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This study investigates the nonlinear Pochhammer-Chree equation, a model crucial for understanding wave propagation in elastic rods, through the application of the Khater III method. The research aims to derive precise analytical solutions and validate them using He's variational iteration method (VIM). The Pochhammer-Chree equation's relationship to other nonlinear evolution equations, such as the Korteweg-de Vries and nonlinear Schrödinger equations, underscores its significance in the field of nonlinear wave dynamics. The methodology employs the Khater III method for deriving analytical solutions, while He's VIM serves as a numerical validation tool, ensuring the accuracy and stability of the obtained results. This dual approach not only yields novel solutions but also provides a robust framework for analyzing complex wave phenomena in elastic media. The findings of this study have significant implications for material science and engineering applications, offering new insights into the behavior of waves in elastic rods. By bridging the gap between theoretical models and practical applications, this research contributes to the advancement of both mathematical theory and physical understanding of nonlinear wave dynamics. Situated within the domain of applied mathematics, with a focus on nonlinear wave equations, this work exemplifies the interdisciplinary nature of contemporary research in mathematical physics. The results presented herein open new avenues for future investigations in related fields and highlight the potential for innovative applications in material science and engineering.
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The Caudrey-Dodd-Gibbon ( CDG ) model, a variation of the fifth-order KdV equation (fKdV) with significant practical consequences, is solved in this study using a precise and numerical technique. This model shows how gravity-capillary waves, shallow-water waves driven by surface tension, and magneto-acoustic waves move through a plasma medium. With a focus on accuracy, new computational and approximation methods have been made possible by recent improvements in analytical and numerical methods. Numeric information is represented visually in the tables. All simulation results are shown in two and three dimensions to show both the numerical and fundamental behavior of the single soliton. Recent research shows that this method is the best way to solve nonlinear equations that are common in mathematical physics.
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The olfactory receptor OR51E2 is ectopically expressed in prostate tissues and regulates prostate cancer progression, but its function and regulation in oncogenic mitogen-activate protein kinase (MAPK) activation are poorly defined. Here we demonstrate that ß-ionone, an OR51E2 agonist, dose-dependently activates extracellular signal-regulated kinases 1 and 2 (ERK1/2) in prostate cancer cells, with an EC50 value of approximate 20 µM and an efficiency comparable to other receptor agonists. We also find that CRISPR-Cas9-mediated knockout of Golgi-translocating Gγ9 subunit, phosphoinositide 3-kinase γ (PI3Kγ) and the small GTPase ADP-ribosylation factor 1 (ARF1), as well as pharmacological inhibition of Gßγ, PI3Kγ and Golgi-localized ARF1, each abolishes ERK1/2 activation by ß-ionone. We further show that ß-ionone significantly promotes ARF1 translocation to the Golgi and activates ARF1 that can be inhibited by Gγ9 and PI3Kγ depletion. Collectively, our data demonstrate that OR51E2 activates ERK1/2 through the Gßγ-PI3Kγ-ARF1 pathway that occurs spatially at the Golgi, and also provide important insights into MAPK hyper-activation in prostate cancer.
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After activation of G protein-coupled receptors, G protein ßγ dimers may translocate from the plasma membrane to the Golgi apparatus (GA). We recently report that this translocation activates extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) via PI3Kγ; however, how Gßγ-PI3Kγ activates the ERK1/2 pathway is unclear. Here, we demonstrate that chemokine receptor CXCR4 activates ADP-ribosylation factor 1 (ARF1), a small GTPase important for vesicle-mediated membrane trafficking. This activation is blocked by CRISPR-Cas9-mediated knockout of the GA-translocating Gγ9 subunit. Inducible targeting of different Gßγ dimers to the GA can directly activate ARF1. CXCR4 activation and constitutive Gßγ recruitment to the GA also enhance ARF1 translocation to the GA. We further demonstrate that pharmacological inhibition and CRISPR-Cas9-mediated knockout of PI3Kγ markedly inhibit CXCR4-mediated and Gßγ translocation-mediated ARF1 activation. We also show that depletion of ARF1 by siRNA and CRISPR-Cas9 and inhibition of GA-localized ARF1 activation abolish ERK1/2 activation by CXCR4 and Gßγ translocation to the GA and suppress prostate cancer PC3 cell migration and invasion. Collectively, our data reveal a novel function for Gßγ translocation to the GA to activate ARF1 and identify GA-localized ARF1 as an effector acting downstream of Gßγ-PI3Kγ to spatiotemporally regulate G protein-coupled receptor signaling to mitogen-activated protein kinases.
