Mll1 is essential for the senescenceassociated secretory phenotype

Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces “SASP-like” inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression

Gas-phase reactivity of aluminum cluster anions with ethanethiol: Carbon-sulfur bond activation

We report a joint experimental and theoretical study of the gas-phase reactivity of Al cluster anions with ethanethiol (EtSH) in a fast-flow tube reactor. Nearly all Al-n(-) clusters observed are reactive at the presence of sufficient EtSH molecules with minor exceptions. Sulfide species AlnSm- dominate the observed reaction products, indicating C-S bond activation of EtSH. By using DFT calculations we provide an in-depth analysis on the interesting cluster reactivity of Al-n(-) with EtSH. It is demonstrated that the desulfurization leading to AlnSm- products is associated with the dehydrogen processes successively initiated by S-H bond cleavage and C-H bond cracking. (C) 2013 Elsevier B. V. All rights reserved

Cluster reaction of [Ag-8](-)/[Cu-8](-) with chlorine: Evidence for the harpoon mechanism?

To examine the question whether the harpoon mechanism can account for the reactive behavior of microscopic charged systems, we have investigated the reactivity of coinage metal clusters in gas phase. Our studies reveal that the reactivity between [Cu-8](-)/[Ag-8](-) and chlorine gas is consistent with the harpoon mechanism. An increased reactive cross section is noted through our theoretical estimation based on two methods, ascribed to a long-range transfer of valence electrons from the [Cu-8](-)/[Ag-8](-) cluster to chlorine. Insights into this reactivity will be of interest to other researchers working on obtaining a better understanding of the reaction mechanisms of such superatomic species. (C) 2013 Elsevier B.V. All rights reserved

Reactivity of Aluminum Clusters with Water and Alcohols: Competition and Catalysis?

An in-depth investigation is presented on the hydrogen evolution reaction of aluminum clusters with water and methanol/isopropanol. Aluminum clusters were found to undertake an etching effect in the presence of methanol, but also resulted in an addition reaction with isopropanol. Such reactivity without producing hydrogen is different than water, although they all contain an OH group. Further, we studied the competition of water versus alcohols reacting with Al clusters by simultaneously introducing them into a fast-flow tube reactor. Water dominates the competitive reaction with Al clusters, and the O–H bond in water is readily activated to form aluminum hydroxide cluster products. Also found is that water functions as a catalyst in the activation of the O–H bond in alcohol molecules

Reactivity of Silver Clusters Anions with Ethanethiol

We have investigated the gas-phase reactivity of silver clusters with ethanethiol in a fast-flow tube reactor. The primary cluster products observed in this reaction are Ag_<i>n</i>SH^– and Ag_<i>n</i>SH₂^–, indicating C–S bond activation, together with interesting byproducts H₃S^– and (H₃S)₂^–. Ag_<i>n</i>^– clusters with an odd number of valence electrons (<i>n</i> = even) were observed to be more reactive than those with an even number of electronsa feature previously only observed in the reactivity of Ag_<i>n</i>^– with triplet oxygen, indicating that radical active sites play a role in their reactivity. Furthermore, the reactivity dramatically increases with large flow rate of ethanethiol being introduced in the flow tube. Theoretical investigations on the reactivity of Ag₁₃^– and Ag₈^– with ethanethiol indicate that both Ag₁₃^– and Ag₈^– face significant barriers to reactivity with a single ethanethiol molecule. However, Ag₈^– reacts readily in a cooperative reaction with two ethanethiol molecules, consistent with the dramatic increase in reactivity with a large flow rate. Further hydrogen-transfer reactions may then release an ethylene molecule or an ethyl radical resulting in the observed Ag_<i>n</i>SH^– species

Engineering MoS2 nanosheets on spindle-like α-Fe2O3 as high-performance core–shell pseudocapacitive anodes for fiber-shaped aqueous lithium-ion capacitors

