Age group and sex do not influence responses of vitamin K biomarkers to changes in dietary vitamin K.

Inadequate vitamin K intake has been associated with abnormal soft tissue calcification. Older adults may have insufficient intakes of vitamin K and respond less to vitamin K supplementation compared with younger adults. However, little is known about the determinants that influence the response to vitamin K supplementation. Our primary objective was to assess dietary and nondietary determinants of vitamin K status in healthy younger and older adults. In a nonrandomized, nonmasked study, 21 younger (18-40 y) and 21 older (55-80 y) men and women consumed a baseline diet (200 µg phylloquinone/d) for 5 d, a phylloquinone-restricted diet (10 µg phylloquinone/d) for 28 d, and a phylloquinone-supplemented diet (500 µg phylloquinone/d) for 28 d. Changes in vitamin K status markers in response to vitamin K depletion and repletion were studied and the influences of BMI, body fat, and circulating TG were assessed by including them as covariates in the model. Despite baseline differences in measures of vitamin K status, plasma phylloquinone tended to increase (P = 0.07) and the percentage of uncarboxylated osteocalcin and uncarboxylated prothrombin both improved with phylloquinone supplementation (P < 0.007), regardless of age group or sex. Only the excretion of urinary menadione, a vitamin K metabolite, was greater among younger adults in response to depletion than in older adults (P = 0.012), regardless of sex. Adiposity measures and circulating TG did not predict response of any measures. In conclusion, poor vitamin K status can be similarly improved with vitamin K supplementation, regardless of age group or sex.

The anti-interferon activity of conserved viral dUTPase ORF54 is essential for an effective MHV-68 infection.

Gammaherpesviruses such as KSHV and EBV establish lifelong persistent infections through latency in lymphocytes. These viruses have evolved several strategies to counteract the various components of the innate and adaptive immune systems. We conducted an unbiased screen using the genetically and biologically related virus, MHV-68, to find viral ORFs involved in the inhibition of type I interferon signaling and identified a conserved viral dUTPase, ORF54. Here we define the contribution of ORF54 in type I interferon inhibition by ectopic expression and through the use of genetically modified MHV-68. ORF54 and an ORF54 lacking dUTPase enzymatic activity efficiently inhibit type I interferon signaling by inducing the degradation of the type I interferon receptor protein IFNAR1. Subsequently, we show in vitro that the lack of ORF54 causes a reduction in lytic replication in the presence of type I interferon signaling. Investigation of the physiological consequence of IFNAR1 degradation and importance of ORF54 during MHV-68 in vivo infection demonstrates that ORF54 has an even greater impact on persistent infection than on lytic replication. MHV-68 lacking ORF54 expression is unable to efficiently establish latent infection in lymphocytes, although it replicates relatively normally in lung tissues. However, infection of IFNAR-/- mice alleviates this phenotype, emphasizing the specific role of ORF54 in type I interferon inhibition. Infection of mice and cells by a recombinant MHV-68 virus harboring a site specific mutation in ORF54 rendering the dUTPase inactive demonstrates that dUTPase enzymatic activity is not required for anti-interferon function of ORF54. Moreover, we find that dUTPase activity is dispensable at all stages of MHV-68 infection analyzed. Overall, our data suggest that ORF54 has evolved anti-interferon activity in addition to its dUTPase enzymatic activity, and that it is actually the anti-interferon role that renders ORF54 critical for establishing an effective persistent infection of MHV-68.