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Factor 1 de Ribosilacion-ADP/metabolismo , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Aparato de Golgi/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Factor 1 de Ribosilacion-ADP/análisis , Subunidades beta de la Proteína de Unión al GTP/análisis , Células HEK293 , Humanos , Proteínas Quinasas Activadas por Mitógenos/análisis , Células PC-3 , Multimerización de Proteína , Transporte de Proteínas , Receptores Acoplados a Proteínas G/análisis , Transducción de SeñalRESUMEN
G protein-coupled receptors (GPCRs) are important modulators of synaptic functions. A fundamental but poorly addressed question in neurobiology is how targeted GPCR trafficking is achieved. Rab GTPases are the master regulators of vesicle-mediated membrane trafficking, but their functions in the synaptic presentation of newly synthesized GPCRs are virtually unknown. Here, we investigate the role of Rab43, via dominant-negative inhibition and CRISPR-Cas9-mediated KO, in the export trafficking of α2-adrenergic receptor (α2-AR) and muscarinic acetylcholine receptor (mAChR) in primary neurons and cells. We demonstrate that Rab43 differentially regulates the overall surface expression of endogenous α2-AR and mAChR, as well as their signaling, in primary neurons. In parallel, Rab43 exerts distinct effects on the dendritic and postsynaptic transport of specific α2B-AR and M3 mAChR subtypes. More interestingly, the selective actions of Rab43 toward α2B-AR and M3 mAChR are neuronal cell specific and dictated by direct interaction. These data reveal novel, neuron-specific functions for Rab43 in the dendritic and postsynaptic targeting and sorting of GPCRs and imply multiple forward delivery routes for different GPCRs in neurons. Overall, this study provides important insights into regulatory mechanisms of GPCR anterograde traffic to the functional destination in neurons.
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Membrana Celular/metabolismo , Retículo Endoplásmico/metabolismo , Aparato de Golgi/metabolismo , Neuronas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transmisión Sináptica , Proteínas de Unión al GTP rab/metabolismo , Animales , Células HEK293 , Humanos , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/genética , Proteínas de Unión al GTP rab/genéticaRESUMEN
The Golgi apparatus (GA) is a cellular organelle that plays a critical role in the processing of proteins for secretion. Activation of G protein-coupled receptors at the plasma membrane (PM) induces the translocation of G protein ßγ dimers to the GA. However, the functional significance of this translocation is largely unknown. Here, we study PM-GA translocation of all 12 Gγ subunits in response to chemokine receptor CXCR4 activation and demonstrate that Gγ9 is a unique Golgi-translocating Gγ subunit. CRISPR-Cas9-mediated knockout of Gγ9 abolishes activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), two members of the mitogen-activated protein kinase family, by CXCR4. We show that chemically induced recruitment to the GA of Gßγ dimers containing different Gγ subunits activates ERK1/2, whereas recruitment to the PM is ineffective. We also demonstrate that pharmacological inhibition of phosphoinositide 3-kinase γ (PI3Kγ) and depletion of its subunits p110γ and p101 abrogate ERK1/2 activation by CXCR4 and Gßγ recruitment to the GA. Knockout of either Gγ9 or PI3Kγ significantly suppresses prostate cancer PC3 cell migration, invasion, and metastasis. Collectively, our data demonstrate a novel function for Gßγ translocation to the GA, via activating PI3Kγ heterodimers p110γ-p101, to spatiotemporally regulate mitogen-activated protein kinase activation by G protein-coupled receptors and ultimately control tumor progression.
