Rock discontinuities fundamentally impact the mechanical and hydraulic behaviors of a rock mass, and thus it is a critically important task to characterize the geometrical parameters of these rock ...discontinuities. To measure the discontinuity orientation more accurately and efficiently, two well-known point clouds were taken as cases (a cube and a road cut), and an artificial neural network (ANN)-an machine learning algorithm-was established to identify discontinuities from point clouds through learning a small number of training samples, which had been manually selected from the raw point clouds. Four attributes associated with geometrical features of point clouds were specified as input parameters, namely, point XYZ-coordinates, point normal, point curvature, and point density. Two main groups-discontinuity and non-discontinuity-were produced in the output layer, and the number of the discontinuity groups greatly depended on the sets of discontinuities in the real situation. Using principal component analysis (PCA) and density-based spatial clustering of applications with noise (DBSCAN), single discontinuities were extracted from the group discontinuities which were obtained using ANN, and the corresponding orientations were calculated. The results obtained with the proposed method in this study matched the field surveys and results calculated by a modified region-growing algorithm. The computational efficiency was significantly enhanced using the proposed method, only taking several seconds to process a huge data. More importantly, the accuracy of discontinuity detection was greatly improved by specifying the noise data as the non-discontinuity groups during training samples selection in ANN. The ANN approach does not require the engineers have a strong professional background in computer programming, which simplified the detection and characterization process of rock discontinuity. Furthermore, an APP-named DisDetANN-was developed to implement the rock discontinuity detection based on the proposed ANN model, and the full code of the DisDetANN has been freely shared on GitHub.
Highlights
An artificial neural network was created by machine learning to detect group discontinuities from point clouds.
Point coordinate, normal, curvature, and density were considered in input layers of the artificial neural network.
A clustering algorithm was employed to subdivide group discontinuities into single discontinuities.
Both efficiency and accuracy of the discontinuity detection was improved by the proposed approach.
An APP and full codes of the proposed method were freely made available to the engineering community.
Regulatory T cells (Tregs), which secrete transforming growth factor (TGF)-β and interleukin (IL)-10, have essential role in anti-inflammatory and neurotrophic functions. Herein, we explore the ...neuroprotection of Tregs in Parkinson’s disease (PD) by adoptive transfer of Tregs. Tregs, isolated by magnetic sorting, were activated in vitro and then were adoptively transferred to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-treated mice. Neuroinflammation, dopaminergic neuronal loss and behavioral changes of PD mice were evaluated. Live cell imaging system detected a dynamic contact of Tregs with MN9D cells that were stained with CD45 and galectin-1, respectively. Tregs prevented MPTP-induced dopaminergic neuronal loss, behavioral changes, and attenuated the inflammatory reaction in the brain. When blockade the LFA-1 activity in Tregs or the ICAM-1 activity in endothelial cells, the percentage of Tregs in substantia nigra (SN) decreased. CD45 and galectin-1 were expressed by Tregs and MN9D cells, respectively. CD45-labeled Tregs dynamically contacted with galectin-1-labeled MN9D cells. Inhibiting CD45 in Tregs impaired the ability of Tregs to protect dopaminergic neurons against MPP
+
toxicity. Similarly, galectin-1 knockdown in MN9D cells reduced the ability of Tregs neuroprotection. Adoptive transfer of Tregs protects dopaminergic neurons in PD mice by a cell-to-cell contact mechanism underlying CD45-galectin-1 interaction.
Graphical Abstract
T helper (Th)17 cells, a subset of CD4
+
T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of ...Th17 cells in Parkinson’s disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP
+
)-induced PD models. Blood–brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP
+
-treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.
Two small organic molecules, namely potassium terephthalate (K2TP) and potassium 2,5-pyridinedicarboxylate (K2PC), were newly exploited as the highly efficient organic anodes in K-ion batteries. Both ...K2TP and K2PC exhibited the clear and reversible discharge and charge platforms in K-ion half cells, which were resulted from the redox behavior of organic para-aromatic dicarboxylates. The satisfactory and reversible specific capacities were realized in the K2TP- and K2PC-based K-ion cells, with average values of 181 and 190mAhg−1 for 100 cycles, respectively. The currently-obtained achievement of organic anodes could make a forward step for the further development of rocking-chair K-ion batteries.
