Relevant bibliographies by topics / Multiple resistance mechanisms

Academic literature on the topic 'Multiple resistance mechanisms'

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Published: 10 December 2022
Last updated: 28 January 2023

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Journal articles on the topic "Multiple resistance mechanisms"

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EADY, E. ANNE, JEREMY I. ROSS, and JONATHAN H. COVE. "Multiple mechanisms of erythromycin resistance." Journal of Antimicrobial Chemotherapy 26, no. 4 (1990): 461–65. http://dx.doi.org/10.1093/jac/26.4.461.

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Barrio Garcia, Santiago, Umair Munawar, Thorsten Stuehmer, Hermann Einsele, and K. Martin Kortüm. "Molecular Resistance Mechanisms in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 471. http://dx.doi.org/10.1182/blood-2018-99-118700.

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Abstract Mechanisms of drug resistance in Multiple Myeloma (MM) are poorly understood. Mutations and/or changes in the protein expression of the CRBN pathway and proteasome subunits have been identified to induce resistance to IMiDs and PIs. However, only few patients are affected by these alterations. To determine the specific genomic fingerprint of MM relapse we selected 57 MM patients from the CoMMpass trial (version IA11) that have genomic data of paired samples available (diagnosis/relapse). 35 of them have also sequential FISH-seq data. We focused on acquired mutations in first relapse and filtered all mutations and genetic alterations already present at diagnosis. Doing so, we found 1.274 mutations, representing an average of 23 new mutations/patient (range; 2-76). Of interest, 66% of the acquired mutations were present in a sub-clonal level (Variant read frequency (VRF) < 25%). Most common mutations include known hotspots of the RAS pathway (NRAS 12%, KRAS 7% and BRAF 4%). Notably, all 7 NRAS mutations in relapse were located at Q61K, suggesting a functional role of disease progression for this specific and known hotspot location. In total 5 of 35 cases (14%) with FISH-seq data developed a 17p13 deletion in relapse. Of these, three patients acquired a bi-allelic alteration in addition to a preexisting TP53 mutation and one developed a biallelic inactivation of TP53 (VRF = 100%), through parallel acquisition of del17p and TP53 mutation. Gain of 1q21 was observed in relapse in 5 of 35 (14%) cases, and one 1q gain was lost from diagnosis to relapse. Two cases (4%) presented mutations in IMiD treatment related genes, with two mutations in the CRBN pathway. One harbored a missense mutation in the Lenalidomide (LEN) degron sequence of IKZF3 (G159A) (VRF = 36%), known to be essential for the IMiD action in vitro, 45 months after continuous exposition to LEN . The other case presented two subclonal frameshift mutations in CUL4B (VRF = 5% and 32%), detected after more than three years of LEN containing therapy. We functionally validated in vitro LEN resistance through CRISPR/Cas9 knockout of CUL4B, suggesting a resistance inducing effect of the acquired CUL4B mutations. Six cases (11%) harbored acquired mutations in proteasome subunit genes (PSMC2, PSMC6, PSMD8, PSME4, PSMB9 (two mutations)), all of them had undergone prior proteasome inhibitor (PI) containing therapy. We validated earlier the 19S protein subunits PSMC6 and PSMC2 (KO and/or point mutations) as inducers of PI resistance in vitro, thus we hypothesize contribution to resistance induction / disease progression through these 19s mutations. Remarkably ubiquitin (E3, E2 and SUBs) and histone related genes (histones and histone methylases and deacetylases) were found mutated in 51% and 19% of the relapsed patients. Genes for drug transporters (ATP-binding cassette (ABC) and Solute Carrier (SLC) transporters) were hit in 32% of cases and genes for mucins (previously related with genotoxic agents and immunotherapy resistance) in 19%. Notably, RRBP1 presented 10 mutations in 6 patients (11%) with the mutations clustering within 30 amino-acids (aa) of exons 9 and 10 and 3 hotspots (2 patients each) in aa Q426P, K430R and Q436P. RRBP1 is involved in the binding of the ribosome to the endoplasmic reticulum (ER) and is related with the unfolded protein response and ER stress via GRP78. All the patients with RRBP1 mutations were pretreated with PI inhibitors and exhibited worst survival outcome affecting PFS (Pval<0.001) and OS (Pval=0.0016) in this limited dataset. The mutations were detected on average 433 days (range: 258-568) after diagnosis. Five of the 6 patients died on average 180 days after RRBP1 mutation detection (range: 18-446) further suggesting high risk features of such acquired mutations. In summary, we observe clonal selection of known high-risk related alterations like TP53 mutations, 17p deletions or 1q13 in early relapse data of the CoMMpass trial. Furthermore we identify RRBP1 mutations as a new acquired high-risk biomarker of MM. Alterations are specifically related to subclonal selection by therapy, thus we suggest that the definition of high-risk disease in MM needs to be revisited and should also include clonal selection processes under anti-tumor therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Baguley, Bruce C. "Multiple Drug Resistance Mechanisms in Cancer." Molecular Biotechnology 46, no. 3 (August 18, 2010): 308–16. http://dx.doi.org/10.1007/s12033-010-9321-2.

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Deng, Wei, Zhiwen Duan, Yang Li, Cheng Peng, and Shuzhong Yuan. "Multiple Resistance Mechanisms Involved in Glyphosate Resistance in Eleusine indica." Plants 11, no. 23 (November 23, 2022): 3199. http://dx.doi.org/10.3390/plants11233199.

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Glyphosate is a non-selective herbicide and is widely used for weed control in non-cultivated land in China. One susceptible (S) and five putative glyphosate-resistant (R1, R2, R3, R4, and R5) Eleusine indica biotypes were selected to investigate their resistance levels and the potential resistance mechanisms. Based on the dose–response assays, the R3 and R5 biotypes showed a low-level (2.4 to 3.5-fold) glyphosate resistance, and the R1, R2, and R4 biotypes exhibited a moderate- to high-level (8.6 to 19.2-fold) resistance, compared with the S biotype. The analysis of the target-site resistance (TSR) mechanism revealed that the P106A mutation and the heterozygous double T102I + P106S mutation were found in the R3 and R4 biotypes, respectively. In addition, the similar EPSPS gene overexpression was observed in the R1, R2, and R5 biotypes, suggesting that additional non-target-site resistance (NTSR) mechanisms may contribute to glyphosate resistance in R1 and R2 biotypes. Subsequently, an RNA-Seq analysis was performed to identify candidate genes involved in NTSR. In total, ten differentially expressed contigs between untreated S and R1 or R2 plants, and between glyphosate-treated S and R1 or R2 plants, were identified and further verified with RT-qPCR. One ATP-binding cassette (ABC) transporter gene, one aldo-keto reductases (AKRs) gene and one cytochrome P450 monooxygenase (CytP450) gene were up-regulated in R1 or R2 plants. These results indicated that EPSPS overexpression, single or double mutation was a common TSR mechanisms in E. indica. Additional NTSR mechanisms could play an essential role in glyphosate resistance. Three genes, ABCC4, AKR4C10, and CYP88, could serve as important candidate genes and deserve further functional studies.
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Higgins, Christopher F. "Multiple molecular mechanisms for multidrug resistance transporters." Nature 446, no. 7137 (April 2007): 749–57. http://dx.doi.org/10.1038/nature05630.

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Nikesitch, Nicholas, and Silvia C. W. Ling. "Molecular mechanisms in multiple myeloma drug resistance." Journal of Clinical Pathology 69, no. 2 (November 23, 2015): 97–101. http://dx.doi.org/10.1136/jclinpath-2015-203414.

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Dimaano, Niña Gracel, Tohru Tominaga, and Satoshi Iwakami. "Thiobencarb resistance mechanism is distinct from CYP81A-based cross-resistance in late watergrass (Echinochloa phyllopogon)." Weed Science 70, no. 2 (January 20, 2022): 160–66. http://dx.doi.org/10.1017/wsc.2022.4.

