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Summary Protein machines are multi-subunit protein complexes that orchestrate highly regulated biochemical tasks. An example is the Anaphase-Promoting Complex/Cyclosome (APC/C), a thirteen-subunit ubiquitin ligase that initiates the metaphase-anaphase transition and mitotic exit by targeting proteins such as securin and cyclin B1 for ubiquitin-dependent destruction by the proteasome1,2. Because blocking mitotic exit is an effective approach for inducing tumor cell death3,4, the APC/C represents a potential novel target for cancer therapy. APC/C activation in mitosis requires binding of Cdc205, which forms a co-receptor with the APC/C to recognize substrates containing a Destruction box (D-box)6-14. Here we demonstrate that we can synergistically inhibit APC/C-dependent proteolysis and mitotic exit by simultaneously disrupting two protein-protein interactions within the APC/C-Cdc20-substrate ternary complex. We identified a small molecule, called apcin (APC inhibitor), which binds to Cdc20 and competitively inhibits the ubiquitylation of D-box-containing substrates. Analysis of the crystal structure of the apcin-Cdc20 complex suggests that apcin occupies the D-box-binding pocket on the side face of the WD40-domain. The ability of apcin to block mitotic exit is synergistically amplified by co-addition of tosyl-L-arginine methyl ester (TAME), a small molecule that blocks the APC/C-Cdc20 interaction15,16. This work suggests that simultaneous disruption of multiple, weak protein-protein interactions is an effective approach for inactivating a protein machine.

Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4. Importantly, inhibition of CMA stabilized GPX4 and reduced ferroptosis. Our results suggest that activation of CMA is involved in the execution of ferroptosis.

Highlights d RNA-BisSeq revealed a dynamic RNA m 5 C landscape during zebrafish embryogenesis d Ybx1 preferentially recognizes m 5 C-modified mRNAs d Ybx1 deficiency leads to early gastrulation defects in zebrafish embryos d Ybx1 and Pabpc1a coordinately regulate m 5 C-modified maternal mRNA stability

Titanium oxide (TiO2) has been commonly used as an electron transport layer (ETL) of regular‐structure perovskite solar cells (PSCs), and so far the reported PSC devices with power conversion efficiencies (PCEs) over 21% are mostly based on mesoporous structures containing an indispensable mesoporous TiO2 layer. However, a high temperature annealing (over 450 °C) treatment is mandatory, which is incompatible with low‐cost fabrication and flexible devices. Herein, a facile one‐step, low‐temperature, nonhydrolytic approach to in situ synthesizing amino‐functionalized TiO2 nanoparticles (abbreviated as NH2‐TiO2 NPs) is developed by chemical bonding of amino (‐NH2) groups, via TiN bonds, onto the surface of TiO2 NPs. NH2‐TiO2 NPs are then incorporated as an efficient ETL in n‐i‐p planar heterojunction (PHJ) PSCs, affording PCE over 21%. Cs0.05FA0.83MA0.12PbI2.55Br0.45 (abbreviated as CsFAMA) PHJ PSC devices based on NH2‐TiO2 ETL exhibit the best PCE of 21.33%, which is significantly higher than that of the devices based on the pristine TiO2 ETL (19.82%) and is close to the record PCE for devices with similar structures and fabrication procedures. Besides, due to the passivation of the surface trap states of perovskite film, the hysteresis of current–voltage response is significantly suppressed, and the ambient stability of devices is improved upon amino functionalization.

Few-layer black phosphorus (BP) with an anisotropic two-dimensional (2D)-layered structure shows potential applications in photoelectric conversion and photocatalysis, but is easily oxidized under ambient condition preferentially at its edge sites. Improving the ambient stability of BP nanosheets has been fulfilled by chemical functionalization, however this functionalization is typically non-selective. Here we show that edge-selective functionalization of BP nanosheets by covalently bonding stable C60 molecules leads to its significant stability improvement. Owing to the high stability of the hydrophobic C60 molecule, C60 functions as a sacrificial shield and effectively protects BP nanosheets from oxidation under ambient condition. C60 bonding leads to a rapid photoinduced electron transfer from BP to C60, affording enhanced photoelectrochemical and photocatalytic activities. The selective passivation of the reactive edge sites of BP nanosheets by sacrificial C60 molecules paves the way toward ambient processing and applications of BP.

RankComp is implemented in R script that is freely available from Supplementary Materials.

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