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Melting in the deep rocky parts of planets plays an important role in geological processes such as planet formation, seismicity, magnetic field generation, thermal convection, and crustal evolution. Such processes are the key way to understanding the dynamics of planetary interiors and the history as well as mechanisms of planetary evolution. We herein investigate the melting curves and pressure-temperature ( P - T )-phase diagrams for CaO 3 , a candidate mineral for the lower mantle, by means of the deep learning potential model. Using first-principles, molecular dynamics, and quasi-harmonic approximation, the reliability of the deep learning potential model is verified by calculating the high-temperature and high-pressure equations of state and phase transition pressures for the orthorhombic and tetragonal structures of CaO 3 described by space groups Aea 2 and P 4̅2 1 m , respectively. The melting temperatures of 975, 850, and 755 K at zero pressure are obtained by the single-phase, void, and two-phase methods, respectively, and their melting temperatures are analyzed by the radial distribution function and mean-square displacement to analyze the melting process. Finally, the melting phase diagrams of CaO 3 at 0-135 GPa were obtained by the two-phase method.

Selectively targeting the cancer-specific protein - protein interaction (PPI) between Hsp70 and Bim has been discovered as a promising strategy for treating chronic myeloid leukemia (CML). The first Hsp70 - Bim PPI inhibitor, S1g-2 , has been identified to overcome the on-target toxicity of known Hsp70 inhibitors when it induces apoptosis of CML cells. Herein, we carried out a hit-to-lead optimization of S1g-2 , yielding S1g-10 , which exhibited a 10-fold increase in Hsp70/Bim suppressing potency. Furthermore, S1g-10 not only exhibited a 5- to 10-fold stronger antitumor activity in the sub-μM range against CML cells than S1g-2 in vitro, but it also overcame BCR-ABL-independent tyrosine kinase inhibitor resistance in CML in vivo depending on the Hsp70 - Bim signaling pathway. Moreover, through structure - activity relationship analysis, TROSY-HSQC NMR, molecular dynamics simulation, and point mutation validation, two hydrophobic pockets composed of eight key residues were demonstrated to produce predominant interactions with either Bim or S1g-10 , regarded as the "hot-spots" in the Hsp70 - Bim PPI interface.

Increasing insertion host materials are developed as high-performance anodes of "rocking-chair" zinc ion batteries. However, most of them show unsatisfactory rate capabilities. Herein, layered BiOIO 3 is reported as an excellent insertion host and a zinc ion conductor, i.e., Zn 3 (PO 4 ) 2 ·4H 2 O (ZPO), is introduced to construct a BiOIO 3 @ZPO heterojunction with a built-in electric field (BEF). Both ZPO and a BEF obviously enhance Zn 2+ transfer and storage, which is proven by theoretical calculations and experimental studies. The conversion-type mechanism of BiOIO 3 is revealed through ex situ characterizations. The optimized electrode exhibits a high reversible capacity of 130 mAh g -1 at 0.1 A g -1 , a low average discharge voltage of 0.58 V, an ultrahigh rate performance with 68 mAh g -1 at 5 A g -1 (52% of capacity at 0.1 A g -1 ), and an ultralong cyclic life of 6000 cycles at 5 A g -1 . Significantly, the BiOIO 3 @ZPO//Mn 3 O 4 full cell shows a good cyclic life of 67 mAh g -1 over 1000 cycles at 0.1 A g -1 . This work provides a new insight into the design of anodes with excellent rate capability.

The key challenge of developing reaction-based turn-on probes is to establish latent electrophilic fluorophores exhibiting high reactivity only upon binding to a specific protein(s). Herein, we identified such a fluorophore, 6-arylthioether-substituted 3-cyano-1-oxo-1 H -phenalene-2-carboxylate, which chemoselectively labels binding site Cys or Lys residues. Based on this fluorophore, we developed the first reaction-based turn-on pyruvate kinase M2 isoform (PKM2) fluorescent probe AT-OPC1 , which selectively labels PKM2 with the binding site Lys305. The latent electrophilic reactivity of the fluorophore endows the probe with precise detection of the expression of PKM2 in situ by means of both in-gel fluorescence imaging at the proteome level and real-time no-wash cell imaging approaches, which has the potential to be applied in cancer diagnoses.

