Transcriptional tools: Small molecules for modulating CBP KIX-dependent transcriptional activators

Previously it was demonstrated that amphipathic isoxazolidines are able to functionally replace the transcriptional activation domains of endogenous transcriptional activators. In addition, in vitro binding studies suggested that a key binding partner of these molecules is the CREB Binding Protein (CBP), more specifically the KIX domain within this protein. Here we show that CBP plays an essential role in the ability of isoxazolidine transcriptional activation domains to activate transcription in cells. Consistent with this model, isoxazolidines are able to function as competitive inhibitors of the activators MLL and Jun, both of which utilize a binding interaction with KIX to up-regulate transcription. Further, modification of the N2 side chain produced three analogs with enhanced potency against Jun-mediated transcription, although increased cytotoxicity was also observed. Collectively these small KIX-binding molecules will be useful tools for dissecting the role of the KIX domain in a variety of pathological processes. © 2010 Wiley Periodicals, Inc. Biopolymers 95: 17–23, 2011.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78234/1/21548_ftp.pd

Garcinolic Acid Distinguishes Between GACKIX Domains and Modulates Interaction Networks

Natural products are often uniquely suited to modulate protein-protein interactions (PPIs) due to their architectural and functional group complexity relative to synthetic molecules. Here we demonstrate that the natural product garcinolic acid allosterically blocks the CBP/p300 KIX PPI network and displays excellent selectivity over related GACKIX motifs. It does so via a strong interaction (KD 1 μM) with a non-canonical binding site containing a structurally dynamic loop in CBP/p300 KIX. Garcinolic acid engages full-length CBP in the context of the proteome and in doing so effectively inhibits KIX-dependent transcription in a leukemia model. As the most potent small-molecule KIX inhibitor yet reported, garcinolic acid represents an important step forward in the therapeutic targeting of CBP/p300

Placing Joseph Banks in the North Pacific

The South Pacific was a fulcrum of Joseph Banks's maritime world and global networks. The North Pacific was a distance and intangible fringe. This article is concerned with how Banks should be ‘placed’ in the North Pacific. It tracks how Banks's activities have been delineated in terms of languages and categories of global and local, and centre and margin, and then considers the historical and geographical specifics apposite to his connection to the North Pacific. In this setting, ideas of place (as location and assignment) and capital (as a circulatory and everyday practice of exchange and opportunism) come into view and question the distinction between science and commerce in Banks historiography. The article considers a diverse group of non-Indigenous figures – explorers, traders, cartographers, scientists, collectors – operating in the North Pacific in the 1780s and 1790s whose initiatives and missives passed across Banks's desk, and assesses their place in Banks's archive by drawing on Peter Sloterdijk's ideas about the interiorising and exteriorising logic of capital.PostprintPeer reviewe

Preliminary Acceptability of a Home-Based Peripheral Blood Collection Device for Viral Load Testing in the Context of Analytical Treatment Interruptions in HIV Cure Trials: Results from a Nationwide Survey in the United States

Frequent viral load testing is necessary during analytical treatment interruptions (ATIs) in HIV cure-directed clinical trials, though such may be burdensome and inconvenient to trial participants. We implemented a national, cross-sectional survey in the United States to examine the acceptability of a novel home-based peripheral blood collection device for HIV viral load testing. Between June and August 2021, we distributed an online survey to people with HIV (PWH) and community members, biomedical HIV cure researchers and HIV care providers. We performed descriptive analyses to summarize the results. We received 73 survey responses, with 51 from community members, 12 from biomedical HIV cure researchers and 10 from HIV care providers. Of those, 51 (70%) were cisgender men and 50 (68%) reported living with HIV. Most (>80% overall) indicated that the device would be helpful during ATI trials and they would feel comfortable using it themselves or recommending it to their patients/participants. Of the 50 PWH, 42 (84%) indicated they would use the device if they were participating in an ATI trial and 27 (54%) also expressed a willingness to use the device outside of HIV cure studies. Increasing sensitivity of viral load tests and pluri-potency of the device (CD4 count, chemistries) would augment acceptability. Survey findings provide evidence that viral load home testing would be an important adjunct to ongoing HIV cure-directed trials involving ATIs. Survey findings may help inform successful implementation and uptake of the device in the context of personalized HIV care

Concern level assessment: building domain knowledge into a visual system to support network-security situation awareness

Information officers and network administrators require tools to help them achieve situation awareness about potential network threats. We describe a response to mini-challenge 1 of the 2012 IEEE VAST challenge in which we developed a visual analytic solution to a network security situation awareness problem. To support conceptual design, we conducted a series of knowledge elicitation sessions with domain experts. These provided an understanding of the information they needed to make situation awareness judgements as well as a characterisation of those judgements in the form of production rules which define a parameter we called the ‘Concern Level Assessment’ (CLA). The CLA was used to provide heuristic guidance within a visual analytic system called MSIEVE. An analysis of VAST challenge assessment sessions using M-SIEVE provides some evidence that intelligent heuristics like this can provide useful guidance without unduly dominating interaction and understanding