Potassium salts of para-aromatic dicarboxylates were initially exploited as the highly advanced organic anodes in K-ion batteries. And the usage of organic anodes could effectively avoid the risk of producing highly-reactive K metal. Display omitted
•Para-aromatic dicarboxylates could be the organic anodes in K-ion battery.•Satisfactory rate and cyclic capability were achieved in K-ion battery.•Specific capacity of average ~190mAhg−1 was obtained for 100 cycles.
•IL-17A deficiency alleviates neuroinflammation and neurodegeneration in PD mice.•Blocking IL-17A in the brain is beneficial to ameliorating PD symptoms.•IL-17A does not directly kill dopaminergic ...neurons in vitro.•Microglial TNF-α mediates IL-17A injury to dopaminergic neurons.
Neuroinflammation has been involved in pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disease characterized neuropathologically by progressive dopaminergic neuronal loss in the substantia nigra (SN). We recently have shown that helper T (Th)17 cells facilitate dopaminergic neuronal loss in vitro. Herein, we demonstrated that interleukin (IL)-17A, a proinflammatory cytokine produced mainly by Th17 cells, contributed to PD pathogenesis depending on microglia. Mouse and rat models for PD were prepared by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or striatal injection of 1-methyl-4-phenylpyridinium (MPP+), respectively. Both in MPTP-treated mice and MPP+-treated rats, blood–brain barrier (BBB) was disrupted and IL-17A level increased in the SN but not in cortex. Effector T (Teff) cells that were adoptively transferred via tail veins infiltrated into the brain of PD mice but not into that of normal mice. The Teff cell transfer aggravated nigrostriatal dopaminergic neurodegeneration, microglial activation and motor impairment. Contrarily, IL-17A deficiency alleviated BBB disruption, dopaminergic neurodegeneration, microglial activation and motor impairment. Anti-IL-17A-neutralizing antibody that was injected into lateral cerebral ventricle in PD rats ameliorated the manifestations mentioned above. IL-17A activated microglia but did not directly affect dopaminergic neuronal survival in vitro. IL-17A exacerbated dopaminergic neuronal loss only in the presence of microglia, and silencing IL-17A receptor gene in microglia abolished the IL-17A effect. IL-17A-treated microglial medium that contained higher concentration of tumor necrosis factor (TNF)-α facilitated dopaminergic neuronal death. Further, TNF-α-neutralizing antibody attenuated MPP+-induced neurotoxicity. The findings suggest that IL-17A accelerates neurodegeneration in PD depending on microglial activation and at least partly TNF-α release.
Two artificial intelligence models-backpropagation neural network (BPNN) and support vector machines (SVM)-were created to investigate the effects of mesostructure characteristics on the shear ...mechanical behaviors of rock joints. This was achieved through learning training samples for the evaluation of the five basic geometrical parameters sensitivity (i.e., slope angle, horizontal orientation, elevation difference, curvature, and aperture distribution), and for determination of the shear failure regions when rock joints were subjected to low-normal and shear loads. First, the digital elevation models (DEMs) of rock joints were produced through point clouds collected using a laser scanning system. Five geometrical parameters were specified as the inputs for the artificial intelligence models, and an approach was developed to calculate the 3D aperture distribution using a point cloud registration algorithm. Shear failure regions were considered as the outputs, which were extracted from images taken after direct shear testing via the global threshold algorithm. Secondly, BPNN and SVM models were employed in order to establish relationships between the geometrical parameters and shear failure areas by machine learning on training samples. Thirdly, the information value (IV) algorithm was used to verify the two trained models. Results showed that the BPNN and SVM models made acceptable determinations of the shear failure areas, which corresponded to the real situation. The predictions from the BPNN and SVM models were more accurate than those from the IV algorithm. Furthermore, shear failure regions depended primarily on the aperture distribution of rock joints during the shearing process, followed by horizontal orientation, elevation difference, and then the slope angle. The effect of parameter curvature on shear failure was less than the other four parameters.