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AbstractThe genetic and molecular basis of resistance evolution in weeds to multiple herbicides remains unclear despite being a great threat to agriculture. A population of late watergrass [Echinochloa phyllopogon (Stapf.) Koso-Pol.] was reported to exhibit resistance to ≥15 herbicides from six sites of action, including thiobencarb (TB). While previous studies disclosed that the resistance to a majority of herbicides such as acetolactate synthase (ALS) and acetyl-CoA carboxylase inhibitors is caused by the overexpression of herbicide-metabolizing cytochrome P450s (CYP81A12 and CYP81A21), the resistance mechanisms to some herbicides remain unknown. Here, we analyzed the resistance segregation in the progenies between resistant and sensitive populations and performed a transgenic plant sensitivity assay to resolve whether TB resistance is endowed by the same CYP81A12/21-based cross-resistance mechanism or other unknown multiple-resistance mechanisms. In the F6 progenies, resistance to the ALS inhibitor bensulfuron-methyl cosegregated with the resistances to many other herbicides under the CYP81A12/21-based cross-resistance mechanism; however, TB resistance segregated independently. Furthermore, CYP81A12/21 failed to confer TB resistance in transgenic Arabidopsis thaliana L. Heynh, thus confirming that TB resistance in resistant E. phyllopogon is not endowed by the two P450s that are responsible for the metabolism-based cross-resistance. This study provides evidence that resistance in E. phyllopogon to herbicides with multiple sites of action is endowed by both P450-based and other uncharacterized non–target site based mechanisms. Our findings add another layer in the understanding of resistance evolution to multiple herbicides in E. phyllopogon. Identification of the key genes endowing TB resistance will be the future direction of this research.
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Jiménez-Alcázar, Miguel, Álvaro Curiel-García, Paula Nogales, Javier Perales-Patón, Alberto J. Schuhmacher, Marcos Galán-Ganga, Lucía Zhu, Scott W. Lowe, Fátima Al-Shahrour, and Massimo Squatrito. "Dianhydrogalactitol Overcomes Multiple Temozolomide Resistance Mechanisms in Glioblastoma." Molecular Cancer Therapeutics 20, no. 6 (April 12, 2021): 1029–38. http://dx.doi.org/10.1158/1535-7163.mct-20-0319.

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Vazquez, V. Figueroa, S. S. Mughal, B. Brors, and M. S. Raab. "Characterization of dabrafenib resistance mechanisms in multiple myeloma." European Journal of Cancer 61 (July 2016): S116. http://dx.doi.org/10.1016/s0959-8049(16)61411-9.

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Waldschmidt, Johannes M., Jake Kloeber, Tushara Vijaykumar, Antonis Kokkalis, Praveen Anand, Sayalee Potdar, Julia Frede, et al. "Determining resistance mechanisms in BRAF-mutated multiple myeloma." Clinical Lymphoma Myeloma and Leukemia 19, no. 10 (October 2019): e22. http://dx.doi.org/10.1016/j.clml.2019.09.032.

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Dissertations / Theses on the topic "Multiple resistance mechanisms"

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Scott, F. M. "Drug resistance mechanisms in multiple myeloma." Thesis, University of Edinburgh, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.661665.

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The aim of this thesis was to investigate expression of putative drug resistance markers in myeloma both by examining clinical material and through the development of a xenograft model. Pgp expression was examined in 57 samples from 37 patients with myeloma. Of 23 samples at presentation and 37 at relapse, 7 and 26 respectively were Pgp positive. A myeloma xenograft model was established to examine the acute effects of cytotoxic drugs on the expression of "classical" drug resistance markers and genes involved in regulation of apoptosis. The untreated xenografts were Pgp negative, expressed low levels of glutathione S-transferase-P (GSTP) and had readily detectable topo I and II. Little p62 myc or p53 were detected, whereas bcl-2 was strongly expressed. Treated xenografts contained only scattered apoptotic cells, but the majority demonstrated cell cycle arrest at the G2/M transition, and GSTP and topo IIα expression were increased. Pgp expression was also increased in animals treated on 3 consecutive days. C-myc was detected in dead or dying cells, but there was no mutational inactivation of p53, and bcl-2 expression was unaltered. The increased Pgp and GSTP expression following therapy, rather than inducing a resistant phenotype, may reflect activation of expression by drug administration. Cellular resistance occurred despite evidence of DNA damage suggesting that resistance arose from failure to engage apoptosis, possibly due to the strong bcl-2 expression. Bcl-2 expression was therefore evaluated in 40 samples from 31 individuals, with strong expression observed in over 80% of cases. This was not associated with rearrangement of the bcl-2 locus. The presence of abundant bcl-2 protein in the majority of cases has potentially important implications for drug resistance in this disease and suggests that future assessment of drug resistance in myeloma may be better directed downstream of immediate drug-target interactions to regulation of engagement of apoptosis.
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Doherty, Catherine Jean. "Drug resistance mechanisms in multiple myeloma." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/22154.

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Abbaszadegan, Mohammad Reza. "Mechanisms of resistance to chemosensitizers in a multidrug resistant human multiple myeloma cell line." Diss., The University of Arizona, 1995. http://hdl.handle.net/10150/187140.

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Tumor cells in cancer patients acquire drug resistance as a result of chemotherapy. One type of acquired drug resistance is multidrug resistance (MDR) caused by the overexpression of P-glycoprotein, a transmembrane efflux protein. Inhibitors of P-glycoprotein or chemosensitizers such as verapamil are used to reverse MDR in cancer patients. Clinical studies have shown that some patients with P-glycoprotein positive cancer cells respond to the chemosensitizing effect of verapamil. However, this response is short lived and tumor cells become resistant to chemosensitizers. In order to study the mechanism of resistance to chemosensitizers, a human myeloma cell line, 8226/MDR₁₀V, was selected from a P-glycoprotein positive cell line, 8226/Dox₄₀, in the continuous presence of doxorubicin and verapamil. MDR₁₀V cells are consistently more resistant to MDR drugs than the parent cells, Dox₄₀. Chemosensitizers were less effective in reversing resistance in the MDR₁₀V compared to D0X₄₀ cells. Despite higher resistance to cytotoxic agents, MDR₁₀V expresses less P-glycoprotein in the plasma membrane compared to Dox₄₀. However, total cellular P-glycoprotein was the same in both cell lines suggesting a relocation of P-glycoprotein from plasma membrane into cytoplasm. Confocal immunofluorescence microscopy showed 2.5X more P-glycoprotein in the cytoplasm of MDR₁₀V cells as compared to D0X₄₀ cells. The relocation of P-glycoprotein was associated with a redistribution of doxorubicin. In D0X40 cells, doxorubicin was concentrated in the nucleus, whereas in MDR₁₀V cells, 90% of doxorubicin was found in the cytoplasm. We hypothesized that P-glycoprotein trafficking from the endoplasmic reticulum to the plasma membrane may be interrupted resulting in a higher concentration in the cytoplasm. To test this hypothesis, endoglycosidase H sensitivity of newly sensitized P-glycoprotein was examined. Medial Golgi processing of P-glycoprotein was identical between the two cell lines and the N-glycosylation of P-glycoprotein was complete by 3 hours. No mutations were found in MDR1 cDNA from MDR₁₀V cells compared to Dox₄₀ cells. These results suggest that increased resistance to cytotoxic drugs and chemosensitizers is associated with an altered intracellular location of P-glycoprotein which in turn causes a redistribution of doxorubicin.
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Blackhall, William J. "Genetic variation and multiple mechanisms of anthelmintic resistance in Haemonchus contortus." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0034/NQ64519.pdf.

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Blackhall, William James. "Genetic variation and multiple mechanisms of anthelmintic resistance in Haemonchus contortus." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37596.

