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  1. Article ; Online: mTOR'ing across the Cortex by Chopping the Cilia.

    Di Nardo, Alessia / Sahin, Mustafa

    Neuron

    2018  Volume 99, Issue 1, Page(s) 3–5

    Abstract: Somatic mutation of the MTOR gene is a genetic etiology of focal malformations of cortical development. In this issue of Neuron, Park et al. (2018) identify defective autophagy-dependent ciliogenesis/Wnt signaling as an underlying mechanism affecting ... ...

    Abstract Somatic mutation of the MTOR gene is a genetic etiology of focal malformations of cortical development. In this issue of Neuron, Park et al. (2018) identify defective autophagy-dependent ciliogenesis/Wnt signaling as an underlying mechanism affecting neuronal migration and cortical lamination.
    MeSH term(s) Brain ; Cilia ; Mutation ; Neurons ; TOR Serine-Threonine Kinases/genetics
    Chemical Substances TOR Serine-Threonine Kinases (EC 2.7.1.1)
    Language English
    Publishing date 2018-07-12
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2018.06.042
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  2. Article ; Online: A Cell-Based Assay Optimized for High-Content Cilia Imaging with Primary Rat Hippocampal Neurons.

    Di Nardo, Alessia / Vasquez, Sara / Sahin, Mustafa

    STAR protocols

    2020  Volume 1, Issue 3, Page(s) 100189

    Abstract: Genetic manipulations of dissociated rodent neurons provide ... ...

    Abstract Genetic manipulations of dissociated rodent neurons provide translatable
    MeSH term(s) Animals ; Cells, Cultured ; Cilia/metabolism ; Cilia/physiology ; Cilia/ultrastructure ; Hippocampus/diagnostic imaging ; Hippocampus/metabolism ; Image Processing, Computer-Assisted/methods ; Microscopy/methods ; Neurogenesis ; Neurons/metabolism ; Neurons/physiology ; Primary Cell Culture/methods ; Rats
    Language English
    Publishing date 2020-12-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2020.100189
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  3. Article ; Online: A Comparison of Vessel Patch Materials in Tetralogy of Fallot Patients Using Virtual Surgery Techniques.

    Di Nardo, Alessia / Louvelle, Leslie / Romero, David A / Doyle, Matthew / Forbes, Thomas L / Amon, Cristina H

    Annals of biomedical engineering

    2023  Volume 51, Issue 7, Page(s) 1420–1435

    Abstract: Tetralogy of Fallot (ToF) is characterized by stenosis causing partial obstruction of the right ventricular outflow tract, typically alleviated through the surgical application of a vessel patch made from a biocompatible material. In this study, we use ... ...

    Abstract Tetralogy of Fallot (ToF) is characterized by stenosis causing partial obstruction of the right ventricular outflow tract, typically alleviated through the surgical application of a vessel patch made from a biocompatible material. In this study, we use computational simulations to compare the mechanical performance of four patch materials for various stenosis locations. Nine idealized pre-operative ToF geometries were created by imposing symmetrical stenoses on each of three anatomical sub-regions of the pulmonary arteries of three patients with previously repaired ToF. A virtual surgery methodology was implemented to replicate the steps of vessel de-pressurization, surgical patching, and subsequent vessel expansion after reperfusion. Significant differences in patch average stress (p < 0.001) were found between patch materials. Biological patch materials (porcine xenopericardium, human pericardium) exhibited higher patch stresses in comparison to synthetic patch materials (Dacron and PTFE). Observed differences were consistent across the various stenosis locations and were insensitive to patient anatomy.
    MeSH term(s) Humans ; Animals ; Swine ; Tetralogy of Fallot/surgery ; Constriction, Pathologic ; Heart Ventricles ; Pulmonary Artery ; Pericardium
    Language English
    Publishing date 2023-02-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 185984-5
    ISSN 1573-9686 ; 0191-5649 ; 0090-6964
    ISSN (online) 1573-9686
    ISSN 0191-5649 ; 0090-6964
    DOI 10.1007/s10439-023-03144-x
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  4. Article: Integrative Treatment of Lung Cancer Patients: Observational Study of 57 Cases

    Anelli, Lorenzo / Di Nardo, Alessia / Bonucci, Massimo

    Asian Journal of Oncology

    2021  Volume 07, Issue 02, Page(s) 64–75

    Abstract: Introduction: A retrospective clinical study was performed to identify the characteristics of patients with lung cancer treated with integrative cancer treatment in addition to conventional medicine.: Materials and Methods: We reviewed medical ... ...

