Characterization of the mechanical properties of urea-formaldehyde microcapsules filled with epoxy resin is of importance for achieving self-healing of cementitious composites. In this study, the ...morphology of microcapsules, including diameter and thickness, was characterized using scanning electron microscopy. The mechanical properties of single microcapsules, including Young's modulus and hardness, were determined through a nanoindentation technology based on the elastic contact theory using a Berkovich indenter. Moreover, to investigate the structural effects of microcapsules, a diamond plate indenter was used, and the Young's modulus of the microcapsule wall was calculated through the ordinary least square optimization method according to three analytical solutions on the basis of thin shell theory, namely Reissner, Pogorelov, and Lukasiewicz methods. It is shown that the results of the contact and thin shell theory were similar, in which the similarity occurs only in the case of a small deformation. When the deformation was large (indentation depth >900 nm), the structural effect became significant. In addition, the finite element method was applied to simulate the mechanical response of the microcapsules using the results obtained. The validity of the approach was approved.
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•Determination of Young's modulus of urea-formaldehyde microcapsules.•Comparison between the result from the contact model and that from shell theory.•The approach was validated by finite element method (FEM) simulation.
Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from ...oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone–aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.
Dynamic correlation plays an important role in the accurate calculation of chemical compounds such as the description of equilibrium structures in chemical systems. A model for the fast estimation of ...dynamic correlation energy is introduced in this work. This model is based on the idea of decomposition of the contribution of dynamic correlation energy calculated by nth order Møller–Plesset perturbation (MPn) theory with respect to atomic regions. Multiple levels of theory, including MP2, MP2.5, and MP4, are used as the reference, and the corresponding correlation energy densities are calculated. The proposed model is concise, fast, and promising for practical use, such as the prediction of reaction energies. It can also work as a baseline model or pretrained model for follow-up studies of machine learning.
•An UPLC–MS/MS method was established to determinate multi-mycotoxin in milk.•The optimal solid phase extraction (SPE) cartridge was selected at 0.025μgkg−1.•The optimal SPE conditions were ...screened.•The matrix effects of different milk matrixes were evaluated and compensated.
In this study, a sensitive and rapid method has been developed for the simultaneous determination of aflatoxin M1, ochratoxin A, zearalenone and α-zearalenol in milk by ultra high performance liquid chromatography combined with electrospray ionisation triple quadrupole tandem mass spectrometry (UHPLC–ESI–MS/MS). The milk samples were purified using Oasis HLB cartridge. The matrix effects were evaluated by determining the signal suppression–enhancement (SSE) and corrected by external matrix-matched calibration. The limits of quantity (LOQ) of the mycotoxins were in the range of 0.003–0.015μgkg−1. The high correlation coefficients (R2⩾0.996) were obtained in the range of 0.01–1.00μgkg−1 of the mycotoxins, along with good recovery (87.0–109%), repeatability (3.4–9.9%) and intra-laboratory reproducibility (4.0–9.9%) at the concentrations of 0.025, 0.1 and 0.5μgkg−1. The detected rates of the mycotoxins were from 16.7% to 96.7% in raw milk, liquid milk and milk powder samples collected from the dairy farms and supermarkets in Beijing. The method proposed is suitable for the simultaneous determination of aflatoxin M1, ochratoxin A, zearalenone, and α-zearalenol, and could be performed for analysing the mycotoxins in milk.
We have previously shown that miR-486-5p is one of the most downregulated micro RNAs in lung cancer. The objective of the study was to investigate the role of miR-486-5p in the progression and ...metastasis of non-small-cell lung cancer (NSCLC). We evaluated miR-486-5p expression status on 76 frozen and 33 formalin-fixed paraffin-embedded tissues of NSCLC by quantitative reverse transcriptase PCR to determine its clinicopathologic significance. We then performed function analysis of miR-486-5p to determine its potential roles on cancer cell migration and invasion in vitro and metastasis in vivo. We also investigated the target genes of miR-486-5p in lung tumorigenesis. miR-486-5p expression level was significantly lower in lung tumors compared with their corresponding normal tissues (P<0.0001), and associated with stage (P=0.0001) and lymph node metastasis of NSCLC (P=0.0019). Forced expression of miR-486-5p inhibited NSCLC cell migration and invasion in vitro and metastasis in mice by inhibiting cell proliferation. Furthermore, ectopic expression of miR-486-5p in cancer cells reduced ARHGAP5 expression level, whereas miR-486-5p silencing increased its expression. Luciferase assay demonstrated that miR-486-5p could directly bind to the 3'-untranslated region of ARHGAP5. The expression level of miR-486-5p was inversely correlated with that of ARHGAP5 in lung tumor tissues (P=0.0156). Reduced expression of ARHGAP5 considerably inhibited lung cancer cell migration and invasion, resembling that of miR-486-5p overexpression. miR-486-5p may act as a tumor-suppressor contributing to the progression and metastasis of NSCLC by targeting ARHGAP5. miR-486-5p would provide potential diagnostic and therapeutic targets for the disease.