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Anthelmintic treatment of livestock is an important aspect of the control of gastrointestinal parasites. Resistance to anthelmintics is common, and an understanding of resistance requires knowledge of an anthelmintic's mode(s) of action and mechanism(s) of resistance. The parasitic nematode, Haemonchus contortus, has developed resistance to benzimidazoles and avermectins/milbemycins. Proposed mechanisms of resistance are here supported by genetic changes observed in genes whose protein products are believed to interact with these anthelmintics. Statistically significant differences in allele frequencies were observed between untreated and ivermectin- and moxidectin-treated strains in a gene encoding a putative glutamate-gated chloride channel alpha subunit, a proposed target of avermectins/milbemycins. One allele appeared to be associated with resistance. Similar changes in allele frequencies in the same strains occurred in a gene encoding a subunit of a gamma-aminobutyric acid receptor. Significant differences in allele frequencies of a gene encoding a P-glycoprotein were found in strains of H. contortus treated with ivermectin and moxidectin compared to derived, untreated strains. In all treated strains, one allele appeared to be associated with resistance. Similarly, allele frequencies of this gene were significantly different between a cambendazole-treated strain and its derived, untreated strain. These results implicate glutamate-gated chloride channels and gamma-aminobutyric acid receptors in mechanisms of resistance to avermectins/milbemycins and implicate P-glycoprotein in a mechanism of resistance to avermectins/milbemycins and benzimidazoles in H. contortus.
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Baran, Yusuf. "Multiple Drug Resistance Mechanisms In Imatinib Resistat Human Chronic Myeloid Leukemia Cells." Phd thesis, METU, 2006. http://etd.lib.metu.edu.tr/upload/12607612/index.pdf.

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In this study, mechanisms of resistance to Imatinib-induced apoptosis in human K562 and Meg-1 chronic myeloid leukemia (CML) cells were examined. Continuous exposure of cells to step-wise increasing concentrations of Imatinib resulted in the selection of 0.2 and 1 &
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M imatinib resistant cells. Measurement of endogenous ceramide levels showed that treatment with Imatinib increased the generation of C18-ceramide significantly, which is mainly synthesized by the human longevity assurance gene 1 (hLASS1), in sensitive, but not in resistant cells. Mechanistically, analysis of mRNA and enzyme activity levels of hLASS1 in the absence or presence of Imatinib did not show any significant differences in the resistant cells when compared to its sensitive counterparts, suggesting that accumulation and/or metabolism, but not the synthesis of ceramide, might be altered in resistant cells. iv Indeed, further studies demonstrated that expression levels, and enzyme activity of sphingosine kinase-1 (SK-1), increased significantly in resistant K562 or Meg-1 cells. The expression levels of glucosyl ceramide synthase (GCS) also increased in resistant cells, comparing to the sensitive counterparts, which indicates conversion of pro-apoptotic ceramide to glucosyl ceramide. Expression analyses of BCR-ABL gene demonstrated that expression levels of BCR-ABL gene increased gradually as the cells acquired the resistance. However, Nucleotide sequence analyses of ABL kinase gene revealed that there was no mutation in Imatinib binding region of the gene in resistant cells. There was also an increase in expression levels of MDR1 gene in resistant cells, which transport the toxic substances outside of cells. In conclusion, these data show, for the first time, a role for endogenous ceramide synthesis via hLASS1 in Imatinib-induced apoptosis, and those alterations of the balance between the levels of ceramide and S1P. Mainly the overexpression of SK-1 seems to result in resistance to Imatinib in K562 cells. The cellular resistance may also result from conversion of ceramide to glucosyl ceramide, from overexpression of BCR-ABL and MDR1 genes but not due to mutations in Imatinib binding site of ABL kinase.
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Parrish, Jason Thomas. "Investigations into Multiple–Herbicide-Resistant Ambrosia artemisiifolia (Common Ragweed) in Ohio and Glyphosate-Resistance Mechanisms." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1420789335.

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Demirel, Kars Meltem. "Molecular Mechanisms Of Vincristine And Paclitaxel Resistance In Mcf-7 Cell Line." Phd thesis, METU, 2008. http://etd.lib.metu.edu.tr/upload/3/12610241/index.pdf.

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Resistance to broad spectrum of chemotherapeutic agents in cancer cell lines and tumors has been called multiple drug resistance (MDR). In this study, the molecular mechanisms of resistance to two anticancer agents (paclitaxel and vincristine) in mammary carcinoma cell line MCF-7 were investigated. MCF-7 cells were selected in the presence of paclitaxel and vincristine by stepwise dose increments. The cell viability and growth profiles of resistant sublines were examined. As the resistance indices increased, the growth rates of sublines were found to decrease. Gene and protein expression levels of the basic drug resistance proteins P-gp and MRP1 were studied in sensitive and drug resistant MCF-7 cells. It was shown that P-gp overexpression is significantly contributing to the developed drug resistance phenotype. Mutation analysis of beta tubulin gene which encodes the target of paclitaxel and vincristine was performed. Single histidine to proline mutation was identified near GTP binding site of beta tubulin in vincristine resistant subline which was not reported before. Apoptosis related BCL-2 and BAX were examined at both gene and protein expression levels and they were not found to be significantly related to the developed resistance in the sublines. The reversal of drug resistance by various inhibitory agents of P-gp and MRP1 was investigated by using flow cytometry. Synthetic silicon compounds were found to be the most effective MDR reversal agents. The effects of various combinations of anticancer drugs and reversal agents on cell proliferation were examined by checkerboard microplate method. ALIS409-paclitaxel and paclitaxel-doxorubicin pairs seem to have highest antiproliferative effects on resistant sublines. The microarray expression profiling of sensitive and resistant MCF-7 cells was performed for a much detailed and comprehensive analysis of drug resistance. The results indicated that the upregulation of MDR1 gene is the dominating mechanism of paclitaxel and vincristine drug resistance. Additionally up regulation of the genes encoding the detoxifying enzymes (i.e. GSTP1) was observed. Significant down regulation of apoptotic genes (i.e. PDCD2/4/6/8) and alterations in expression levels of genes related to invasion and metastasis (MMPs, ADAMs, COL4A2, LAMA etc.) were detected. Upregulation of some oncogenes (i.e. ETS, RAS) and cell cycle regulatory genes (CDKN2A, CCNA2 etc.) was seen which may be in close relation to MDR in breast cancer. Further studies will demonstrate the relationship between the components contributing to drug resistance phenotype in breast cancer cells.
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Lembersky, Dmitry. "THE SECOND GENERATION PROTEASOME INHIBITOR CARFILZOMIB INTERACTS SYNERGISTICALLY WITH HDAC INHIBITORS IN DIFFUSE LARGE B-CELL LYMPHOMA CELLS THROUGH MULTIPLE MECHANISMS AND CIRCUMVENTS BORTEZOMIB RESISTANCE." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1800.

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Mechanisms underlying the interactions between the proteasome inhibitor carfilzomib and HDAC inhibitors were examined in both germinal center (GC) and activated B-cell (ABC) subtypes of human diffuse large B-cell lymphoma (DLBCL). Simultaneous exposure to minimally toxic concentrations of carfilzomib and HDAC inhibitor vorinostat resulted in the release of mitochondrial pro-apoptotic proteins SMAC and cytochrome c, pro-apoptotic caspase activation, and synergistic induction in apoptosis in both ABC and GC DLBCL subtypes. These events were associated with a marked increase in the stress kinase JNK, ROS generation, G2-M cell cycle arrest, as well as induction of DNA damage. Genetic knockdown of JNK resulted in a significant decrease in carfilzomib/vorinostat induced cell death. Co-administration of the antioxidant MnTBAP significantly reduced carfilzomib/vorinostat induced cell death, and resulted in a marked decrease in caspase-3 as well as a striking decrease in JNK phosphorylation. Tumor growth reduction was also observed in animal models that were treated with a combined regimen of carfilzomib and vorinostat. Finally, the combined treatment of carfilzomib/vorinostat was able to overcome any cross-resistance to carfIlzomib in bortezomib resistant cells. Collectively, these finding indicate that the combined regimen of carfilzomib and HDAC inhibitors promote lethality in ABC and GC human DLBCL cells by a variety of mechanisms both in vitro and in vivo. Further studies are necessary for clinical development of this drug regimen.
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Tong, Zhichao [Verfasser], Jürgen E. [Akademischer Betreuer] Gschwend, Jürgen E. [Gutachter] Gschwend, and Dieter [Gutachter] Saur. "Functional genomics identifies multiple clinically actionable resistance mechanisms to CDK4/6 inhibition in bladder cancer / Zhichao Tong ; Gutachter: Jürgen E. Gschwend, Dieter Saur ; Betreuer: Jürgen E. Gschwend." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1189815451/34.

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Books on the topic "Multiple resistance mechanisms"

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Kellen, John A. Alternative Mechanisms of Multidrug Resistance in Cancer. Birkhauser, 2012.

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A, Kellen John, ed. Alternative mechanisms of multidrug resistance in cancer. Boston: Birkhäuser, 1995.

