Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related ...molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.
DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development. Dysregulation of this process is implicated in various ...diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-ångström crystal structure of the DNMT3A-DNMT3L-DNA complex in which two DNMT3A monomers simultaneously attack two cytosine-phosphate-guanine (CpG) dinucleotides, with the target sites separated by 14 base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain, a catalytic loop, and DNMT3A homodimeric interface. Arg836 of the target recognition domain makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Haematological cancer-associated somatic mutations of the substrate-binding residues decrease DNMT3A activity, induce CpG hypomethylation, and promote transformation of haematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease.
Full text
Available for:
KISLJ, NUK, SBMB, UL, UM, UPUK
Despite recent interests in developing lysine‐targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell‐active ...covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde‐based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR‐ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug‐resistant ABL mutations. Among them, the salicylaldehyde‐containing A5 is the first‐ever reversible covalent ABL inhibitor that possessed time‐dependent ABL inhibition with prolonged residence time and few cellular off‐targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome.
A general approach to develop cell‐active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine is reported. Amongst lead compounds, the salicylaldehyde‐containing A5 is the first‐ever reversible covalent ABL inhibitor that possessed time‐dependent nanomolar inhibition against endogenous ABL kinase, with prolonged residence time and few cellular off‐targets.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary of main observation and conclusion
An atroposelective synthesis of a new class of 3,3’‐bisindoles bearing axial and central chirality has been established via catalytic asymmetric addition ...reactions using isatin‐derived imines as electrophiles (23 examples, up to 80% yield, > 95 : 5 dr, 98 : 2 er). This approach takes advantage of chiral phosphoric acid‐catalyzed dynamic kinetic resolution of 2‐substituted 3,3’‐bisindoles via nucleophilic addition of such substrates with isatin‐derived imines. In this approach, isatin‐derived imines acted as a class of competent electrophiles due to their high reactivity and bulky size, which provided an easy access to axially chiral 3,3'‐bisindoles incorporated with a biologically important chiral 3‐aminooxindole unit. This approach has greatly expanded the generality and applicability of the strategy of dynamic kinetic resolution for the synthesis of enantioenriched 3,3’‐bisindole derivatives bearing both axial and central chirality.
An atroposelective synthesis of 3,3’‐bisindoles bearing axial and central chirality has been established via catalytic asymmetric addition reactions using isatin‐derived imines as electrophiles.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Nonbiaryl N-C atropisomer is an important structural scaffold, which is present in natural products, medicines and chiral ligands. However the direct enantioselective C-H amination to access ...optically pure N-C atropisomer is still difficult and rare. Here we report a π-π interaction and dual H-bond concerted control strategy to develop the chiral phosphoric acids (CPAs) catalyzed direct intermolecular enantioselective C-H amination of N-aryl-2-naphthylamines with azodicarboxylates as amino sources for the construction of atroposelective naphthalene-1,2-diamines. This type of N-C atropisomers is stabilized by intramolecular hydrogen bond and the method features a broad range of substrates, high yields and ee values, providing a strategy to chirality transfer via the modification of N-C atropisomers.
With the development of advanced electronic devices and electric power systems, polymer-based dielectric film capacitors with high energy storage capability have become particularly important. ...Compared with polymer nanocomposites with widespread attention, all-organic polymers are fundamental and have been proven to be more effective choices in the process of scalable, continuous, and large-scale industrial production, leading to many dielectric and energy storage applications. In the past decade, efforts have intensified in this field with great progress in newly discovered dielectric polymers, fundamental production technologies, and extension toward emerging computational strategies. This review summarizes the recent progress in the field of energy storage based on conventional as well as heat-resistant all-organic polymer materials with the focus on strategies to enhance the dielectric properties and energy storage performances. The key parameters of all-organic polymers, such as dielectric constant, dielectric loss, breakdown strength, energy density, and charge–discharge efficiency, have been thoroughly studied. In addition, the applications of computer-aided calculation including density functional theory, machine learning, and materials genome in rational design and performance prediction of polymer dielectrics are reviewed in detail. Based on a comprehensive understanding of recent developments, guidelines and prospects for the future development of all-organic polymer materials with dielectric and energy storage applications are proposed.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
To provide self-healing ability to polyurethane elastomer, alkoxyamine-based diol was synthesized and reacted with tri-functional homopolymer of hexamethylene diisocyanate (tri-HDI) and polyethylene ...glycol (PEG). Because alkoxyamines acted as crosslinkers of the resultant polyurethane, the thermally reversible fission/recombination of C–ON bonds in alkoxyamine moieties enabled repeated crosslinking and de-crosslinking of polyurethane chains at certain temperature and hence crack healing. Both qualitative and quantitative characterizations demonstrated that the reversibly crosslinked polyurethane was capable of re-bonding ruptured parts and restoring mechanical strength. The remendability was a function of molecular structure and compositions of the components, which can be purposely tuned according to different application demands.
