| 1. |
- Xu, Yongtao, et al.
(author)
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Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation
- 2022
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In: Molecules. - : MDPI AG. - 1420-3049. ; 27:23
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Journal article (peer-reviewed)abstract
- Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, (Formula presented.) = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, (Formula presented.) = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors.
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| 2. |
- Klomp, Matthijs, 1976, et al.
(author)
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Longitudinal Velocity and Road Slope Estimation in Hybrid Electric Vehicles Employing Early Detection of Excessive Wheel Slip
- 2014
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In: Vehicle System Dynamics. - : Taylor & Francis. - 0042-3114 .- 1744-5159. ; 52:SUPPL. 1, s. 172-188
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Journal article (peer-reviewed)abstract
- Vehicle speed is one of the important quantities in vehicle dynamics control. Estimation of the slope angle is in turn a necessity for correct dead reckoning from vehicle acceleration. In the present work, estimation of vehicle speed is applied to a hybrid vehicle with an electric motor on the rear axle and a combustion engine on the front axle. The wheel torque information, provided by electric motor, is used to early detect excessive wheel slip and improve the accuracy of the estimate. A best-wheel selection approach is applied as the observation variable of a Kalman filter which reduces the influence of slipping wheels as well as reducing the computational effort. The performance of the proposed algorithm is illustrated on a test data recorded at a winter test ground with excellent results, even for extreme conditions such as when all four wheels are spinning.
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| 3. |
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| 4. |
- Klomp, Matthijs, 1976, et al.
(author)
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Robust Estimation of Longitudinal Velocity and Road Slope in Hybrid Electric Vehicles using an Adaptive Kalman Filter
- 2013
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In: Proceedings of the 23st International Symposium on Dynamics of Vehicles on Roads and Tracks.
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Conference paper (peer-reviewed)abstract
- Accurate knowledge of the vehicle longitudinal velocity is essential for wheel slip control. Estimation of the slope angle in turn is important for real-life fuel economy optimization and improved traction control. In order to meet these demands also during slippery conditions, an accurate and efficient method of longitudinal velocity and slope estimation is proposed in paper. The research object of this work is a hybrid vehicle with an electric motor on the rear axle and a combustion engine on the front axle. The wheel torque, which offered by electric motor is used to find out over-slipping wheels. Also, only one wheel speed is selected as the observation variable of Kalman Filter by means of a best-wheel selection method, which reduces the influence of slipping wheels as well as the calculation quantity. Furthermore, the slope estimation and accelerometer bias are also taken into consideration. Finally, this algorithm is verified on a winter test ground with excellent results also when all four wheels are spinning.
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| 5. |
- Wu, Jieyu, et al.
(author)
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Disruption of the Clock Component Bmal1 in Mice Promotes Cancer Metastasis through the PAI-1-TGF-beta-myoCAF-Dependent Mechanism
- 2023
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In: Advanced Science. - : WILEY. - 2198-3844. ; 10:24
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Journal article (peer-reviewed)abstract
- The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-beta into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-beta signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.
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| 6. |
- Wu, Jing, et al.
(author)
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Interleukin-33 is a Novel Immunosuppressor that Protects Cancer Cells from TIL Killing by a Macrophage-Mediated Shedding Mechanism
- 2021
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In: Advanced Science. - : Wiley. - 2198-3844. ; 8:21
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Journal article (peer-reviewed)abstract
- Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy.
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| 7. |
- Xue, Yuan, et al.
(author)
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PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells
- 2012
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In: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 18:1, s. 100-110
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Journal article (peer-reviewed)abstract
- The platelet-derived growth factor (PDGF) signaling system contributes to tumor angiogenesis and vascular remodeling. Here we show in mouse tumor models that PDGF-BB induces erythropoietin (EPO) mRNA and protein expression by targeting stromal and perivascular cells that express PDGF receptor-beta (PDGFR-beta). Tumor-derived PDGF-BB promoted tumor growth, angiogenesis and extramedullary hematopoiesis at least in part through modulation of EPO expression. Moreover, adenoviral delivery of PDGF-BB to tumor-free mice increased both EPO production and erythropoiesis, as well as protecting from irradiation-induced anemia. At the molecular level, we show that the PDGF-BB PDGFR-beta signaling system activates the EPO promoter, acting in part through transcriptional regulation by the transcription factor Atf3, possibly through its association with two additional transcription factors, c-Jun and Sp1. Our findings suggest that PDGF-BB-induced EPO promotes tumor growth through two mechanisms: first, paracrine stimulation of tumor angiogenesis by direct induction of endothelial cell proliferation, migration, sprouting and tube formation, and second, endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia.
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| 8. |
- Zou, Wei, et al.
(author)
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Minimising efficiency roll-off in high-brightness perovskite light-emitting diodes
- 2018
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Efficiency roll-off is a major issue for most types of light-emitting diodes (LEDs), and its origins remain controversial. Here we present investigations of the efficiency roll-off in perovskite LEDs based on two-dimensional layered perovskites. By simultaneously measuring electroluminescence and photoluminescence on a working device, supported by transient photoluminescence decay measurements, we conclude that the efficiency roll-off in perovskite LEDs is mainly due to luminescence quenching which is likely caused by non-radiative Auger recombination. This detrimental effect can be suppressed by increasing the width of quantum wells, which can be easily realized in the layered perovskites by tuning the ratio of large and small organic cations in the precursor solution. This approach leads to the realization of a perovskite LED with a record external quantum efficiency of 12.7%, and the efficiency remains to be high, at approximately 10%, under a high current density of 500 mA cm(-2).
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