Chemical Perturbation of Mcl‑1 Pre-mRNA Splicing to Induce Apoptosis in Cancer Cells

The myeloid cell leukemia-1 (<i>MCL1</i>) gene encodes antiapoptotic Mcl-1_L and proapoptotic Mcl-1_S proteins. In cancer, the Mcl-1_L/Mcl-1_S ratio is very high, accounting for the antiapoptotic nature of cancer cells. As such, reducing this ratio can render the cancer cells prone to apoptosis. The Mcl-1_L/Mcl-1_S ratio is determined in the alternative pre-mRNA splicing step that is regulated by splicing factor 3B1 (SF3B1). Here, we report that meayamycin B, a potent inhibitor of SF3B1, reversed the dominant isoform from Mcl-1_L to Mcl-1_S at the mRNA and protein levels. The resulting proapoptotic cellular environment was further exploited; when meayamycin B was combined with Bcl-x_L inhibitor ABT-737, the combination treatment triggered apoptosis in nonsmall cell lung cancer A549 and H1299 cells that were otherwise resistant to ABT-737. These results demonstrate that perturbation of the <i>MCL1</i> splicing with small molecule inhibitors of SF3B1 provides a means to sensitize cancer cells toward Bcl-x_L inhibitors

The nexus between the cultural and creative industries and the Sustainable Development Goals: a network perspective

Scholars and policymakers have widely claimed that the cultural and creative industries (CCIs) provide positive knowledge externalities that can help address sustainable development challenges, yet questions remain about the pathways through which this occurs. In this study, we hypothesise that several features of knowledge networks in the CCIs relate to a location’s sustainable development outcomes. We use data of ownership networks between 22,455 cultural heritage-related firms across 292 cities in China to empirically test our hypotheses. We find that the density of the CCI network has a positive relation with a city’s performance in terms of several Sustainable Development Goal measures. Moreover, the scale of local CCIs has an inverted ‘U’-shaped relationship with a city’s sustainability performance. Finally, a city’s degree of trans-local ties has an inverted ‘U’-shaped relation with a city’s sustainability performance.</p

K and Na content in shoot tissues of tall fescue as affected by sodium chloride, sodium carbonate, sodium sulfate, and calcium chloride.

<p>Ion content was measured in weekly intervals over a period of five weeks. Data were combined for two cultivars, Tar Heel II and Wolfpack. * and ** denote significance at 0.05 and 0.01 probability levels, respectively.</p

Shoot and root biomass of tall fescue as affected by sodium chloride, sodium carbonate, sodium sulfate, and calcium chloride.

<p>Data were combined for two cultivars, Tar Heel II and Wolfpack. * and ** denote significance at 0.05 and 0.01 probability levels, respectively.</p

Analysis of variation of ion uptake in the shoots of tall fescue as affected by cultivar, salt types and salt concentrations.

<p>Analysis of variation of ion uptake in the shoots of tall fescue as affected by cultivar, salt types and salt concentrations.</p

Total Synthesis and Biological Studies of TMC-205 and Analogues as Anticancer Agents and Activators of SV40 Promoter

TMC-205 is a natural fungal metabolite with antiproliferative activity against cancer cell lines. The light- and air-sensitivity prevented in-depth exploitation of this novel indole derivative. Herein, we report the first synthesis of TMC-205. On the basis of its reactivity with reactive oxygen species, we developed air-stable analogues of TMC-205. These analogues are 2–8-fold more cytotoxic than TMC-205 against HCT-116 colon cancer cell line. Importantly, at noncytotoxic dose levels, these analogues activated the transcription of luciferase reporter gene driven by simian virus 40 promoter (SV40). Further, these small molecules also inhibit firefly luciferase, presumably by direct interaction

Ion uptake in tall fescue as affected by different salts with data pooled for cultivars (Tar Heel II and Wolfpack) and salt concentrations.

a<p>Y (g kg⁻¹) as a response variable affected by salt concentration × (mM).</p><p>*, **, *** significant at 0.05, 0.01, and 0.001 probability levels, respectively.</p

Salt properties at different molar concentrations in deionized water.

<p>a) Electrical conductivity, b) pH, and c) osmotic potential.</p

Ion content in tall fescue as affected by different salts with data pooled for cultivars (Tar Heel II and Wolfpack) and salt concentrations.

a<p>means followed by same letter within a column are not different at 0.05 probability level.</p

Large Eddy Simulations of Blockage Ratio Effect on a Square Cylinder In a Uniform Flow

This paper was reviewed and accepted by the APCWE-IX Programme Committee for Presentation at the 9th Asia-Pacific Conference on Wind Engineering, University of Auckland, Auckland, New Zealand, held from 3-7 December 2017