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The elastic properties and electronic structure of interfaces in Ti-Si-N nanocomposite films were calculated using first principles based on density functional theory (DFT). The results showed that the mechanical moduli of the single-substitution interface (1Si-6N) were higher than those of the double-substitution interface and interstitial interface (1Si-4Ti4N). The single-substitution interface (1Si-6N) was revealed to be characterized as the more elastically isotropic structure in different directions, whereas the Young's moduli significantly varied in different directions in the interstitial interface (1Si-4Ti4N). The electronic structures of interfaces indicated that the structures were conductors with intersecting bands. Strongly delocalized d states of titanium and silicon ions were spread over a wide region of about 10-12 eV and were strongly hybridized with the nitrogen 2p states. The overall appearance of the calculated cross-sections of the electron density difference changed drastically. [ABSTRACT FROM AUTHOR]

The transition metal‐related centers of diamond exhibit good properties. Herein, a first‐principles method based on density functional theory (DFT) is used to study single‐doped Ti‐related point defect structures and codoped structures of Ti and B or N, which possibly exist in diamond; the electronic structure and formation energy are also calculated. The results from structural calculations show that Ti is more likely to be located adjacent to a vacancy to form a TiV structure, which is more stable than other configurations. Ti doping introduces impurity levels into the pure diamond band gap, and the possible energy level transitions are determined. The results from the calculations of the codoped system show that the incorporation of N or B atoms is beneficial for the formation of defect structures and that the incorporation of N optimizes the energy band structure of the defects. When a substitutional Ti atom is located adjacent to a B atom and forms a Ti–B structure, and when four N atoms replace the corresponding neighboring C atoms around TiV to form a TiV–4N structure (which is similar to the NE8 configuration), the structure shows a better energy band structure, which presents new color centers. [ABSTRACT FROM AUTHOR]

Although several covalent KRASG12C inhibitors have made great progress in the treatment of KRASG12C-mutant cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRASG12C Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRASG12C-dependent cancer cells growth with nanomolar IC 50 and DC 50 values, and ＞ 95 % maximum degradation (D max). Molecular dynamics (MD) simulation showed that YN14 induced a stable KRASG12C: YN14 : VHL ternary complex with low binding free energy (ΔG). Notably, YN14 led to tumor regression with tumor growth inhibition (TGI%) rates more than 100 % in the MIA PaCa-2 xenograft model with well-tolerated dose-schedules. We also found that KRASG12C degradation exhibited advantages in overcoming adaptive KRASG12C feedback resistance over KRASG12C inhibition. Furthermore, combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRASG12C-mutant cancer cells. Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRASG12C-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination. A novel exceptionally potent and highly selective KRASG12C degrader namely YN14 was developed. YN14 significantly inhibited tumor cells growth and induced potent KRASG12C degradation in vitro and in vivo. [Display omitted] • YN14 significantly inhibited KRASG12C-dependent cancer cells growth with nanomolar IC 50 and DC 50 values. • YN14 led to tumor regression with tumor growth inhibition (TGI%) rates more than 100 % in the MIA PaCa-2 xenograft model. • YN14 exhibited advantages in overcoming adaptive KRASG12C feedback resistance over KRASG12C inhibition of AMG510. • Combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRASG12C-mutant cancer cells. [ABSTRACT FROM AUTHOR]