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Fosfatidilinositol 3-Quinasa Clase Ib/genética , Subunidades beta de la Proteína de Unión al GTP/genética , Subunidades gamma de la Proteína de Unión al GTP/genética , Aparato de Golgi/genética , Receptores CXCR4/genética , Membrana Celular/genética , Dimerización , Células HEK293 , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Fosfatidilinositol 3-Quinasas/genética , Transporte de Proteínas/genética , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Both bone marrow mesenchymal stem cell (BM-MSC) and transforming growth factor-ß1 (TGF-ß1) have a strong anti-inflammatory capacity in stroke. But their relationship has not been well addressed. In this study, we investigated how intravenous BM-MSC transplantation in rats effected the expression of TGF-ß1 48 h post cerebral ischemia, and we analyzed the main cells that produce TGF-ß1. METHODS: We used a distal middle cerebral artery occlusion (dMCAO) model in twenty Sprague-Dawley (SD) rats. The rats were randomly divided into two groups: the ischemic control group and the postischemic BM-MSC transplantation group. One hour after the dMCAO model was established, the rats were injected in the tail vein with either 1 ml saline or 1 × 106 BM-MSCs suspended in 1 ml saline. ELISAs were used to detect TGF-ß1 content in the brain infarct core area, striatum and the plasma at 48 h after cerebral infarction. Immunofluorescent staining of brain tissue sections for TGF-ß1, Iba-1, CD68 and NeuN was performed to determine the number and the proportion of double stained cells and to detect possible TGF-ß1 producing cells in the brain tissue. RESULTS: Forty-eight hours after ischemia, the TGF-ß1 content in the infarcted area of the BM-MSC transplantation group (23.94 ± 4.48 pg/ml) was significantly lower than it was in the ischemic control group (34.18 ± 4.32 pg/ml) (F = 13.534, P = 0.006). The TGF-ß1 content in the rat plasma in the BM-MSC transplantation group (75.91 ± 12.53 pg/ml) was significantly lower than it was in the ischemic control group (131.18 ± 16.07 pg/ml) (F = 36.779, P = 0.0002), suggesting that after transplantation of BM-MSCs, TGF-ß1 levels in the plasma decreased, but there was no significant change in the striatum area. Immunofluorescence staining showed that the total number of nucleated cells (1037.67 ± 222.16 cells/mm2) in the infarcted area after transplantation was significantly higher than that in the ischemic control group (391.67 ± 69.50 cells/mm2) (F = 92.421, P < 0.01); the number of TGF-ß1+ cells after transplantation (35.00 ± 13.66 cells/mm2) was significantly reduced in comparison to that in the ischemic control group (72.33 ± 32.08 cells/mm2) (F = 37.680, P < 0.01). The number of TGF-ß1+/Iba-1+ microglia cells in the transplantation group (3.67 ± 3.17 cells/mm2) was significantly reduced in comparison to that of the ischemic control group (13.67 ± 5.52 cells/mm2) (F = 29.641, P < 0.01). The proportion of TGF-ß1+/Iba-1+ microglia cells out of all Iba-1+ microglia cells after transplantation (4.38 ± 3.18%) was significantly decreased compared with that in the ischemic control group (12.81 ± 4.86%) (F = 28.125, P < 0.01). CONCLUSIONS: Iba-1+ microglia is one of the main cell types that express TGF-ß1. Intravenous transplantation of BM-MSCs does not cooperate with TGF-ß1+ cells in immune-regulation, but reduces the TGF-ß1 content in the infarcted area and in the plasma at 48 h after cerebral infarction.
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This paper investigates the exact traveling wave solutions of the fractional model of the human immunodeficiency virus (HIV-1) infection for CD4 + T-cells. This model also treats with the effect of antiviral drug therapy. These solutions calculate both the boundary and initial conditions that allow employing the septic-B-spline scheme which is one of the most recent schemes in the numerical field. We use the obtained computational solutions via the modified Khater, the extended simplest equation, and sech-tanh methods through Atangana-Baleanu derivative operator. The comparison between the exact and numerical evaluated solutions is illustrated by some distinct sketches. The functioning of our numerical method is tested under three computational obtained solutions.
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Leiomyosarcoma is the most frequent subtype of the deadly uterine sarcoma and shares many common clinical grounds with leiomyoma, which is in turn the most common solid benign uterine neoplasm. With the recent progress in minimally invasive techniques for managing leiomyomas, accurate preoperative diagnosis of uterine masses has become the most important selection criterion for the safest therapeutic option. Therefore, different imaging modalities would be playing a key role in management of uterine masses. Testing for a sarcoma-specific promoter that expresses its downstream reporter gene only in leiomyosarcoma and not in leiomyoma or healthy uterine tissue. Adenoviral vectors were utilized both in vitro and in vivo to test the specificity of the promoters. Quantitative studies of downstream gene expression of these promoters was carried out both in vitro and in vivo. Our data indicated that human leiomyosarcoma cells highly expressed the reporter gene downstream to survivin promoter (Ad-SUR-LUC) when compared with benign leiomyoma or normal cells (p value of 0.05). Our study suggested that survivin is the unique promoter capable of distinguishing between the deadly sarcoma and the benign counterparts.
