inhibit ethylene action was tested on a wide scope of systems like: climacteric fruits (banana, avocado and tomato), the triple response (etiolated peas), and leaf abscission (citrus). As the putative inhibitors are suspected to compete for the site of binding and a competitive type of inhibition could be considered, a high concentration of ethylene (300 m1.L-1) was used to induce ripening and other physiological processes. The tests were conducted under extreme conditions which hasten ripening like treatment and storage at 22 to 25oC. There were fluctuations in the responses as related to the concentrations of the inhibitors. Some required much higher concentration to exert the same effect, while some, when applied at the same concentration, blocked the receptor for a longer period of time than the others. Some fruits and other plant organs responded differently to the same inhibitor, indicating differences in characteristics and availability of the ethylene receptors in the various tissues. The potency of the putative inhibitors was found to be greatly affected by their molecular structural and size. In addition, it was found that treatment with the inhibitor should be given before the onset of ethylene action In the case of fruit, treatment should be carried out before the pre-climacteric stage. Simultaneous treatment with ethylene and the inhibitors reduced the inhibitors' effect. The relationship between ethylene and the inhibitors is of a non-competitive nature. All the fruits treated with the putative inhibitors resumed normal ripening after recovery from the inhibition. This fact is of great importance when considering the inhibitors for practical use. The advantage of using inhibitors of ethylene action over inhibitors of ethylene production lies in the ability of the inhibitors of ethylene action to protect the tissue against both endogenous and exogenous ethylene, thus providing better overall protection. Our findings indicate that 1-MCP and its structural analogues are potent inhibitors of ethylene action capable of providing good protection against endogenous and exogenous ethylene. The fact that the compounds are in a gas phase and are non-phytotoxic, odorless and effective at minute concentrations, renders them promising candidates for commercial use. However, the development of water-soluble inhibitors will expand the potential use of the inhibitors in agriculture.
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Song, Xiaoling. Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors. Office of Scientific and Technical Information (OSTI), January 2010. http://dx.doi.org/10.2172/1048513.
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Kazi, Armina A. Investigating the Regulation and Potential Role of Nonhypoxic Hypoxia-Inducible Factor 1 (HIF-1) in Aromatase Inhibitor Resistant Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, October 2012. http://dx.doi.org/10.21236/ada568100.
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Kazi, Armina A. Investigation the Regulation and Potential Role of Nonhypoic Hypoxia-Inducible Factor 1 (HIF-1) in Aromatase Inhibitor-Resistant Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, October 2014. http://dx.doi.org/10.21236/ada625486.
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Droby, Samir, Michael Wisniewski, Martin Goldway, Wojciech Janisiewicz, and Charles Wilson. Enhancement of Postharvest Biocontrol Activity of the Yeast Candida oleophila by Overexpression of Lytic Enzymes. United States Department of Agriculture, November 2003. http://dx.doi.org/10.32747/2003.7586481.bard.