Currently, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of non-small cell lung cancer (NSCLC). However, the inevitable drug resistance and side effects are the current main obstacle, which motivating novel therapies. Proteolysis targeting chimera (PROTAC), a lately-developed technology to target proteins for degradation, has been utilized for drug development. Therefore, we designed, synthesized and evaluated a series of CRBN-recruiting EGFR degraders. Among them, 13a and 13b significantly inhibited NCI–H1975 cells proliferation with IC 50 values of 58.08 nM and 46.82 nM, respectively, whereas exhibited more than 100 μM against A549 or H1299 cells, whose selectivity was more than 1700-fold. 13a and 13b potently induced the EGFRL858R/T790M degradation by ubiquitin proteasome system in a time- and dose-dependent manner but not that of EGFRWT, and the DC 50 values of 13b was 13.2 nM, which was the most potent compound in current known CRBN-recruiting EGFRL858R/T790M degraders. 13a and 13b dramatically induced cell apoptosis, cell cycle arrest and inhibited downstream signaling pathways. Furthermore, 13a and 13b effectively and selectively inhibited NCI–H1975 xenograft tumor growth with good pharmacokinetics (PK) properties in vivo. These findings demonstrate that 13a and 13b could serve as candidates for developing the drug for treating NSCLC. [Display omitted] • 13b exhibited highly inhibitory activity and selectivity (H1299 vs. NCI–H1975) more than 1700-fold. • The DC 50 of 13b was 13.2 nM, which was the most potent molecular in current CRBN-recruiting EGFRL858R/T790M degrader. • 13a and 13b showed dual function namely inhibition and degradation effects. • The tumor growth inhibition (TGI%) value of 13b was 63.7% on NCI–H1975 xenograft tumor model. [ABSTRACT FROM AUTHOR]

[Display omitted] • 1b and 1f showed 2.9 ∼ 4.5-fold more potent TRPV4 inhibition activity than RN9893. • The IC 50 s of 1b and 1f against TRPV4 are 0.71 ± 0.21 and 0.46 ± 0.08 μM, respectively. • 1b and 1f significantly alleviated acute lung injury symptoms in mice. • RN9893 analogues are potent TRPV4 inhibitors. RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC 50 = 0.71 ± 0.21 μM and 0.46 ± 0.08 μM, respectively) in vitro , in comparison to RN-9893 (IC 50 = 2.07 ± 0.90 μM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 μM, against RN-9893′s 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment. [ABSTRACT FROM AUTHOR]

• BR and SBR have two HRR peaks at heat fluxes lower than 20 kWm−2. • At the ignition time, the crosslink degree of surface layer reaches 84.23–100 %. • The model considering the crosslink reaction can predict the two-peak HRR curve. • At low heat flux the crosslink reaction has a long residence time before ignition. • The first HRR peak results from the crosslink reaction. Understanding the combustion behavior of rubbers is crucial for predicting their fire hazards. The cone calorimeter experimental results in this study confirm that the combustion behavior of raw rubbers depends on the rubber type and the heat flux. Natural rubber and ethylene-propylene-diene monomer rubber exhibit heat release rate (HRR) curves with only one peak at the end of the burning stage under all tested heat fluxes. At higher heat fluxes, the HRR curves of polybutadiene rubber (BR) and styrene butadiene rubber (SBR) exhibit a single peak; at heat fluxes lower than 20 kWm−2, two HRR peaks were observed. The proposed mechanism model with the crosslink reaction as the key factor can explain the emergence of two-peak HRR curve and has been proved through experiments and simulations. For BR and SBR at 15 kWm−2, the specimens exhibit two upper layers at ignition time. The surface pyrolysis layer seems to be covered by black film or char, with the crosslink degree as high as 84.23–100 %. The second crosslink reaction layer exhibits a higher decomposition temperature T d, 5 % than the original rubber. Based on reaction kinetics and thermodynamics data derived from TG/DSC experiments, the novel pyrolysis model taking crosslink reaction and thermal decomposition of crosslinked intermediate into account well predicts the HRR curves obtained at varied heat fluxes. The conversion of raw rubber to the crosslinked intermediate plays an important role in the reduction of HRR immediately after ignition, resulting in the first HRR peak. [ABSTRACT FROM AUTHOR]

