SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells.

The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs). Upon induction of differentiation SOX2 O-GlcNAcylation at serine 248 is decreased. Replacing wild type with an O-GlcNAc-deficient SOX2 (S248A) increases reprogramming efficiency. ESCs with O-GlcNAc-deficient SOX2 exhibit alterations in gene expression. This change correlates with altered protein-protein interactions and genomic occupancy of the O-GlcNAc-deficient SOX2 compared to wild type. In addition, SOX2 O-GlcNAcylation impairs the SOX2-PARP1 interaction, which has been shown to regulate ESC self-renewal. These findings show that SOX2 activity is modulated by O-GlcNAc, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor.

Transcription factor competition allows embryonic stem cells to distinguish authentic signals from noise.

Stem cells occupy variable environments where they must distinguish stochastic fluctuations from developmental cues. Here, we use optogenetics to investigate how the pluripotency network in embryonic stem (ES) cells achieves a robust response to differentiation cues but not to gene expression fluctuations. We engineered ES cells in which we could quantitatively ontrol the endogenous mechanism of neural differentiation through a light-inducible Brn2 transgene and monitor differentiation status through a genome-integrated Nanog-GFP reporter. By exposing cells to pulses of Brn2, we find that the pluripotency network rejects Brn2 inputs that are below specific magnitude or duration thresholds, but allows rapid differentiation when both thresholds are satisfied. The filtering properties of the network arise through its positive feedback architecture and the intrinsic half-life of Nanog, which determines the duration threshold in the network. Together our results suggest that the dynamic properties of positive-feedback networks might determine how inputs are classified as signal or noise by stem cells.

Immediate allergic reactions after vaccinations--a post-marketing surveillance review.

UNLABELLED: Immediate systemic allergic reactions after vaccination with commonly used vaccines are very rare. Consequently, the risk of these reactions cannot be verified before widespread use. A data analysis of spontaneously reported suspected adverse drug reactions following the administration of 15 marketed vaccines, from 1994 to 1998, shows an average reporting rate for "allergic" reactions of one case report per 450,000 vaccine doses sold. Of these, potentially life-threatening events are extremely rare. In 31% of our case reports the reaction was reported after the first vaccination. In these cases a pre-sensitisation or a pseudo-allergic reaction can be assumed. There was no evidence for an increased risk of "allergic" reactions for patients with atopy. CONCLUSION: our data support a high level of safety for the vaccines included in the analysis. They also emphasise the importance of a careful vaccination management after occurrence of "allergic" reactions and the necessity of a post-marketing surveillance system for recording adverse drug reactions.

TBE booster immunization according to the rapid immunization schedule: are 3-year booster intervals really necessary?

In order to evaluate the need for further booster immunizations, 222 subjects aged 20-52 years, who had received the first booster dose with a new tick-borne encephalitis (TBE) vaccine in a preceding study, were invited for a serological follow-up. A total of 191 and 182 adult subjects were analyzed for the persistence of neutralizing TBE antibodies at 1 and 2 years following the first booster immunization, respectively. Both serological follow-ups revealed high levels of neutralizing TBE antibodies in more than 99% of subjects. Although an expected decline of the respective geometric mean titers (GMTs) was noted after booster immunization, the titers were still far above the values noted after primary immunization at the 2-year follow-up. The kinetic curve clearly indicates a longer persistence of neutralizing TBE antibodies than currently expected. To conclude, these results suggest that the administration of a further booster dose 3 years after the first one (according to current recommendations) does not seem to be necessary in this study population.