Foreign Policy and the Electoral Connection

Public opinion is central to representation, democratic accountability, and decision making. Yet, the public was long believed to be relatively uninterested in foreign affairs, absent an immediate threat to safety and welfare. It had become conventional to say that voting ends at water\u27s edge. We start the examination of the scholarly understanding of the role of foreign affairs in public opinion and voting at that low point of view. Much subsequent development saw an increasing degree of holding and using of attitudes and beliefs about foreign affairs among the public. Moving in parallel with developments in political psychology, theoretical and methodological advances led to an increasingly widely shared view that the public holds reasonably sensible and nuanced views, that these help shape their political behaviors, and that these, in turn, help shape and constrain foreign policy making

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.National Institutes of Health (U.S.) (Grant HG002668)National Institutes of Health (U.S.) (Grant CA109901