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Kellen, John A. Alternative Mechanisms of Multidrug Resistance in Cancer. Birkhauser Verlag, 2012.

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Torra, Joel, Maria D. Osuna, Aldo Merotto Junior, and Martin Vila-Aiub, eds. Multiple Herbicide-Resistant Weeds and Non-target Site Resistance Mechanisms: A Global Challenge for Food Production. Frontiers Media SA, 2021. http://dx.doi.org/10.3389/978-2-88971-908-2.

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Aslanian, Ara M. Multiple nutrient adaptive mechanisms affect asparaginase resistance in MOLT-4 human leukemia cells. 2000.

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Levy, Jerrold H., and David Faraoni. Pathophysiology and causes of severe hypertension. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0162.

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Hypertension affects multiple groups of patients characterized by different clinical presentations and a spectrum of potential causes. The pathophysiology is complex and multifactorial. Although most patients are labelled ‘essential hypertension’, multiple mechanisms are involved in blood pressure regulation. Factors that influence blood pressure homeostasis include endothelial function, the renin-angiotensin system, and the sympathetic nervous system. In elderly patients, hypertension is common as the vascular system and arterial stiffness also contribute. Other important factors include inflammatory processes as part of systemic diseases, including atherosclerosis,which may contribute to renal and vascular injury. Hypertension is also associated with metabolic disturbances including dyslipidaemia that manifests in obese patients who also have insulin resistance. These different pathways all represent potential targets for treatment, but also increase the challenge of multimodal pathophysiology.
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Hube, Bernhard, and Oliver Kurzai. Candida species. Edited by Christopher C. Kibbler, Richard Barton, Neil A. R. Gow, Susan Howell, Donna M. MacCallum, and Rohini J. Manuel. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198755388.003.0011.

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Most pathogenic Candida species are members of the microbiota, but also cause superficial or invasive infections. C. albicans is predominant, followed by C. glabrata, C. parapsilosis, and C. tropicalis. C. albicans is polymorphic and grows as yeast, pseudohyphae, or hyphae. The cell wall has multiple functions in pathogenesis. Metabolism and nutrient up-take strategies facilitate growth in multiple niches within the host. Drug resistance is an intrinsic property of C. glabrata and C. krusei, but can be developed by C. albicans and other Candida species during antifungal therapy. Pathogenicity mechanisms include host cell attachment, invasion, and destructive activities; immune evasion; and biofilm production. A disbalanced microbiota and impaired immunity favour superficial infections, and disturbance of the mucosal barriers, together with compromised immunity, enables Candida to invade the human bloodstream and cause invasive infection. Even with antifungal therapy (e.g. azoles or echinocandins), disseminated candidiasis has a high mortality (40–50%).
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Sentissi, Kinza, and Stephanie Yacoubian. Physiologic Airflow Disruption. Edited by Matthew D. McEvoy and Cory M. Furse. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190226459.003.0017.

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Airflow disruption can be triggered through multiple mechanisms. The obstruction can stem from within the airway lumen, airway walls, or the tissues surrounding it. This section focuses on airflow disruption initiated by bronchospasm, obstructive lung disease, asthma and status asthmaticus. Bronchospasm presents with increased airway resistance secondary to airway hyperreactivity or anaphylaxis. Asthma and chronic obstructive pulmonary disease (COPD) are obstructive and inflammatory lung pathologies. Airflow disruption in asthma is reversible between exacerbations. The airway obstruction in COPD is not fully reversible. Status asthmaticus is the most severe presentation of asthma and can be life threatening. Poorly controlled obstructive lung disease can result in perioperative complications. Patients should therefore be medically optimized before undergoing operative procedures.
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Dussaule, Jean-Claude, Martin Flamant, and Christos Chatziantoniou. Function of the normal glomerulus. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0044_update_001.

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Glomerular filtration, the first step leading to the formation of primitive urine, is a passive phenomenon. The composition of this primitive urine is the consequence of the ultrafiltration of plasma depending on renal blood flow, on hydrostatic pressure of glomerular capillary, and on glomerular coefficient of ultrafiltration. Glomerular filtration rate (GFR) can be precisely measured by the calculation of the clearance of freely filtrated exogenous substances that are neither metabolized nor reabsorbed nor secreted by tubules: its mean value is 125 mL/min/1.73 m² in men and 110 mL/min/1.73 m² in women, which represents 20% of renal blood flow. In clinical practice, estimates of GFR are obtained by the measurement of creatininaemia followed by the application of various equations (MDRD or CKD-EPI) and more recently by the measurement of plasmatic C-cystatin. Under physiological conditions, GFR is a stable parameter that is regulated by the intrinsic vascular and tubular autoregulation, by the balance between paracrine and endocrine agents acting as vasoconstrictors and vasodilators, and by the effects of renal sympathetic nerves. The mechanisms controlling GFR regulation are complex. This is due to the variety of vasoactive agents and their targets, and multiple interactions between them. Nevertheless, the relative stability of GFR during important variations of systemic haemodynamics and volaemia is due to three major operating mechanisms: autoregulation of the afferent arteriolar resistance, local synthesis and action of angiotensin II, and the sensitivity of renal resistance vessels to respond to NO release.
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O’Neal, M. Angela. Multiple Ovarian Cysts in a Woman with Epilepsy. Edited by Angela O’Neal. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190609917.003.0007.

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This chapter explores how epilepsy can affect reproductive function. The National Institute of Health consensus definition of PCOS includes the presence of menstrual dysfunction, clinical evidence of hyperandrogenism, and exclusion of other endocrinopathies, such as Cushing’s syndrome and hypothyroidism. The etiology of PCOS is felt to be heterogenous, related to a complex interaction between both genetic and environmental factors. PCOS develops when the ovaries are stimulated to produce excessive testosterone. The diagnosis and pathogenesis of polycystic ovarian syndrome is explored; in particular, how valproate contributes to the condition in women with epilepsy. Valproate is the AED most associated with PCOS, as it can directly increase ovarian testosterone production. It can also cause weight gain leading to insulin resistance, another mechanism contributing to PCOS.
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Book chapters on the topic "Multiple resistance mechanisms"

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McDermott, Patrick F. "Multiple Antimicrobial Resistance Mechanisms." In Frontiers in Antimicrobial Resistance, 149. Washington, DC, USA: ASM Press, 2014. http://dx.doi.org/10.1128/9781555817572.part3.

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Damia, G., and M. D’Incalci. "Mechanisms of resistance to alkylating agents." In Multiple Drug Resistance in Cancer 2, 165–73. Dordrecht: Springer Netherlands, 1998. http://dx.doi.org/10.1007/978-94-017-2374-9_10.

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Preston, Christopher, Francois J. Tardif, and Stephen B. Powles. "Multiple Mechanisms and Multiple Herbicide Resistance inLolium rigidum." In ACS Symposium Series, 117–29. Washington, DC: American Chemical Society, 1996. http://dx.doi.org/10.1021/bk-1996-0645.ch013.

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Thornley, Margaret J., Jehudith Sinai, and John Yudkin. "Multiple Mechanisms of Acquired Drug Resistance." In Novartis Foundation Symposia, 141–64. Chichester, UK: John Wiley & Sons, Ltd., 2008. http://dx.doi.org/10.1002/9780470719053.ch8.

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Papadas, Athanasios, and Fotis Asimakopoulos. "Mechanisms of Resistance in Multiple Myeloma." In Mechanisms of Drug Resistance in Cancer Therapy, 251–88. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/164_2017_10.

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Doyle, Michael P., and Brian R. Duling. "Conducted Vasomotion in Isolated Arterioles: Evidence for Multiple Cellular Mechanisms." In The Resistance Arteries, 171–82. Totowa, NJ: Humana Press, 1994. http://dx.doi.org/10.1007/978-1-4757-2296-3_17.

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Preston, Christopher, and Stephen B. Powles. "Mechanisms of Multiple Herbicide Resistance inLolium rigidum." In ACS Symposium Series, 150–60. Washington, DC: American Chemical Society, 2001. http://dx.doi.org/10.1021/bk-2002-0808.ch009.

