SIRT2-and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models

There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders

Behind the veil of good intentions: power analysis of the nuclear non-proliferation regime

Susan Strange argued that one of the main problems with the use of the concept of regime in IR is the way in which it ‘distort[s] reality implying an exaggerated measure of predictability and order in the system’. Instead, she claimed, scholars should look at the numerous and dynamic bargains on which regimes are based. This article examines four bargains displaying various operations of power that have underpinned the nuclear non-proliferation regime. The four bargains are: first, the superpower collusion in the establishment of the non-proliferation treaty; second, coercive diplomacy and the use of force in preventing access to nuclear materials and technology; third, institutional contestation regarding the aims of the non-proliferation regime and its technical maintenance; and fourth, the creation of particular hierarchies of states via the non-proliferation norm. These bargains have been hidden behind the veil of good intensions, which is the conviction that preventing the spread of nuclear weapons is an unquestionable global good. The veil of good intentions, in turn, has helped to maintain the unequal distribution of material capabilities at the heart of the non-proliferation regim