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Leiomioma/diagnóstico por imagen , Leiomiosarcoma/diagnóstico por imagen , Técnicas de Sonda Molecular , Neoplasias Uterinas/diagnóstico por imagen , Adenoviridae/fisiología , Biomarcadores de Tumor/genética , Femenino , Expresión Génica , Genes Reporteros , Humanos , Leiomioma/genética , Leiomiosarcoma/genética , Sondas Moleculares , Regiones Promotoras Genéticas , Transfección , Neoplasias Uterinas/genéticaRESUMEN
G-protein-coupled receptors (GPCRs) constitute the largest superfamily of cell surface signaling proteins. However, the molecular mechanisms underlying their cell surface delivery after synthesis remain poorly understood. Here, we screen the TBC domain-containing proteins, putative Rab GTPase-activating proteins (GAPs), in the intracellular trafficking of GPCRs and identify several TBC proteins that activity-dependently regulate the anterograde transport, en route from the endoplasmic reticulum to the Golgi or from the Golgi to the cell surface, of several prototypic GPCR members without affecting other plasma membrane proteins. We also show that TBC1D6 functions as a GAP for Rab26, physically associates with Rab26, and attenuates Rab26 interaction with GPCRs. Furthermore, both overexpression and depletion of TBC1D6 inhibit the post-Golgi traffic of GPCRs. These data demonstrate important roles of the TBC proteins in forward trafficking of nascent GPCRs and reveal regulatory mechanisms of GPCR targeting to the functional destination.
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Retículo Endoplásmico/metabolismo , Aparato de Golgi/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Movimiento Celular , Humanos , Transducción de Señal , TransfecciónRESUMEN
This study investigates the solitary wave solutions of the nonlinear fractional Jimbo-Miwa (JM) equation by using the conformable fractional derivative and some other distinct analytical techniques. The JM equation describes the certain interesting (3+1)-dimensional waves in physics. Moreover, it is considered as a second equation of the famous Painlev'e hierarchy of integrable systems. The fractional conformable derivatives properties were employed to convert it into an ordinary differential equation with an integer order to obtain many novel exact solutions of this model. The conformable fractional derivative is equivalent to the ordinary derivative for the functions that has continuous derivatives up to some desired order over some domain (smooth functions). The obtained solutions for each technique were characterized and compared to illustrate the similarities and differences between them. Profound solutions were concluded to be powerful, easy and effective on the nonlinear partial differential equation.
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G-protein-coupled receptors (GPCRs) constitute the largest superfamily of cell-surface signaling proteins. However, mechanisms underlying their surface targeting and sorting are poorly understood. Here, we screen the Rab family of small GTPases in the surface transport of multiple GPCRs. We find that manipulation of Rab43 function significantly alters the surface presentation and signaling of all GPCRs studied without affecting non-GPCR membrane proteins. Rab43 specifically regulates the transport of nascent GPCRs from the endoplasmic reticulum (ER) to the Golgi. More interestingly, Rab43 directly interacts with GPCRs in an activation-dependent fashion. The Rab43-binding domain identified in the receptors effectively converts non-GPCR membrane protein transport into a Rab43-dependent pathway. These data reveal a crucial role for Rab43 in anterograde ER-Golgi transport of nascent GPCRs, as well as the ER sorting of GPCR members by virtue of its ability to interact directly.
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Retículo Endoplásmico/genética , Aparato de Golgi/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Sitios de Unión , Células HEK293 , Humanos , Células MCF-7 , Unión Proteica , Transporte de Proteínas , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Unión al GTP rab/química , Proteínas de Unión al GTP rab/genéticaRESUMEN
OBJECTIVE: To study whether efficient transduction and subsequent elimination of fibroid tumor-initiating stem cells during debulking of tumor cells will aid in completely eradicating the tumor as well as decreasing the likelihood of recurrence. DESIGN: Case control study. SETTING: Research laboratory. PATIENT(S): None. INTERVENTION(S): Magnetic nanoparticles (MNPs) complexed to adenovirus (Ad-GFP) or (Ad-LacZ) used to transfect differentiated human fibroid cells in vitro. MAIN OUTCOME MEASURE(S): Rate of transduction and tumor growth inhibition. RESULT(S): We have developed a localized nonsurgical adenovirus-based alternative for the treatment of uterine fibroids that combines viral-based gene delivery with nanotechnology for more efficient targeting. Magnetic nanoparticles complexed to adenovirus, in the presence of an external magnetic field, accelerate adenovirus transduction. We observed a statistically significant increase in transduction efficiency among differentiated human fibroid cells at two different multiplicities of infection (MOI), 1 and 10, respectively, with MNPs as compared with adenovirus alone. Human fibroid stem cells transfected with Ad-LacZ expressed ß-galactosidaze at a MOI of 1, 10, and 50 at 19%, 62%, and 90%, respectively, which were statistically significantly enhanced with MNPs. CONCLUSION(S): When applied with adenovirus herpes simplex thymidine kinase, magnetofection statistically significantly suppressed proliferation and induced apoptosis in both cell types. Through the use of magnetofection, we will prove that a lower viral dose will effectively increase the overall safety profile of suicide gene therapy against fibroid tumors.