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Compared with Si–C(sp2 and sp) bonds bearing neighboring π-bond hyperconjugative interactions, the activation of robust Si–C(sp3) bonds has proved to be a challenge. Herein, two distinct Si–C(sp3) bond cleavages have been realized by rare-earth-mediated and nucleophilic addition of unsaturated substrates. The reactions of TpMe2Y[κ2-(C,N)-CH(SiH2Ph)SiMe2NSiMe3](THF) (1) with CO or CS2 gave two endocyclic Si–C bond cleavage products, TpMe2Y[κ2-(O,N)-OC＝CH(SiH2Ph)SiMe2NSiMe3](THF) (2) and TpMe2Y[κ2-(S,N)-SSiMe2NSiMe3](THF) (3), respectively. However, 1 reacted with nitriles such as PhCN and p-R′C6H4CH2CN in a 1 : 1 molar ratio to yield the exocyclic Si–C bond products TpMe2Y[κ2-(N,N)-N(SiH2Ph)C(R)＝CHSiMe2NSiMe3](THF) (R = Ph (4); R = C6H5CH2 (6H); R = p-F-C6H4CH2 (6F); and R = p-MeO-C6H4CH2 (6MeO)), respectively. Moreover, complex 4 can continuously react with an excess of PhCN to form a TpMe2-supported yttrium complex with a novel pendant silylamido-substituted β-diketiminato ligand, TpMe2Y[κ3-(N,N,N)-N(SiH2Ph)C(Ph)＝CHC(Ph)＝N-SiMe2NSiMe3](PhCN) (5). [ABSTRACT FROM AUTHOR]

Current action mechanisms for aptamer‐based therapeutics depend on occupancy‐driven pharmacology to mediate protein functions. We report a new mechanism where aptamers leverage cellular proteasomal degradation system to degrade proteins for cancer treatment. A DNA aptamer (hereinafter referred to as c‐Met‐Ap) binds to the extracellular domain of mesenchymal‐epithelial transition factor (c‐Met) and selectively induces c‐Met phosphorylation at Y1003 and Y1349. The phosphorylation of Y1003 recruits E3 ubiquitin ligase casitas B‐lineage lymphoma, causing c‐Met ubiquitination and degradation in the proteasome. Furthermore, c‐Met‐Ap can induce a decrease in the heterodimeric partner proteins of c‐Met and the downstream effector proteins in the c‐Met signal axis, effectively inhibiting tumor growth in A549 tumor‐bearing BALB/c mice. Our study uncovers a novel, actionable mechanism for aptamer therapeutics and opens a new avenue for developing highly efficient anticancer drugs. [ABSTRACT FROM AUTHOR]

Current action mechanisms for aptamer‐based therapeutics depend on occupancy‐driven pharmacology to mediate protein functions. We report a new mechanism where aptamers leverage cellular proteasomal degradation system to degrade proteins for cancer treatment. A DNA aptamer (hereinafter referred to as c‐Met‐Ap) binds to the extracellular domain of mesenchymal‐epithelial transition factor (c‐Met) and selectively induces c‐Met phosphorylation at Y1003 and Y1349. The phosphorylation of Y1003 recruits E3 ubiquitin ligase casitas B‐lineage lymphoma, causing c‐Met ubiquitination and degradation in the proteasome. Furthermore, c‐Met‐Ap can induce a decrease in the heterodimeric partner proteins of c‐Met and the downstream effector proteins in the c‐Met signal axis, effectively inhibiting tumor growth in A549 tumor‐bearing BALB/c mice. Our study uncovers a novel, actionable mechanism for aptamer therapeutics and opens a new avenue for developing highly efficient anticancer drugs. [ABSTRACT FROM AUTHOR]

The rare‐earth/lithium cooperative effect on functionalization of white phosphorus has been investigated. The reaction of diazabutadiene‐supported yttrium hydride chelated a LiPPh2 molecule (LY ⋅ THF)2(μ‐H)2[μ‐PPh2(Li)] (1, L=N,N'‐di(2,6‐diisopropylphenyl)‐1,4‐diazabutadiene) with P4 gave two novel mixed Y/Li multinuclear polyphosphorus complexes (LY ⋅ THF)2[cyclo‐P3]Li(THF)3 (2) and [Li(THF)4]+[(LY ⋅ THF)3(norborane‐P7)Li(THF)]− (3), accompanied with the elimination of diphosphorus compound Ph2PPPh2 (4) and H2. However, the comparative reaction of yttrium hydride (LY ⋅ THF)2(μ‐H)2 with P4 afforded a trinuclear yttrium pyramid‐P4 complex (LY ⋅ THF)3(μ3‐P(PH)3) (5). Further investigations show that 5 cannot continuously react with LiPPh2 to form 2 and 3, and LiPPh2 reacted with P4 to form a Zintl‐P7 lithium complex (TMEDA⋅Li)3(Zintl‐P7) (6) and 4. These results indicated that the cooperation of Y/Li for activation of P4 is a key for the formation of 2 and 3. All new compounds have been characterized by NMR spectroscopy and single‐crystal X‐ray diffraction studies. [ABSTRACT FROM AUTHOR]