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Enhancing the activity of biocontrol agents could be the most important factor in their success in controlling fruit disease and their ultimate acceptance in commercial disease management. Direct manipulation of a biocontrol agent resulting in enhancement of diseases control could be achieved by using recent advances in molecular biology techniques. The objectives of this project were to isolate genes from yeast species that were used as postharvest biocontrol agents against postharvest diseases and to determine their role in biocontrol efficacy. The emphasis was to be placed on the yeast, Candida oleophila, which was jointly discovered and developed in our laboratories, and commercialized as the product, Aspire. The general plan was to develop a transformation system for C . oleophila and either knockout or overexpress particular genes of interest. Additionally, biochemical characterization of the lytic peptides was conducted in the wild-type and transgenic isolates. In addition to developing a better understanding of the mode of action of the yeast biocontrol agents, it was also our intent to demonstrate the feasibility of enhancing biocontrol activity via genetic enhancement of yeast with genes known to code for proteins with antimicrobial activity. Major achievements are: 1) Characterization of extracellular lytic enzymes produced by the yeast biocontrol agent Candida oleophila; 2) Development of a transformation system for Candida oleophila; 3) Cloning and analysis of C.oleophila glucanase gene; 4) Overexpression of and knockout of C. oleophila glucanase gene and evaluating its role in the biocontrol activity of C. oleophila; 5) Characterization of defensin gene and its expression in the yeast Pichiapastoris; 6) Cloning and Analysis of Chitinase and Adhesin Genes; 7) Characterization of the rnase secreted by C . oleophila and its inhibitory activity against P. digitatum. This project has resulted in information that enhanced our understanding of the mode of action of the yeast C . oleophila. This was important step towards enhancing the biocontrol activity of the yeast. Fungal cell wall enzymes produced by the yeast antagonist were characterized. Different substrates were identified to enhance there production in vitro. Exo-b-1, 3 glucanase, chitinase and protease production was stimulated by the presence of cell-wall fragments of Penicillium digitatum in the growing medium, in addition to glucose. A transformation system developed was used to study the role of lytic enzymes in the biocontrol activity of the yeast antagonist and was essential for genetic manipulation of C . oleqphila. After cloning and characterization of the exo-glucanase gene from the yeast, the transformation system was efficiently used to study the role of the enzyme in the biocontrol activity by over-expressing or knocking out the activity of the enzyme. At the last phase of the research (still ongoing) the transformation system is being used to study the role of chitinase gene in the mode of action. Knockout and over expression experiments are underway.
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Dudley, Lynn M., Uri Shani, and Moshe Shenker. Modeling Plant Response to Deficit Irrigation with Saline Water: Separating the Effects of Water and Salt Stress in the Root Uptake Function. United States Department of Agriculture, March 2003. http://dx.doi.org/10.32747/2003.7586468.bard.
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Standard salinity management theory, derived from blending thermodynamic and semi- empirical considerations leads to an erroneous perception regarding compensative interaction among salinity stress factors. The current approach treats matric and osmotic components of soil water potential separately and then combines their effects to compute overall response. With deficit water a severe yield decrease is expected under high salinity, yet little or no reduction is predicted for excess irrigation, irrespective of salinity level. Similarly, considerations of competition between chloride and nitrate ions have lead to compensation hypothesis and to application of excess nitrate under saline conditions. The premise of compensative interaction of growth factors behind present practices (that an increase in water application alleviates salinity stress) may result in collateral environmental damage. Over-irrigation resulting in salinization and elevated ground water threatens productivity on a global scale. Other repercussions include excessive application of nitrate to compensate for salinity, unwillingness to practice deficit irrigation with saline water, and under-utilization of marginal water. The objectives for the project were as follows: 1) To develop a database for model parameterization and validation by studying yield and transpiration response to water availability, excessive salinity and salt composition. 2) To modify the root sink terms of an existing mechanism-based model(s) of water flow, transpiration, crop yield, salt transport, and salt chemistry. 3) To develop conceptual and quantitative models of ion uptake that considers the soil solution concentration and composition. 4) To develop a conceptual and quantitative models of effects of NaCl and boron accumulation on yield and transpiration. 5) To add a user interface to the water flow, transpiration, crop yield, salt transport, chemistry model to make it easy for others to use. We conducted experiments in field plots and lysimeters to study biomass production and transpiration of com (Zeamays cv. Jubilee), melon (Cucumismelo subsp. melo cv. Galia), tomato (Lycopersiconesculentum Mill. cv. 5656), onion (Alliumcepa L. cv. HA 944), and date palms (Phoenix Dactylifera L. cv. Medjool) under salinity combined with water or with nitrate (growth promoters) or with boron (growth inhibitor). All factors ranged from levels not limiting to plant function to severe inhibition. For cases of combined salinity with water stress, or excess boron, we observed neither additive nor compensative effects on plant yield and transpiration. In fact, yield and transpiration at each combination of the various factors were primarily controlled by one of them, the most limiting factor to plant activity. We proposed a crop production model of the form Yr = min{gi(xi), where Yr = Yi ym-1 is relative yield,Ym is the maximum yield obtained in each experiment, Xi is an environmental factor, gi is a piecewise-linear response function, Yi is yield of a particular treatment. We selected a piecewise-linear approach because it highlights the irrigation level where the response to one factor ceases and a second factor begins. The production functions generate response "envelopes" containing possible yields with diagonal lines represent response to Xi alone and the lines parallel to the X-axis represent response to salinity alone. A multiplicative model was also derived approximating the limiting behaviour for incorporation in a hydrochemical model. The multiplicative model was selected because the response function was required to be continuous. The hydrochemical model was a better predictor of field-measured water content and salt profiles than models based on an additive and compensative model of crop response to salinity and water stress.