[Display omitted] • Using microwave plasma chemical vapor deposition (MPCVD) and low-density crystal planting process to grow diamond single crystal particles with flat crystal surfaces. • The diameter and spacing of the nano-pillar etching mask were controlled by the cyclic dewetting process of copper film on the surface of diamond for the first time. • The prepared single crystal diamond nanopillars have a uniform diameter and dense arrangement, which can enhance the luminescence of diamond color centers. Diamond nanopillars can effectively improve the spontaneous emission efficiency and coupling-out efficiency of diamond-color-center single-photon sources. In this paper, a low-cost and controllable method for preparing diamond nanopillar clusters is proposed. By choosing the crystal planting method and adjusting the methane concentration of the grown diamonds, isolated single-crystal diamond particles with a flat surface were prepared. Etching masks with individually controllable diameters and spacings were prepared through the cyclic deposition and dewetting of metal films on the surface of microcrystalline diamond particles. Using inductively coupled reactive ion etching technology, diamond nanopillar clusters were prepared through oxygen plasma etching. The nanopillars were uniform in diameter and densely arranged. The single-crystal properties of the diamond nanopillars and their enhancement effect on the photoluminescence of diamond color centers were confirmed through the analysis of Raman and photoluminescence spectra. The results provide a foundation for the deviceization of diamond-color-center single-photon sources. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) is the most attractive target for drug research in non-small cell lung cancer (NSCLC). There have been three generation drugs developed to treat of NSCLC. The third-generation EGFR tyrosine kinase inhibitors (TKIs) Rociletinib and Osimertinib (AZD9291) achieved remarkable clinical efficacy. However, due to the inhibitory activity against the wild-type EGFR, the side effect of associated skin rash and gastrointestinal toxicity appeared. Thus, there is still an urgent need to develop novel inhibitors with potent inhibitory activity and high selectivity for T790M-containing EGFR over EGFRWT. Herein, guided by the molecular dynamic simulation results, a series of potent and selective Osimertinib derivatives were designed, synthesized and evaluated. The promising compounds 7f , 7g , 7k , 7m and 7n demonstrated excellent kinase inhibitory activity and high selectivity for EGFRT790M/L858R mutant. The selectivity of 7m to EGFRT790M/L858R was the highest in the current known compounds near to 2500-fold. In addition, the compound 7m showed considerable activity against NCI–H1975 and HCC827 cells, arrested NCI–H1975 cell cycle at the G2/M stage and significantly induced apoptosis in NCI–H1975 cell. These encouraged results indicated that 7m will be used as a candidate targeting EGFRT790M/L858R for further pharmacodynamic and pharmacokinetic studies, and all these studies provide important clues for the discovery of potent EGFRT790M/L858R inhibitors with high selectivity. [Display omitted] • MD simulation was used to design highly selective EGFRT790M/L858R inhibitors. • The most promising compound 7m showed the highest selectivity near to 2500-fold. • 7m exhibited higher inhibitory activity against NCI–H1975 cells than Osimertinib. • 7m significantly induced G2/M phase arrest and apoptosis in NCI–H1975 cells. [ABSTRACT FROM AUTHOR]