• A novel frameshift mutation of the NHS gene was identified in a Chinese family. • The inheritance pattern was consistent with X-linked dominant inheritance. • The nhsb gene of zebrafish plays an important role in development of lens. • Frameshift mutation of nhsb may lead to the loss of its function causing lens opacity. [ABSTRACT FROM AUTHOR]

Purpose. Based on the differential gene expression analysis for predictive biomarkers with RNA-Sequencing data from Fuchs endothelial corneal dystrophy (FECD) patients, we are aiming to evaluate the efficacy of Library of Integrated Network-based Cellular Signatures (LINCS) perturbagen prediction software to identify novel pharmacotherapeutic targets that can revert the pathogenic gene expression signatures and reverse disease phenotype in FECD. Methods. A publicly available RNA-seq dataset was used to compare corneal endothelial specimens from controls and patients with FECD. Based on the differential gene expression analysis for predictive biomarkers, we evaluated the efficacy of LINCS perturbagen prediction software to identify novel therapeutic targets that can revert the pathogenic gene expression signatures and reverse disease phenotypes in FECD. Results. The RNA-seq dataset of the corneal endothelial cells from FECD patients revealed the differential gene expression signatures of FECD. Many of the differential expressed genes are related to canonical pathways of the FECD pathogenesis, such as extracellular matrix reorganization and immunological response. The expression levels of genes VSIG2, IL18, and ITGB8 were significantly increased in FECD compared with control. Meanwhile, the expression levels of CNGA3, SMOX, and CERS1 were significantly lower in the FECD than in control. We employed LINCS L1000 Characteristic Direction Signature Search Engine (L1000-CDS2) to investigate pathway-based molecular treatment. L1000-CDS2 predicted that small molecule drugs such as histone deacetylase (HDAC) inhibitors might be a potential candidate to reverse the pathological gene expression signature in FECD. Conclusions. Based on differential gene expression signatures, several candidate drugs have been identified to reverse the disease phenotypes in FECD. Gene expression signature with LINCS small molecule prediction software can discover novel preclinical drug candidates for FECD. [ABSTRACT FROM AUTHOR]

The oxidation behavior of the alloy Fe−25%Cr−6%Al-RE (rich in lanthanum) was investigated by means of TEM analysis. The results show that after 2 hr oxidation of the alloy, in pure oxygen at 1200° C, La precipitated in the oxide scale at the top of α-AlO grains and at the grain-boundary regions in the form of tiny particles of hexagonal LaO. These tiny particles prevented aluminum from diffusing toward the surface and suppressed lateral growth of the oxide scale. The rare-earth constituents accelerated the internal oxidation of the alloy during thermal cycling between 1200° C and room temperature. They appeared as particles of aluminum oxide and lanthanum oxide. Particles of cubic LaO precipitated in the alloy matrix near the oxide scale-metal interface in a direction parallel to grain boundaries. [ABSTRACT FROM AUTHOR]

Viral myocarditis (VMC) is a type of inflammation affecting myocardial cells caused by viral infection and has been an important cause of dilated cardiomyopathy (DCM) worldwide. Type B3 coxsackievirus (CVB3), a non-enveloped positive-strand RNA virus of the Enterovirus genus, is one of most common agent of viral myocarditis. Till now, effective treatments for VMC are lacking due to lack of drugs or vaccine. Lithium chloride (LiCl) is applied in the clinical management of manic depressive disorders. Accumulating evidence have demonstrated that LiCl, also as an effective antiviral drug, exhibited antiviral effects for specific viruses. However, there are few reports of evaluating LiCl's antiviral effect in mice model. Here, we investigated the inhibitory influence of LiCl on the CVB3 replication in vitro and in vivo and the development of CVB3-induced VMC. We found that LiCl significantly suppressed CVB3 replication in HeLa via inhibiting virus-induced cell apoptosis. Moreover, LiCl treatment in vivo obviously inhibited virus replication within the myocardium and alleviated CVB3-induced acute myocarditis. Collectively, our data demonstrated that LiCl inhibited CVB3 replication and negatively regulated virus-triggered inflammatory responses. Our finding further expands the antiviral targets of LiCl and provides an alternative agent for viral myocarditis. • Lithium chloride inhibits coxsackievirus B3 virus replication in vitro and in vivo. • Lithium chloride inhibits CVB3 replication via inhibiting virus-induced cell apoptosis. • LiCl treatment in vivo obviously alleviated CVB3-induced acute myocarditis. [ABSTRACT FROM AUTHOR]