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Liu, Miao, Hongan Wang, Jing Lu, Zhiyue Zhu, Chaoqun Song, Ye Tian, Xinzhi Chen, et al. Vitamin D supplementation in the treatment of Myasthenia Gravis A protocol for a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, September 2022. http://dx.doi.org/10.37766/inplasy2022.9.0129.
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Review question / Objective: The patients should meet the internationally recognized diagnostic criteria for myasthenia gravis and be definitely diagnosed as myasthenia gravis, excluding MG patients caused by congenital, drug and other factors, as well as patients with serious primary diseases, autoimmune diseases or mental diseases. Patients are not restricted by race, region, gender, age, background, course of disease and other factors. We will focus on trials using vitamin D as an intervention at any dose and in any regimen (eg daily/weekly/monthly intake). The control group was routinely given western medicine, including cholinesterase inhibitors, glucocorticoids, immunosuppressants, alone or in combination, or placebo. The intervention group was treated with vitamin D on the basis of western medicine treatment in the control group. The specific dosage form and dose were not limited, and the shortest course of treatment should be 4 weeks. Main outcome measures: (1) Quantitative score of myasthenia gravis (QMG); (2) Recurrence rate; (3) Effective. Secondary outcome measures: (1) The level of serum acetylcholine receptor antibody (AchRab); (2) The levels of inflammatory factors such as IL-6 and IL-10; (3) Clinical absolute score; (4) TCM syndrome score scale; (5) Quality of life score (QOL); (6) Incidence rate of adverse events. All randomized controlled trials (RCT) literatures from the establishment to September 2022 were retrieved and classified.
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Applebaum, Shalom W., Lawrence I. Gilbert, and Daniel Segal. Biochemical and Molecular Analysis of Juvenile Hormone Synthesis and its Regulation in the Mediterranean Fruit Fly (Ceratitis capitata). United States Department of Agriculture, 1995. http://dx.doi.org/10.32747/1995.7570564.bard.
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Original Objectives and revisions: (1) "To determine the biosynthetic pathway of JHB3 in the adult C. capitata CA in order to establish parameters for the future choice and synthesis of suitable inhibitors". Modified: to determine the pattern of FR-7 biosynthesis during normal reproductive maturation, and identify enzymes potentially involved in its synthesis. (2) "To correlate allatal epoxidase activity to the biosynthesis of JHB3 at different stages of reproductive maturation/vitellogenesis and evaluate the hypothesis that a specific JH-epoxidase may be rate limiting". Modified: to study the effects of epoxidase inhibitors on the pattern of allatal JH biosynthesis in vitro and on female reproduction in vive. (3) "To probe and clone the gene homologous to ap from C. capitata, determine its exon-intron organization, sequence it and demonstrate its spatial and temporal expression in larvae, pupae and adults." The "Medfly" (Ceratitis capitata) is a serious polyphagous fruit pest, widely distributed in subtropical regions. Damage is caused by oviposition and subsequent development of larvae. JH's are dominant gonadotropic factors in insects. In the higher Diptera, to which the Medfly belongs, JHB3 is a major homolog. It comprises 95% of the total JH produced in vitro in D. melanogaster, with JH-III found as a minor component. The biosynthesis of both JH-III and JHB3 is dependent on epoxidation of double bonds in the JH molecule. The specificity of such epoxidases is unknown. The male accessory gland D. melanogaster produces a Sex Peptide, transferred to the female during copulation. SP reduces female receptivity while activating specific JH biosynthesis in vitro and inducing oviposition in vive. It also reduces pheromone production and activates CA of the moth Helicoverpa armigera. In a previous study, mutants of the apterous (ap) gene of D. melanogaster were analyzed. This gene induces previteilogenic arrest