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Tardif, F. J., C. Preston, and S. B. Powles. "Mechanisms of Herbicide Multiple Resistance in Lolium Rigidum." In Weed and Crop Resistance to Herbicides, 117–24. Dordrecht: Springer Netherlands, 1997. http://dx.doi.org/10.1007/978-94-011-5538-0_12.

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Byrne, Daragh, Carmel Daly, Roisin NicAmhlaoibh, Anthony Howlett, Kevin Scanlon, and Martin Clynes. "Use of ribozymes and antisense oligodeoxynucleotides to investigate mechanisms of drug resistance." In Multiple Drug Resistance in Cancer 2, 113–36. Dordrecht: Springer Netherlands, 1998. http://dx.doi.org/10.1007/978-94-017-2374-9_7.

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Poirel, Laurent, and Patrice Nordmann. "Acinetobacter baumannii: Mechanisms of Resistance, Multiple ß-Lactamases." In Acinetobacter Biology and Pathogenesis, 129–43. New York, NY: Springer US, 2008. http://dx.doi.org/10.1007/978-0-387-77944-7_7.

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Conference papers on the topic "Multiple resistance mechanisms"

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Kwok, B., A. Katz, J. Papadopoulos, and R. M. Goldenberg. "A Case of Anticoagulation Resistance Due to Multiple Mechanisms." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a1715.

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Leggas, Markos, Eleftheria Tsakalozou, Tamer Ahmed, Kuei-Ling Kuo, Jamie Horn, Narsimha Penthala, and Peter Crooks. "Abstract C216: Small molecule antitubulin drugs that evade multiple drug resistance mechanisms." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-c216.

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Zhou, Chengfang, DongYa Shen, WeiLi Wang, Shangchen Xie, Ping Liao, Xiang Chen, Howard L. McLeod, and Yijing He. "Abstract 1186: Propranolol could overcome BRAF inhibitors resistance by multiple mechanisms in melanoma." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-1186.

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Lau, Gee W., Zhizhou Kuang, Yonghua Hao, Daniel J. Hassett, and Henry Akinbi. "Pseudomonas Aeruginosa Flagellum Regulates Multiple Mechanisms Of Resistance To Pulmonary Surfactant Protein-A." In American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a6105.

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Huang, Fei, Warren Hurlburt, Ann Greer, Karen A. Reeves, Stephen Hillerman, Han Chang, Stuart Emanuel, Friedrich Finckenstein, Marco M. Gottardis, and Joan M. Carboni. "Abstract A153: Mechanisms of acquired resistance to an IGF‐1R inhibitor in multiple models." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-a153.

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Dillon, Rachelle L., Shilpa Chooniedass, Arjune Premsukh, Gregory P. Adams, Joycelyn Entwistle, Glen C. MacDonald, and Jeannick Cizeau. "Abstract 2961: deBouganin conjugated to trastuzumab overcomes multiple mechanisms of T-DM1 drug resistance." 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.am2016-2961.

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Kumar, Amar N., Amiya Nayak, Alka Srivastava, Udit K. Roy, and Prakash C. Patnaik. "TiAl Intermetallics for Aerospace Applications: Fracture Resistance and Cracking Mechanisms." In ASME Turbo Expo 2009: Power for Land, Sea, and Air. ASMEDC, 2009. http://dx.doi.org/10.1115/gt2009-59566.

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Research on TiAl aluminides has been undertaken to further advance the understanding of deformation and fracture mechanisms, vis-a`-vis the heat treatment effects on microstructure, fracture resistance and cracking mechanisms. Two TiAl grades considered comprise of Al-Nb-Mn-Cr-Bal Ti with two different microstructures, namely duplex and lamellar types. The size of colonies in fully lamellar structure also varied widely from 50 micron to 700 microns. Fracture toughness and crack growth resistance are studied under three point bend loading of SEN specimens at room temperature and at higher temperatures (700 °C and 900°C). The fracture resistance behavior for the intermetallics is studied following two methods, namely fracture toughness and crack growth resistance curves (KI vs. Δa). An appreciable improvement (around 50 percent) at 700°C is observed as compared to room temperature data. The crack size analysis is done by elastic compliance method and a normalized compliance curve (NCC) with a power law function for the aluminides is obtained irrespective of temperature. The mechanism of crack initiation as well as crack growth in different microstructures of the alloy is looked into to get an insight of the deformation and cracking process. In lamellar microstructure, colony boundaries appear to be the most preferred path for the crack growth, while multiple cracking mechanisms is observed in duplex structure.
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Ng, Charlotte K. Y., Britta Weigelt, Roger A'Hern, and Jorge S. Reis-Filho. "Abstract 4029: The impact of multiple drug resistance mechanisms on microarray predictive gene signature performance." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-4029.

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To, Kenneth K. W., Daniel C. Poon, XG Chen, Ge Lin, and Li-wu Fu. "Abstract 976: CUDC-101, a hybrid molecular targeted agent, reverses multiple mechanisms of drug resistance." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-976.

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Thirukkumaran, Chandini M., Zhong-Qiao Shi, Joanne Luider, Karen Kopciuk, Paola Neri, Nizar Bahlis, and Don Morris. "Abstract 3815: Synergistic mechanisms of oncolytic reovirus with bortezomib in overcoming therapy resistance of multiple myeloma." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3815.

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Reports on the topic "Multiple resistance mechanisms"

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Fahima, Tzion, and Jorge Dubcovsky. Map-based cloning of the novel stripe rust resistance gene YrG303 and its use to engineer 1B chromosome with multiple beneficial traits. United States Department of Agriculture, January 2013. http://dx.doi.org/10.32747/2013.7598147.bard.

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Research problem: Bread wheat (Triticumaestivum) provides approximately 20% of the calories and proteins consumed by humankind. As the world population continues to increase, it is necessary to improve wheat yields, increase grain quality, and minimize the losses produced by biotic and abiotic stresses. Stripe rust, caused by Pucciniastriiformisf. sp. tritici(Pst), is one of the most destructive diseases of wheat. The new pathogen races are more virulent and aggressive than previous ones and have produced large economic losses. A rich source for stripe-rust resistance genes (Yr) was found in wild emmer wheat populations from Israel. Original Project goals: Our long term goal is to identify, map, clone, characterize and deploy in breeding, novel wild emmer Yr genes, and combine them with multiple beneficial traits. The current study was aiming to map and clone YrG303 and Yr15, located on chromosome 1BS and combine them with drought resistance and grain quality genes. Positional cloning of YrG303/Yr15: Fine mapping of these genes revealed that YrG303 is actually allelic to Yr15. Fine genetic mapping using large segregating populations resulted in reduction of the genetic interval spanning Yr15 to less than 0.1 cM. Physical mapping of the YrG303/Yr15 locus was based on the complete chromosome 1BS physical map of wheat constructed by our group. Screening of 1BS BAC library with Yr15 markers revealed a long BAC scaffold covering the target region. The screening of T. dicoccoidesaccession-specific BAC library with Yr15 markers resulted in direct landing on the target site. Sequencing of T. dicoccoidesBAC clones that cover the YrG303/Yr15 locus revealed a single candidate gene (CG) with conserved domains that may indicate a role in disease resistance response. Validation of the CG was carried out using EMS mutagenesis (loss-of- function approach). Sequencing of the CG in susceptible yr15/yrG303 plants revealed three independent mutants that harbour non-functional yr15/yrG303 alleles within the CG conserved domains, and therefore validated its function as a Pstresistance gene. Evaluation of marker-assisted-selection (MAS) for Yr15. Introgressions of Yr15 into cultivated wheat are widely used now. Recently, we have shown that DNA markers linked to Yr15 can be used as efficient tools for introgression of Yr15 into cultivated wheat via MAS. The developed markers were consistent and polymorphic in all 34 tested introgressions and are the most recommended markers for the introgression of Yr15. These markers will facilitate simultaneous selection for multiple Yr genes and help to avoid escapees during the selection process. Engineering of improved chromosome 1BS that harbors multiple beneficial traits. We have implemented the knowledge and genetic resources accumulated in this project for the engineering of 1B "super-chromosome" that harbors multiple beneficial traits. We completed the generation of a chromosome including the rye 1RS distal segment associated with improved drought tolerance with the Yr gene, Yr15, and the strong gluten allele 7Bx-over-expressor (7Bxᴼᴱ). We have completed the introgression of this improved chromosome into our recently released variety Patwin-515HP and our rain fed variety Kern, as well as to our top breeding lines UC1767 and UC1745. Elucidating the mechanism of resistance exhibited by Yr36 (WKS1). The WHEAT KINASE START1 (WKS1) resistance gene (Yr36) confers partial resistance to Pst. We have shown that wheat plants transformed with WKS1 transcript are resistant to Pst. WKS1 is targeted to the chloroplast where it phosphorylates the thylakoid-associatedascorbateperoxidase (tAPX) and reduces its ability to detoxify peroxides. Based on these results, we propose that the phosphorylation of tAPX by WKS1 reduces the ability of the cells to detoxify ROS and contributes to cell death. Distribution and diversity of WKS in wild emmer populations. We have shown that WKS1 is present only in the southern distribution range of wild emmer in the Fertile Crescent. Sequence analysis revealed a high level of WKS1 conservation among wild emmer populations, in contrast to the high level of diversity observed in NB-LRR genes. This phenomenon shed some light on the evolution of genes that confer partial resistance to Pst. Three new WKS1 haplotypes displayed a resistance response, suggesting that they can be useful to improve wheat resistance to Pst. In summary, we have improved our understanding of cereals’ resistance mechanisms to rusts and we have used that knowledge to develop improved wheat varieties.
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Levin, Ilan, John W. Scott, Moshe Lapidot, and Moshe Reuveni. Fine mapping, functional analysis and pyramiding of genes controlling begomovirus resistance in tomato. United States Department of Agriculture, November 2014. http://dx.doi.org/10.32747/2014.7594406.bard.

