Articoli di riviste: "Erg3"

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Khan, Noman Ahmed Jang, Mahmoud Abdallah, Todd W. Gress e Mohamed Farouq Alsharedi. "Association between estrogen receptor status and Oncotype Dx breast recurrence score." Journal of Clinical Oncology 39, n. 15_suppl (20 maggio 2021): e12519-e12519. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e12519.

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e12519 Background: The 21 gene assay Oncotype Dx Breast Recurrence Score (RS) is currently the standard of care to determine if adjuvant chemotherapy is needed in early stage node negative, hormone receptor positive, HER-2 negative breast cancer. In current American society of clinical oncology (ASCO) guidelines there is little or no benefit of adjuvant chemotherapy in patients older than 50 years whose tumors have Oncotype DX RS <26, and for patients 50 years or less whose tumors have Oncotype DX RS <16. We sought to evaluate the percentage of estrogen receptor (ER) expression as a surrogate measure of determining adjuvant chemotherapy by examining the relationship between ER expression and RS. Methods: We identified 301 patients from years 2015 to 2019 from our cancer registry with early stage hormone receptor positive breast cancer and had oncotype DX testing performed. We divided patients into three groups: Group 1 (ERG1) with ER <10%; Group 2 (ERG2) with ER 10-49%; and Group 3 (ERG3) with ER equal or >50%. We also collected information on tumor size (cm), tumor grade, Nottingham score, and ki-67 percentage. A sub-group analysis was performed for patients < 50 years age (n=30). We compared all continuous variables across ER groups using the Kruskal-Wallis rank test and individual between group comparisons using the Wilcoxon rank sum test. All statistical tests performed utilized a two-tailed p value of <0.05 with the Bonferroni correction for multiple comparisons. Results: Among 301 patients with early stage hormone receptor positive breast cancer, 89.1% were ductal, 7.9% lobular, and 2.9% mixed histology. Median age was 68, 58 and 66 for ERG1, ERG2, and ERG3, respectively (p = 0.41). Median RS was 36 (ERG1), 23 (ERG2), and 16 (ERG3) (p = 0.78 for ERG1 vs. ERG2; p = 0.01 for ERG1 vs. ERG3). As expected, tumor grade, tumor size, and Nottingham score decreased significantly from ERG1 to ERG3. For patients <50 years, median age was 44, 46 and 45 for ERG1, ERG2, and ERG3, respectively (p = 0.75). Median RS was 10 (ERG1), 24 (ERG2) and 18 (ERG3) (p = 0.04 for ERG1 vs. ERG2; p = 0.17 for ERG1 vs. ERG3). Conclusions: We found a significant association between estrogen receptor levels and Oncotype Dx recurrence score (RS) in patients with early stage hormone receptor positive breast cancer patients. Further studies are needed to determine the predictive ability of hormone receptor levels on the outcomes of patients treated for early stage hormone receptor positive breast cancer.

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De Backer, Marianne D., Tatiana Ilyina, Xiao-Jun Ma, Sandy Vandoninck, Walter H. M. L. Luyten e Hugo Vanden Bossche. "Genomic Profiling of the Response of Candida albicans to Itraconazole Treatment Using a DNA Microarray". Antimicrobial Agents and Chemotherapy 45, n. 6 (1 giugno 2001): 1660–70. http://dx.doi.org/10.1128/aac.45.6.1660-1670.2001.

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ABSTRACT The application of genome-wide expression profiling to determine how drugs achieve their therapeutic effect has provided the pharmaceutical industry with an exciting new tool for drug mode-of-action studies. We used DNA chip technology to study cellular responses to perturbations of ergosterol biosynthesis caused by the broad-spectrum antifungal agent itraconazole. Simultaneous examination of over 6,600 Candida albicans gene transcript levels, representing the entire genome, upon treatment of cells with 10 μM itraconazole revealed that 296 genes were responsive. For 116 genes transcript levels were decreased at least 2.5-fold, while for 180 transcript levels were similarly increased. A global upregulation ofERG genes in response to azole treatment was observed.ERG11 and ERG5 were found to be upregulated approximately 12-fold. In addition, a significant upregulation was observed for ERG6, ERG1, ERG3, ERG4, ERG10, ERG9, ERG26, ERG25, ERG2, IDII, HMGS, NCP1, and FEN2, all of which are genes known to be involved in ergosterol biosynthesis. The effects of itraconazole on a wide variety of known metabolic processes are discussed. As over 140 proteins with unknown function were responsive to itraconazole, our analysis might provide—in combination with phenotypic data—first hints of their potential function. The present report is the first to describe the application of DNA chip technology to study the response of a major human fungal pathogen to drug treatment.

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White, Elizabeth J., Sung Jin Park, Jane A. Foster e Jan D. Huizinga. "Ether-a-go-go-related gene 3 is the main candidate for the E-4031-sensitive potassium current in the pacemaker interstitial cells of Cajal". American Journal of Physiology-Gastrointestinal and Liver Physiology 295, n. 4 (ottobre 2008): G691—G699. http://dx.doi.org/10.1152/ajpgi.90348.2008.

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The interstitial cells of Cajal (ICC), as pacemaker cells of the gut, contribute to rhythmic peristalsis and muscle excitability through initiation of slow-wave activity, which subsequently actively propagates into the musculature. An E-4031-sensitive K+ current makes a critical contribution to membrane potential in ICC. This study provides novel features of this current in ICC in physiological solutions and seeks to identify the channel isoform. In situ hybridization and Kit immunohistochemistry were combined to assess ether-a-go-go-related gene (ERG) mRNA expression in ICC in mouse jejunum, while the translated message was assessed by immunofluorescence colocalization of ERG and Kit proteins. E-4031-sensitive currents in cultured ICC were studied by the whole cell patch-clamp method, with physiological K+ concentration in the bath and the pipette. In situ hybridization combined with Kit immunohistochemistry detected m-erg1 and m-erg3, but not m-erg2, mRNA in ICC. ERG3 protein was colocalized with Kit-immunoreactive ICC in jejunum sections, but ERG1 protein was visualized only in the smooth muscle cells. At physiological K+ concentration, the E-4031-sensitive outward current in ICC was different from its counterpart in cardiac and gut smooth muscle cells. In particular, inactivation upon depolarization and recovery from inactivation by hyperpolarization were modest in ICC. In summary, the E-4031-sensitive currents influence the kinetics of the pacemaker activity in ICC and contribute to maintenance of the resting membrane potential in smooth muscle cells, which together constitute a marked effect on tissue excitability. Whereas this current is mediated by ERG1 in smooth muscle, it is primarily mediated by ERG3 in ICC.

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Yu, Li-hua, Xin Wei, Ming Ma, Xiao-jun Chen e Shuang-bo Xu. "Possible Inhibitory Molecular Mechanism of Farnesol on the Development of Fluconazole Resistance in Candida albicans Biofilm". Antimicrobial Agents and Chemotherapy 56, n. 2 (21 novembre 2011): 770–75. http://dx.doi.org/10.1128/aac.05290-11.

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ABSTRACTCandida albicansbiofilm infections are usually treated with azole antifungals such as fluconazole. However, the development of resistance to this drug inC. albicansbiofilms is very common, especially in immunocompromised individuals. The upregulation of the sterol biosynthetic pathway geneERGand the efflux pump genesCDRandMDRmay contribute to this azole tolerance inCandidaspecies. We hypothesize that farnesol, an endogenous quorum sensing molecule with possible antimicrobial properties which is also the precursor of ergosterols inC. albicans, may interfere with the development of fluconazole resistance inC. albicansbiofilms. To test this hypothesis, MICs were compared and morphology changes were observed by confocal laser scanning microscopy (CLSM) for farnesol-treated and -untreated and fluconazole-resistant groups. The expression of possible target genes (ERG11,ERG25,ERG6,ERG5,ERG3,ERG1,MDR1,CDR1, andCDR2) in biofilms was analyzed by reverse transcription-PCR (RT-PCR) and quantitative PCR (qPCR) to investigate the molecular mechanisms of the inhibitory effects of farnesol. The results showed a decreased MIC of fluconazole and thinner biofilms for the farnesol-treated group, indicating that farnesol inhibited the development of fluconazole resistance. The sterol biosynthetic pathway may contribute to the inhibitory effects of farnesol, as the transcription levels of theERG11,ERG25,ERG6,ERG3, andERG1genes decreased in the farnesol-treated group.