Transition-metal sulfide is a good kind of material for supercapacitors because of the large capacity. Nevertheless, the low electroconductivity, slow reaction kinetics, and limited active centers lead to poor electrochemical properties such as long-term cycling stability. In the present work, nano nickel metal-organic framework (Ni-MOF) was constructed by using the nitrogen-rich functional group ligand 2,4,6-tris(3,5-dicarboxylphenylamino)-1,3,5-triazin and compounded with carbon nanotubes (CNTs) to prepare Ni-MOF/CNTs composite, which was used as a precursor to prepare the MOFs-derived NC/Ni-Ni 3 S 4 /CNTs composite with the Ni 3 S 4 uniformly distributed in the three-dimensional (3D) conductive network. The rich nitrogen doping and 3D conductive network constructed by CNTs improved the conductivity, prompted the rapid entry of electrolyte, and improved the reaction kinetics of NC/Ni-Ni 3 S 4 /CNTs, thus obtained excellent specific capacitance, coulomb efficiency, and cyclic stability. The specific capacitance of NC/Ni-Ni 3 S 4 /CNTs is 1489.9 F/g at 1 A/g, which remains 800 F/g at 10 A/g, showing good rate performance.

Fluorescence responses of two BINOL-based diastereomeric salicylaldimines toward a variety of metal cations have been studied in methanol solution. It is revealed that both compounds show great fluorescence enhancements in the presence of Zn 2+ but not with any other metal ions. Moreover, these two diastereomers exhibit dramatically different responses toward Zn 2+ under the same conditions. That is, one can produce much stronger fluorescence enhancement also at a longer wavelength than the other. This fluorescence recognition of Zn 2+ also shows distinctive color changes under a UV lamp. Mass and NMR spectroscopic analyses have been used to study the mechanism, which indicates the formation of 2+nZn 2+ complexes (n = 2, 3). This work has shed new light on the mechanism of an enantioselective fluorescent recognition of chiral amines promoted by Zn 2+ .

During the development of recombinant monoclonal antibody (rMAb) drugs, glycosylation receives particular focus because changes in the attached glycans can have a significant impact on the antibody effector functions. The vast heterogeneity of structures that exist across glycosylation sites hinders the in-depth analysis of glycan changes specific to an individual protein within a complex mixture. In this study, we established a sensitive and specific method for monitoring site-specific glycosylation in rMAbs using multiple reaction monitoring (MRM) on an ultrahigh-performance liquid chromatography-triple quadrupole MS (UHPLC-QqQ-MS). Our results showed that irrespective of the IgG subclass expressed in the drugs, the N-glycopeptide profiles are nearly the same but differ in abundances. In all rMAb drugs, a single subclass of IgG comprised over 97% of the total IgG content and showed over 97% N-glycan site occupancy. This study demonstrates the utility of an MRM-based method to rapidly characterize over 130 distinct glycopeptides and determine the extent of site occupancy within minutes. Such multilevel structural characterization is important for the successful development of therapeutic antibodies.

No α-helical mimetic that exhibits Bcl-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the α-helixes at their binding interfaces. Herein, we extracted a one-turn α-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn α-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.

Nanostructured silicon hybrid solar cells are promising candidates for a new generation photovoltaics because of their light-trapping abilities and solution processes. However, the performance of hybrid organic/Si nanostructure solar cells is hindered because of carrier recombination at surface and poor coverage of organic material poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (, Pedot: PSS) on nanostructures. Here we demonstrate low-pressure-assisted coating method of, Pedot: PSS on surface-modified silicon nanotips with broadband light-trapping characteristics to improve interface property and to achieve high-efficiency hybrid solar cells through a solution process. The approach enhances the effective minority-carrier lifetime and the coverage of, Pedot: PSS on the surface of nanostructures. Hybrid solar cells fabricated with surface-modified nanotips exhibit a high fill factor of 70.94%, short-circuit current density of 35.36 mA/cm(2), open-circuit voltage of 0.528 V, and power conversion efficiency of 13.36%. The high efficiency and the high fill factor are achieved because of conformal coating of, Pedot: PSS via a low-pressure-assisted coating process, excellent light harvesting without sacrificing the minority-carrier lifetime, and efficient charge separation/collection of photogenerated carriers.