    Abstract Introduction: A retrospective clinical study was performed to identify the characteristics of patients with lung cancer treated with integrative cancer treatment in addition to conventional medicine.
    Materials and Methods: We reviewed medical records for lung cancer patients who visited a single integrative setting in Rome, Italy. A total of 57 patients were included, and the majority had advanced-stage cancer. All of them underwent integrative therapy with nutrition and phytotherapy indications. The diet was designed to reduce most of possible factors promoting cancer proliferation, inflammation, and obesity. Foods with anti-inflammatory, prebiotic, antioxidant, and anticancer properties had been chosen. Herbal supplements with known effects on lung cancer were prescribed. In particular, astragal, apigenine, fucosterol, polydatin, epigallocatechin gallate, cannabis, curcumin, and inositol were used. Furthermore, medical mushrooms and other substances were used to improve the immune system and to reduce chemotherapy side effects. Five key parameters have been evaluated for 2 years starting at the first surgery: nutritional status, immune status, discontinuation of therapy, quality of life, and prognosis of the disease.
    Results: A relevant improvement in parameters relative to nutritional status, immune status, and quality of life has been observed after integrative therapy compared with the same parameters at the first medical visit before starting such approach.
    Conclusion: The results suggest that integrative therapy may have benefits in patients with lung cancer. Even though there are limitations, the study suggests that integrative therapy could improve nutritional status and quality of life, with possible positive effect on overall survival.
    Keywords herbal medicine ; integrative oncology ; lung cancer ; nutrition ; oncology
    Language English
    Publishing date 2021-04-14
    Publisher Thieme Medical and Scientific Publishers Pvt. Ltd.
    Publishing place Stuttgart ; New York
    Document type Article
    ISSN 2455-4618 ; 2454-6798
    ISSN (online) 2455-4618
    ISSN 2454-6798
    DOI 10.1055/s-0040-1722380
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  5. Article ; Online: Phenotypic characterization of Cdkl5-knockdown neurons establishes elongated cilia as a functional assay for CDKL5 Deficiency Disorder.

    Di Nardo, Alessia / Rühmkorf, Alina / Award, Patricia / Brennecke, Ashton / Fagiolini, Michela / Sahin, Mustafa

    Neuroscience research

    2021  Volume 176, Page(s) 73–78

    Abstract: CDKL5 Deficiency Disorder (CDD) is a severe encephalopathy characterized by intractable epilepsy, infantile spasms, and cognitive disabilities. The detrimental CNS manifestations and lack of therapeutic interventions represent unmet needs, necessitating ... ...

    Abstract CDKL5 Deficiency Disorder (CDD) is a severe encephalopathy characterized by intractable epilepsy, infantile spasms, and cognitive disabilities. The detrimental CNS manifestations and lack of therapeutic interventions represent unmet needs, necessitating identification of CDD-dependent phenotypes for in vitro disease modeling and therapeutic testing. Here, we optimized a high-content assay to quantify cilia in CDKL5-deficient neurons. Our work shows that Cdkl5-knockdown neurons have elongated cilia and uncovers cilium lengthening in hippocampi of Cdkl5 knockout mice. Collectively, our findings identify cilia length alterations under CDKL5 activity loss in vitro and in vivo and reveal elongated cilia as a robust functional phenotype for CDD.
    MeSH term(s) Animals ; Cilia ; Epileptic Syndromes/genetics ; Mice ; Neurons ; Phenotype ; Protein Serine-Threonine Kinases/genetics
    Chemical Substances Protein Serine-Threonine Kinases (EC 2.7.11.1) ; CDKL5 protein, mouse (EC 2.7.11.22)
    Language English
    Publishing date 2021-10-05
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 605842-5
    ISSN 1872-8111 ; 0168-0102 ; 0921-8696
    ISSN (online) 1872-8111
    ISSN 0168-0102 ; 0921-8696
    DOI 10.1016/j.neures.2021.10.001
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  6. Article ; Online: Phenotypic Screen with TSC-Deficient Neurons Reveals Heat-Shock Machinery as a Druggable Pathway for mTORC1 and Reduced Cilia.