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Alcazar-Fuoli, Laura, Emilia Mellado, Guillermo Garcia-Effron, Maria J. Buitrago, Jordi F. Lopez, Joan O. Grimalt, J. Manuel Cuenca-Estrella e Juan L. Rodriguez-Tudela. "Aspergillus fumigatus C-5 Sterol Desaturases Erg3A and Erg3B: Role in Sterol Biosynthesis and Antifungal Drug Susceptibility". Antimicrobial Agents and Chemotherapy 50, n. 2 (febbraio 2006): 453–60. http://dx.doi.org/10.1128/aac.50.2.453-460.2006.

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ABSTRACT Two erg3 genes encoding C-5 sterol desaturase enzymes (Erg3A and Erg3B) in Aspergillus fumigatus were characterized with respect to their nucleotide sequences and null mutant phenotypes. Targeted disruption of the erg3A and erg3B genes and a double gene knockout, erg3A − erg3B −, showed that they are not essential for A. fumigatus viability. Mutant phenotypes clearly showed that Erg3B is a C-5 sterol desaturase, but no apparent role for Erg3A in A. fumigatus ergosterol biosynthesis was found. Susceptibility to amphotericin B, itraconazole, fluconazole, voriconazole, and ketoconazole was not altered in isolates in which erg3A and erg3B were knocked out alone and in combination.

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Baldus, Claudia D., Cornelia Schlee, Julia Thibaut, Sandra Heesch, Arend Bohne, Eckhard Thiel e Wolf K. Hofmann. "Differential Expression of ERG Isoforms in Acute Myeloid and T-Lymphoblastic Leukemia Is Regulated by DNA-Methylation." Blood 110, n. 11 (16 novembre 2007): 2126. http://dx.doi.org/10.1182/blood.v110.11.2126.2126.

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Abstract The oncogenic ETS transcription factor ERG is involved in various cellular pathways including developmental regulation, proliferation, and differentiation. In hematopoiesis ERG plays a specific role during normal T-cell differentiation showing high expression levels in stem cells and down regulation in the progenitor compartment. In this regard, it is intriguing that aberrant expression of ERG was found in a subset of patients with acute T-lymphoblastic leukemia (T-ALL) and was associated with an inferior outcome. Furthermore, high level ERG expression was of adverse prognostic significance in patients with newly diagnosed acute myeloid leukemia (AML), thus highlighting ERG’s potential role in myeloid as well as T-lineage leukemogenesis. ERG3 (NM_182918) and ERG2 (NM_004449) represent the main isoforms and show abundant expression in myeloid and lymphoid hematopoietic progenitor cells. The expression pattern of specific ERG isoforms in acute leukemias has yet to be investigated. To further elucidate the nature of aberrant ERG expression we have determined the existence and transcriptional regulation of ERG isoforms in pretreatment bone marrow samples of adult T-ALL (n=21) and AML (n=20) patients as well as in normal CD34+ hematopoietic cells of healthy volunteers (n=5). 5′RACE revealed the presence of a new ERG isoform (ERG3Δex12) characterized by expression of exon 5 and absence of exon 12. Expression of ERG3Δex12 was verified by RT-PCR in AML, T-ALL, and CD34+ cells. In addition, real-time RT-PCR showed concomitant expression of the two main isoforms ERG2 and ERG3 in AML and normal CD34+ cells. In contrast, T-ALL patients lacked expression of ERG isoforms harboring exon 4 (ERG2). Promoter analyses of ERG2 and ERG3 revealed the presence of two CpG islands in the ERG2 promoter region, whereas no CpG island was predicted in the ERG3 promoter. Bisulfit conversion of genomic DNA and sequencing of cloned PCR products revealed a significantly higher degree of methylation of CpG island 2 in T-ALL samples (median: 86.4%, range: 16.0 – 98.8%) as compared to AML (median: 38.1%, range: 10.9 – 60.7%; P-value=0.0002 - two sided T-test). As for CpG island 1, CD34+ cells had the lowest rate of methylation in CpG island 2 (median: 7.7%, range: 2.4 – 20.7%). Thus, the differential expression of ERG isoforms is mediated by epigenetic silencing of exon 4 containing transcripts in T-ALL. In conclusion, the identification of the new ERG isoform (ERG3Δex12) suggests the association with different partners as the central exons, including exon 12, guide the interaction with different proteins. Furthermore, the distinct expression of specific ERG transcripts controlled by methylation adds to the complexity of ERG directed downstream pathways in different leukemic subtypes.

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Martel, Claire M., Josie E. Parker, Oliver Bader, Michael Weig, Uwe Gross, Andrew G. S. Warrilow, Nicola Rolley, Diane E. Kelly e Steven L. Kelly. "Identification and Characterization of Four Azole-Resistant erg3 Mutants of Candida albicans". Antimicrobial Agents and Chemotherapy 54, n. 11 (23 agosto 2010): 4527–33. http://dx.doi.org/10.1128/aac.00348-10.

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ABSTRACT Sterol analysis identified four Candida albicans erg3 mutants in which ergosta 7,22-dienol, indicative of perturbations in sterol Δ5,6-desaturase (Erg3p) activity, comprised >5% of the total sterol fraction. The erg3 mutants (CA12, CA488, CA490, and CA1008) were all resistant to fluconazole, voriconazole, itraconazole, ketoconazole, and clotrimazole under standard CLSI assay conditions (MIC values, ≥256, 16, 16, 8, and 1 μg ml−1, respectively). Importantly, CA12 and CA1008 retained an azole-resistant phenotype even when assayed in the presence of FK506, a multidrug efflux inhibitor. Conversely, CA488, CA490, and three comparator isolates (CA6, CA14, and CA177, in which ergosterol comprised >80% of the total sterol fraction and ergosta 7,22-dienol was undetectable) all displayed azole-sensitive phenotypes under efflux-inhibited assay conditions. Owing to their ergosterol content, CA6, CA14, and CA177 were highly sensitive to amphotericin B (MIC values, <0.25 μg ml−1); CA1008, in which ergosterol comprised <2% of the total sterol fraction, was less sensitive (MIC, 1 μg ml−1). CA1008 harbored multiple amino acid substitutions in Erg3p but only a single conserved polymorphism (E266D) in sterol 14α-demethylase (Erg11p). CA12 harbored one substitution (W332R) in Erg3p and no residue changes in Erg11p. CA488 and CA490 were found to harbor multiple residue changes in both Erg3p and Erg11p. The results suggest that missense mutations in ERG3 might arise in C. albicans more frequently than currently supposed and that the clinical significance of erg3 mutants, including those in which additional mechanisms also contribute to resistance, should not be discounted.

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Chau, Andrew S., Maya Gurnani, Robyn Hawkinson, Michel Laverdiere, Anthony Cacciapuoti e Paul M. McNicholas. "Inactivation of Sterol Δ5,6-Desaturase Attenuates Virulence in Candida albicans". Antimicrobial Agents and Chemotherapy 49, n. 9 (settembre 2005): 3646–51. http://dx.doi.org/10.1128/aac.49.9.3646-3651.2005.

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ABSTRACT Two clinical Candida albicans isolates that exhibited high-level resistance to azoles and modest decreases in susceptibility to amphotericin B were cultured from unrelated patients. Both isolates harbored homozygous nonsense mutations in ERG3, which encodes an enzyme, sterol Δ5,6-desaturase, involved in ergosterol synthesis. Extraction and analysis of the sterols from both isolates confirmed the absence of sterol Δ5,6-desaturase activity. Although the loss of sterol Δ5,6-desaturase activity is known to confer resistance to azoles, this mechanism of resistance has rarely been seen in clinical isolates, suggesting that such mutants are at a competitive disadvantage. To test this hypothesis, the virulence of the erg3 mutants was assayed by using a mouse systemic infection model. The mutants were significantly less virulent than the wild-type comparator strains. However, the kidney fungal burdens in mice infected with the erg3 mutants were similar to those in mice infected with the wild-type strains. Similar results were obtained by using a laboratory-generated homozygous erg3 deletion mutant (D. Sanglard et al., Antimicrob. Agents Chemother. 47:2404-2412, 2003). Reintroduction of a wild-type ERG3 allele into the homozygous deletion mutant restored virulence, ergosterol synthesis, and susceptibility to azoles, confirming that these phenotypic changes were solely due to the inactivation of Erg3p.

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Wimmers, Sönke, Iris Wulfsen, Christiane K. Bauer e Jürgen R. Schwarz. "Erg1, erg2 and erg3 K channel subunits are able to form heteromultimers". Pfl�gers Archiv European Journal of Physiology 441, n. 4 (15 gennaio 2001): 450–55. http://dx.doi.org/10.1007/s004240000467.

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Li, Guohui, Wenxuan Fu, Yu Deng e Yunying Zhao. "Role of Calcium/Calcineurin Signalling in Regulating Intracellular Reactive Oxygen Species Homeostasis in Saccharomyces cerevisiae". Genes 12, n. 9 (25 agosto 2021): 1311. http://dx.doi.org/10.3390/genes12091311.

