Variation in the TGF-β signaling pathway is emerging as an important mechanism by which gonadal sex determination is controlled in teleosts. Here we show that amhy, a Y-specific duplicate of the anti-Müllerian hormone (amh) gene, induces male sex determination in Nile tilapia. amhy is a tandem duplicate located immediately downstream of amhΔ-y on the Y chromosome. The coding sequence of amhy was identical to the X-linked amh (amh) except a missense SNP (C/T) which changes an amino acid (Ser/Leu92) in the N-terminal region. amhy lacks 5608 bp of promoter sequence that is found in the X-linked amh homolog. The amhΔ-y contains several insertions and deletions in the promoter region, and even a 5 bp insertion in exonVI that results in a premature stop codon and thus a truncated protein product lacking the TGF-β binding domain. Both amhy and amhΔ-y expression is restricted to XY gonads from 5 days after hatching (dah) onwards. CRISPR/Cas9 knockout of amhy in XY fish resulted in male to female sex reversal, while mutation of amhΔ-y alone could not. In contrast, overexpression of Amhy in XX fish, using a fosmid transgene that carries the amhy/amhΔ-y haplotype or a vector containing amhy ORF under the control of CMV promoter, resulted in female to male sex reversal, while overexpression of AmhΔ-y alone in XX fish could not. Knockout of the anti-Müllerian hormone receptor type II (amhrII) in XY fish also resulted in 100% complete male to female sex reversal. Taken together, these results strongly suggest that the duplicated amhy with a missense SNP is the candidate sex determining gene and amhy/amhrII signal is essential for male sex determination in Nile tilapia. These findings highlight the conserved roles of TGF-β signaling pathway in fish sex determination.

The 8-parameter multiplicative model performed the best in the study and therefore was used to generate the EQ-5D-5L value set for China. We recommend using rescaled values whereby 1 represents the value of instrument-defined full health in economic evaluation of health technologies in China whenever the EQ-5D-5L data are available.

As a global pandemic is inevitable, real-time monitoring of transmission is vital for containing the spread of COVID-19. The main objective of this study was to report the real-time effective reproduction numbers (R(t)) and case fatality rates (CFR) in Europe. Methods: Data for this study were obtained mainly from the World Health Organization website, up to March 9, 2020. R(t) were estimated by exponential growth rate (EG) and time-dependent (TD) methods. 'R0' package in R was employed to estimate R(t) by fitting the existing epidemic curve. Both the naïve CFR (nCFR) and adjusted CFR (aCFR) were estimated. Results: With the EG method, R(t) was 3.27 (95% confidence interval (CI) 3.17-3.38) for Italy, 6.32 (95% CI 5.72-6.99) for France, 6.07 (95% CI 5.51-6.69) for Germany, and 5.08 (95% CI 4.51-5.74) for Spain. With the TD method, the R value for March 9 was 3.10 (95% CI 2.21-4.11) for Italy, 6.56 (95% CI 2.04-12.26) for France, 4.43 (95% CI 1.83-7.92) for Germany, and 3.95 (95% CI 0-10.19) for Spain. Conclusions: This study provides important findings on the early outbreak of COVID-19 in Europe. Due to the recent rapid increase in new cases of COVID-19, real-time monitoring of the transmissibility and mortality in Spain and France is a priority.

A total of 49 patients with hemorrhagic fever caused by HYSV were included; 8 (16.3%) patients died. A fatal outcome was associated with high viral RNA load in blood at admission, as well as higher serum liver transaminase levels, more pronounced coagulation disturbances (activated partial thromboplastin time, thrombin time), and higher levels of acute phase proteins (phospholipase A, fibrinogen, hepcidin), cytokines (interleukin [IL]-6, IL-10, interferon-γ), and chemokines (IL-8, monocyte chemotactic protein 1, macrophage inflammatory protein 1b). The levels of these host parameters correlated with viral RNA levels. Blood viral RNA levels gradually declined over 3-4 weeks after illness onset, accompanied by resolution of symptoms and laboratory abnormalities. Viral RNA was also detectable in throat, urine, and fecal specimens of a substantial proportion of patients, including all fatal cases assayed. CONCLUSIONS. Viral replication and host immune responses play an important role in determining the severity and clinical outcome in patients with infection by HYSV.