We present a neural network-based method for solving linear and nonlinear partial differential equations, by combining the ideas of extreme learning machines (ELM), domain decomposition and local ...neural networks. The field solution on each sub-domain is represented by a local feed-forward neural network, and Ck continuity conditions are imposed on the sub-domain boundaries. Each local neural network consists of a small number of hidden layers, while its last hidden layer can be wide. The weight/bias coefficients in all the hidden layers of the local neural networks are pre-set to random values and fixed throughout the computation, and only the weight coefficients in the output layers of the local neural networks are training parameters. The overall neural network is trained by a linear or nonlinear least squares computation, not by the back-propagation type algorithms. We introduce a block time-marching scheme together with the presented method for long-time simulations of time-dependent linear/nonlinear partial differential equations. The current method exhibits a clear sense of convergence with respect to the degrees of freedom in the neural network. Its numerical errors typically decrease exponentially or nearly exponentially as the number of training parameters, or the number of training data points, or the number of sub-domains increases. Extensive numerical experiments have been performed to demonstrate the computational performance of the presented method. We also demonstrate its capability for long-time dynamic simulations with some test problems. We compare the presented method with the deep Galerkin method (DGM) and the physics-informed neural network (PINN) method in terms of the accuracy and computational cost. The current method exhibits a clear superiority, with its numerical errors and network training time considerably smaller (typically by orders of magnitude) than those of DGM and PINN. We also compare the current method with the classical finite element method (FEM). The computational performance of the current method is on par with, and often exceeds, the FEM performance in terms of the accuracy and computational cost.
•PDE solution represented by local neural networks on sub-domains, Ck continuity across sub-domain boundaries.•Hidden-layer coefficients are randomly set and fixed, and output-layer coefficients are trained.•Network training by linear or nonlinear least squares computations, not by back propagation type algorithm.•Method considerably superior to DGM and PINN in terms of accuracy and computational cost.•Method is on par with, and often exceeds, classical finite element method in terms of accuracy and computational cost.
Tumor cells undergo metabolic rewiring from oxidative phosphorylation towards aerobic glycolysis to maintain the increased anabolic requirements for cell proliferation. It is widely accepted that ...specific expression of the M2 type pyruvate kinase (PKM2) in tumor cells contributes to this aerobic glycolysis phenotype. To date, researchers have uncovered myriad forms of functional regulation for PKM2, which confers a growth advantage on the tumor cells to enable them to adapt to various microenvironmental signals. Here the richness of our understanding on the modulations and functions of PKM2 in tumor progression is reviewed, and some new insights into the paradoxical expression and functional differences of PKM2 in distinct cancer types are offered.
•The expression of PKM2 is regulated at different levels.•PKM2 activity is regulated by protein modification, protein interaction and metabolites.•PKM2 exhibits both metabolic and non-metabolic functions.•PKM2 is a molecule of important clinical implications.
Lipid metabolism that correlates tightly to the glucose metabolic regulation in malignant cells includes hepatocellular carcinoma (HCC) cells. The transcription factor Sterol Regulatory Element ...Binding Protein 1 (SREBP-1), a regulator of fatty acid synthesis, has been shown to pivotally regulate the proliferation and metastasis of HCC cells. However, the intrinsic mechanism by which SREBP-1 regulates the survival of HCC cells remains unclear. In this study, among HCC patients who had dismal responses to Sorafenib, a high SREBP-1 level was found in the tumors and correlated to poor survival. This observation suggested the negative role of SREBP-1 in clinical HCC prognosis. Our mechanistical studies reveal that the inhibition of SREBP-1 via its inhibitor Betulin suppresses cellular glucose metabolism. In addition to the reduced glycolytic activity, a thwarted metastatic potential was observed in HCC cells upon Betulin administration. Moreover, our data show that SREBP-1 inhibition facilitated the antitumor effects of Sorafenib on HCC cells and xenograft tumors.
Abstract
Background
Neuroinflammation is the major pathogenesis of cerebral ischemia. Microglia are activated and polarized to either the pro-inflammatory M1 phenotype or anti-inflammatory M2 ...phenotype, which act as a critical mediator of neuroinflammation. Sestrin2 has pro-survival properties against ischemic brain injury. However, whether sestrin2 has an anti-inflammatory function by shifting microglia polarization and its underlying mechanism is unknown.