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The calcium/calcineurin signalling pathway is required for cell survival under various environmental stresses. Using Saccharomyces cerevisiae, we explored the mechanism underlying calcium-regulated homeostasis of intracellular reactive oxygen species (ROS). We found that deletion of acyltransferase Akr1 and C-5 sterol desaturase Erg3 increased the intracellular ROS levels and cell death, and this could be inhibited by the addition of calcium. The hexose transporter Hxt1 and the amino acid permease Agp1 play crucial roles in maintaining intracellular ROS levels, and calcium induced the expression of the HXT1 and AGP1 genes. The cytosolic calcium concentration was decreased in both the akr1Δ and erg3Δ mutants relative to wild-type cells, potentially lowering basal expression of HXT1 and AGP1. Moreover, the calcium/calcineurin signalling pathway also induced the expression of AKR1 and ERG3, indicating that Akr1 and Erg3 might perform functions that help yeast cells to survive under high calcium concentrations. Our results provided mechanistic insight into how calcium regulated intracellular ROS levels in yeast.

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Sharma, Ruby, Shanti P. Gangwar e Ajay K. Saxena. "Comparative structure analysis of the ETSi domain of ERG3 and its complex with the E74 promoter DNA sequence". Acta Crystallographica Section F Structural Biology Communications 74, n. 10 (21 settembre 2018): 656–63. http://dx.doi.org/10.1107/s2053230x1801110x.

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ERG3 (ETS-related gene) is a member of the ETS (erythroblast transformation-specific) family of transcription factors, which contain a highly conserved DNA-binding domain. The ETS family of transcription factors differ in their binding to promoter DNA sequences, and the mechanism of their DNA-sequence discrimination is little known. In the current study, crystals of the ETSi domain (the ETS domain of ERG3 containing a CID motif) in space group P41212 and of its complex with the E74 DNA sequence (DNA9) in space group C2221 were obtained and their structures were determined. Comparative structure analysis of the ETSi domain and its complex with DNA9 with previously determined structures of the ERGi domain (the ETS domain of ERG containing inhibitory motifs) in space group P65212 and of the ERGi–DNA12 complex in space group P41212 were performed. The ETSi domain is observed as a homodimer in solution as well as in the crystallographic asymmetric unit. Superposition of the structure of the ETSi domain on that of the ERGi domain showed a major conformational change at the C-terminal DNA-binding autoinhibitory (CID) motif, while minor changes are observed in the loop regions of the ETSi-domain structure. The ETSi–DNA9 complex in space group C2221 forms a structure that is quite similar to that of the ERG–DNA12 complex in space group P41212. Upon superposition of the complexes, major conformational changes are observed at the 5′ and 3′ ends of DNA9, while the conformation of the core GGA nucleotides was quite conserved. Comparison of the ETSi–DNA9 structure with known structures of ETS class 1 protein–DNA complexes shows the similarities and differences in the promoter DNA binding and specificity of the class 1 ETS proteins.

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Smith, S. J., J. H. Crowley e L. W. Parks. "Transcriptional regulation by ergosterol in the yeast Saccharomyces cerevisiae." Molecular and Cellular Biology 16, n. 10 (ottobre 1996): 5427–32. http://dx.doi.org/10.1128/mcb.16.10.5427.

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Sterol biosynthesis in the yeast Saccharomyces cerevisiae is an energy-expensive, aerobic process, requiring heme and molecular oxygen. Heme, also synthesized exclusively during aerobic growth, not only acts as an enzymatic cofactor but also is directly and indirectly responsible for the transcriptional control of several yeast genes. Because of their biosynthetic similarities, we hypothesized that ergosterol, like heme, may have a regulatory function. Sterols are known to play a structural role in membrane integrity, but regulatory roles have not been characterized. To test possible regulatory roles of sterol, the promoter for the ERG3 gene, encoding the sterol C-5 desaturase, was fused to the bacterial lacZ reporter gene. This construct was placed in strains making aberrant sterols, and the effect of altered sterol composition on gene expression was monitored by beta-galactosidase activity. The absence of ergosterol resulted in a 35-fold increase in the expression of ERG3 as measured by beta-galactosidase activity. The level of ERG3 mRNA was increased as much as ninefold in erg mutant strains or wild-type strains inhibited in ergosterol biosynthesis by antifungal agents. The observed regulatory effects of ergosterol on ERG3 are specific for ergosterol, as several ergosterol derivatives failed to elicit the same controlling effect. These results demonstrate for the first time that ergosterol exerts a regulatory effect on gene transcription in S. cerevisiae.

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Miyazaki, Taiga, Yoshitsugu Miyazaki, Koichi Izumikawa, Hiroshi Kakeya, Shunichi Miyakoshi, John E. Bennett e Shigeru Kohno. "Fluconazole Treatment Is Effective against a Candida albicans erg3/erg3 Mutant In Vivo Despite In Vitro Resistance". Antimicrobial Agents and Chemotherapy 50, n. 2 (febbraio 2006): 580–86. http://dx.doi.org/10.1128/aac.50.2.580-586.2006.

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ABSTRACT Candida albicans ERG3 encodes a sterol C5,6-desaturase which is essential for synthesis of ergosterol. Defective sterol C5,6 desaturation has been considered to be one of the azole resistance mechanisms in this species. However, the clinical relevance of this resistance mechanism is still unclear. In this study, we created a C. albicans erg3/erg3 mutant by the “Ura-blaster” method and confirmed the expected azole resistance using standard in vitro testing and the presence of ergosta-7,22-dien-3β-ol instead of ergosterol. For in vivo studies, a wild-type URA3 was placed back into its native locus in the erg3 homozygote to avoid positional effects on URA3 expression. Defective hyphal formation of the erg3 homozygote was observed not only in vitro but in kidney tissues. A marked attenuation of virulence was shown by the longer survival and the lower kidney burdens of mice inoculated with the reconstituted Ura+ erg3 homozygote relative to the control. To assess fluconazole efficacy in a murine model of disseminated candidiasis, inoculum sizes of the control and the erg3 homozygote were chosen which provided a similar organ burden. Under these conditions, fluconazole was highly effective in reducing the organ burden in both groups. This study demonstrates that an ERG3 mutation causing inactivation of sterol C5,6-desaturase cannot confer fluconazole resistance in vivo by itself regardless of resistance measured by standard in vitro testing. The finding questions the clinical significance of this resistance mechanism.

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Hirayama, Tatsuro, Taiga Miyazaki, Makoto Sumiyoshi, Nobuyuki Ashizawa, Takahiro Takazono, Kazuko Yamamoto, Yoshifumi Imamura et al. "ERG3-Encoding Sterol C5,6-DESATURASE in Candida albicans Is Required for Virulence in an Enterically Infected Invasive Candidiasis Mouse Model". Pathogens 10, n. 1 (31 dicembre 2020): 23. http://dx.doi.org/10.3390/pathogens10010023.

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Gastrointestinal colonization by Candida species is considered the main source of candidemia. The ERG3 gene in Candida albicans encodes a sterol C5,6-desaturase, which is essential for ergosterol biosynthesis. Although ERG3 inactivation shows reduced virulence in mouse models of disseminated candidiasis, the role of ERG3 in intestinal infections is unknown. Here, we infected mice with the C. albicans strains CAE3DU3 and CAF2-1, containing mutant and wild-type ERG3, respectively, and studied gut infection and colonization by these strains. We found that the CAE3DU3 strain showed reduced colonization, pathogenesis, damage to gut mucosa, and chemokine production in the mouse model of invasive candidiasis. Additionally, mice inoculated with CAE3DU3 showed lower mortality than mice inoculated with CAF2-1 (p < 0.0001). Chemokines were less induced in the gut inoculated with CAE3DU3 than in the gut inoculated with CAF2-1. Histopathologically, although the wild-type gene was associated with a higher pathogenicity and invasion of the gut mucosa and liver tissues causing remarkable tissue necrosis, the erg3/erg3 mutant was associated with a higher accumulation of cells and lower damage to surrounding tissues than wild-type ERG3. These results establish that the ergosterol biosynthetic pathway may be associated with C. albicans gut colonization and subsequent dissemination.

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Yadav, Anamika, Anubhav Singh, Yue Wang, Merlijn HI van Haren, Ashutosh Singh, Theun de Groot, Jacques F. Meis, Jianping Xu e Anuradha Chowdhary. "Colonisation and Transmission Dynamics of Candida auris among Chronic Respiratory Diseases Patients Hospitalised in a Chest Hospital, Delhi, India: A Comparative Analysis of Whole Genome Sequencing and Microsatellite Typing". Journal of Fungi 7, n. 2 (26 gennaio 2021): 81. http://dx.doi.org/10.3390/jof7020081.

