Members of the Fusarium graminearum species (Fg) complex, which are homothallic ascomycetous species, carry two opposite mating-type (MAT) loci in a single nucleus for controlling sexual development. We investigated the roles of three (MAT1-1-1, MAT1-1-2, and MAT1-1-3) and two (MAT1-2-1 and MAT1-2-3) transcripts located at both loci in representative Fg complex species (F. graminearum and Fusarium asiaticum). In self-fertile F. graminearum strains, the transcript levels of MAT1-1-1, MAT1-2-1, and MAT1-2-3 peaked 2 days after sexual induction (dai) and then remained high until 12 dai, whereas MAT1-1-2 and MAT1-1-3 transcripts reached peak levels between 4 and 8 dai. In contrast, all of the MAT transcripts in self-sterile F. asiaticum strains accumulated at much lower levels than those in F. graminearum during the entire time. Targeted gene deletions confirmed that MAT1-1-1, MAT1-1-2, MAT1-1-3, and MAT1-2-1 were essential for self-fertility in F. graminearum, but MAT1-2-3 was not. All MAT-deleted strains (except ΔMAT1-2-3) produced recombinant perithecia when outcrossed to a self-fertile strain. These results indicate that developmental up-regulation of the individual MAT genes in both a proper fashion and quantity is critical for sexual development, and that alterations in the gene expression could be attributed to the variation in self-sterility among the Fg complex.
Regorafenib and nivolumab are drugs approved for second-line treatment of patients with hepatocellular carcinoma (HCC) after sorafenib failure. However, the effectiveness of regorafenib and nivolumab following sorafenib has not been directly compared. This study retrospectively evaluated 373 patients with HCC who were treated with regorafenib (n = 223) or nivolumab (n = 150) after sorafenib failure between July 2017 and February 2019. Progression-free survival (PFS; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.06; P = 0.150), time to progression (TTP; HR, 0.95; 95% CI, 0.77-1.19; P = 0.680), and overall survival (OS; HR, 0.83; 95% CI, 0.64-1.07; P = 0.154) did not differ significantly between groups of patients treated with regorafenib and nivolumab, findings consistently observed by multivariable-adjusted, propensity score-matched, and inverse probability treatment weighting (IPTW) analyses. However, the objective response rate was significantly higher in the nivolumab than in the regorafenib group (13.3% vs. 4.0%; P = 0.002). When the effectiveness of regorafenib and nivolumab was compared in nonprogressors to treatment, defined as patients who achieved complete response, partial response, or stable disease after first response evaluation, PFS (HR, 0.50; 95% CI, 0.33-0.75; P = 0.001), TTP (HR, 0.48; 95% CI, 0.31-0.73; P < 0.001), and OS (HR, 0.51; 95% CI, 0.31-0.87; P = 0.013) were significantly longer in the 59 nonprogressors to nivolumab than in the 104 nonprogressors to regorafenib, findings also observed by multivariable-adjusted and IPTW analyses. Conclusion: Survival outcomes in patients treated with regorafenib and nivolumab after sorafenib failure did not differ significantly. However, nivolumab may be more effective than regorafenib in nonprogressors. In this retrospective comparative study, the effectiveness of regorafenib and nivolumab following sorafenib in HCC was investigated. The oncological outcomes were not different between the regorafenib and nivolumab groups. However, nivolumab showed better outcomes than regorafenib when progressors to each were excluded.
Tocopherols and tocotrienols, collectively known as tocochromanols, are lipid-soluble molecules that belong to the group of vitamin E compounds. Among them, α-tocopherol (αΤ) is one of the antioxidants with diverse functions and benefits for humans and animals. Thus, understanding the genetic basis of these traits would be valuable to improve nutritional quality by breeding in rice. Genome-wide association study (GWAS) has emerged as a powerful strategy for identifying genes or quantitative trait loci (QTL) underlying complex traits in plants. To discover the genes or QTLs underlying the naturally occurring variations of αΤ content in rice, we performed GWAS using 1.44 million high-quality single-nucleotide polymorphisms acquired from re-sequencing of 137 accessions from a diverse rice core collection. Thirteen candidate genes were found across 2-year phenotypic data, among which gamma-tocopherol methyltransferase (OsγTMT) was identified as the major factor responsible for the αΤ content among rice accessions. Nucleotide variations in the coding region of OsγTMT were significantly associated with the αΤ content variations, while nucleotide polymorphisms in the promoter region of OsγTMT also could partly demonstrate the correlation with αΤ content variations, according to our RNA expression analyses. This study provides useful information for genetic factors underlying αΤ content variations in rice, which will significantly contribute the research on αΤ biosynthesis mechanisms and αΤ improvement of rice.
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