Fiber-shaped aqueous lithium-ion capacitors (FALICs) featured with high energy and power densities together with outstanding safety characteristics are emerging as promising electrochemical energy-storage devices for future portable and wearable electronics. However, the lack of high-capacitance fibrous anodes is a major bottleneck to achieve high performance FALICs. Here, hierarchical MoS2@α-Fe2O3 core–shell heterostructures consisting of spindle-shaped α-Fe2O3 cores and MoS2 nanosheet shells on a carbon nanotube fiber (CNTF) are successfully fabricated. Originating from the unique core/shell architecture and prominent synergetic effects for multi-components, the resulting MoS2@α-Fe2O3/CNTF anode delivers a remarkable specific capacitance of 2077.5 mF cm−2 (554.0 F cm−3) at 2 mA cm−2, substantially outperforming most of the previously reported fibrous anode materials. Further density functional theory calculations reveal that the MoS2@α-Fe2O3 nano-heterostructure possesses better electrical conductivity and stronger adsorption energy of Li+ than those of the individual MoS2 and α-Fe2O3. By paring with the self-standing LiCoO2/CNTF battery-type cathode, a prototype quasi-solid-state FALIC with a maximum operating voltage of 2.0 V is constructed, achieving impressive specific capacitance (253.1 mF cm−2) and admirable energy density (39.6 mWh cm−3). Additionally, the newly developed FALICs can be woven into the flexible textile to power wearable electronics. This work presents a novel effective strategy to design high-performance anode materials for next-generation wearable ALICs.Ministry of Education (MOE)National Research Foundation (NRF)This work was supported in part by the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2019-T2-2-127), the Singapore Ministry of Education Academic Research Fund Tier 1 (MOE2019-T1-001-103 and MOE2019-T1-001-111) and the Singapore National Research Foundation Competitive Research Program (NRF-CRP18-2017-02). This work was also supported in part by the National Natural Science Foundation of China (No. 51972162) and Nanyang Technological University. Dr. W. Gong was grateful to the support from the Natural Science Foundation of Jiangsu Province (BK20190228) and Guangdong Basic and Applied Basic Research Foundation (2019A1515110859).Conflict of InterestThe authors declare no conflict of interest.Keywordsaqueous lithium-ion capacitors, core–shell heterostructures, fiber electronics, pseudocapacitive anode, self-standing electrodesReceived: May 7, 2020Revised: June 3, 2020Published online: July 6, 2020Adv. Funct. Mater.2020, 30, 200396

Combinatorial genetics in liver repopulation and carcinogenesis with a in vivo CRISPR activation platform.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 activation (CRISPRa) systems have enabled genetic screens in cultured cell lines to discover and characterize drivers and inhibitors of cancer cell growth. We adapted this system for use in vivo to assess whether modulating endogenous gene expression levels can result in functional outcomes in the native environment of the liver. We engineered the catalytically dead CRISPR-associated 9 (dCas9)-positive mouse, cyclization recombination-inducible (Cre) CRISPRa system for cell type-specific gene activation in vivo. We tested the capacity for genetic screening in live animals by applying CRISPRa in a clinically relevant model of liver injury and repopulation. We targeted promoters of interest in regenerating hepatocytes using multiple single guide RNAs (gRNAs), and employed high-throughput sequencing to assess enrichment of gRNA sequences during liver repopulation and to link specific gRNAs to the initiation of carcinogenesis. All components of the CRISPRa system were expressed in a cell type-specific manner and activated endogenous gene expression in vivo. Multiple gRNA cassettes targeting a proto-oncogene were significantly enriched following liver repopulation, indicative of enhanced division of cells expressing the proto-oncogene. Furthermore, hepatocellular carcinomas developed containing gRNAs that activated this oncogene, indicative of cancer initiation events. Also, we employed our system for combinatorial cancer genetics in vivo as we found that while clonal hepatocellular carcinomas were dependent on the presence of the oncogene-inducing gRNAs, they were depleted for multiple gRNAs activating tumor suppressors.ConclusionThe in vivo CRISPRa platform developed here allows for parallel and combinatorial genetic screens in live animals; this approach enables screening for drivers and suppressors of cell replication and tumor initiation. (Hepatology 2017)

Spin Accommodation and Reactivity of Silver Clusters with Oxygen: The Enhanced Stability of Ag₁₃^–

Spin accommodation is demonstrated to play a determining role in the reactivity of silver cluster anions with oxygen. Odd-electron silver clusters are found to be especially reactive, while the anionic 13-atom cluster exhibits unexpected stability against reactivity with oxygen. Theoretical studies show that the odd–even selective behavior is correlated with the excitation needed to activate the O–O bond in O₂. Furthermore, by comparison with the reactivity of proximate even-electron clusters, we demonstrate that the inactivity of Ag₁₃^– is associated with its large spin excitation energy, ascribed to a crystal-field-like splitting of the orbitals caused by the bilayer atomic structure, which induces a large gap despite not having a magic number of valence electrons