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Abstract. Tomato yellow leaf curl virus (TYLCV), a monopartitebegomovirus, is one of the most devastating viruses of cultivated tomatoes and poses increasing threat to tomato production worldwide. Because all accessions of the cultivated tomato are susceptible to these viruses, wild tomato species have become a valuable resource of resistance genes. QTL controlling resistance to TYLCV and other begomoviruses (Ty loci) were introgressed from several wild tomato species and mapped to the tomato genome. Additionally, a non-isogenic F₁diallel study demonstrated that several of these resistance sources may interact with each other, and in some cases generate hybrid plants displaying lower symptoms and higher fruit yield compared to their parental lines, while their respective resistance genes are not necessarily allelic. This suggests that pyramiding genes originating from different resistance sources can be effective in obtaining lines and cultivars which are highly resistant to begomoviruses. Molecular tools needed to test this hypothesis have been developed by our labs and can thus significantly improve our understanding of the mechanisms of begomovirus resistance and how to efficiently exploit them to develop wider and more durable resistance. Five non-allelic Ty loci with relatively major effects have been mapped to the tomato genome using molecular DNA markers, thereby establishing tools for efficient marker assisted selection, pyramiding of multiple genes, and map based gene cloning: Ty-1, Ty-2, Ty-3, Ty-4, and ty-5. This research focused on Ty-3 and Ty-4 due to their broad range of resistance to different begomoviruses, including ToMoV, and on ty-5 due to its exceptionally high level of resistance to TYLCV and other begomoviruses. Our aims were: (1) clone Ty-3, and fine map Ty-4 and Ty-5 genes, (2)introgress each gene into two backgroundsand develop semi isogenic lines harboring all possible combinations of the three genes while minimizing linkage-drag, (3) test the resulting lines, and F₁ hybrids made with them, for symptom severity and yield components, and (4) identify and functionally characterize candidate genes that map to chromosomal segments which harbor the resistance loci. During the course of this research we have: (1) found that the allelic Ty-1 and Ty-3 represent two alternative alleles of the gene coding DFDGD-RDRP; (2) found that ty-5is highly likely encoded by the messenger RNA surveillance factor PELOTA (validation is at progress with positive results); (3) continued the map-based cloning of Ty-4; (4) generated all possible gene combinations among Ty-1, Ty-3 and ty-5, including their F₁ counterparts, and tested them for TYLCV and ToMoV resistance; (5) found that the symptomless line TY172, carrying ty-5, also carries a novel allele of Ty-1 (termed Ty-1ⱽ). The main scientific and agricultural implications of this research are as follows: (1) We have developed recombination free DNA markers that will substantially facilitate the introgression of Ty-1, Ty-3 and ty-5 as well as their combinations; (2) We have identified the genes controlling TYLCV resistance at the Ty-1/Ty-3 and ty-5 loci, thus enabling an in-depth analyses of the mechanisms that facilitate begomovirus resistance; (3) Pyramiding of Ty resistance loci is highly effective in providing significantly higher TYLCV resistance.
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Glazer, Itamar, Alice Churchill, Galina Gindin, and Michael Samish. Genomic and Organismal Studies to Elucidate the Mechanisms of Infectivity of Entomopathogenic Fungi to Ticks. United States Department of Agriculture, January 2013. http://dx.doi.org/10.32747/2013.7593382.bard.

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The overall goal of this research was to elucidate the factors affecting early development of Metarhizium spp. (previously named M. anisopliae) on ticks or tick cuticle extracts and the molecular basis of these early infection processes. The original objectives were: 1. Characterize the pre-penetration events (adhesion, germination and appressorium formation) of spores of M. anisopliae strains with high or low virulence during tick infection. 2. Create GFP-expressing strains of M. anisopliae tick pathogens having high and low virulence to compare their progress of infection by microscopy. 3. Use microarray analyses, primarily with existing M. anisopliae EST sequences in GenBank, to identify and characterize fungal genes whose expression is regulated in response to host cuticle extracts. Objective 3 was later modified (as approved by BARD) to use RNAseq to characterize the early stages of fungal gene expression during infection of intact host cuticles. This new method provides a massively larger and more informative dataset and allows us to take advantage of a) recently published genomes of Metarhizium robertsii and M. acridum for RNAseq data analysis, and b) newly developed and highly efficient cDNA sequencing technologies that are relatively low cost and, therefore, allow deep sequencing of multiple transcriptome samples. We examined pre-penetration and penetration events that differentiate high and low virulence strains of Metarhizium spp., focusing on spore adhesion, germination, appressorium formation, and penetration of tick integuments. Initiation of fungal infection was compared on susceptible and resistant tick species at different tick developmental stages. In vitro studies comparing the effects of protein and fatty acid profiles from tick cuticle extracts demonstrated that resistant tick cuticles contain higher concentrations of specific lipids that inhibit fungal development than do susceptible tick cuticles, suggesting one mechanism of Ixodidae resistance to fungal entomopathogens (Objective 1). We used molecular markers to determine that the three M. anisopliae strains from Israel that we studied actually were three distinct species. M. brunneum is highly virulent against the tick Rhipicephalus annulatus, M. pingshaense and M. robertsii are intermediate in virulence, and M. majus is of low virulence. We transformed all four Metarhizium species to express GFP and used them in pathogenicity assays against diverse tick species. Key findings were that a) resistant ticks inhibit Metarhizium infection prior to hemocoel invasion by reducing fungal viability on the cuticle surface (Objective 2), as was supported by the in vitro studies of Objective 1, and b) Metarhizium kills susceptible ticks after cuticle penetration but prior to hemocoel colonization. Transcriptome studies of the most virulent species, M. brunneum, are in progress and include analyses of ungerminated conidia and conidia germination and development on a low nutrient medium or on susceptible R. annulatus exoskeleton (Objective 3). We anticipate these studies will contribute to identifying fungal genetic factors that increase virulence and speed of kill and may help reveal tick chemistries that could be included in biocontrol formulations to increase efficacy. Methodologies developed to screen tick cuticle extracts for ability to support conidia germination and development may help in the selection of wild fungi with increased virulence against resistant ticks. The overall knowledge gained should contribute not only to the improvement of tick control but also to the control of other blood-sucking arthropods and related plant pests. Use of bio-based agents for controlling arthropods will contribute to a healthier, more sustainable environment and serve a growing number of organic food farmers.
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Gal-On, Amit, Shou-Wei Ding, Victor P. Gaba, and Harry S. Paris. role of RNA-dependent RNA polymerase 1 in plant virus defense. United States Department of Agriculture, January 2012. http://dx.doi.org/10.32747/2012.7597919.bard.