Ab initio molecular dynamics (AIMD) has become a popular simulation technique but long simulation times are often hampered due to its high computational effort. Alternatively, classical molecular ...dynamics (MD) based on force fields may be used, which, however, has certain shortcomings compared to AIMD. In order to alleviate that situation, a trajectory-based machine learning (TrajML) approach is introduced for the construction of force fields by learning from AIMD trajectories. Only nuclear trajectories are required, which can be obtained by other methods beyond AIMD as well. We developed an easy-to-use MD machine learning package (TrajML MD) for instant modelling of the force field and system-focussed prediction of molecular configurations for MD trajectories. It consumes similar computational resources as classical MD but can simulate complex systems with a higher accuracy due to the targeted learning on the system of interest.
To obtain the mechanical parameters for a microcapsule, such as the Young's modulus, yield stress, and hardening coefficients using different mechanical constitutive models, parameter identification ...must be implemented using inverse analysis. In the present study, a new approach combining the finite-element method and an optimisation procedure is proposed for determining the constitutive parameters of urea-formaldehyde microcapsules, in which three types of elastic-plastic constitutive models are considered: the power-law hardening model, the elastic-perfectly plastic model, and the elastic-perfectly plastic model with linear hardening. A nonlinear optimisation procedure is applied to determine the minimum of the multivariable objective function, which is defined as the norm of the difference between the numerical and experimental results. The efficiency and robustness of the proposed method are verified with different initial values and numbers of elements. The force-displacement curves from a numerical simulation show good agreement with the experimental data, indicating that the proposed approach and the mechanical parameters determined are reliable.
•Studied permeability of self-healing cementitious composites, including pore structure.•Small amounts of microcapsules positively affect pore structure and impermeability.•Self-healing efficiency ...increases with increasing microcapsule content and particle size.•Series relationships were obtained to predict relationship of impermeability vs. pore structure parameters.
The effects of adding organic microcapsules having various particle sizes and composition on the permeability, carbonation resistance, pore structure, and self-healing efficiency of cementitious composite material were studied using rapid chloride migration, water pressure penetration, carbonation, and mercury intrusion porosimetry tests. It was found that increasing microcapsule content to 3% improved pore structure and impermeability. However, with 6% microcapsule content, the material impermeability became even lower than that of a specimen without microcapsules. The variation of particle sizes had a slight negative impact on impermeability although it improved pore structure. Increasing microcapsule content and particle size enhanced impermeability, pore structure, and self-healing efficiency of specimens.
Pulmonary hypertension (PH) is a multifaceted condition characterized by elevated pulmonary arterial pressure, which can result in right ventricular dysfunction and failure. Disorders of lung ...development can present with secondary PH, which is a leading cause of mortality in infants with bronchopulmonary dysplasia (BPD). DDR1 (discoidin domain receptor 1) is a collagen-binding receptor that regulates tissue fibrosis and inflammation and controls cellular growth and migration. However, the roles of DDR1 in lung development or the pathogenesis of PH are unknown. Studying mice with a DDR1 deletion (
), we have noted 35% mortality between 1 and 4 months of age, and we demonstrate that DDR1 deficiency results in reduced right ventricular contractility and muscularization of distal pulmonary arteries, consistent with PH. Pathology analysis revealed enlarged alveolar spaces in
mice by Postnatal Day 7, consistent with impaired alveolar development. Gene expression analysis showed that
mice have reduced concentrations of alveologenesis factors and epithelial-to-mesenchymal transition markers. Mechanistic studies
confirmed that DDR1 mediated epithelial-to-mesenchymal transition, migration, and growth of alveolar epithelial cells. Taken together, these data suggest that DDR1 plays important roles mediating alveolarization during lung development. Our studies also describe a new model of spontaneous PH and bronchopulmonary dysplasia in mice.
Dexmedetomidine, a sedative agent, provides neuroprotection when administered during or before brain ischaemia. This study was designed to determine whether dexmedetomidine post-treatment induces ...neuroprotection against subarachnoid haemorrhage (SAH) and the mechanisms for this effect.
Subarachnoid haemorrhage was induced by endovascular perforation to the junction of the right middle and anterior cerebral arteries in adult rats. Dexmedetomidine was applied immediately or 2 h after onset of SAH. Neurological outcome was evaluated 2 days after SAH. Right frontal cortex area 1 was harvested 24 h after SAH for western blotting.
Subarachnoid haemorrhage reduced neurological scores and increased brain oedema and blood–brain barrier permeability. These effects were attenuated by dexmedetomidine post-treatment. Neuroprotection by dexmedetomidine was abolished by PD98095, an inhibitor of extracellular signal-regulated kinase (ERK) activation. Phospho-ERK, the activated form of ERK, was increased by dexmedetomidine; this activation was inhibited by PD98095.
Dexmedetomidine post-treatment provides neuroprotection against SAH. This effect appears to be mediated by ERK.
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