• In this paper, the formation mechanism of germanium vacancy color center is calculated by first principles. • VASP software was used to calculate the adsorption and migration process of germanium on different diamond surfaces. The differential charge, Bader and magnetic moment of germanium before and after adsorption were calculated. The adsorption energy, bonding strength and migration energy of germanium on different diamond surfaces were obtained. Germanium-vacancy (GeV) color centers in diamond are superior to other color centers in terms of luminescence intensity. The Ge-doping process is key to the successful preparation of GeV color centers in diamond. In this study, the formation mechanism of GeV color centers is explored via first-principles calculations of the adsorption and migration of Ge on the (001) surface of diamond. The results reveal that Ge atoms on the surface of completely hydrogenated diamond have a negative adsorption energy, indicating that they cannot be adsorbed. In contrast, the adsorption energy of Ge atoms on the surface of non-perhydrogenated diamond is relatively large, which indicates that the surface of non-perhydrogenated diamond can adsorb Ge atoms. When Ge atoms are closer to hydrogen defects, their adsorption energy is greater. As the extent of hydrogen deficiency increases, the overall adsorption energy increases accordingly. The hydrogen deficiency of the diamond surface may determine the extent of the Ge content on the diamond surface. Magnetic moment, differential charge, and Bader analyses reveal that charge is transferred between Ge and carbon atoms on the diamond surface. In addition, the Ge and carbon atoms form covalent bonds at positions where the adsorption energy is maximum. Finally, the migration of Ge atoms on the diamond surface enables them to reach a stable position easily. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • The composite layered SEI with synergistic regulates the uniform deposition of lithium. • The heterostructure of NGs/Li 3 N affects the diffusion energy of lithium. • The change in the diffusion energy reveals different concentrations of nitrogen-doped graphene. • The mechanical strength is beneficial to the interface diffusion of NG-2/Li 3 N. An artificial solid electrolyte interface (SEI) provides an effective way to solve the instability of the metal lithium anode interface, avoid the growth of lithium dendrites and alleviate the interface fluctuations caused by volume expansion. A first principles method was used to calculate the stability of the double-layer SEI of nitrogen-doped graphene composites with lithium nitride (NGs/Li 3 N), including low-concentration doped graphene (NG-1, NG-2 and NG-3) with nitrogen atoms (1–3), graphene nitride (C 2 N) and graphite phase carbon nitride (g-C 3 N 4) in the doped state. The adsorption and migration of lithium ions on the surface and interface of the heterostructure and the ability of the critical tensile strain to regulate the diffusion of lithium at the interface of the heterostructure were calculated. The optimal diffusion path of the NG-2/Li 3 N heterostructure graphene terminal and the interface is the same. The difference (0.114 eV) in the diffusion energy is the smallest. Under mechanical strength, the NG-2/Li 3 N heterostructure limits the interface deformation caused by the adsorption of lithium and increases the stability of the adsorption of lithium at the interface. A nitrogen-doped graphene composite lithium nitride layered SEI exhibiting a synergistic interface effect was constructed to regulate the deposition of lithium and inhibit the growth of dendrites. [ABSTRACT FROM AUTHOR]

Background: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness., Methods: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression., Results: We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment., Conclusions: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors., (© 2024. The Author(s).)

In order to elucidate the diffusion behaviour of ions in alumina during the anodic alumina process, the effects of electric field strength, hydration content, and electrolyte on amorphous alumina and hydrated alumina were studied using ab initio molecular dynamics. The results show that the diffusion rate of ions in alumina increases with the increase in electric field strength, but there is an extreme value. The maximum diffusion rate of Al ions in alumina monohydrate is 21.8 μm 2 /ms/V, while in alumina trihydrate, it is 16.7 μm 2 /ms/V. The ionic diffusion rate of hydrated alumina is one to two orders of magnitude larger than that of anhydrous amorphous alumina due to the effect of the drag of H ions, which reduces the migration activation energy. Electrolytes also affect the diffusion rate of alumina through the action of H ions. The increase in H ions will not only enhance the diffusion rate of hydrated alumina but also render the hydrous compound more vulnerable to breakdown., (© 2024. The Author(s).)

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC 50 values and achieved picomolar DC 50 values and >99% of maximum degradation ( D max ) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET Y1230H and c-MET D1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations., Competing Interests: The authors declare no conflict of interest., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Mechanical metamaterials constitute a nascent category of architected structures comprising arranged periodic components with tailored geometrical features. These materials are now being employed as advanced medical implants due to their extraordinary mechanical properties over traditional devices. Nevertheless, to achieve desired tissue integration and regeneration, it is critical to study how the microarchitecture affects interactions between metamaterial scaffolds and living biological tissues. Based on human induced pluripotent stem cell technology and multiphoton lithography, we report the establishment of an in vitro microtissue model to study the integration and remodeling of human mesenchymal tissues on metamaterial scaffolds with different unit geometries. Microtissues showed distinct tissue morphologies and cellular behaviors between architected octet-truss and bowtie structures. Under the active force generated from mesenchymal tissues, the octet-truss and bowtie metamaterial scaffolds demonstrated unique instability phenomena, significantly different from uniform loading using conventional mechanical testing., Competing Interests: No competing financial interests exist., (Copyright 2022, Mary Ann Liebert, Inc., publishers.)