Methods
Adult male C57BL/6 mice (
N
= 108) underwent transient middle cerebral artery occlusion (tMCAO) and were treated with exogenous sestrin2. Neurological deficit scores and infarct volume were determined. Cell apoptosis was examined by TUNEL staining and Western blotting. The expression of inflammatory mediators, M1/M2-specific markers, and signaling pathways were detected by reverse transcription-polymerase chain reaction, immunostaining, and Western blotting. To explore the underlying mechanism, primary neurons were subjected to oxygen-glucose deprivation (OGD) and then treated with oxygenated condition medium of BV2 cells incubated with different doses of sestrin2.
Results
Sestrin2 attenuated the neurological deficits, infarction volume, and cell apoptosis after tMCAO compared to those in the control (
p
< 0.05). Sestrin2 had an anti-inflammatory effect and could suppress M1 microglia polarization and promote M2 microglia polarization
.
Condition medium from BV2 cells cultured with sestrin2 reduced neuronal apoptosis after OGD in vitro. Furthermore, we demonstrated that sestrin2 drives microglia to the M2 phenotype by inhibiting the mammalian target of rapamycin (mTOR) signaling pathway and restoring autophagic flux.
Conclusions
Sestrin2 exhibited neuroprotection by shifting microglia polarization from the M1 to M2 phenotype in ischemic mouse brain, which may be due to suppression of the mTOR signaling pathway and the restoration of autophagic flux.
We address mathematical modelling of respiratory mechanics and put forward a model based on double-exponential and fractional calculus for parameter estimation, model simulation, and evaluation based ...on actual data. Our model has been implemented on a publicly available executable code with adjustable parameters, making it suitable for different applications. Our analysis represents the first application of fractional calculus and double-exponential modelling to respiratory mechanics, and allows us to propose a hybrid model fitting experimental data in different ventilation modes. Furthermore, our model can be used to study the mechanical features of the respiratory system, improve the safety of ventilation techniques, reduce ventilation damages, and provide strong support for fast and adaptive determination of ventilation parameters.
•GRP78 is detected in secretions of two colon cancer cell lines.•Secreted GRP78 facilitates differentiation of BMSCs to CAFs.•GRP78 induce BMSCs–CAFs transition through activating TGF-β/Smad ...signaling pathway.
Cancer-associated fibroblasts (CAFs), one type of tumor-associated stromal cells, have been shown to provide a favorable environment for the malignant tumor progression. Extensive reports have demonstrated that mesenchymal stem cells (MSCs) can function as precursors for CAFs. However, the mechanisms by which tumor cells induce the transition of MSCs to CAFs have not been well established. GRP78, traditionally known as an endoplasmic reticulum (ER) chaperone, has been identified to overexpress in a variety of tumor entities and be involved in promoting survival and chemoresistance of tumor cells. Here, we interrogated the role of GRP78 in the generation of CAFs from MSCs. The results showed that GRP78 treatment induced expression of α-smooth muscle actin (α-SMA), a marker for CAFs, in human bone marrow mesenchymal stem cells (HBMSCs) as well as murine bone marrow mesenchymal stem cells (BMMSCs). This phenomenon was correlated with the stimulated phosphorylation of Smad2/3. Furthermore, the GRP78-induced α-SMA expression in HBMSCs was obviously attenuated by SB431542, a TGF-β type I receptor kinase inhibitor. Taken together, the present data suggested that tumor-derived secreted GRP78 elicited the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) to CAFs through activating TGF-β/Smad signaling pathway, which may represent a novel mechanism for transition of BMSCs to CAFs and a hitherto unknown function of GRP78 in the tumor microenvironment.