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Objectives: Our BARD proposal on the impact of RNA-dependent RNA polymerase 1 (RDR1) in plant defense against viruses was divided into four original objectives. 1. To examine whether a high level of dsRNA expression can stimulate RDR1 transcription independent of salicylic acid (SA) concentration. 2. To determine whether the high or low level of RDR1 transcript accumulation observed in virus resistant and susceptible cultivars is associated with viral resistance and susceptibility. 3. To define the biogenesis and function of RDR1-dependent endogenous siRNAs. 4. To understand why Cucumber mosaic virus (CMV) can overcome RDR1-dependent resistance. The objectives were slightly changed due to the unique finding that cucumber has four different RDR1 genes. Background to the topic: RDR1 is a key plant defense against viruses. RDR1 is induced by virus infection and produces viral and plant dsRNAs which are processed by DICERs to siRNAs. siRNAs guide specific viral and plant RNA cleavage or serve as primers for secondary amplification of viral-dsRNA by RDR. The proposal is based on our preliminary results that a. the association of siRNA and RDR1 accumulation with multiple virus resistance, and b. that virus infection induced the RDR1-dependent production of a new class of endogenous siRNAs. However, the precise mechanisms underlying RDR1 induction and siRNA biogenesis due to virus infection remain to be discovered in plants. Major conclusions, solutions and achievements: We found that in the cucurbit family (cucumber, melon, squash, watermelon) there are 3-4 RDR1 genes not documented in other plant families. This important finding required a change in the emphasis of our objectives. We characterized 4 RDR1s in cucumber and 3 in melon. We demonstrated that in cucumber RDR1b is apparently a new broad spectrum virus resistance gene, independent of SA. In melon RDR1b is truncated, and therefore is assumed to be the reason that melon is highly susceptible to many viruses. RDR1c is dramatically induced due to DNA and RNA virus infection, and inhibition of RDR1c expression led to increased virus accumulation which suggested its important on gene silencing/defense mechanism. We show that induction of antiviral RNAi in Arabidopsis is associated with production of a genetically distinct class of virus-activated siRNAs (vasiRNAs) by RNA dependent RNA polymerase-1 targeting hundreds of host genes for RNA silencing by Argonaute-2. Production of vasiRNAs is induced by viruses from two different super groups of RNA virus families, targeted for inhibition by CMV, and correlated with virus resistance independently of viral siRNAs. We propose that antiviral RNAi activate broad-spectrum antiviral activity via widespread silencing of host genes directed by vasiRNAs, in addition to specific antiviral defense Implications both scientific and agricultural: The RDR1b (resistance) gene can now be used as a transcription marker for broad virus resistance. The discovery of vasiRNAs expands the repertoire of siRNAs and suggests that the siRNA-processing activity of Dicer proteins may play a more important role in the regulation of plant and animal gene expression than is currently known. We assume that precise screening of the vasiRNA host targets will lead in the near future for identification of plant genes associate with virus diseases and perhaps other pathogens.
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Brown Horowitz, Sigal, Eric L. Davis, and Axel Elling. Dissecting interactions between root-knot nematode effectors and lipid signaling involved in plant defense. United States Department of Agriculture, January 2014. http://dx.doi.org/10.32747/2014.7598167.bard.

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Root-knot nematodes, Meloidogynespp., are extremely destructive pathogens with a cosmopolitan distribution and a host range that affects most crops. Safety and environmental concerns related to the toxicity of nematicides along with a lack of natural resistance sources threaten most crops in Israel and the U.S. This emphasizes the need to identify genes and signal mechanisms that could provide novel nematode control tactics and resistance breeding targets. The sedentary root-knot nematode (RKN) Meloidogynespp. secrete effectors in a spatial and temporal manner to interfere with and mimic multiple physiological and morphological mechanisms, leading to modifications and reprogramming of the host cells' functions, resulted in construction and maintenance of nematodes' feeding sites. For successful parasitism, many effectors act as immunomodulators, aimed to manipulate and suppress immune defense signaling triggered upon nematode invasion. Plant development and defense rely mainly on hormone regulation. Herein, a metabolomic profiling of oxylipins and hormones composition of tomato roots were performed using LC-MS/MS, indicating a fluctuation in oxylipins profile in a compatible interaction. Moreover, further attention was given to uncover the implication of WRKYs transcription factors in regulating nematode development. In addition, in order to identify genes that might interact with the lipidomic defense pathway induced by oxylipins, a RNAseq was performed by exposing M. javanicasecond-stage juveniles to tomato protoplast, 9-HOT and 13-KOD oxylipins. This transcriptome generated a total of 4682 differentially expressed genes (DEGs). Being interested in effectors, we seek for DEGs carrying a predicted secretion signal peptide. Among the DEGs including signal peptide, several had homology with known effectors in other nematode species, other unknown potentially secreted proteins may have a role as root-knot nematodes' effectors which might interact with lipid signaling. The molecular interaction of LOX proteins with the Cyst nematode effectors illustrate the nematode strategy in manipulating plant lipid signals. The function of several other effectors in manipulating plant defense signals, as well as lipids signals, weakening cell walls, attenuating feeding site function and development are still being studied in depth for several novel effectors. As direct outcome of this project, the accumulating findings will be utilized to improve our understanding of the mechanisms governing critical life-cycle phases of the parasitic M. incognita RKN, thereby facilitating design of effective controls based on perturbation of nematode behavior—without producing harmful side effects. The knowledge from this study will promote genome editing strategies aimed at developing nematode resistance in tomato and other nematode-susceptible crop species in Israel and the United States.
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Chejanovsky, Nor, and Bruce A. Webb. Potentiation of Pest Control by Insect Immunosuppression. United States Department of Agriculture, January 2010. http://dx.doi.org/10.32747/2010.7592113.bard.

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The restricted host range of many baculoviruses, highly pathogenic to Lepidoptera and non-pathogenic to mammals, limits their use to single or few closely related Lepidopteran species and is an obstacle to extending their implementation for pest control. The insect immune response is a major determinant of the ability of an insect pathogen to efficiently multiply and propagate. We have developed an original model system to study the Lepidopteran antiviral immune response based on Spodoptera littoralis resistance to AcMNPV (Autographa californica multiple nucleopolyhedrovirus) infection and the fascinating immunosuppressive activity of polydnaviruses .Our aim is to elucidate the mechanisms through which the immunosuppressive insect polydnaviruses promote replication of pathogenic baculoviruses in lepidopteran hosts that are mildly or non-permissive to virus- replication. In this study we : 1- Assessed the extent to which and the mechanisms whereby the immunosuppressive Campoletis sonorensis polydnavirus (CsV) or its genes enhanced replication of a well-characterized pathogenic baculovirus AcMNPV, in polydnavirus-immunosuppressedH. zea and S. littoralis insects and S. littoralis cells, hosts that are mildly or non-permissive to AcMNPV. 2- Identified CsV genes involved in the above immunosuppression (e.g. inhibiting cellular encapsulation and disrupting humoral immunity). We showed that: 1. S. littoralis larvae mount an immune response against a baculovirus infection. 2. Immunosuppression of an insect pest improves the ability of a viral pathogen, the baculovirus AcMNPV, to infect the pest. 3. For the first time two PDV-specific genes of the vankyrin and cystein rich-motif families involved in immunosuppression of the host, namely Pvank1 and Hv1.1 respectively, enhanced the efficacy of an insect pathogen toward a semipermissive pest. 4. Pvank1 inhibits apoptosis of Spodopteran cells elucidating one functional aspect of PDVvankyrins. 5. That Pvank-1 and Hv1.1 do not show cooperative effect in S. littoralis when co-expressed during AcMNPV infection. Our results pave the way to developing novel means for pest control, including baculoviruses, that rely upon suppressing host immune systems by strategically weakening insect defenses to improve pathogen (i.e. biocontrol agent) infection and virulence. Also, we expect that the above result will help to develop systems for enhanced insect control that may ultimately help to reduce transmission of insect vectored diseases of humans, animals and plants as well as provide mechanisms for suppression of insect populations that damage crop plants by direct feeding.
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7

Sessa, Guido, and Gregory Martin. A functional genomics approach to dissect resistance of tomato to bacterial spot disease. United States Department of Agriculture, January 2004. http://dx.doi.org/10.32747/2004.7695876.bard.