    Di Nardo, Alessia / Lenoël, Isadora / Winden, Kellen D / Rühmkorf, Alina / Modi, Meera E / Barrett, Lee / Ercan-Herbst, Ebru / Venugopal, Pooja / Behne, Robert / Lopes, Carla A M / Kleiman, Robin J / Bettencourt-Dias, Mónica / Sahin, Mustafa

    Cell reports

    2020  Volume 31, Issue 12, Page(s) 107780

    Abstract: Tuberous sclerosis complex (TSC) is a neurogenetic disorder that leads to elevated mechanistic targeting of rapamycin complex 1 (mTORC1) activity. Cilia can be affected by mTORC1 signaling, and ciliary deficits are associated with neurodevelopmental ... ...

    Abstract Tuberous sclerosis complex (TSC) is a neurogenetic disorder that leads to elevated mechanistic targeting of rapamycin complex 1 (mTORC1) activity. Cilia can be affected by mTORC1 signaling, and ciliary deficits are associated with neurodevelopmental disorders. Here, we examine whether neuronal cilia are affected in TSC. We show that cortical tubers from TSC patients and mutant mouse brains have fewer cilia. Using high-content image-based assays, we demonstrate that mTORC1 activity inversely correlates with ciliation in TSC1/2-deficient neurons. To investigate the mechanistic relationship between mTORC1 and cilia, we perform a phenotypic screen for mTORC1 inhibitors with TSC1/2-deficient neurons. We identify inhibitors of the heat shock protein 90 (Hsp90) that suppress mTORC1 through regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Pharmacological inhibition of Hsp90 rescues ciliation through downregulation of Hsp27. Our study uncovers the heat-shock machinery as a druggable signaling node to restore mTORC1 activity and cilia due to loss of TSC1/2, and it provides broadly applicable platforms for studying TSC-related neuronal dysfunction.
    MeSH term(s) Aging/metabolism ; Animals ; Benzoquinones/pharmacology ; Brain/pathology ; Cilia/metabolism ; Down-Regulation/drug effects ; HSP27 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Heat-Shock Response/drug effects ; Humans ; Lactams, Macrocyclic/pharmacology ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice, Knockout ; Neurons/drug effects ; Neurons/metabolism ; Phenotype ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Sirolimus/pharmacology ; Time Factors ; Tuberous Sclerosis Complex 1 Protein/metabolism ; Tuberous Sclerosis Complex 2 Protein/metabolism ; Up-Regulation/drug effects
    Chemical Substances Benzoquinones ; HSP27 Heat-Shock Proteins ; HSP90 Heat-Shock Proteins ; Lactams, Macrocyclic ; Tuberous Sclerosis Complex 1 Protein ; Tuberous Sclerosis Complex 2 Protein ; tanespimycin (4GY0AVT3L4) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2020-06-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2020.107780
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  7. Article ; Online: Vigabatrin can enhance electroretinographic responses in pigmented and albino rats.

    Akula, James D / Noonan, Emily R / Di Nardo, Alessia / Favazza, Tara L / Zhang, Nan / Sahin, Mustafa / Hansen, Ronald M / Fulton, Anne B

    Documenta ophthalmologica. Advances in ophthalmology

    2015  Volume 131, Issue 1, Page(s) 1–11

    Abstract: Purpose: To evaluate the effects of the antiepileptic medication vigabatrin (VGB) on the retina of pigmented rats.: Methods: Scotopic and photopic electroretinograms were recorded from dark- and light-adapted Long-Evans (pigmented) and Sprague Dawley ...