•Two AI algorithms (BPNN and SVM) were used to determine the shear failure regions.•Five geometrical parameters were extracted from point clouds as the input parameters.•3D aperture distribution was calculated via the feature-based registration algorithm.•Weights of five input parameters were estimated through trained BPNN and SVM models.
Regulatory T (Treg) cells have been associated with neuroprotection by inhibiting microglial activation in animal models of Parkinson's disease (PD), a progressive neurodegenerative disease ...characterized by dopaminergic neuronal loss in the nigrostriatal system. Herein, we show that Treg cells directly protect dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity via an interaction between the two transmembrane proteins CD47 and signal regulatory protein α (SIRPA).
Primary ventral mesencephalic (VM) cells or VM neurons were pretreated with Treg cells before MPP+ treatment. Transwell co-culture of Treg cells and VM neurons was used to assess the effects of the Treg cytokines transforming growth factor (TGF)-β1 and interleukin (IL)-10 on dopaminergic neurons. Live cell imaging system detected a dynamic contact of Treg cells with VM neurons that were stained with CD47 and SIRPA, respectively. Dopaminergic neuronal loss, which was assessed by the number of tyrosine hydroxylase (TH)-immunoreactive cells, was examined after silencing CD47 in Treg cells or silencing SIRPA in VM neurons.
Treg cells prevented MPP+-induced dopaminergic neuronal loss and glial inflammatory responses. TGF-β1 and IL-10 secreted from Treg cells did not significantly prevent MPP+-induced dopaminergic neuronal loss in transwell co-culture of Treg cells and VM neurons. CD47 and SIRPA were expressed by Treg cells and VM neurons, respectively. CD47-labeled Treg cells dynamically contacted with SIRPA-labeled VM neurons. Silencing CD47 gene in Treg cells impaired the ability of Treg cells to protect dopaminergic neurons against MPP+ toxicity. Similarly, SIRPA knockdown in VM neurons reduced the ability of Treg cell neuroprotection. Rac1/Akt signaling pathway in VM neurons was activated by CD47-SIRPA interaction between Treg cells and the neurons. Inhibiting Rac1/Akt signaling in VM neurons compromised Treg cell neuroprotection.
Treg cells protect dopaminergic neurons against MPP+ neurotoxicity by a cell-to-cell contact mechanism underlying CD47-SIRPA interaction and Rac1/Akt activation.
Transforming growth factor (TGF)-β1 is a pleiotropic cytokine with immunosuppressive and anti-inflammatory properties. Recently we have shown that TGF-β1 pretreatment in vitro protects against ...1-methyl-4-phenylpyridinium (MPP
+
)-induced dopaminergic neuronal loss that characterizes in Parkinson’s disease (PD). Herein, we aimed to demonstrate that TGF-β1 administration in vivo after MPP
+
toxicity has neuroprotection that is achieved by a mediation of microglia. A rat model of PD was prepared by injecting MPP
+
unilaterally in the striatum. At 14 days after MPP
+
injection, TGF-β1 was administrated in the right lateral cerebral ventricle. Primary ventral mesencephalic (VM) neurons and cerebral cortical microglia were treated by MPP
+
, respectively, and TGF-β1 was applied to neuronal or microglial cultures at 1 h after MPP
+
treatment. As expected, MPP
+
resulted in decrease in TGF-β1 production in the substantia nigra and in primary VM neurons and microglia. TGF-β1 intracerebroventricular administration alleviated MPP
+
-induced PD-like changes in pathology, motor coordination and behavior. Meanwhile, TGF-β1 ameliorated MPP
+
-induced microglial activation and inflammatory cytokine production in vivo. Interestingly, TGF-β1 treatment was not able to ameliorate MPP
+
-induced dopaminergic neuronal loss and caspase-3/9 activation in mono-neuron cultures, but TGF-β1 alleviated MPP
+
-induced microglial activation and inflammatory cytokine production in microglia-enriched cultures. This effect of TGF-β1 inhibiting microglial inflammatory response was blocked by Smad3 inhibitor SIS3. Importantly, neuronal exposure to supernatants of primary microglia that had been treated with TGF-β1 reduced dopaminergic neuronal loss and caspase-3/9 activation induced by MPP
+
-treated microglial supernatants. These findings establish that TGF-β1 exerts neuroprotective property in PD by inhibiting microglial inflammatory response via Smad3 signaling.
