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This study explores the socio-demographic and economic differences in the perceived influences of natural disasters and travel risk on international travel. A sample of 354 visitors to South Florida was surveyed as to their perceptions of the influence of natural disasters and travel risk on international travel. A Principal Components Analysis identified two groups of natural disasters, 'Snow and fire ' and 'Wind and water', and two groups of perceived travel risk, 'Socio-cultural and psychological' and 'Physical'. A t-test

Interactions between WD40 repeat domain protein 5 (WDR5) and its various partners such as mixed lineage leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in human cancers. However, inhibitors that block protein-protein interactions (PPIs) between WDR5 and its binding partners exhibit modest cancer cell killing effects and lack in vivo efficacy. Here, we present pharmacological degradation of WDR5 as a promising therapeutic strategy for treating WDR5-dependent tumors and report two high-resolution crystal structures of WDR5degrader-E3 ligase ternary complexes. We identified an effective WDR5 degrader via structure-based design and demonstrated its in vitro and in vivo antitumor activities. On the basis of the crystal structure of an initial WDR5 degrader in complex with WDR5 and the E3 ligase von Hippel-Lindau (VHL), we designed a WDR5 degrader, MS67, and demonstrated the high cooperativity of MS67 binding to WDR5 and VHL by another ternary complex structure and biophysical characterization. MS67 potently and selectively depleted WDR5 and was more effective than WDR5 PPI inhibitors in suppressing transcription of WDR5-regulated genes, decreasing the chromatin-bound fraction of MLL complex components and c-MYC, and inhibiting the proliferation of cancer cells. In addition, MS67 suppressed malignant growth of MLL-rearranged acute myeloid leukemia patient cells in vitro and in vivo and was well tolerated in vivo. Collectively, our results demonstrate that structure-based design can be an effective strategy to identify highly active degraders and suggest that pharmacological degradation of WDR5 might be a promising treatment for WDR5-dependent cancers.

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Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1-and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.

Double-stranded ribonucleic acid-activated protein kinase (PKR) downregulates translation as a defense mechanism against viral infection. In fish species, PKZ, a PKR-like protein kinase containing left-handed deoxyribonucleic acid (Z-DNA) binding domains, performs a similar role in the antiviral response. To understand the role of PKZ in Z-DNA recognition and innate immune response, we performed structural and functional studies of the Z-DNA binding domain (Zα) of PKZ from Carassius auratus (caZαPKZ). The 1.7-Å resolution crystal structure of caZαPKZ:Z-DNA revealed that caZαPKZ shares the overall fold with other Zα, but has discrete structural features that differentiate its DNA binding mode from others. Functional analyses of caZαPKZ and its mutants revealed that caZαPKZ mediates the fastest B-to-Z transition of DNA among Zα, and the minimal interaction for Z-DNA recognition is mediated by three backbone phosphates and six residues of caZαPKZ. Structure-based mutagenesis and B-to-Z transition assays confirmed that Lys56 located in the β-wing contributes to its fast B-to-Z transition kinetics. Investigation of the DNA binding kinetics of caZαPKZ further revealed that the B-to-Z transition rate is positively correlated with the association rate constant. Taking these results together, we conclude that the positive charge in the β-wing largely affects fast B-to-Z transition activity by enhancing the DNA binding rate.