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Electron transport through metal-organic frameworks by ahopping mechanism between discrete redox active sites is coupled to diffusion-migration of charge-balancing counter cations. Experimentally determinedapparent diffusion coefficients,Deapp, that characterize this form of chargetransport thus contain contributions from both processes. While this is wellestablished for MOFs, microscopic descriptions of this process are largelylacking. Herein, we systematically lay out different scenarios for cation-coupledelectron transfer processes that are at the heart of charge diffusion throughMOFs. Through systematic variations of solvents and electrolyte cations, it isshown that theDeappfor charge migration through a PIZOF-type MOF,Zr(dcphOH-NDI) that is composed of redox-active naphthalenediimide(NDI) linkers, spans over 2 orders of magnitude. More importantly, however,the microscopic mechanisms for cation-coupled electron propagation arecontingent on differing factors depending on the size of the cation and its propensity to engage in ion pairs with reduced linkers,either non-specifically or in defined structural arrangements. Based on computations and in agreement with experimental results, weshow that ion pairing generally has an adverse effect on cation transport, thereby slowing down charge transport. In Zr(dcphOH-NDI), however, specific cation-linker interactions can open pathways for concerted cation-coupled electron transfer processes thatcan outcompete limitations from reduced cationflux.

Supplementary Table S1 Sequences of primers used in the study.

Supplementary Figure S3 Single-cell imaging of HA-tagged TC32 cells treated with 2.5 nM trabectedin or lurbinectedin for 6 h shows EWS-FLI1 (green) localized into the nucleolus (red). DAPI (blue) staining of the nucleus.

There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here, we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analogue lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect, and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30% to 70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma. Cancer Res; 76(22); 6657–68. ©2016 AACR.

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The vast majority of reductions in aerosol emissions are projected to take place in the near future; however, associated impacts on the large-scale circulation over the populated Asian monsoon region remain uncertain. Using the state-of-the-art UK Earth System Model version 1 (UKESM1), this study examines the response of the South Asian and East Asian summer monsoon (SASM and EASM) to idealized reductions in anthropogenic emissions of carbonaceous aerosols and SO2. The analysis focuses on changes in the monsoon temporal extent and intensity of precipitation following decreases in either scattering (SCT), absorbing (ABS) aerosols, or decreases in both. For SCT, the combination of the early transition of land-sea thermal contrast and sea level pressure gradient during the pre-monsoon season together with the late transition in the post-monsoon season associated with the tropospheric warming, advances the monsoon onset but delays its withdrawal, which leads to an extension of the summer rainy season across South and East Asia. The northward shift of the upper-tropospheric Asian jet forced by the SCT reduction causes the anomalous convergence of tropospheric moisture and low-level ascent over northern India and eastern China. The intensification of the South Asian High (SAH) due to the warming over land also contributes to the dynamic instability over Asia. These changes enhance the rainy season of these regions in boreal summer. Reductions in absorbing aerosol act in the opposite sense, making the Asia's rainy season shorter and weaker due to the opposite impacts on land-sea contrast, Asian jet displacement and SAH intensity. With reductions in both SCT and ABS aerosol together the monsoon systems intensify, as the overall impact is dominated by aerosol scattering effects and results in the strengthening of monsoon precipitation and 850-hPa circulation. Although aerosol scattering and absorption play quite different roles in the radiation budget, their effects on the monsoon precipitation seem to add almost linearly. Specifically, the patterns of monsoon-related large-scale responses from reducing both SCT and ABS together are similar to the linear summation of separate effect of reducing SCT or ABS alone, despite of the inherent nonlinearity of the atmospheric systems. Our findings suggest that emission controls that target e.g. emissions of black carbon that warm the climate would have a different response to those that target overall aerosol emissions.