To decrease the mortality of lung cancer, better screening and diagnostic tools as well as treatment options are needed. Protein glycosylation is one of the major post-translational modifications that is altered in cancer, but it is not exactly clear which glycan structures are affected. A better understanding of the glycan structures that are differentially regulated in lung tumor tissue is highly desirable and will allow us to gain greater insight into the underlying biological mechanisms of aberrant glycosylation in lung cancer. Here, we assess differential glycosylation patterns of lung tumor tissue and nonmalignant tissue at the level of individual glycan structures using nLC-chip-TOF-MS. Using tissue samples from 42 lung adenocarcinoma patients, 29 differentially expressed (FDR < 0.05) glycan structures were identified. The levels of several oligomannose type glycans were upregulated in tumor tissue. Furthermore, levels of fully galactosylated glycans, some of which were of the hybrid type and mostly without fucose, were decreased in cancerous tissue, whereas levels of non- or low-galactosylated glycans mostly with fucose were increased. To further assess the regulation of the altered glycosylation, the glycomics data was compared to publicly available gene expression data from lung adenocarcinoma tissue compared to nonmalignant lung tissue. The results are consistent with the possibility that the observed N-glycan changes have their origin in differentially expressed glycosyltransferases. These results will be used as a starting point for the further development of clinical glycan applications in the fields of imaging, drug targeting, and biomarkers for lung cancer.

Glycosylation is an important post-translational modification of proteins present in the vast majority of human proteins. For this reason, they are potentially new sources of biomarkers and active targets of therapeutics and vaccines. However, the absence of a biosynthetic template as in the genome and the general complexity of the structures have limited the development of methods for comprehensive structural analysis. Even now, the exact structures of many abundant N-glycans in serum are not known. Structural elucidation of oligosaccharides remains difficult and time-consuming. Here, we introduce a means of rapidly identifying released N-glycan structures using their accurate masses and retention times based on a glycan library. This serum glycan library, significantly expanded from a previous one covering glycans released from a handful of serum glycoproteins, has more than 170 complete and partial structures and constructed instead from whole serum. The method employs primarily nanoflow liquid chromatography and accurate mass spectrometry. The method allows us to readily profile N-glycans in biological fluids with deep structural analysis. This approach is used to determine the relative abundances and variations in the N-glycans from several individuals providing detailed variations in the abundances of the important N-glycans in blood.

The glycosylation in recombinant monoclonal antibody (rMab) drugs is a major concern in the biopharmaceutical industry as it impacts the drugs' many attributes. Characterization is important but complicated by the intricate structures, microheterogeneity, and the limitations of current tools for structural analysis. In this study, we developed a liquid chromatography-mass spectrometry (LC-MS) N-glycan library based on eight commercial rMab drugs. A library of over 70 structures was developed for the rapid characterization of rMab. N-Glycans were separated on a porous graphitized carbon (PGC) column incorporated on a chip and then analyzed by an electrospray ionization hybrid quadrupole time-of-flight (ESI-Q-TOF) MS. The retention time and accurate mass for each N-glycan were recorded in the library. The complete structures were obtained through exoglycosidase sequencing. The results showed that most of the N-glycans between different antibodies are nearly the same with different abundances. The utility of this library enables one to identify structures in a rapid manner by matching LC retention times and accurate masses.

Bim BH3 peptide features an α-helix with hotspot residues on multiple faces. Compound 5 (6-bromo-2,3-dihydroxyanthracene-9,10-dione), which adopts a rigid-plan amphipathic conformation, was designed and evaluated as a scaffold to mimic two faces of Bim α-helix. It reproduced the functionalities of both D67 and I65 on two opposing helical sides. Moreover, it maintained the two-faced binding mode during further evolution. A putative BH3 α-helix mimic and nanomolar Bcl-2/Mcl-1 dual inhibitor, 6, was obtained based on the structure of 5.

