Key pointsr Transcription is recruited by noradrenaline in the hippocampus. r Epigenetic mechanisms are recruited by hippocampal noradrenergic receptor activation. r Epigenetic regulation by noradrenaline offers a novel mechanism for long-term potentiation Abstract Noradrenaline (NA) is a neuromodulator that can effect long-lasting changes in synaptic strength such as long-term potentiation (LTP), a putative cellular mechanism for memory formation in the mammalian brain. Persistent LTP requires alterations in gene expression that may involve epigenetic mechanisms such as DNA methylation, histone acetylation and histone phosphorylation. It is known that β-adrenergic receptors and NA can boost LTP maintenance by regulating translation. However, it is unclear whether NA can additionally engage epigenetic mechanisms to regulate transcription and boost LTP endurance. To address this issue, we probed NA-treated mouse hippocampal slices with pharmacological inhibitors targeting epigenetic regulatory pathways and discovered that NA activates β-adrenergic receptors to boost LTP maintenance in area CA1 through DNA methylation and post-translational histone modifications. Specifically, NA paired with 100 Hz stimulation enhanced histone H3 acetylation and phosphorylation, both of which were required for NA-induced boosting of LTP maintenance. Together, our findings identify NA as a neuromodulatory transmitter capable of triggering epigenetic, transcriptional control of genes required for establishing persistent LTP in the mouse hippocampus. These modifications may contribute to the stabilization of memory.

Salirasib therapy was well tolerated. The recommended dose for phase II studies is 600 mg twice daily.

BackgroundThe mitotic exit network (MEN) is required for events at the end of mitosis such as degradation of mitotic cyclins and cytokinesis. Bub2 and its binding partner Bfa1 act as a GTPase activating protein (GAP) to negatively regulate the MEN GTPase Tem1. The Bub2/Bfa1 checkpoint pathway is required to delay the cell cycle in response to mispositioned spindles. In addition to its role in mitotic exit, Tem1 is required for actomyosin ring contraction.ResultsTo test the hypothesis that the Bub2 pathway prevents premature actin ring assembly, we compared the timing of actin ring formation in wild type, bub2Δ, mad2Δ, and bub2Δmad2Δ cells both with and without microtubules. There was no difference in the timing of actin ring formation between wild type and mutant cells in a synchronized cell cycle. In the presence of nocodazole, both bub2Δ and mad2Δ cells formed rings after a delay of the same duration. Double mutant bub2Δmad2Δ and bfa1Δmad2Δ cells formed rings at the same time with and without nocodazole. To determine if Bub2 has an effect on actomyosin ring contraction through its regulation of Tem1, we used live cell imaging of Myo1-GFP in a bub2Δ strain. We found a significant decrease in the total time of contraction and an increase in rate of contraction compared to wild type cells. We also examined myosin contraction using Myo1-GFP in cells overexpressing an epitope tagged Bub2. Surprisingly, overexpression of Bub2 also led to a significant increase in the rate of contraction, as well as morphological defects. The chained cell phenotype caused by Bub2 overexpression could be rescued by co-overexpression of Tem1, and was not rescued by deletion of BFA1.ConclusionOur data indicate that the Bub2 checkpoint pathway does not have a specific role in delaying actin ring formation. The observed increase in the rate of myosin contraction in the bub2Δ strain provides evidence that the MEN regulates actomyosin ring contraction. Our data suggest that the overexpression of the Bub2 fusion protein acts as a dominant negative, leading to septation defects by a mechanism that is Tem1-dependent.

Despite recent advances in the prevention of cervical cancer, the disease remains a leading cause of cancer-related deaths in women worldwide. By applying the GISTIC2.0 and/or the MutSig2CV algorithms on 430 whole-exome-sequenced cervical carcinomas, we identified previously unreported significantly mutated genes (SMGs) (including MSN, GPX1, SPRED3, FAS, and KRT8), amplifications (including NFIA, GNL1, TGIF1, and WDR87) and deletions (including MIR562, PVRL1, and NTM). Subset analyses of 327 squamous cell carcinomas and 86 non-squamous cell carcinomas revealed previously unreported SMGs in BAP1 and IL28A, respectively. Distinctive copy number alterations related to tumors predominantly enriched for *CpG- and Tp*C mutations were observed. CD274, GRB2, KRAS, and EGFR were uniquely significantly amplified within the Tp*C-enriched tumors. A high frequency of aberrations within DNA damage repair and chromatin remodeling genes were detected. Facilitated by the large sample size derived from combining multiple datasets, this study reveals potential targets and prognostic markers for cervical cancer.

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