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Candida auris is a nosocomial pathogen responsible for an expanding global public health threat. This ascomycete yeast has been frequently isolated from hospital environments, representing a significant reservoir for transmission in healthcare settings. Here, we investigated the relationships among C. auris isolates from patients with chronic respiratory diseases admitted in a chest hospital and from their fomites, using whole-genome sequencing (WGS) and multilocus microsatellite genotyping. Overall, 37.5% (n = 12/32) patients developed colonisation by C. auris including 9.3% of the screened patients that were colonised at the time of admission and 75% remained colonised till discharge. Furthermore, 10% of fomite samples contained C. auris in rooms about 8.5 days after C. auris colonised patients were admitted. WGS and microsatellite typing revealed that multiple strains contaminated the fomites and colonised different body sites of patients. Notably, 37% of C. auris isolates were resistant to amphotericin B but with no amino acid substitution in ERG2, ERG3, ERG5, and ERG6 as compared to the reference strain B8441 in any of our strains. In addition, 55% of C. auris isolates likely had two copies of the MDR1 gene. Our results suggest significant genetic and ecological diversities of C. auris in healthcare setting. The WGS and microsatellite genotyping methods provided complementary results in genotype identification.

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Sanglard, Dominique, Françoise Ischer, Tania Parkinson, Derek Falconer e Jacques Bille. "Candida albicans Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents". Antimicrobial Agents and Chemotherapy 47, n. 8 (agosto 2003): 2404–12. http://dx.doi.org/10.1128/aac.47.8.2404-2412.2003.

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ABSTRACT The role of sterol mutations in the resistance of Candida albicans to antifungal agents has not been thoroughly investigated. Previous work reported that clinical C. albicans strains resistant to both azole antifungals and amphotericin B were defective in ERG3, a gene encoding sterol Δ5,6-desaturase. It is also believed that a deletion of the lanosterol 14α-demethylase gene, ERG11, is possible only under aerobic conditions when ERG3 is not functional. We tested these hypotheses by creating mutants by targeted deletion of the ERG3 and ERG11 genes and subjecting those mutants to antifungal susceptibility testing and sterol analysis. The homozygous erg3/erg3 mutant created, DSY1751, was resistant to azole derivatives, as expected. This mutant was, however, slightly more susceptible to amphotericin B than the parent wild type. It was possible to generate erg11/erg11 mutants in the DSY1751 background but also, surprisingly, in the background of a wild-type isolate with functional ERG3 alleles under aerobic conditions. This mutant (DSY1769) was obtained by exposure of an ERG11/erg11 heterozygous strain in a medium containing 10 μg of amphotericin B per ml. Amphotericin B-resistant strains were obtained only from ERG11/erg11 heterozygotes at a frequency of approximately 5 × 10−5 to 7 × 10−5, which was consistent with mitotic recombination between the first disrupted erg11 allele and the other remaining functional ERG11 allele. DSY1769 was also resistant to azole derivatives. The main sterol fraction in DSY1769 contained lanosterol and eburicol. These studies showed that erg11/erg11 mutants of a C. albicans strain harboring a defective erg11 allele can be obtained in vitro in the presence of amphotericin B. Amphotericin B-resistant strains could therefore be selected by similar mechanisms during antifungal therapy.

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Lo, Hsiu-Jung, Jang-Shiun Wang, Chih-Yang Lin, Chia-Geun Chen, Ting-Yin Hsiao, Chia-Tung Hsu, Chia-Li Su, Ming-Ji Fann, Yu-Tai Ching e Yun-Liang Yang. "Efg1 Involved in Drug Resistance by Regulating the Expression of ERG3 in Candida albicans". Antimicrobial Agents and Chemotherapy 49, n. 3 (marzo 2005): 1213–15. http://dx.doi.org/10.1128/aac.49.3.1213-1215.2005.

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ABSTRACT The ERG3 gene in Candida albicans was identified as a gene whose mRNA level was higher in the cph1/cph1 efg1/efg1 double mutant than in the wild-type cells. Further study showed that Efg1, but not Cph1, negatively regulated ERG3. Mutations in EFG1 consistently increased the susceptibility of the cells to antifungal agents.

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Xia, Zhikuan, Haiying Yu, Congmin Wang, Xiao Ding, Dequan Zhang, Xinyu Tan, Jianghan Chen, Songnian Hu e Rongya Yang. "Genomic and transcriptome identification of fluconazole-resistant genes for Trichosporon asahii". Medical Mycology 58, n. 3 (22 agosto 2019): 393–400. http://dx.doi.org/10.1093/mmy/myz088.

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Abstract Trichosporon asahii infection is difficult to control clinically. This study identified a case with over 15 years of T. asahii infection-related systemic dissemination disease and conducted genome and transcriptome sequencing to identify fluconazole-resistant genes in fluconazole-resistant versus susceptible strains isolated from this patient's facial skin lesions. The data revealed mutations of the ergosterol biosynthetic pathway-related genes in the T. asahii genome of the fluconazole-resistant strain, that is, there were 36 novel mutations of the ERG11 gene, three point mutations (V458L, D457V, and D334S) in the ERG3, and a missense mutation (E349D) in ERG5 in the fluconazole-resistant strain of the T. asahii genome. To ensure that ERG11 is responsible for the fluconazole resistance, we thus simultaneously cultured the strains in vitro and cloned the ERG11 CDS sequences of both fluconazole-susceptible and -resistant strains into the Saccharomyces cerevisiae. These experiments confirmed that these mutations of ERG11 gene affected fluconazole resistance (> 64 μg/ml vs. <8 μg/ml of the MIC value between fluconazole-resistant and -susceptible strains) in Saccharomyces cerevisiae. In addition, expression of ergosterol biosynthesis pathway genes and drug transporter was upregulated in the fluconazole-resistant strain of T. asahii. Collectively, the fluconazole resistance in this female patient was associated with mutations of ERG11, ERG3, and ERG5 and the differential expression of drug transporter and fatty acid metabolic genes.

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Simons, Veronika, John P. Morrissey, Maita Latijnhouwers, Michael Csukai, Adam Cleaver, Carol Yarrow e Anne Osbourn. "Dual Effects of Plant Steroidal Alkaloids on Saccharomyces cerevisiae". Antimicrobial Agents and Chemotherapy 50, n. 8 (agosto 2006): 2732–40. http://dx.doi.org/10.1128/aac.00289-06.

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ABSTRACT Many plant species accumulate sterols and triterpenes as antimicrobial glycosides. These secondary metabolites (saponins) provide built-in chemical protection against pest and pathogen attack and can also influence induced defense responses. In addition, they have a variety of important pharmacological properties, including anticancer activity. The biological mechanisms underpinning the varied and diverse effects of saponins on microbes, plants, and animals are only poorly understood despite the ecological and pharmaceutical importance of this major class of plant secondary metabolites. Here we have exploited budding yeast (Saccharomyces cerevisiae) to investigate the effects of saponins on eukaryotic cells. The tomato steroidal glycoalkaloidα -tomatine has antifungal activity towards yeast, and this activity is associated with membrane permeabilization. Removal of a single sugar from the tetrasaccharide chain of α-tomatine results in a substantial reduction in antimicrobial activity. Surprisingly, the complete loss of sugars leads to enhanced antifungal activity. Experiments with α-tomatine and its aglycone tomatidine indicate that the mode of action of tomatidine towards yeast is distinct from that of α-tomatine and does not involve membrane permeabilization. Investigation of the effects of tomatidine on yeast by gene expression and sterol analysis indicate that tomatidine inhibits ergosterol biosynthesis. Tomatidine-treated cells accumulate zymosterol rather than ergosterol, which is consistent with inhibition of the sterol C24 methyltransferase Erg6p. However, erg6 and erg3 mutants (but not erg2 mutants) have enhanced resistance to tomatidine, suggesting a complex interaction of erg mutations, sterol content, and tomatidine resistance.

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Papa, Michele, Francesca Boscia, Adriana Canitano, Pasqualina Castaldo, Stefania Sellitti, Lucio Annunziato e Maurizio Taglialatela. "Expression pattern of the ether-a-gogo-related (ERG) k+ channel-encoding genes ERG1, ERG2, and ERG3 in the adult rat central nervous system". Journal of Comparative Neurology 466, n. 1 (19 settembre 2003): 119–35. http://dx.doi.org/10.1002/cne.10886.