    Abstract Purpose: To evaluate the effects of the antiepileptic medication vigabatrin (VGB) on the retina of pigmented rats.
    Methods: Scotopic and photopic electroretinograms were recorded from dark- and light-adapted Long-Evans (pigmented) and Sprague Dawley (albino) rats administered, daily, 52-55 injections of 250 mg·kg(-1)·day(-1) VGB or 25-26 injections of 500 mg·kg(-1)·day(-1) VGB, or a corresponding number of sham injections. Sensitivity and saturated amplitude of the rod photoresponse (S, Rm(P3)) and postreceptor response (1/σ, Vm) were derived, as were sensitivity and amplitude of the cone-mediated postreceptor response (1/σ(cone), Vm(cone)). The oscillatory potentials and responses to a series of flickering lights (6.25, 12.5, 25 and 50 Hz) were studied in the time and frequency domains. A subset of rats' eyes was harvested for Western blotting or histology.
    Results: Of the parameters derived from dark-adapted ERG responses, in both pigmented and albino rats, VGB repeatedly and reliably enhanced electroretinographic parameters; no significant ERG deficits were noted. No significant alterations were observed in ER/oxidative stress or in the Akt cell death/survival pathway. There were migrations of photoreceptor nuclei toward the RPE and outgrowths of bipolar cell dendrites into the outer nuclear layer in VGB-treated rats; these were never observed in sham-treated animals.
    Conclusions: Although VGB is associated with retinal dysfunction in patients and VGB toxicity has been demonstrated by other laboratories in the albino rat, in our pigmented and albino rats, VGB did not induce deficits in, but rather enhanced, retinal function. Nonetheless, retinal neuronal dysplasia was observed.
    MeSH term(s) Albinism/physiopathology ; Animals ; Anticonvulsants/pharmacology ; Biomarkers/metabolism ; Blotting, Western ; Dark Adaptation ; Electroretinography/drug effects ; Light ; Male ; Photoreceptor Cells, Vertebrate/physiology ; Rats ; Rats, Long-Evans ; Rats, Sprague-Dawley ; Retinal Pigment Epithelium/physiopathology ; Vigabatrin/pharmacology
    Chemical Substances Anticonvulsants ; Biomarkers ; Vigabatrin (GR120KRT6K)
    Language English
    Publishing date 2015-08
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 212594-8
    ISSN 1573-2622 ; 0012-4486
    ISSN (online) 1573-2622
    ISSN 0012-4486
    DOI 10.1007/s10633-015-9491-0
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  8. Article ; Online: Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex.

    Ercan, Ebru / Han, Juliette M / Di Nardo, Alessia / Winden, Kellen / Han, Min-Joon / Hoyo, Leonie / Saffari, Afshin / Leask, Andrew / Geschwind, Daniel H / Sahin, Mustafa

    The Journal of experimental medicine

    2017  Volume 214, Issue 3, Page(s) 681–697

    Abstract: Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking ... ...

    Abstract Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal
    MeSH term(s) Animals ; Connective Tissue Growth Factor/physiology ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Myelin Sheath/physiology ; Neurons/physiology ; Oligodendroglia/physiology ; Rats ; TOR Serine-Threonine Kinases/physiology ; Tuberous Sclerosis/physiopathology ; Tuberous Sclerosis Complex 1 Protein ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins/physiology
    Chemical Substances CCN2 protein, mouse ; TSC1 protein, human ; Tsc1 protein, mouse ; Tsc1 protein, rat ; Tuberous Sclerosis Complex 1 Protein ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins ; Connective Tissue Growth Factor (139568-91-5) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1)
    Language English
    Publishing date 2017-02-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20160446
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  9. Article: Mouse profilin 2 regulates endocytosis and competes with SH3 ligand binding to dynamin 1.

    Gareus, Ralph / Di Nardo, Alessia / Rybin, Vladimir / Witke, Walter

    The Journal of biological chemistry

    2005  Volume 281, Issue 5, Page(s) 2803–2811

    Abstract: Mammalian profilins are abundantly expressed actin monomer-binding proteins, highly conserved with respect to their affinities for G-actin, poly-L-proline, and phosphoinositides. Profilins associate with a large number of proline-rich proteins; the ... ...

    Abstract Mammalian profilins are abundantly expressed actin monomer-binding proteins, highly conserved with respect to their affinities for G-actin, poly-L-proline, and phosphoinositides. Profilins associate with a large number of proline-rich proteins; the physiological significance and regulation of which is poorly understood. Here we show that profilin 2 associates with dynamin 1 via the C-terminal proline-rich domain of dynamin and thereby competes with the binding of SH3 ligands such as endophilin, amphiphysin, and Grb2, thus interfering with the assembly of the endocytic machinery. We also present a novel role for the brain-specific mouse profilin 2 as a regulator of membrane trafficking. Overexpression of profilin 2 inhibits endocytosis, whereas lack of profilin 2 in neurons results in an increase in endocytosis and membrane recycling. Phosphatidylinositol 4,5-bisphosphate releases profilin 2 from the profilin 2-dynamin 1 complex as well as from the profilin 2-actin complex, suggesting that profilin 2 is diverging the phosphoinositide signaling pathway to actin polymerization as well as endocytosis.
    MeSH term(s) Actins/metabolism ; Animals ; Binding Sites ; Dynamin I/metabolism ; Endocytosis ; Ligands ; Mice ; Multiprotein Complexes/metabolism ; Neurons/metabolism ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Profilins/metabolism ; Profilins/physiology ; Protein Binding ; Signal Transduction ; src Homology Domains
    Chemical Substances Actins ; Ligands ; Multiprotein Complexes ; Pfn2 protein, mouse ; Phosphatidylinositol 4,5-Diphosphate ; Profilins ; Dynamin I (EC 3.5.1.50)
    Language English
    Publishing date 2005-11-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M503528200
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  10. Article ; Online: The Stress-Induced Atf3-Gelsolin Cascade Underlies Dendritic Spine Deficits in Neuronal Models of Tuberous Sclerosis Complex.