Display omitted
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Polymer‐based film capacitors with high breakdown strength and excellent flexibility are crucial in the field of advanced electronic devices and electric power systems. Although massive works are ...carried to enhance the energy storage performances, it is still a great challenge to improve the energy density of polymer composites under the premise of large‐scale industrial production. Herein, a general strategy is proposed to improve the intrinsic breakdown strength and energy storage performances by blending core‐shell structured methyl methacrylate‐butadiene‐styrene (MBS) rubber particles into a polymer matrix. Good compatibility and uniform dispersion state of MBS particles are observed in the matrix. Polarizing microscopy images show that blended films exhibit clear reduction of crystalline grains with the addition of MBS particles. Accordingly, an increased breakdown strength of 515 MV m−1 and discharged energy density of 12.33 J cm−3 are observed in poly(vinylidene fluoride‐co‐hexafluoropropylene)‐based composite films. Through comprehensive characterizations, it is believed that the superior energy storage performance of composite films is attributed to decreased crystalline grains, improved mechanical properties, and restriction on carrier motion. These results provide a novel design of dielectric polymers for high breakdown strength and discharged energy density applications.
All‐organic dielectrics are fabricated by blending core‐shell structured methyl methacrylate‐butadiene‐styrene rubber particles and poly(vinylidene fluoride‐co‐hexafluoropropylene) through solution casting method. The blended composite films are found to increase the breakdown strength and discharged energy density of the polymer matrix. The all‐organic films with quick/simple fabrication, improved dielectric, and energy storage performances provide a novel design of dielectrics for energy storage applications.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Dirac semimetal is an emerging class of quantum matters, ranging from 2D category, such as, graphene and surface states of topological insulator to 3D category, for instance, Cd3As2 and Na3Bi. As 3D ...Dirac semimetals typically possess Fermi‐arc surface states, the 2D–3D Dirac van der Waals heterostructures should be promising for future electronics. Here, graphene–Cd3As2 heterostructures are fabricated through direct layer‐by‐layer stacking. The electronic coupling results in a notable interlayer charge transfer, which enables us to modulate the Fermi level of graphene through Cd3As2. A planar graphene p–n–p junction is achieved by selective modification, which demonstrates quantized conductance plateaus. Moreover, compared with the bare graphene device, the graphene–Cd3As2 hybrid device presents large nonlocal signals near the Dirac point due to the charge transfer from the spin‐polarized surface states in the adjacent Cd3As2. The results enrich the family of van der Waals heterostructure and should inspire more studies on the application of Dirac/Weyl semimetals in spintronics.
Dirac van der Waals heterostructures are fabricated through direct stacking of 3D Dirac semimetal Cd3As2 on 2D graphene. The enhancement of nonlocal signals near the Dirac point in modulated graphene is proposed to result from the spin‐polarized charges injected from the surface states of Cd3As2 to graphene, suggesting that the Dirac semimetal can serve as a spin injector.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Baseline drift always blurs or even swamps signals and deteriorates analytical results, particularly in multivariate analysis. It is necessary to correct baseline drift to perform further data ...analysis. Simple or modified polynomial fitting has been found to be effective to some extent. However, this method requires user intervention and is prone to variability especially in low signal-to-noise ratio environments. A novel algorithm named adaptive iteratively reweighted Penalized Least Squares (airPLS) that does not require any user intervention and prior information, such as peak detection
etc.
, is proposed in this work. The method works by iteratively changing weights of sum squares errors (SSE) between the fitted baseline and original signals, and the weights of the SSE are obtained adaptively using the difference between the previously fitted baseline and the original signals. The baseline estimator is fast and flexible. Theory, implementation, and applications in simulated and real datasets are presented. The algorithm is implemented in R language and MATLAB™, which is available as open source software (
http://code.google.com/p/airpls
).
A novel algorithm named adaptive iteratively reweighted Penalized Least Squares (airPLS) is proposed for baseline correction in analytical chemistry. By investigating the correction result using real data, it proved to be simple but flexible, valid and fast for baseline estimation.
PDF