which can be rescued by external application of JH. Considerable progress has been made in recombinant DNA technology of the Medfly. When fully operative, it might be possible to effectively transfer D. melanogaster endocrine gene-lesions into the Medfly as a strategy for their genetic control. A marked heterogeneity in the pattern of JH homologs produced by Medfly CA was observed. Contrary to the anticipated biosynthesis of JHB;, significant amounts of an unknown JH-like compound, of unknown structure and provisionally termed FR-7, were produced, in addition to significant amounts of JH-III and JHB3. Inhibitors of monooxygenases, devised for their effects on ecdysteroid biosynthesis, affect Medfly JH biosynthesis but do not reduce egg deposition. FR-7 was isolated from incubation media of Medfly CA and examined by various MS procedures, but its structure is not yet resolved. MS analysis is being done in collaboration with Professor R.R.W. Rickards of the Australian National University in Canberra, Australia. A homologue of the ap gene of D. melanogaster exists in the Medfly. LIM domains and the homeo-domain, important for the function of the D. melanogaster ap gene, are conserved here too. Attempts to clone the complete gene were unsuccessful. Due to the complexity of JH homologs, presence of related FR-7 in the biosynthetic products of Medfly CA and lack of reduction in eggs deposited in the presence of monooxygenase inhibitors, inhibition of epoxidases is not a feasible alternative to control Medfly reproduction, and raises questions which cannot be resolved within the current dogma of hormonal control of reproduction in Diptera. The Medfly ap gene has similar domains to the D. melanogaster ap gene. Although mutant ap genes are involved in JH deficiency, ap is a questionable candidate for an endocrine lesion, especially since the D. melanogoster gene functions is a transcription factor.
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Barash, Itamar, J. Mina Bissell, Alexander Faerman, and Moshe Shani. Modification of Milk Composition via Transgenesis: The Role of the Extracellular Matrix in Regulating Transgene Expression. United States Department of Agriculture, July 1995. http://dx.doi.org/10.32747/1995.7570558.bard.
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Altering milk composition via transgenesis depends on three main factors. (1) The availability of an efficient regulatory sequences for targeting transgene(s) to the mammary gland; (2) a reliable in vitro model to test the expression of transgenes prior to their introduction to the animal genome; and (3) better understanding of the major factors which determine the rate of gene expression and protein synthesis. The current studies provide the necessary means and knowledge to alter milk protein composition via transgenesis. The following specific goals were achieved: a: Identifying regulatory regions in the b-lactoglobulin (BLG) gene and the cross-talk between elements which enabled us to construct an efficient vector for the expression of desirable cDNA's in the mammary gland. b: The establishment of a sheep mammary cell line that serves as a model for the analysis of endogenous and exogenous milk protein synthesis in the mammary gland of livestock. c: An accurate comparison of the potency of the 5' regulatory sequences from the BLG and whey acidic protein (WAP) promoters in directing the expression of human serum albumin (HSA) to the mammary gland in vitro and in vivo. In this study we have also shown that sequences within the coding region may determine a specific pattern of expression for the transgene, distinct from that of the native milk protein genes. d: Characterizing the dominant role of ECM in transgene expression in mammary epithelial cells. e: Further characterization of the BCE-1 enhancer element in the promoter of the b-casein gene as a binding site for the c/EBP-b and Stat5. Identifying its interaction with chromatin and its up regulation by inhibitors of histone deacetylation. f: Identifying a mechanism of translational control as a mediator for the synergistic effect of insulin and prolactin on protein synthesis in the mammary gland.