No abstract

Dependence on the 26S proteasome is an Achilles’ heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.

Cyanoacrylic and carboxyl groups have been developed as the most extensively used electron acceptor and anchoring group for the design of sensitizers for dye-sensitized solar cells. In terms of the photoelectric conversion efficiency, each of them has been demonstrated to be superior to the other one in certain cases. Herein, to further understand the effect of these two groups on cell efficiencies, a series of porphyrin sensitizers were designed and synthesized, with the acceptors systematically varied, and the effect of the neighboring ethynylene unit was also investigated. Compared with the sensitizer XW5 which contains a carboxyphenyl anchoring moiety directly linked to the meso-position of the porphyrin framework, the separate introduction of a strongly electron-withdrawing cyanoacrylic acid as the anchoring group or the insertion of an ethynylene unit can achieve broadened light absorption and IPCE response, resulting in higher Jsc and higher efficiency. Thus, compared with the efficiency of 4.77% for XW5, dyes XW1 and XW6 exhibit higher efficiencies of 7.09% and 5.92%, respectively. Simultaneous introduction of the cyanoacrylic acid and the ethynylene units into XW7 can further broaden light absorption and thus further improve the Jsc. However, XW7 exhibits the lowest Voc value, which is not only related to the floppy structure of the cyanoacrylic group but also related to the aggravated dye aggregation effect due to the extended framework. As a result, XW7 exhibits a relatively low efficiency of 5.75%. These results indicate that the combination of the ethynylene and cyanoacrylic groups is an unsuccessful approach. To address this problem, a cyano substituent was introduced to XW8 at the ortho position of the carboxyl group in the carboxyphenyl acceptor. Thus, XW8 exhibits the highest efficiency of 7.59% among these dyes. Further cosensitization of XW8 with XS3 dramatically improved the efficiency to 9.31%.

Modulating lasing wavelength flexibly and repeatedly on a single rod is essential to the practical applications of micro/nanorod lasers. In this paper, a structure that decouples the gain medium and optical cavity is proposed, where the corresponding mechanism for the lasing wavelength shift is explained. Based on the above structure, one kind of wavelength continuously variable lasers is achieved on a single GaN/InGaN core-shell microrod without modifying the geometry of the resonant cavity or cutting the microrod. By using this method, lasing wavelength can be modulated from 372 to 408 nm flexibly and repeatedly in a 10 μm facilely synthesized microrod. This approach demonstrates a big application potential in numerous fields consisting of optical telecommunication and environmental monitoring.