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21

Simone, Polvani, Masi Alessio, Pillozzi Serena, Gragnani Laura, Crociani Olivia, Olivotto Massimo, Becchetti Andrea, Wanke Enzo e Arcangeli Annarosa. "Developmentally regulated expression of the mouse homologues of the potassium channel encoding genes m-erg1, m-erg2 and m-erg3". Gene Expression Patterns 3, n. 6 (dicembre 2003): 767–76. http://dx.doi.org/10.1016/s1567-133x(03)00124-8.

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22

Liu, Teresa T., Robin E. B. Lee, Katherine S. Barker, Richard E. Lee, Lai Wei, Ramin Homayouni e P. David Rogers. "Genome-Wide Expression Profiling of the Response to Azole, Polyene, Echinocandin, and Pyrimidine Antifungal Agents in Candida albicans". Antimicrobial Agents and Chemotherapy 49, n. 6 (giugno 2005): 2226–36. http://dx.doi.org/10.1128/aac.49.6.2226-2236.2005.

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ABSTRACT Antifungal agents exert their activity through a variety of mechanisms, some of which are poorly understood. We examined changes in the gene expression profile of Candida albicans following exposure to representatives of the four currently available classes of antifungal agents used in the treatment of systemic fungal infections. Ketoconazole exposure increased expression of genes involved in lipid, fatty acid, and sterol metabolism, including NCP1, MCR1, CYB5, ERG2, ERG3, ERG10, ERG25, ERG251, and that encoding the azole target, ERG11. Ketoconazole also increased expression of several genes associated with azole resistance, including CDR1, CDR2, IFD4, DDR48, and RTA3. Amphotericin B produced changes in the expression of genes involved in small-molecule transport (ENA21), and in cell stress (YHB1, CTA1, AOX1, and SOD2). Also observed was decreased expression of genes involved in ergosterol biosynthesis, including ERG3 and ERG11. Caspofungin produced changes in expression of genes encoding cell wall maintenance proteins, including the β-1,3-glucan synthase subunit GSL22, as well as PHR1, ECM21, ECM33, and FEN12. Flucytosine increased the expression of proteins involved in purine and pyrimidine biosynthesis, including YNK1, FUR1, and that encoding its target, CDC21. Real-time reverse transcription-PCR was used to confirm microarray results. Genes responding similarly to two or more drugs were also identified. These data shed new light on the effects of these classes of antifungal agents on C. albicans.

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Davies, Brandon S. J., Helen S. Wang e Jasper Rine. "Dual Activators of the Sterol Biosynthetic Pathway of Saccharomyces cerevisiae: Similar Activation/Regulatory Domains but Different Response Mechanisms". Molecular and Cellular Biology 25, n. 16 (15 agosto 2005): 7375–85. http://dx.doi.org/10.1128/mcb.25.16.7375-7385.2005.

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ABSTRACT Genes encoding biosynthetic enzymes that make ergosterol, the major fungal membrane sterol, are regulated, in part, at the transcriptional level. Two transcription factors, Upc2p and Ecm22p, bind to the promoters of most ergosterol biosynthetic (ERG) genes, including ERG2 and ERG3, and activate these genes upon sterol depletion. We have identified the transcriptional activation domains of Upc2p and Ecm22p and found that UPC2-1, a mutation that allows cells to take up sterols aerobically, increased the potency of the activation domain. The equivalent mutation in ECM22 also greatly enhanced transcriptional activation. The C-terminal regions of Upc2p and Ecm22p, which contained activation domains, also conferred regulation in response to sterol levels. Hence, the activation and regulatory domains of these proteins overlapped. However, the two proteins differed markedly in how they respond to an increased need for sterols. Upon inducing conditions, Upc2p levels increased, and chromatin immunoprecipitation experiments revealed more Upc2p at promoters even when the activation/regulatory domains were tethered to a different DNA-binding domain. However, induction resulted in decreased Ecm22p levels and a corresponding decrease in the amount of Ecm22p bound to promoters. Thus, these two activators differ in their contributions to the regulation of their targets.

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Lotfali, Ensieh, Ali Ghajari, Parivash Kordbacheh, Farideh Zaini, Hossein Mirhendi, Rasoul Mohammadi, Fatemeh Noorbakhsh e Sassan Rezaie. "Regulation of ERG3, ERG6, and ERG11 Genes in Antifungal-Resistant isolates of Candida parapsilosis". Iranian Biomedical Journal 21, n. 4 (1 luglio 2017): 275–81. http://dx.doi.org/10.18869/acadpub.ibj.21.4.275.

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25

Vik, Åshild, e Jasper Rine. "Upc2p and Ecm22p, Dual Regulators of Sterol Biosynthesis in Saccharomyces cerevisiae". Molecular and Cellular Biology 21, n. 19 (1 ottobre 2001): 6395–405. http://dx.doi.org/10.1128/mcb.21.19.6395-6405.2001.

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Abstract (sommario):

ABSTRACT Sterol levels affect the expression of many genes in yeast and humans. We found that the paralogous transcription factors Upc2p and Ecm22p of yeast were sterol regulatory element (SRE) binding proteins (SREBPs) responsible for regulating transcription of the sterol biosynthetic genes ERG2 and ERG3. We defined a 7-bp SRE common to these and other genes, including many genes involved in sterol biosynthesis. Upc2p and Ecm22p activatedERG2 expression by binding directly to this element in the ERG2 promoter. Upc2p and Ecm22p may thereby coordinately regulate genes involved in sterol homeostasis in yeast. Ecm22p and Upc2p are members of the fungus-specific Zn[2]-Cys[6] binuclear cluster family of transcription factors and share no homology to the analogous proteins, SREBPs, that are responsible for transcriptional regulation by sterols in humans. These results suggest that Saccharomyces cerevisiae and human cells regulate sterol synthesis by different mechanisms.

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26

Anderson, James B., Caroline Sirjusingh, Ainslie B. Parsons, Charles Boone, Claire Wickens, Leah E. Cowen e Linda M. Kohn. "Mode of Selection and Experimental Evolution of Antifungal Drug Resistance in Saccharomyces cerevisiae". Genetics 163, n. 4 (1 aprile 2003): 1287–98. http://dx.doi.org/10.1093/genetics/163.4.1287.

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Abstract We show that mode of selection, degree of dominance of mutations, and ploidy are determining factors in the evolution of resistance to the antifungal drug fluconazole in yeast. In experiment 1, yeast populations were subjected to a stepwise increase in fluconazole concentration over 400 generations. Under this regimen, two mutations in the same two chromosomal regions rose to high frequency in parallel in three replicate populations. These mutations were semidominant and additive in their effect on resistance. The first of these mutations mapped to PDR1 and resulted in the overexpression of the ABC transporter genes PDR5 and SNQ2. These mutations had an unexpected pleiotropic effect of reducing the residual ability of the wild type to reproduce at the highest concentrations of fluconazole. In experiment 2, yeast populations were subjected to a single high concentration of fluconazole. Under this regimen, a single recessive mutation appeared in each of three replicate populations. In a genome-wide screen of ∼4700 viable deletion strains, 13 were classified as resistant to fluconazole (ERG3, ERG6, YMR102C, YMR099C, YPL056C, ERG28, OSH1, SCS2, CKA2, SML1, YBR147W, YGR283C, and YLR407W). The mutations in experiment 2 all mapped to ERG3 and resulted in the overexpression of the gene encoding the drug target ERG11, but not PDR5 and SNQ2. Diploid hybrids from experiments 1 and 2 were less fit than the parents in the presence of fluconazole. In a variation of experiment 2, haploids showed a higher frequency of resistance than diploids, suggesting that degree of dominance and ploidy are important factors in the evolution of antifungal drug resistance.

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Yu, Lu, Wenliang Zhang, Lingling Wang, Jian Yang, Tao Liu, Junping Peng, Wenchuan Leng, Lihong Chen, Ruoyu Li e Qi Jin. "Transcriptional Profiles of the Response to Ketoconazole and Amphotericin B in Trichophyton rubrum". Antimicrobial Agents and Chemotherapy 51, n. 1 (23 ottobre 2006): 144–53. http://dx.doi.org/10.1128/aac.00755-06.