    Nie, Duyu / Chen, Zehua / Ebrahimi-Fakhari, Darius / Di Nardo, Alessia / Julich, Kristina / Robson, Victoria K / Cheng, Yung-Chih / Woolf, Clifford J / Heiman, Myriam / Sahin, Mustafa

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2015  Volume 35, Issue 30, Page(s) 10762–10772

    Abstract: Hyperactivation of the mechanistic target of rapamycin (mTOR) kinase, as a result of loss-of-function mutations in tuberous sclerosis complex 1 (TSC1) or TSC2 genes, causes protein synthesis dysregulation, increased cell size, and aberrant neuronal ... ...

    Abstract Hyperactivation of the mechanistic target of rapamycin (mTOR) kinase, as a result of loss-of-function mutations in tuberous sclerosis complex 1 (TSC1) or TSC2 genes, causes protein synthesis dysregulation, increased cell size, and aberrant neuronal connectivity. Dysregulated synthesis of synaptic proteins has been implicated in the pathophysiology of autism spectrum disorder (ASD) associated with TSC and fragile X syndrome. However, cell type-specific translational profiles in these disease models remain to be investigated. Here, we used high-fidelity and unbiased Translating Ribosome Affinity Purification (TRAP) methodology to purify ribosome-associated mRNAs and identified translational alterations in a rat neuronal culture model of TSC. We find that expression of many stress and/or activity-dependent proteins is highly induced while some synaptic proteins are repressed. Importantly, transcripts for the activating transcription factor-3 (Atf3) and mitochondrial uncoupling protein-2 (Ucp2) are highly induced in Tsc2-deficient neurons, as well as in a neuron-specific Tsc1 conditional knock-out mouse model, and show differential responses to the mTOR inhibitor rapamycin. Gelsolin, a known target of Atf3 transcriptional activity, is also upregulated. shRNA-mediated block of Atf3 induction suppresses expression of gelsolin, an actin-severing protein, and rescues spine deficits found in Tsc2-deficient neurons. Together, our data demonstrate that a cell-autonomous program consisting of a stress-induced Atf3-gelsolin cascade affects the change in dendritic spine morphology following mTOR hyperactivation. This previously unidentified molecular cascade could be a therapeutic target for treating mTORopathies.
    Significance statement: Tuberous sclerosis complex (TSC) is a genetic disease associated with epilepsy and autism. Dysregulated protein synthesis has been implicated as a cause of this disease. However, cell type-specific translational profiles that are aberrant in this disease are unknown. Here we show that expression of many stress and/or activity-dependent proteins is highly induced while some synaptic proteins are repressed in neurons missing the Tsc2 gene expression. Identification of genes whose translation is abnormal in TSC may provide insights to previously unidentified therapeutic targets.
    MeSH term(s) Activating Transcription Factor 3/metabolism ; Animals ; Blotting, Western ; Dendritic Spines/metabolism ; Dendritic Spines/pathology ; Disease Models, Animal ; Female ; Gelsolin/metabolism ; Hippocampus/metabolism ; Hippocampus/pathology ; Immunohistochemistry ; Male ; Mice ; Mice, Mutant Strains ; Oligonucleotide Array Sequence Analysis ; RNA, Small Interfering ; Rats ; Real-Time Polymerase Chain Reaction ; Signal Transduction/physiology ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; Transcriptome ; Transfection ; Tuberous Sclerosis/metabolism ; Tuberous Sclerosis/pathology
    Chemical Substances Activating Transcription Factor 3 ; Gelsolin ; RNA, Small Interfering ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2015-07-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.4796-14.2015
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