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The research problem. Bacterial spot disease in tomato is of great economic importance worldwide and it is particularly severe in warm and moist areas affecting yield and quality of tomato fruits. Causal agent of spot disease is the Gram-negative bacterium Xanthomonas campestris pv. vesicatoria (Xcv), which can be a contaminant on tomato seeds, or survive in plant debris and in association with certain weeds. Despite the economic significance of spot disease, plant protection against Xcvby cultural practices and chemical control have so far proven unsuccessful. In addition, breeding for resistance to bacterial spot in tomato has been undermined by the genetic complexity of the available sources of resistance and by the multiple races of the pathogen. Genetic resistance to specific Xcvraces have been identified in tomato lines that develop a hypersensitive response and additional defense responses upon bacterial challenge. Central goals of this research were: 1. To identify plant genes involved in signaling and defense responses that result in the onset of resistance. 2. To characterize molecular properties and mode of action of bacterial proteins, which function as avirulence or virulence factors during the interaction between Xcvand resistant or susceptible tomato plants, respectively. Our main achievements during this research program are in three major areas: 1. Identification of differentially expressed genes during the resistance response of tomato to Xcvrace T3. A combination of suppression subtractive hybridization and microarray analysis identified a large set of tomato genes that are induced or repressed during the response of resistant plants to avirulent XcvT3 bacteria. These genes were grouped in clusters based on coordinate expression kinetics, and classified into over 20 functional classes. Among them we identified genes that are directly modulated by expression of the type III effector protein AvrXv3 and genes that are induced also during the tomato resistance response to Pseudomonas syringae pv. tomato. 2. Characterization of molecular and biochemical properties of the tomato LeMPK3MAP kinase. A detailed molecular and biochemical analysis was performed for LeMPK3 MAP kinase, which was among the genes induced by XcvT3 in resistant tomato plants. LeMPK3 was induced at the mRNA level by different pathogens, elicitors, and wounding, but not by defense-related plant hormones. Moreover, an induction of LeMPK3 kinase activity was observed in resistant tomato plants upon Xcvinfection. LeMPK3 was biochemically defined as a dual-specificity MAP kinase, and extensively characterized in vitro in terms of kinase activity, sites and mechanism of autophosphorylation, divalent cation preference, Kₘand Vₘₐₓ values for ATP. 3. Characteriztion of molecular properties of the Xcveffector protein AvrRxv. The avirulence gene avrRxvis involved in the genetic interaction that determines tomato resistance to Xcvrace T1. We found that AvrRxv functions inside the plant cell, localizes to the cytoplasm, and is sufficient to confer avirulence to virulent Xcvstrains. In addition, we showed that the AvrRxv cysteine protease catalytic core is essential for host recognition. Finally, insights into cellular processes activated by AvrRxv expression in resistant plants were obtained by microarray analysis of 8,600 tomato genes. Scientific and agricultural significance: The findings of these activities depict a comprehensive and detailed picture of cellular processes taking place during the onset of tomato resistance to Xcv. In this research, a large pool of genes, which may be involved in the control and execution of plant defense responses, was identified and the stage is set for the dissection of signaling pathways specifically triggered by Xcv.
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8

Shpigel, Nahum, Raul Barletta, Ilan Rosenshine, and Marcelo Chaffer. Identification and characterization of Mycobacterium paratuberculosis virulence genes expressed in vivo by negative selection. United States Department of Agriculture, January 2004. http://dx.doi.org/10.32747/2004.7696510.bard.

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Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of a severe inflammatory bowel disease (IBD) in ruminants, known as Johne’s disease or paratuberculosis. Johne’s disease is considered to be one of the most serious diseases affecting dairy cattle both in Israel and worldwide. Heavy economic losses are incurred by dairy farmers due to the severe effect of subclinical infection on milk production, fertility, lower disease resistance and early culling. Its influence in the United States alone is staggering, causing an estimated loss of $1.5 billion to the agriculture industry every year. Isolation of MAP from intestinal tissue and blood of Crohn's patients has lead to concern that it plays a potential pathogenic role in promoting human IDB including Crohn’s disease. There is great concern following the identification of the organism in animal products and shedding of the organism to the environment by subclinically infected animals. Little is known about the molecular basis for MAP virulence. The goal of the original proposed research was to identify MAP genes that are required for the critical stage of initial infection and colonization of ruminants’ intestine by MAP. We proposed to develop and use signature tag mutagenesis (STM) screen to find MAP genes that are specifically required for survival in ruminants upon experimental infection. This research projected was approved as one-year feasibility study to prove the ability of the research team to establish the animal model for mutant screening and alternative in-vitro cell systems. In Israel, neonatal goat kids were repeatedly inoculated with either one of the following organisms; MAP K-10 strain and three transposon mutants of K-10 which were produced and screened by the US PI. Six months after the commencement of inoculation we have necropsied the goats and taken multiple tissue samples from the jejunum, ileum and mesenteric lymph nodes. Both PCR and histopathology analysis indicated on efficient MAP colonization of all the inoculated animals. We have established several systems in the Israeli PI’s laboratory; these include using IS900 PCR for the identification of MAP and using HSP65-based PCR for the differentiation between MAV and MAP. We used Southern blot analysis for the differentiation among transposon mutants of K-10. In addition the Israeli PI has set up a panel of in-vitro screening systems for MAP mutants. These include assays to test adhesion, phagocytosis and survival of MAP to/within macrophages, assays that determine the rate of MAPinduced apoptosis of macrophages and MAP-induced NO production by macrophages, and assays testing the interference with T cell ã Interferon production and T cell proliferation by MAP infected macrophages (macrophage studies were done in BoMac and RAW cell lines, mouse peritoneal macrophages and bovine peripheral blood monocytes derived macrophages, respectively). All partners involved in this project feel that we are currently on track with this novel, highly challenging and ambitious research project. We have managed to establish the above described research systems that will clearly enable us to achieve the original proposed scientific objectives. We have proven ourselves as excellent collaborative groups with very high levels of complementary expertise. The Israeli groups were very fortunate to work with the US group and in a very short time period to master numerous techniques in the field of Mycobacterium research. The Israeli group has proven its ability to run this complicated animal model. This research, if continued, may elucidate new and basic aspects related to the pathogenesis MAP. In addition the work may identify new targets for vaccine and drug development. Considering the possibility that MAP might be a cause of human Crohn’s disease, better understanding of virulence mechanisms of this organism might also be of public health interest as well.
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9

EFFECTS OF THE NUMBERS OF STORIES AND SPANS ON THE COLLAPSE-RESISTANCE PERFORMANCE OF MULTI-STORY STEEL FRAME STRUCTURES WITH REDUCED BEAM SECTION CONNECTIONS. The Hong Kong Institute of Steel Construction, June 2022. http://dx.doi.org/10.18057/ijasc.2022.18.2.10.

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The progressive collapse of a building structure under an accidental load involves a relatively complex mechanical behavior. To date, the collapse of single-story beam-column assemblies has been investigated extensively, revealing the resistance development of beams during progressive collapse. However, few studies of the progressive collapse behavior of multi-story frame structures have performed a systematic analysis of the Vierendeel action (VA) at a comprehensive level. It is difficult to convert quantitative analysis results accurately from the component level to the overall structure level to evaluate the collapse resistances of structures. To investigate the effects of the numbers of stories and spans on the collapse resistances of steel frame structures, a refined numerical simulation study of a multi-story frame model with different numbers of stories and spans was performed. First, the correctness of the finite element modeling method was verified by the collapse test results of a single-story and two-story frame. Then, the finite element modeling method was applied to study the collapse resistances of multi-story frame structures with different stories and spans. The load–displacement response, internal force development, deformation characteristics, and resistance mechanisms were analyzed, and the contributions of the flexural and catenary mechanisms of each story were separated quantitatively. The results illustrated that the VA can improve the load-carrying capacity to a certain extent in the small deformation stage, but can also cause the frame structures to undergo progressive collapse from the failure story to the top story. The bearing capacity of the multi-story frame did not have a simple multiple relationship with the number of stories. Increasing the number of spans can improve the collapse resistance in the large deformation stage, which is more obvious when the number of stories is smaller, and this accelerates the upward transmission of the axial tension force among the stories, although this effect is minimal for frames with few stories.
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