Lung cancer has one of the highest mortalities of any cancer worldwide. Triptolide (TP) is a promising tumor suppressor extracted from the Chinese herb Tripterygium wilfordii. Our previous proteomics ...analysis revealed that TP significantly interfered with the ribosome biogenesis pathway; however, the underlying molecular mechanism remains poorly understood. The aim of the present study was to determine the molecular mechanism of TP's anticancer effect by investigating the association between ribosomal stress and p53 activation. It was found that TP induces nucleolar disintegration together with RNA polymerase I (Pol I) and upstream binding factor (UBF) translocation. TP interrupted ribosomal (r)RNA synthesis through inhibition of RNA Pol I and UBF transcriptional activation. TP treatment increased the binding of ribosomal protein L23 (RPL23) to mouse double minute 2 protein (MDM2), resulting in p53 being released from MDM2 and stabilized. Activation of p53 induced apoptosis and cell cycle arrest by enhancing the activation of p53 upregulated modulator of apoptosis, caspase 9 and caspase 3, and suppressing BCL2. In vivo experiments showed that TP significantly reduced xenograft tumor size and increased mouse body weight. Immunohistochemical assays confirmed that TP significantly increased the p53 level and induced nucleolus disintegration, during which nucleolin distribution moved from the nucleolus to the nucleoplasm, and RPL23 clustered at the edge of the cell membrane. Therefore, it was proposed that TP induces ribosomal stress, which leads to nucleolus disintegration, and inhibition of rRNA transcription and synthesis, resulting in increased binding of RPL23 with MDM2. Consequently, p53 is activated, which induces apoptosis and cell cycle arrest.
Dopamine (DA), a neurotransmitter in the nervous system, has been shown to modulate immune function. We have previously reported that five subtypes of DA receptors, including D1R, D2R, D3R, D4R and ...D5R, are expressed in T lymphocytes and they are involved in regulation of T cells. However, roles of these DA receptor subtypes and their coupled signal-transduction pathway in modulation of natural killer (NK) cells still remain to be clarified. The spleen of mice was harvested and NK cells were isolated and purified by negative selection using magnetic activated cell sorting. After NK cells were incubated with various drugs for 4 h, flow cytometry measured cytotoxicity of NK cells against YAC-1 lymphoma cells. NK cells expressed the five subtypes of DA receptors at mRNA and protein levels. Activation of D1-like receptors (including D1R and D5R) with agonist SKF38393 enhanced NK cell cytotoxicity, but activation of D2-like receptors (including D2R, D3R and D4R) with agonist quinpirole attenuated NK cells. Simultaneously, SKF38393 elevated D1R and D5R expression, cAMP content, and phosphorylated cAMP-response element-binding (CREB) level in NK cells, while quinpirole reduced D3R and D4R expression, cAMP content, and phosphorylated CREB level in NK cells. These effects of SKF38393 were blocked by SCH23390, an antagonist of D1-like receptors, and quinpirole effects were abolished by haloperidol, an antagonist of D2-like receptors. In support these results, H89, an inhibitor of phosphokinase A (PKA), prevented the SKF38393-dependent enhancement of NK cells and forskolin, an activator of adenylyl cyclase (AC), counteracted the quinpirole-dependent suppression of NK cells. These findings show that DA receptor subtypes are involved in modulation of NK cells and suggest that D1-like receptors facilitate NK cells by stimulating D1R/D5R-cAMP-PKA-CREB signaling pathway and D2-like receptors suppress NK cells by inhibiting D3R/D4R-cAMP-PKA-CREB signaling pathway. The results may provide more targets of therapeutic strategy for neuroimmune diseases.
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