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2. Age-induced nitrative stress decreases retrograde transport of proNGF via TrkA and increases proNGF retrograde transport and neurodegeneration via p75NTR.

Author

Kropf, Erika, Shekari, Arman, Jaberi, Sama, Puri, Anish, Chengbiao Wu, and Fahnestock, Margaret

Subjects
NEUROTROPHIN receptors, NERVE growth factor, NITRIC-oxide synthases, AXONAL transport, NEURODEGENERATION, QUANTUM dots
Abstract

Introduction: Axonal transport of pro nerve growth factor (proNGF) is impaired in aged basal forebrain cholinergic neurons (BFCNs), which is associated with their degeneration. ProNGF is neurotrophic in the presence of its receptor tropomyosin-related kinase A (TrkA) but induces apoptosis via the pan-neurotrophin receptor (p75NTR) when TrkA is absent. It is well established that TrkA is lost while p75NTR is maintained in aged BFCNs, but whether aging differentially affects transport of proNGF via each receptor is unknown. Nitrative stress increases during aging, but whether age-induced nitrative stress differentially affects proNGF transport via TrkA versus p75NTR has not yet been studied. Answering these questions is essential for developing an accurate understanding of the mechanisms contributing to age-induced loss of proNGF transport and BFCN degeneration. Methods: In this study, fluorescence microscopy was used to analyze axonal transport of quantum dot labeled proNGF in rat BFCNs in vitro. Receptor specific effects were studied with proNGF mutants that selectively bind to either TrkA (proNGF-KKE) or p75NTR (proNGF-Δ9-13). Signaling factor activity was quantified via immunostaining. Results: Young BFCNs transported proNGF-KKE but not proNGF-Δ9-13, and proNGF transport was not different in p75NTR knockout BFCNs compared to wildtype BFCNs. These results indicate that young BFCNs transport proNGF via TrkA. In vitro aging increased transport of proNGF-Δ9-13 but decreased transport of proNGF-KKE. Treatment with the nitric oxide synthase inhibitor L-NAME reduced retrograde transport of proNGF-Δ9-13 in aged BFCNs while increasing retrograde transport of proNGF-KKE but did not affect TrkA or p75NTR levels. ProNGF-Δ9-13 induced greater pro-apoptotic signaling and neurodegeneration and less pro-survival signaling relative to proNGF-KKE. Discussion: Together, these results indicate that age-induced nitrative stress decreases proNGF transport via TrkA while increasing proNGF transport via p75NTR. These transport deficits are associated with decreased survival signaling, increased apoptotic signaling, and neurodegeneration. Our findings elucidate the receptor specificity of age-and nitrative stress-induced proNGF transport deficits. These results may help to rescue the neurotrophic signaling of proNGF in aging to reduce age-induced loss of BFCN function and cognitive decline. [ABSTRACT FROM AUTHOR]

Published
2023
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3. Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

Author

Chokshi, Chirayu R., Shaikh, Muhammad Vaseem, Brakel, Benjamin, Rossotti, Martin A., Tieu, David, Maich, William, Anand, Alisha, Chafe, Shawn C., Zhai, Kui, Suk, Yujin, Kieliszek, Agata M., Miletic, Petar, Mikolajewicz, Nicholas, Chen, David, McNicol, Jamie D., Chan, Katherine, Tong, Amy H. Y., Kuhlmann, Laura, Liu, Lina, Alizada, Zahra, Mobilio, Daniel, Tatari, Nazanin, Savage, Neil, Aghaei, Nikoo, Grewal, Shan, Puri, Anish, Subapanditha, Minomi, McKenna, Dillon, Ignatchenko, Vladimir, Salamoun, Joseph M., Kwiecien, Jacek M., Wipf, Peter, Sharlow, Elizabeth R., Provias, John P., Lu, Jian-Qiang, Lazo, John S., Kislinger, Thomas, Lu, Yu, Brown, Kevin R., Venugopal, Chitra, Henry, Kevin A., Moffat, Jason, and Singh, Sheila K.

Abstract

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2(protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood–brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50–100% of mice. Our study identifies a promising multi-targetable PTP4A–ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.

Published
2024
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4. Numerical analysis of subcritical open channel flow by the penalty function finite element method

Author

Puri, Anish N. and Civil Engineering

Subjects
Physics::Fluid Dynamics, Finite element method, Turbulence -- Simulation methods, Hydrodynamics -- Simulation methods, LD5655.V856 1983.P875
Abstract

Many free surface flow problems encountered in hydraulic engineering can be accurately analyzed by utilizing the depth-averaged equations of motion. A consequence of adopting this depth-averaged modeling approach is that closure approximations must be implemented to represent the so-called effective stresses. These effective stresses consist of the depth-averaged viscous stresses, which are usually small and therefore neglected, the depth-averaged turbulent Reynold's stresses, and additional stresses resulting from depth-averaging of the nonlinear 'convective acceleration terms (often called momentum dispersion terms). Attention is focused on examining closure for both the depth-averaged Reynold's stresses and the momentum dispersion terms. In the present study, the penalty function finite element technique is utilized to solve the governing hydrodynamic and turbulence model equations for a variety of flow domains. Alternative momentum dispersion and turbulence closure models are proposed and evaluated by comparing model predictions with experimental data for strongly curved open channel flow. The results of these simulations indicate that the depth-averaged (k-ε) turbulence model yields excellent agreement with experimental observations. In addition, it appears that neither the streamline curvature modification of the depth-averaged (k-ε) model, nor the momentum dispersion models based on the assumption of helicoidal flow in a curved channel, yield significant improvement in model predictions. Overall model predictions are found to be as good as those of a more complex and restricted three dimensional model. Ph. D.

Published
1983

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