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Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator and transcription cofactor whose phosphorylation by casein kinase II (CK2) and dephosphorylation by protein phosphatase 2A (PP2A) modulates its function in gene-specific targeting and recruitment of transcriptional regulators and chromatin modifiers. BRD4 has emerged as an important cancer therapeutic target due to widely available small compound inhibitors, such as JQ1 and I-BET, targeting the bromodomain and extra-terminal (BET) family members. Besides transcriptional regulation, BRD4 also plays crucial roles in regulating diverse cellular processes, including cell cycle progression, DNA damage response, chromatin structure maintenance, stem cell reprogramming, cell lineage differentiation, and viral latency and reactivation. While BET inhibitors and degraders show promising anticancer effects, issues related to drug resistance upon prolonged treatment remain a challenge in BET-targeted therapeutics development. Recently, we identified specific small compound inhibitors targeting phosphorylation-dependent BRD4 interaction with distinct transcription/replication components and DNA damage response (DDR) factors, including p53, c-Myc, AP-1, and cancer-associated human papillomavirus E2 proteins. Some of these compounds effectively block cancer cell growth and migration and specifically inhibit p53 interaction with BRD4. These new types of protein-protein interaction (PPI) inhibitors highlight molecular action distinct from the widely used BET bromodomain inhibitors.

Thick halite sequences are common in the Earth’s geologic record; they were accumulated in deep perennial hypersaline water bodies, saturated to halite and subjected to negative water balance. For decades, evaporites research gained insights from exploring modern shallow hypersaline environments, including the relations between the hydroclimatic forcing and the deposited halite layers. However, there is a knowledge gap in understanding limnological controls on accreted halite sequences in deep water bodies. Such water bodies rarely exist today on Earth, but were common through Earth geological history. The Dead Sea is currently the closest and probably the only modern analog for such environments. Recently, based on direct field measurements, laboratory experiments, direct numerical simulations, and sedimentological investigation, we have shown that there are fundamental differences between deposition at deep basins versus shallow basins, specifically in the seasonal to multi-annual scales and variations of halite solubility with depth. We have found that during the dry summer the epilimnion is warmer, saltier and undersaturated to halite, and that double diffusion flux delivers dissolved salt from the epilimnion into the hypolimnion, resulting in the continuously supersaturated hypolimnion and seasonally undersaturated epilimnion. Thus the stratified structure of the lake’s water column results in focusing of halite deposits into the deep parts of the basin and thinned deposits, or entirely dissolved, in the marginal parts. We further explore the role of laterally variable hydroclimatic conditions to the spatiotemporal dynamics of evaporitic deposits in a deep hypersaline waterbody. We focus on the role of diluted buoyant plume, overlaying part of the Dead Sea surface that laterally spreads from freshwater inflow. The lateral surface salinity variations results in lateral variations in evaporation, double diffusion fluxes, and hence evaporitic layer thickness. These can contribute to the study of the depositional environments of halite units throughout the geological record, following the concept of “the present as key to the past”. At the end of the talk, I will share some management ideas regarding the future of the Dead Sea.

Computing the structure of protein molecules was a grand challenge problem for half a century. The problem has now been solved using deep learning methods, with many calculated structures rivalling experiment in accuracy. In this talk I’ll describe how the field advanced to this point and the nature of the solution. I’ll also discuss some implications for other areas of structural biology, and broader implications for how science is done.