Essential role of Fkbp6 in male fertility and homologous chromosome pairing in meiosis

Meiosis is a critical stage of gametogenesis in which alignment and synapsis of chromosomal pairs occur, allowing for the recombination of maternal and paternal genomes. Here we show that FK506 binding protein (Fkbp6) localizes to meiotic chromosome cores and regions of homologous chromosome synapsis. Targeted inactivation of Fkbp6 in mice results in aspermic males and the absence of normal pachytene spermatocytes. Moreover, we identified the deletion of Fkbp6 exon 8 as the causative mutation in spontaneously male sterile as/as mutant rats. Loss of Fkbp6 results in abnormal pairing and misalignments between homologous chromosomes, nonhomologous partner switches, and autosynapsis of X chromosome cores in meiotic spermatocytes. Fertility and meiosis are normal in Fkbp6 mutant females. Thus, Fkbp6 is a component of the synaptonemal complex essential for sex-specific fertility and for the fidelity of homologous chromosome pairing in meiosis.     

Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase

Cells respond to DNA double-strand breaks by recruiting factors such as the DNA-damage mediator protein MDC1, the p53-binding protein 1 (53BP1), and the breast cancer susceptibility protein BRCA1 to sites of damaged DNA. Here, we reveal that the ubiquitin ligase RNF8 mediates ubiquitin conjugation and 53BP1 and BRCA1 focal accumulation at sites of DNA lesions. Moreover, we establish that MDC1 recruits RNF8 through phosphodependent interactions between the RNF8 forkhead-associated domain and motifs in MDC1 that are phosphorylated by the DNA-damage activated protein kinase ataxia telangiectasia mutated (ATM). We also show that depletion of the E2 enzyme UBC13 impairs 53BP1 recruitment to sites of damage, which suggests that it cooperates with RNF8. Finally, we reveal that RNF8 promotes the G2/M DNA damage checkpoint and resistance to ionizing radiation. These results demonstrate how the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination.     

Investigation of the effect of Equivac® HeV Hendra virus vaccination on Thoroughbred racing performance

Objective

To evaluate the effect of Equivac® HeV Hendra virus vaccine on Thoroughbred racing performance.

Design

Retrospective pre‐post intervention study.

Methods

Thoroughbreds with at least one start at one of six major south‐eastern Queensland race tracks between 1 July 2012 and 31 December 2016 and with starts in the 3‐month periods before and after Hendra virus vaccinations were identified. Piecewise linear mixed models compared the trends in ‘Timeform rating’ and ‘margin to winner’ before and after initial Hendra virus vaccination. Generalised linear mixed models similarly compared the odds of ‘winning’, ‘placing’ (1st–3rd) and ‘winning any prize money’. Timeform rating trends were also compared before and after the second and subsequent vaccinations.

Results

Analysis of data from 4208 race starts by 755 horses revealed no significant difference in performance in the 3 months before versus 3 months after initial Hendra vaccination for Timeform rating (P = 0.32), ‘Margin to winner’ (P = 0.45), prize money won (P = 0.25), wins (P = 0.64) or placings (P = 0.77). Further analysis for Timeform rating for 7844 race starts by 928 horses failed to identify any significant change in Timeform rating trends before versus after the second and subsequent vaccinations (P = 0.16) or any evidence of a cumulative effect for the number of vaccines received (P = 0.22).

Conclusion

No evidence of an effect of Hendra virus vaccination on racing performance was found. The findings allow owners, trainers, industry regulators and animal health authorities to make informed decisions about vaccination.