Highly flexible, robust, and sensitive infrared nanosensors were fabricated based on carbon nanoparticles that were synthesized through a simple and low-cost flame method. The infrared nanosensor devices showed sharp infrared photoresponse with a response time of ∼68 ms and a maximum photocurrent change of ∼52.9%. The devices showed a superhydrophobic property with a contact angle larger than 150° and a sliding angle of ∼4°. The mechanism for the enhanced infrared photoresponse from carbon nanoparticles is discussed.

We recently described the discovery of a dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1). Here we report a structure-guided design in combination with structure-activity relationship studies to exploit the difference in the p2 binding pocket of Bcl-2 and Mcl-1, from which a novel dual inhibitor 3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (6h) was obtained, which showed significant enhanced IC(50) value against Mcl-1 (5 nM), greater Mcl-1/Bak disruption potential, and accordingly a 10-fold increased cytotoxicity over 3.

Small molecule inhibitors always exhibit poor water solubility due to the inherent hydrophobic property. It is an important challenge when they are developed as a real drug. S1, a structure-specific Bcl-2 inhibitor encountered this issue when moved forward in preclinical development. Herein, we prepared a 1:1 type of S1-gamma-cyclodextrin (S1-gamma-CD) inclusion complex to enhance the solubility. Bioevaluation of this new formulation was carried out totally in water solution. The cell internalization and cellular accumulation of S1-gamma-CD was illustrated by its fluorescence analogue S2. Disruption of Bcl-2/Bax heterodimerization in MCF-7 cells further revealed S1-gamma-CD could reach the subcellular function site. Moreover, the even stronger disruption by S1-gamma-CD than free S1 was found due to the higher local concentrations. Furthermore, the in vivo antitumor activity of S1-gamma-CD was evaluated in the H22 xenograft model. Results showed it exhibited significant antitumor activity with a decrease of tumor size (average tumor volume = 234 +/- 76 mm(3) vs control group, 398 +/- 121 mm(3), P < 0.01, and S1 group, 296 +/- 65 mm(3), P < 0.05), and a much longer survival time (the median time to the end point = 39.9 days vs control group, 29.2 days, P < 0.01). More importantly, the similar disruption of Bcl-2/Bax was found in S1-gamma-CD treated mice and free S1 treated ones. It demonstrated that S1-gamma-CD not only obtains a pharmaceutical level in vivo but also maintains the mechanism-based antitumor ability of S1 itself. It has been identified that cyclodextrin is appropriate to deliver a structure-specific molecule to its subcellular function site without any adverse effects on its mechanism-based potency, in either cultured cells or animals.

We have previously shown the binding modes of two DNA interacting analogues (1)a {3-(4-methyl-piperazin)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile} and (3)a {3-(3-dimethylamino-propylamino)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile} with the DNA double helix. In this study, we have determined the notably different DNA damage signal pathway elicited by (1)a and (3)a due to the different extents to which they unwind the DNA double helix. First, we have identified that ataxia-telangiectasia-mutated (ATM) protein kinase can respond to DNA double helix unwinding caused by both (1)a and (3)a. In addition, the amount of ATM activation is consistent with the degree to which the DNA double helix was unwound. Consequently, we used (1)a and (3)a to semiquantitatively probe the response of RNA polymerase II (RNAPII) and p53 toward DNA double helix unwinding in vivo. By means of flow cytometry, immunocytochemistry, ChIP, quantitative real-time polymerase chain reaction, and Western blot analyses, we measured the level of p53 and RNAPII phosphorylation, in addition to the dynamics of the RNAPII distribution along the c-Myc gene. These results provided novel evidence for the impact of subtle DNA structural changes on the activity of RNAPII and p53. Moreover, DNA double helix conformational damage-dependent apoptosis was studied for the first time. These results indicated that (1)a can induce transcriptional blockage following a shift of the unphosphorylated IIa form of RNAPII to the phosphorylated IIo form, while (3)a is unable to induce the same effect. Subsequently, p53 accumulation and phosphorylation events occur that lead to apoptosis in the case of (1)a exposure. This suggests that the transcriptional blockage is also correlated to the degree of double helix unwinding. Furthermore, we found that the degree of DNA conformational damage determines whether or not apoptosis occurs through transcriptional blockage. Under our experimental conditions, ATM does not participate in the downstream events even when it has been activated. Thus, p53-mediated apoptosis may be independently triggered by transcriptional blockage.