Neptune to the Common-wealth of England (1652): the republican Britannia and the continuity of interests

In the seventeenth century, John Kerrigan reminds us, “models of empire did not always turn on monarchy”. In this essay, I trace a vision of “Neptune’s empire” shared by royalists and republicans, binding English national interest to British overseas expansion. I take as my text a poem entitled “Neptune to the Common-wealth of England”, prefixed to Marchamont Nedham’s 1652 English translation of Mare Clausum (1635), John Selden’s response to Mare Liberum (1609) by Hugo Grotius. This minor work is read alongside some equally obscure and more familiar texts in order to point up the ways in which it speaks to persistent cultural and political interests. I trace the afterlife of this verse, its critical reception and its unique status as a fragment that exemplifies the crossover between colonial republic and imperial monarchy at a crucial moment in British history, a moment that, with Brexit, remains resonant

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists

Faery queene /

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