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TRF1 is a critical regulator of telomere length. As such, TRF1 levels are regulated by ubiquitin-dependent proteolysis via an SCF E3 ligase where Fbx4 contributes substrate specification. Here we report the crystal structure of the Fbx4-TRF1 complex at 2.4 Å resolution. Fbx4 contains a unusual substrate-binding domain that adopts a small GTPase fold. Strikingly, this atypical GTPase domain of Fbx4 binds to a globular domain of TRF1 through an intermolecular β sheet, instead of recognizing short peptides/degrons as often seen in other F-box protein-substrate complexes. Importantly, mutations in this interface abrogate Fbx4-dependent TRF1 binding and ubiquitination. Furthermore, the data demonstrate that recognition of TRF1 by SCFFbx4 is regulated by another telomere protein TIN2. Our results reveal an atypical small GTPase domain within Fbx4 as a substrate-binding motif for SCFFbx4 and uncover a mechanism for selective ubiquitination and degradation of TRF1 in telomere homeostasis control.

After the successful completion of the human genome project (HGP), biological research in the postgenome era urgently needs an efficient approach for functional analysis of genes. Utilization of knockout mouse models has been powerful for elucidating the function of genes as well as finding new therapeutic interventions for human diseases. Gene trapping and gene targeting are two independent techniques for making knockout mice from embryonic stem (ES) cells. Gene trapping is high-throughput, random, and sequence-tagged while gene targeting enables the knockout of specific genes. It has been about 20 years since the first gene targeting and gene trapping mice were generated. In recent years, new tools have emerged for both gene targeting and gene trapping, and organizations have been formed to knock out genes in the mouse genome using either of the two methods. The knockout mouse project (KOMP) and the international gene trap consortium (IGTC) were initiated to create convenient resources for scientific research worldwide and knock out all the mouse genes. Organizers of KOMP regard it as important as the HGP. Gene targeting methods have changed from conventional gene targeting to high-throughput conditional gene targeting. The combined advantages of trapping and targeting elements are improving the gene trapping spectrum and gene targeting efficiency. As a newly-developed insertional mutation system, transposons have some advantages over retrovirus in trapping genes. Emergence of the international knockout mouse consortium (IKMP) is the beginning of a global collaboration to systematically knock out all the genes in the mouse genome for functional genomic research.

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An efficient and multifunctional brucite/3-aminopropyltriethoxysilane (APTES)/nickel alginate/APTES (B/A/Nia/A) hybrid flame retardant was fabricated via the layer-by-layer assembly technique with brucite, silane coupling agents, nickel chloride, and sodium alginate. The morphology, chemical composition, and structure of the hybrid flame retardant were characterized. The results confirmed the multilayer structure and indicated that the assembled driving forces were electrostatic interactions, dehydration condensation, hydrogen bonds, and coordination bonds. When used in ethylene-vinyl acetate (EVA) resin, the multifunctional flame retardant had better performance than brucite in improving the flame retardancy, smoke suppression, and mechanical properties. With 130 phr loading, the multifunctional flame retardant achieved a limiting oxygen index value of 32.3% and a UL 94 V-0 rating, whereas the brucite achieved only 31.1% and a V-2 rating, respectively. The peak heat release rate and total heat released decreased by 41.5% and 8.9%, respectively. The multifunctional flame retardant had an excellent performance in reducing the smoke, CO, and CO2 production rates. These improvements could be attributed to the catalyzing carbonization of nickel compounds and the formation of more protective char layers. Moreover, the elongation at break increased by 97.5%, which benefited from the improved compatibility and the sacrificial bonds in the nickel alginate. The mechanism of flame retardant, smoke suppression, and toughening is proposed.

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Alginates (nickel alginate, NiA; copper alginate, CuA; zinc alginate, ZnA) and 3-aminopropyltriethoxysilane (APTES) were alternately deposited on a magnesium hydroxide (MH) surface by the spray-drying-assisted layer-by-layer assembly technique, fabricating some efficient and environmentally benign flame retardants (M-FR, including Ni-FR, Cu-FR, and Zn-FR). The morphology, chemical compositions, and structures of M-FR were investigated. With 50 wt % loading, compared with EVA28+MH, the peak heat release rate, smoke production rate, and CO production rate of EVA28+Ni-FR decreased by 50.78%, 61.76%, and 66.67%, respectively. The metals or metal oxide nanoparticles arising from alginates could catalyze the pyrolysis intermediates of EVA into graphene and amorphous carbon, which could bind the inorganic compounds (the decomposition products of MH and APTES) together and form some more protective barriers. For each M-FR, the flame retardant and smoke suppression efficiency were different, which were caused by the diverse carbonization and graphitization behaviors of three alginates. ZnA generated some ZnO aggregations and could not catalyze the graphitization of intermediates. For CuA, the catalytic graphitization was limited by the tightly binding graphene layer. As for NiA, the configuration of the Ni atom could not provide strong binding of Ni substrate and carbon. The liquid-like Ni nanoparticles could restructure and get out from firm graphene shells, so the catalytic graphitization of NiA was efficient and sustainable. This work displayed the catalytic graphitization mechanism of alginates while exploring a simple and novel strategy for fabricating efficient green flame retardants.