Cryptococcosis, caused by the basidiomycetous fungus Cryptococcus neoformans, is responsible for more than 600,000 deaths annually in AIDS patients. Flucytosine is one of the most commonly used antifungal drugs for its treatment, but its resistance and regulatory mechanisms have never been investigated at the genome scale in C. neoformans. In the present study, we performed comparative transcriptome analysis by employing two-component system mutants (tco1⌬ and tco2⌬) exhibiting opposing flucytosine susceptibility. As a result, a total of 177 flucytosine-responsive genes were identified, and many of them were found to be regulated by Tco1 or Tco2. Among these, we discovered an APSES-like transcription factor, Mbs1 (Mbp1-and Swi4-like protein 1). Expression analysis revealed that MBS1 was regulated in response to flucytosine in a Tco2/Hog1-dependent manner. Supporting this, C. neoformans with the deletion of MBS1 exhibited increased susceptibility to flucytosine. Intriguingly, Mbs1 played pleiotropic roles in diverse cellular processes of C. neoformans. Mbs1 positively regulated ergosterol biosynthesis and thereby affected polyene and azole drug susceptibility. Mbs1 was also involved in genotoxic and oxidative stress responses. Furthermore, Mbs1 promoted production of melanin and capsule and thereby was required for full virulence of C. neoformans. In conclusion, Mbs1 is considered to be a novel antifungal therapeutic target for treatment of cryptococcosis.
Objectives: The aim of this study was to investigate the utility of a combined compressed sensing and parallel imaging (C-SENSE) technique for single breath-hold, double arterial phase (AP) examinations in gadoxetate-enhanced magnetic resonance imaging (MRI) of the liver. Materials and Methods: We retrospectively reviewed single breath-hold, double AP images obtained by using a C-SENSE technique for gadoxetate-enhanced dynamic liver MRI in a total of 127 patients (89 men and 38 women; mean age, 62.6 ± 7.5 [range, 29-87] years). For qualitative analysis, 3 readers independently scored the timing of the AP images, degree of artifacts, and overall image quality on both the first and second AP images (AP1 and AP2, respectively). The combined scores of AP1 and AP2 (AP1 + AP2) were determined by using the better scores from the 2 sets. Focal lesion detectability was assessed for 124 lesions with arterial enhancement on AP1 and AP2, and on simultaneous review of both AP1 and AP2. Then, in 62 patients whose previous gadoxetate-enhanced single AP images were available, AP timing and overall image quality were compared between single and double AP images. Wilcoxon signed rank test was performed for each comparison. Fleiss kappa value was calculated for analysis of interreader agreement. Results: Optimal AP timing was achieved in 86% of AP1, 65% of AP2, and 90% of AP1 + AP2 images; results were significantly better for AP1 and AP1 + AP2 images than for AP2 images (P < 0.001 for both comparisons). Respiratory motion artifacts were negligible in 73% of the AP1 + AP2 images, which was significantly better than the corresponding values for the AP1 (61%, P < 0.001) or AP2 (50%, P < 0.001) images. Overall image quality was significantly better for AP1 + AP2 (excellent in 54%) than for AP1 (49%, P < 0.001) or AP2 (39%, P < 0.001) images. Lesion detectability was comparable between AP1 and AP2 images and was significantly better on AP1 + AP2. Comparison of single and double AP imaging techniques showed better AP timing (P = 0.004) and fewer respiratory motion artifacts (P < 0.001) for AP1 + AP2 than for the single AP images. Conclusions: The C-SENSE technique may facilitate single breath-hold, double AP imaging with optimal timing and reduced respiratory motion artifacts in gadoxetate-enhanced dynamic MRI of the liver.
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