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ABSTRACT Trichophyton rubrum is a pathogenic filamentous fungus of increasing medical concern. Two antifungal agents, ketoconazole (KTC) and amphotericin B (AMB), have specific activity against dermatophytes. To identify the mechanisms of action of KTC and AMB against T. rubrum, a cDNA microarray was constructed from the expressed sequence tags of the cDNA library from different developmental stages, and transcriptional profiles of the responses to KTC and AMB were determined. T. rubrum was exposed to subinhibitory concentrations of KTC and AMB for 12 h, and microarray analysis was used to examine gene transcription. KTC exposure induced transcription of genes involved in lipid, fatty acid, and sterol metabolism, including ERG11, ERG3, ERG25, ERG6, ERG26, ERG24, ERG4, CPO, INO1, DW700960, CPR, DW696584, DW406350, and ATG15. KTC also increased transcription of the multidrug resistance gene ABC1. AMB exposure increased transcription of genes involved in lipid, fatty acid, and sterol metabolism (DW696584, EB801458, IVD, DW694010, DW688343, DW684992), membrane transport (Git1, DW706156, DW684040, DMT, DW406136, CCH1, DW710650), and stress-related responses (HSP70, HSP104, GSS, AOX, EB801455, EB801702, TDH1, UBI4) but reduced transcription of genes involved in maintenance of cell wall integrity and signal transduction pathways (FKS1, SUN4, DW699324, GAS1, DW681613, SPS1, DW703091, STE7, DW703091, DW695308) and some ribosomal proteins. This is the first report of the use of microarray analysis to determine the effects of drug action in T. rubrum.

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Anderson, James B., Nicole Ricker e Caroline Sirjusingh. "Antagonism between Two Mechanisms of Antifungal Drug Resistance". Eukaryotic Cell 5, n. 8 (agosto 2006): 1243–51. http://dx.doi.org/10.1128/ec.00048-06.

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ABSTRACT This study tested for interaction between two independently evolved mechanisms of fluconazole resistance in Saccharomyces cerevisiae. One set of strains was from a 400-generation evolution experiment, during which the concentration of fluconazole was increased from 16 to 256 μg/ml in four increments. At 100 generations, populations became fixed for resistance mutations in either of two transcriptional regulators, PDR1 or PDR3. At 400 generations, replicate populations became fixed for another resistance mutation in UNK1, an unmapped gene further increasing resistance. Another genotype used in this study came from a population placed initially in 128 μg/ml of fluconazole; this environment selects for resistance through loss of function at ERG3, resulting in altered sterol metabolism. Mutant strains carrying PDR1 r or PDR3 r were crossed with the erg3 r mutant strain, and the doubly mutant, haploid offspring were identified. The double-mutant strains grew less well than the parent strains at all concentrations of fluconazole tested. In genome-wide assays of gene expression, several ABC transporter genes that were overexpressed in one parent and several ERG genes that were overexpressed in the other parent were also overexpressed in the double mutants. Of the 43 genes that were consistently overexpressed in the PDR1 r parents at generation 100, however, 31 were not consistently overexpressed in the double mutants. Of these 31 genes, 30 were also not consistently overexpressed after a further 300 generations of evolution in the PDR1 r parent populations. The two independently evolved mechanisms of fluconazole resistance are strongly antagonistic to one another.

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Schledermann, Wiebke, Iris Wulfsen, Jürgen R. Schwarz e Christiane K. Bauer. "Modulation of rat erg1, erg2, erg3 and HERG K + currents by thyrotropin‐releasing hormone in anterior pituitary cells via the native signal cascade". Journal of Physiology 532, n. 1 (aprile 2001): 143–63. http://dx.doi.org/10.1111/j.1469-7793.2001.0143g.x.

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30

OuYang, Qiuli, Yangmei Liu, Okwong Reymick Oketch, Miaoling Zhang, Xingfeng Shao e Nengguo Tao. "Citronellal Exerts Its Antifungal Activity by Targeting Ergosterol Biosynthesis in Penicillium digitatum". Journal of Fungi 7, n. 6 (29 maggio 2021): 432. http://dx.doi.org/10.3390/jof7060432.

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Ergosterol (ERG) is a potential target for the development of antifungal agents against Penicillium digitatum, the pathogen of green mold in citrus fruits. This study examined the mechanism by which citronellal, a typical terpenoid of Cymbopogon nardus essential oil, acts on ergosterol to exhibit its antifungal activity against P. digitatum. We previously reported that citronellal inhibited the growth of P. digitatum with minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of 1.36 and 2.72 mg/mL, respectively. In citronellal-treated cells, the membrane integrity and ergosterol contents significantly decreased, whereas lanosterol, which serves as a precursor for ergosterol biosynthesis, massively accumulated. Addition of 150 mg/L of exogenous ergosterol decreased the inhibitory rate of citronellal, restoring the ergosterol content and hence the membrane structure to normal levels, and triggered expression of nearly all ERG genes. Based on our findings, we deduce that citronellal damages the cell membrane integrity of P. digitatum by down-regulating the ERG genes responsible for conversion of lanosterol to ergosterol, the key downregulated gene being ERG3, due to the observed accumulation of ergosta-7,22-dienol.

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Cowen, Leah E., Anne E. Carpenter, Oranart Matangkasombut, Gerald R. Fink e Susan Lindquist. "Genetic Architecture of Hsp90-Dependent Drug Resistance". Eukaryotic Cell 5, n. 12 (20 ottobre 2006): 2184–88. http://dx.doi.org/10.1128/ec.00274-06.

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ABSTRACT Hsp90 potentiates the evolution of azole resistance in the model yeast Saccharomyces cerevisiae and the opportunistic pathogen Candida albicans via calcineurin. Here, we explored effectors downstream of calcineurin regulating this Hsp90-dependent trait. Using S. cerevisiae erg3 mutants as a model, we determined that both Crz1 and Hph1 modulate azole resistance.

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Young, Laura Y., Christina M. Hull e Joseph Heitman. "Disruption of Ergosterol Biosynthesis Confers Resistance to Amphotericin B in Candida lusitaniae". Antimicrobial Agents and Chemotherapy 47, n. 9 (settembre 2003): 2717–24. http://dx.doi.org/10.1128/aac.47.9.2717-2724.2003.

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ABSTRACT Candida lusitaniae is an emerging human pathogen that, unlike other fungal pathogens, frequently develops resistance to the commonly used antifungal agent amphotericin B. Amphotericin B is a member of the polyene class of antifungal drugs, which impair fungal cell membrane integrity. Here we analyzed mechanisms contributing to amphotericin B resistance in C. lusitaniae. Sensitivity to polyenes in the related fungi Saccharomyces cerevisiae and Candida albicans requires the ergosterol biosynthetic gene ERG6. In an effort to understand the mechanisms contributing to amphotericin B resistance in C. lusitaniae, we isolated the ERG6 gene and created a C. lusitaniae erg6Δ strain. This mutant strain exhibited a growth defect, was resistant to amphotericin B, and was hypersensitive to other sterol inhibitors. Based on the similarities between the phenotypes of the erg6Δ mutant and clinical isolates of C. lusitaniae resistant to amphotericin B, we analyzed ERG6 expression levels and ergosterol content in multiple clinical isolates. C. lusitaniae amphotericin B-resistant isolates were found to have increased levels of ERG6 transcript as well as reduced ergosterol content. These changes suggest that another gene in the ergosterol biosynthetic pathway could be mutated or misregulated. Further transcript analysis showed that expression of the ERG3 gene, which encodes C-5 sterol desaturase, was reduced in two amphotericin B-resistant isolates. Our findings reveal that mutation or altered expression of ergosterol biosynthetic genes can result in resistance to amphotericin B in C. lusitaniae.

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Markovich, Sarit, Aya Yekutiel, Itamar Shalit, Yona Shadkchan e Nir Osherov. "Genomic Approach to Identification of Mutations Affecting Caspofungin Susceptibility in Saccharomyces cerevisiae". Antimicrobial Agents and Chemotherapy 48, n. 10 (ottobre 2004): 3871–76. http://dx.doi.org/10.1128/aac.48.10.3871-3876.2004.

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ABSTRACT The antifungal agent caspofungin (CAS) specifically interferes with glucan synthesis and cell wall formation. To further study the cellular processes affected by CAS, we analyzed a Saccharomyces cerevisiae mutant collection (4,787 individual knockout mutations) to identify new genes affecting susceptibility to the drug. This collection was screened for increased CAS sensitivity (CAS-IS) or increased CAS resistance (CAS-IR). MICs were determined by the broth microdilution method. Disruption of 20 genes led to CAS-IS (four- to eightfold reductions in the MIC). Eleven of the 20 genes are involved in cell wall and membrane function, notably in the protein kinase C (PKC) integrity pathway (MID2, FKS1, SMI1, and BCK1), chitin and mannan biosynthesis (CHS3, CHS4, CHS7, and MNN10), and ergosterol biosynthesis (ERG5 and ERG6). Four of the 20 genes (TPO1, VPS65, VPS25, and CHC1) are involved in vacuole and transport functions, 3 of the 20 genes (CCR4, POP2, and NPL3) are involved in the control of transcription, and 2 of the 20 genes are of unknown function. Disruption of nine additional genes led to CAS-IR (a fourfold increase of MIC). Five of these nine genes (SLG1, ERG3, VRP1, CSG2, and CKA2) are involved in cell wall function and signal transduction, and two of the nine genes (VPS67 and SAC2) are involved in vacuole function. To assess the specificity of susceptibility to CAS, the MICs of amphotericin B, fluconazole, flucytosine, and calcofluor for the strains were tested. Seven of 20 CAS-IS strains (with disruption of FKS1, SMI1, BCK1, CHS4, ERG5, TPO1, and ILM1) and 1 of 9 CAS-IR strains (with disruption of SLG1) demonstrated selective susceptibility to CAS. To further explore the importance of PKC in CAS susceptibility, the activity of the PKC inhibitor staurosporine in combination with CAS was tested against eight Aspergillus clinical isolates by the microdilution assay. Synergistic or synergistic-to-additive activities were found against all eight isolates by use of both MIC and minimum effective concentration endpoints.