High glucose-regulated protein 78 (GRP78) expression contributes to the acquisition of a wide range of phenotypic cancer hallmarks, and the pleiotropic oncogenic functions of GRP78 may result from ...its diverse subcellular distribution. Interestingly, GRP78 has been reported to be secreted from solid tumour cells, participating in cell-cell communication in the tumour microenvironment. However, the mechanism underlying this secretion remains elusive. Here, we report that GRP78 is secreted from colon cancer cells via exosomes. Histone deacetylase (HDAC) inhibitors blocked GRP78 release by inducing its aggregation in the ER. Mechanistically, HDAC inhibitor treatment suppressed HDAC6 activity and led to increased GRP78 acetylation; acetylated GRP78 then bound to VPS34, a class III phosphoinositide-3 kinase, consequently preventing the sorting of GRP78 into multivesicular bodies (MVBs). Of note, we found that mimicking GRP78 acetylation by substituting the lysine at residue 633, one of the deacetylated sites of HDAC6, with a glutamine resulted in decreased GRP78 secretion and impaired tumour cell growth in vitro. Our study thus reveals a hitherto-unknown mechanism of GRP78 secretion and may also provide implications for the therapeutic use of HDAC inhibitors.
Obesity is often linked to malignancies including multiple myeloma, and the underlying mechanisms remain elusive. Here we showed that acetyl-CoA synthetase 2 (ACSS2) may be an important linker in ...obesity-related myeloma. ACSS2 is overexpressed in myeloma cells derived from obese patients and contributes to myeloma progression. We identified adipocyte-secreted angiotensin II as a direct cause of adiposity in increased ACSS2 expression. ACSS2 interacts with oncoprotein interferon regulatory factor 4 (IRF4), and enhances IRF4 stability and IRF4-mediated gene transcription through activation of acetylation. The importance of ACSS2 overexpression in myeloma is confirmed by the finding that an inhibitor of ACSS2 reduces myeloma growth both in vitro and in a diet-induced obese mouse model. Our findings demonstrate a key impact for obesity-induced ACSS2 on the progression of myeloma. Given the central role of ACSS2 in many tumors, this mechanism could be important to other obesity-related malignancies.
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•ACSS2 contributes to obesity-induced myelomatous tumorigenesis•Adipocyte-derived angiotensin II enhances ACSS2 expression in myeloma cells•ACSS2-mediated lysine acetylation improves the stability of oncogenic IRF4 protein•Inhibition of the angiotensin II-ACSS2 axis prevents obesity-induced tumor growth
Li et al. demonstrate a mechanistic link between obesity and myeloma. Adipocyte-derived angiotensin II stimulates acetyl-CoA synthase 2 (ACSS2) expression in myeloma cells and increased ACSS2 promotes tumorigenesis through the stabilization of interferon regulatory factor 4. Inhibiting the angiotensin II/ACSS2 axis abolishes obesity-associated myeloma progression, suggesting a potential therapeutic target for obesity-associated tumors.
Many studies have confirmed that circular RNAs (circRNAs) mediate the malignant progression of various tumors including osteosarcoma (OS). Our study is to uncover novel molecular mechanisms by which ...circ_0000376 regulates OS progression.
The expression of circ_0000376, microRNA (miR)-577, hexokinase 2 (HK2) and lactate dehydrogenase-A (LDHA) was determined by quantitative real-time PCR. OS cell proliferation, apoptosis and invasion were measured using cell counting kit 8 assay, colony formation assay, EdU assay, flow cytometry and transwell assay. Besides, cell glycolysis was assessed by testing glucose consumption, lactate production, and ATP/ADP ratios. Protein expression was examined by western blot analysis. The interaction between miR-577 and circ_0000376 or HK2/LADA was verified by dual-luciferase reporter assay. The role of circ_0000376 on OS tumor growth was explored by constructing mice xenograft models.
Circ_0000376 had been found to be upregulated in OS tissues and cells. Functional experiments revealed that circ_0000376 interference hindered OS cell growth, invasion and glycolysis. Circ_0000376 sponged miR-577 to reduce its expression. In rescue experiments, miR-577 inhibitor abolished the regulation of circ_0000376 knockdown on OS cell functions. MiR-577 could target HK2 and LDHA in OS cells. MiR-577 suppressed OS cell growth, invasion and glycolysis, and these effects were reversed by HK2 and LDHA overexpression. Also, HK2 and LDHA expression could be regulated by circ_0000376. In vivo experiments showed that circ_0000376 knockdown inhibited OS tumorigenesis.
Circ_0000376 contributed to OS growth, invasion and glycolysis depending on the regulation of miR-577/HK2/LDHA axis, providing a potential target for OS treatment.
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