Congenital Zika virus (ZIKV) infection was first linked to birth defects during the American outbreak in 2015/2016. It has been proposed that mutations unique to the Asian/American-genotype explain, at least in part, the ability of Asian/American ZIKV to cause congenital Zika syndrome (CZS). Recent studies identified mutations in ZIKV infecting humans that arose coincident with the outbreak in French Polynesia and were stably maintained during subsequent spread to the Americas. Here we show that African ZIKV can infect and harm fetuses and that the S139N substitution that has been associated with the American outbreak is not essential for fetal harm. Our findings, in a vertical transmission mouse model, suggest that ZIKV will remain a threat to pregnant women for the foreseeable future, including in Africa, Southeast Asia, and the Americas. Additional research is needed to better understand the risks associated with ZIKV infection during pregnancy, both in areas where the virus is newly endemic and where it has been circulating for decades.

Primary mediastinal germ cell tumors (M-GCTs) represent a heterogeneous group of tumors that varies with regard to age at presentation, histologic differentiation, and outcome. We retrospectively analyzed archival tissue samples of mediastinal mature and immature teratomas (n = 15) and malignant nonseminomatous M-GCTs (n = 20) with comparative genomic hybridization (CGH). The aim of this study was to define distinct genetic subgroups of M-GCT among the pediatric cohort that may differ in their clinical behavior and prognosis. All pure teratomas showed normal CGH profiles. Malignant M-GCTs in infants and children < 8 years old most frequently showed a gain of 1q, 3, and 20q and a loss of 1p, 4q, and 6q. Gain of 12p and sex chromosomal abnormalities were not observed in this age group. In contrast, the gain of 12p was the most common aberration in M-GCTs that arose in children > or = 8 years old. Additional recurrent changes included the loss of chromosome 13 and the gain of chromosome 21. All ten adolescents with malignant M-GCT were male, and five showed a gain of the X chromosome. In two of these five patients, Klinefelter syndrome was confirmed by cytogenetic analysis or by fluorescence in situ hybridization (FISH). In conclusion, CGH analysis of M-GCTs defines distinct genetic subgroups. Mediastinal teratomas show no genetic gains or losses. Malignant M-GCTs in children < 8 years old show the same pattern of gains and losses identified in sacrococcygeal and testicular GCTs at this age, and they lack sex-chromosomal abnormalities. Malignant M-GCTs in children > or = 8 years old show the same genetic profile previously reported in gonadal GCTs at this age. In addition, approximately 50% demonstrate a gain of the X chromosome, consistent with Klinefelter syndrome. Cooperative group studies reveal a significantly better prognosis of malignant M-GCT arising in infants compared to that in adolescents, suggesting that these genetic differences are associated with differences in clinical behavior.

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We have examined the role of histone acetylation in the very earliest steps of differentiation of mouse embryonic stem cells in response to withdrawal of leukemia inhibitory factor (LIF) as a differentiation signal. The cells undergo dramatic changes in morphology and an ordered program of gene expression changes representing differentiation to all three germ layers over the first 3-5 days of LIF withdrawal. We observed a global increase in acetylation on histone H4 and to a lesser extent on histone H3 over this time period. Treatment of the cells with trichostatin A (TSA), a histone deacetylase inhibitor, induced changes in morphology, gene expression, and histone acetylation that mimicked differentiation induced by withdrawal of LIF. We examined localized histone acetylation in the regulatory regions of genes that were transcriptionally either active in undifferentiated cells, induced during differentiation, or inactive under all treatments. There was striking concordance in the histone acetylation patterns of specific genes induced by both TSA and LIF withdrawal. Increased histone acetylation in local regions correlated best with induction of gene expression. Finally, TSA treatment did not support the maintenance or progression of differentiation. Upon removal of TSA, the cells reverted to the undifferentiated phenotype. We concluded that increased histone acetylation at specific genes played a role in their expression, but additional events are required for maintenance of differentiated gene expression and loss of the pluripotent state.