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Kang, Jiesheng, Xiao-Liang Chen e David Rampe. "The Antipsychotic Drugs Sertindole and Pimozide Block erg3, a Human Brain K+ Channel". Biochemical and Biophysical Research Communications 286, n. 3 (agosto 2001): 499–504. http://dx.doi.org/10.1006/bbrc.2001.5434.

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Klein, E. A., S. M. Falzarano, T. Maddala, D. Cherbavaz, W. F. Novotny, C. Millward e C. Magi-Galluzzi. "Use of TMPRSS2-ERG gene rearrangement and quantitative ERG expression to predict clinical recurrence after radical prostatectomy." Journal of Clinical Oncology 29, n. 7_suppl (1 marzo 2011): 36. http://dx.doi.org/10.1200/jco.2011.29.7_suppl.36.

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36 Background: The association of TMPRSS2-ERG fusions and ERG expression in prostate cancer (PC) with adverse clinical outcomes has been controversial, with mixed results in the literature. We conducted a study to test whether tumor-derived gene expression profiles, including the presence of TMPRSS2-ERG fusions and ERG gene expression, are associated with clinical recurrence (cR) after radical prostatectomy (RP). Methods: All patients with clinical stage T1/T2 prostate cancer treated with RP at CC from 1987 to 2004 were identified (n∼f2,600). A cohort sampling design was used to select 127 patients with cR and 374 patients without cR after RP. For each patient a primary Gleason pattern (GP) sample, secondary (or highest) GP sample, and an adjacent nontumor tissue sample were evaluated. Surgical Gleason Score (GS) and clinical data were centrally reviewed. RNA was extracted from 6 manually dissected 10 μ m formalin-fixed paraffin-embedded sections obtained from RP specimens and expression of TMPRSS2-ERGa, TMPRSS2-ERGb, ERG and reference genes were quantified using RT-PCR. Times to cR, PSA recurrence, and PC death were analyzed using Cox PH regression. Results: Blocks from 441 patients were evaluable. Median F/U was 5.8 years. Patients were mostly Caucasian (83%), clinical stage T1 (66%), had baseline PSA <10 ng/mL (82%), and had surgical Gleason score ≤7 (87%). 848 tumor samples and 410 non-tumor samples were assessed. TMPRSS2-ERGa and/or TMPRSS2-ERGb fusions were present in 51.8% of tumor samples and 7.5% of non-tumor samples. There was 89% concordance (95% CI: 86%, 92%) for TMPRSS2-ERG fusion status between the 2 tumor samples for each patient. High ERG expression was strongly associated with the presence of TMPRSS2-ERG fusions (p <0.01). We did not find an association between TMPRSS2-ERG a/b gene rearrangement or ERG expression with cR, PSA recurrence, PC death, or surgical GS (p > 0.2). Conclusions: This study was notable for the large number of cR events, use of a standardized quantitative assay, and rigorous central review of pathology and clinical data. We did not find an association of TMPRSS2-ERG gene rearrangements or ERG expression with aggressiveness of prostate cancer post RP. [Table: see text]

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Smooha, Gil, Yehudit Birger, Liat Goldberg, Jasmine Jacob-Hirsch, Ninette Amariglio, Gideon Rechavi, Ditsa Levanon et al. "MODELING and Targeting ERG-INDUCED Acute MYELOID LEUKEMIA (AML)." Blood 114, n. 22 (20 novembre 2009): 475. http://dx.doi.org/10.1182/blood.v114.22.475.475.

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Abstract Abstract 475 ERG is an oncogene located on the long arm of human chromosome 21 that encodes an ETS transcription factor that has been reported to be involved in normal and aberrant megakaryopoiesis (Salek-Ardakani et al Cancer Res. 2009;69:4665; Stankiewicz et al Blood 2009;113:3337). High ERG expression has also been reported associated with poor prognosis of cytogenetically normal AML (Marcucci et al J Clin Oncol. 2007;25:3337). Thus, deciphering the molecular targets and oncogenic pathways activated by overexpressed ERG protein is likely to lead to more effective therapy for ERG-related myeloid leukemias. Towards these goals we have combined in-vitro and in-vivo approaches. We have created transgenic mice expressing the ERG3 hematopoietic isoform under the VAV promoter. All these mice die from invasive acute megakaryocytic or undifferentiated myeloid leukemia by the age of 5 months. The leukemias are transplantable, and primary growth factor dependent leukemic cell lines, suitable for pharmacological and molecular studies, have been established. To identify ERG target genes and proteins, we have analyzed gene expression in two “mirror-image” cellular systems – shRNA mediated knockdown of ERG in Meg01 megakaryocytic leukemia cells and overexpression of ERG in K562 erythroleukemia cells. Gene Set Enrichment Analysis (GSEA) demonstrated that the “ERG gene-associated expression signature” in these cell lines is enriched with genes that were also identified in primary human AML characterized by ERG overexpression. By chromatin immunoprecipitation, we then identified specific, direct ERG targets and confirmed their expression in samples from ERG transgenic leukemias and primary human “ERG-overexpressing” AMLs. Surprisingly, we observed that the lymphoid kinase Bruton agammaglobulinemia tyrosine kinase (BTK) is an ERG direct target that is upregulated in both ERG overexpressing mouse and human leukemias. Preliminary experiments have demonstrated activity of a BTK inhibitor on ERG transgenic and ERG overexpressing human AML cells. ERG overexpression also induced marked activation of RAS signaling as supported by elevated levels of RAS-GTP and its downstream targets and significant growth inhibitory activity caused by a novel RAS inhibitor, farnesylthiosalicylic acid (Salirasib), that disrupts the spatiotemporal localization of active Ras (Rotblat et al Methods Enzymol. 2008;439:467) was observed. Dramatic growth inhibitory activity has also been induced by two novel compounds that induce megakaryocytic polyploidization, suggesting a potential role for “differentiation” therapy of ERG-related leukemias. Thus we have created a mouse model for ERG-related AML and characterized several genes and biochemical pathways that are susceptible to pharmacological inhibition. Our studies are not only likely to decipher the mechanisms by which ERG overexpression contributes to leukemogenesis, but also provide a platform for preclinical studies of novel therapeutics of these poor prognosis leukemias. Disclosures: No relevant conflicts of interest to declare.

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Morio, F., F. Pagniez, C. Lacroix, M. Miegeville e P. Le Pape. "Implication des mutations sur le gène erg3 dans la résistance de Candida albicans aux antifongiques azoles". Journal de Mycologie Médicale 22, n. 1 (marzo 2012): 118. http://dx.doi.org/10.1016/j.mycmed.2011.12.059.

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Xiao, Kuo, Zhiming Sun, Xueqin Jin, Weining Ma, Yan Song, Shirong Lai, Qian Chen et al. "ERG3 potassium channel-mediated suppression of neuronal intrinsic excitability and prevention of seizure generation in mice". Journal of Physiology 596, n. 19 (7 settembre 2018): 4729–52. http://dx.doi.org/10.1113/jp275970.

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Brumfield, Kristy M., James V. Moroney, Thomas S. Moore, Tiffany A. Simms e David Donze. "Functional Characterization of the Chlamydomonas reinhardtii ERG3 Ortholog, a Gene Involved in the Biosynthesis of Ergosterol". PLoS ONE 5, n. 1 (11 gennaio 2010): e8659. http://dx.doi.org/10.1371/journal.pone.0008659.

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40

Dewhurst-Maridor, Gisèle, Daniel Abegg, Fabrice P. A. David, Jacques Rougemont, Cameron C. Scott, Alexander Adibekian e Howard Riezman. "The SAGA complex, together with transcription factors and the endocytic protein Rvs167p, coordinates the reprofiling of gene expression in response to changes in sterol composition inSaccharomyces cerevisiae". Molecular Biology of the Cell 28, n. 20 (ottobre 2017): 2637–49. http://dx.doi.org/10.1091/mbc.e17-03-0169.

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Changes in cellular sterol species and concentrations can have profound effects on the transcriptional profile. In yeast, mutants defective in sterol biosynthesis show a wide range of changes in transcription, including a coinduction of anaerobic genes and ergosterol biosynthesis genes, biosynthesis of basic amino acids, and several stress genes. However the mechanisms underlying these changes are unknown. We identified mutations in the SAGA complex, a coactivator of transcription, which abrogate the ability to carry out most of these sterol-dependent transcriptional changes. In the erg3 mutant, the SAGA complex increases its occupancy time on many of the induced ergosterol and anaerobic gene promoters, increases its association with several relevant transcription factors and the SWI/SNF chromatin remodeling complex, and surprisingly, associates with an endocytic protein, Rvs167p, suggesting a moonlighting function for this protein in the sterol-regulated induction of the heat shock protein, HSP42 and HSP102, mRNAs.

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41

Miyazaki, Yoshitsugu, Antonia Geber, Haruko Miyazaki, Derek Falconer, Tanya Parkinson, Christopher Hitchcock, Brian Grimberg, Katherine Nyswaner e John E. Bennett. "Cloning, sequencing, expression and allelic sequence diversity of ERG3 (C-5 sterol desaturase gene) in Candida albicans". Gene 236, n. 1 (agosto 1999): 43–51. http://dx.doi.org/10.1016/s0378-1119(99)00263-2.

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42

Brumfield, Kristy M., James V. Moroney, Thomas S. Moore, Tiffany A. Simms e David Donze. "Correction: Functional Characterization of the Chlamydomonas reinhardtii ERG3 Ortholog, a Gene Involved in the Biosynthesis of Ergosterol". PLOS ONE 10, n. 5 (28 maggio 2015): e0129189. http://dx.doi.org/10.1371/journal.pone.0129189.

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43

Ahmad, Suhail, Leena Joseph, Josie E. Parker, Mohammad Asadzadeh, Steven L. Kelly, Jacques F. Meis e Ziauddin Khan. "ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait". Antimicrobial Agents and Chemotherapy 63, n. 2 (19 novembre 2018): e01900-18. http://dx.doi.org/10.1128/aac.01900-18.

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ABSTRACT Candida glabrata is intrinsically less susceptible to azoles, and resistance to echinocandins and reduced susceptibility (RS) to amphotericin B (AMB) have also been detected. The molecular mechanisms of RS to AMB were investigated in C. glabrata strains in Kuwait by sequence analyses of genes involved in ergosterol biosynthesis. A total of 1,646 C. glabrata isolates were tested by Etest, and results for 12 selected isolates were confirmed by reference broth microdilution. PCR sequencing of three genes (ERG2, ERG6, and ERG11) was performed for all isolates with RS to AMB (RS-AMB isolates) and 5 selected wild-type C. glabrata isolates by using gene-specific primers. The total cell sterol content was analyzed by gas chromatography-mass spectrometry. The phylogenetic relationship among the isolates was investigated by multilocus sequence typing. Wild-type isolates contained only synonymous mutations in ERG2, ERG6, or ERG11, and the total sterol content was similar to that of the reference strains. A nonsynonymous ERG6 mutation (AGA48AAA, R48K) was found in both RS-AMB and wild-type isolates. Four RS-AMB isolates contained novel nonsense mutations at Trp286, Tyr192, and Leu341, and 2 isolates contained a nonsynonymous mutation in ERG6 (V126F or C198F); and the sterol content of these isolates was consistent with ERG6 deficiency. Two other RS-AMB isolates contained a novel nonsynonymous ERG2 mutation (G119S or G122S), and their sterol content was consistent with ERG2 deficiency. Of 8 RS-AMB isolates, 1 fluconazole-resistant isolate also contained nonsynonymous Y141H plus L381M mutations, while 7 isolates contained only synonymous mutations in ERG11. All isolates with ERG6, ERG2, and ERG11 mutations were genotypically distinct strains. Our data show that ERG6 and ERG2 are major targets conferring RS-AMB in clinical C. glabrata isolates.

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44

Laborenz, Janina, Katja Hansen, Cristina Prescianotto-Baschong, Anne Spang e Johannes M. Herrmann. "In vitro import experiments with semi-intact cells suggest a role of the Sec61 paralog Ssh1 in mitochondrial biogenesis". Biological Chemistry 400, n. 9 (27 agosto 2019): 1229–40. http://dx.doi.org/10.1515/hsz-2019-0196.

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AbstractMitochondrial biogenesis relies on the synthesis of hundreds of different precursor proteins in the cytosol and their subsequent import into the organelle. Recent studies suggest that the surface of the endoplasmic reticulum (ER) actively contributes to the targeting of some mitochondrial precursors. In the past,in vitroimport experiments with isolated mitochondria proved to be extremely powerful to elucidate the individual reactions of the mitochondrial import machinery. However, thisin vitroapproach is not well suited to study the influence of non-mitochondrial membranes. In this study, we describe anin vitrosystem using semi-intact yeast cells to test a potential import relevance of the ER proteins Erg3, Lcb5 and Ssh1, all being required for efficient mitochondrial respiration. We optimized the conditions of this experimental test system and found that cells lacking Ssh1, a paralog of the Sec61 translocation pore, show a reduced import efficiency of mitochondrial precursor proteins. Our results suggest that Ssh1, directly or indirectly, increases the efficiency of the biogenesis of mitochondrial proteins. Our findings are compatible with a functional interdependence of the mitochondrial and the ER protein translocation systems.

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45

Sharma, Ruby, Shanti P. Gangwar e Ajay K. Saxena. "Comparative structure analysis of the ETSi domain of ERG3 and its complex with the E74 promoter DNA sequence. Corrigendum". Acta Crystallographica Section F Structural Biology Communications 75, n. 5 (29 aprile 2019): 397–98. http://dx.doi.org/10.1107/s2053230x19003376.

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46

Branco, J., M. Ola, R. M. Silva, E. Fonseca, N. C. Gomes, C. Martins-Cruz, A. P. Silva et al. "Impact of ERG3 mutations and expression of ergosterol genes controlled by UPC2 and NDT80 in Candida parapsilosis azole resistance". Clinical Microbiology and Infection 23, n. 8 (agosto 2017): 575.e1–575.e8. http://dx.doi.org/10.1016/j.cmi.2017.02.002.

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47

Hood, Donald C., William Seiple, Karen Holopigian e Vivienne Greenstein. "A comparison of the components of the multifocal and full-field ERGs". Visual Neuroscience 14, n. 3 (maggio 1997): 533–44. http://dx.doi.org/10.1017/s0952523800012190.

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AbstractThe multi-input technique of Sutter and Tran (1992) yields multiple focal ERGs. The purpose here was to compare the components of this multifocal ERG to the components of the standard, full-field ERG. To record multifocal ERGs, an array of 103 hexagons was displayed on a monitor. Full-field (Ganzfeld) ERGs were elicited by flashes presented upon steady background fields. The latencies of two prominent subcomponents of the full-field ERG were altered by varying the intensity of the incremental flash or the intensity of the background field. By showing that similar manipulations of the multi-input parameters produce similar changes in latency, we were able to relate the components of the multifocal ERG to the components of the full-field ERG. The biphasic responses of the multifocal ERG appear to be generated by the same cells generating the a-wave and positive peaks of the full-field cone ERG.

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48

Geber, A., C. A. Hitchcock, J. E. Swartz, F. S. Pullen, K. E. Marsden, K. J. Kwon-Chung e J. E. Bennett. "Deletion of the Candida glabrata ERG3 and ERG11 genes: effect on cell viability, cell growth, sterol composition, and antifungal susceptibility". Antimicrobial Agents and Chemotherapy 39, n. 12 (1 dicembre 1995): 2708–17. http://dx.doi.org/10.1128/aac.39.12.2708.

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49

Arthington-Skaggs, B. A., D. N. Crowell, H. Yang, S. L. Sturley e M. Bard. "Positive and negative regulation of a sterol biosynthetic gene (ERG3) in the post-squalene portion of the yeast ergosterol pathway". FEBS Letters 392, n. 2 (26 agosto 1996): 161–65. http://dx.doi.org/10.1016/0014-5793(96)00807-1.

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50

Feng, Wenli, Jing Yang, Zhiqin Xi, Ying Ji, Xin Zhu, Lu Yang e Yan Ma. "Regulatory Role of ERG3 and Efg1 in Azoles-Resistant Strains of Candida albicans Isolated from Patients Diagnosed with Vulvovaginal Candidiasis". Indian Journal of Microbiology 59, n. 4 (2 novembre 2019): 514–24. http://dx.doi.org/10.1007/s12088-019-00833-x.

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