--- _id: '6088' abstract: - lang: eng text: P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters at the blood–brain barrier (BBB), which effectively restrict brain distribution of diverse drugs, such as tyrosine kinase inhibitors. There is a crucial need for pharmacological ABCB1 and ABCG2 inhibition protocols for a more effective treatment of brain diseases. In the present study, seven marketed drugs (osimertinib, erlotinib, nilotinib, imatinib, lapatinib, pazopanib, and cyclosporine A) and one nonmarketed drug (tariquidar), with known in vitro ABCB1/ABCG2 inhibitory properties, were screened for their inhibitory potency at the BBB in vivo. Positron emission tomography (PET) using the model ABCB1/ABCG2 substrate [11C]erlotinib was performed in mice. Tested inhibitors were administered as i.v. bolus injections at 30 min before the start of the PET scan, followed by a continuous i.v. infusion for the duration of the PET scan. Five of the tested drugs increased total distribution volume of [11C]erlotinib in the brain (VT,brain) compared to vehicle-treated animals (tariquidar, + 69%; erlotinib, + 19% and +23% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 22%; lapatinib, + 25%; and cyclosporine A, + 49%). For all drugs, increases in [11C]erlotinib brain distribution were lower than in Abcb1a/b(−/−)Abcg2(−/−) mice (+149%), which suggested that only partial ABCB1/ABCG2 inhibition was reached at the mouse BBB. The plasma concentrations of the tested drugs at the time of the PET scan were higher than clinically achievable plasma concentrations. Some of the tested drugs led to significant increases in blood radioactivity concentrations measured at the end of the PET scan (erlotinib, + 103% and +113% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 125%; and cyclosporine A, + 101%), which was most likely caused by decreased hepatobiliary excretion of radioactivity. Taken together, our data suggest that some marketed tyrosine kinase inhibitors may be repurposed to inhibit ABCB1 and ABCG2 at the BBB. From a clinical perspective, moderate increases in brain delivery despite the administration of high i.v. doses as well as peripheral drug–drug interactions due to transporter inhibition in clearance organs question the translatability of this concept. article_processing_charge: No author: - first_name: Alexander full_name: Traxl, Alexander last_name: Traxl - first_name: Severin full_name: Mairinger, Severin last_name: Mairinger - first_name: Thomas full_name: Filip, Thomas last_name: Filip - first_name: Michael full_name: Sauberer, Michael last_name: Sauberer - first_name: Johann full_name: Stanek, Johann last_name: Stanek - first_name: Stefan full_name: Poschner, Stefan last_name: Poschner - first_name: Walter full_name: Jäger, Walter last_name: Jäger - first_name: Viktoria full_name: Zoufal, Viktoria last_name: Zoufal - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 - first_name: Nicolas full_name: Tournier, Nicolas last_name: Tournier - first_name: Martin full_name: Bauer, Martin last_name: Bauer - first_name: Thomas full_name: Wanek, Thomas last_name: Wanek - first_name: Oliver full_name: Langer, Oliver last_name: Langer citation: ama: Traxl A, Mairinger S, Filip T, et al. Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Molecular Pharmaceutics. 2019;16(3):1282-1293. doi:10.1021/acs.molpharmaceut.8b01217 apa: Traxl, A., Mairinger, S., Filip, T., Sauberer, M., Stanek, J., Poschner, S., … Langer, O. (2019). Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Molecular Pharmaceutics. American Chemical Society. https://doi.org/10.1021/acs.molpharmaceut.8b01217 chicago: Traxl, Alexander, Severin Mairinger, Thomas Filip, Michael Sauberer, Johann Stanek, Stefan Poschner, Walter Jäger, et al. “Inhibition of ABCB1 and ABCG2 at the Mouse Blood-Brain Barrier with Marketed Drugs to Improve Brain Delivery of the Model ABCB1/ABCG2 Substrate [11C]Erlotinib.” Molecular Pharmaceutics. American Chemical Society, 2019. https://doi.org/10.1021/acs.molpharmaceut.8b01217. ieee: A. Traxl et al., “Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib,” Molecular Pharmaceutics, vol. 16, no. 3. American Chemical Society, pp. 1282–1293, 2019. ista: Traxl A, Mairinger S, Filip T, Sauberer M, Stanek J, Poschner S, Jäger W, Zoufal V, Novarino G, Tournier N, Bauer M, Wanek T, Langer O. 2019. Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Molecular Pharmaceutics. 16(3), 1282–1293. mla: Traxl, Alexander, et al. “Inhibition of ABCB1 and ABCG2 at the Mouse Blood-Brain Barrier with Marketed Drugs to Improve Brain Delivery of the Model ABCB1/ABCG2 Substrate [11C]Erlotinib.” Molecular Pharmaceutics, vol. 16, no. 3, American Chemical Society, 2019, pp. 1282–93, doi:10.1021/acs.molpharmaceut.8b01217. short: A. Traxl, S. Mairinger, T. Filip, M. Sauberer, J. Stanek, S. Poschner, W. Jäger, V. Zoufal, G. Novarino, N. Tournier, M. Bauer, T. Wanek, O. Langer, Molecular Pharmaceutics 16 (2019) 1282–1293. date_created: 2019-03-10T22:59:19Z date_published: 2019-03-04T00:00:00Z date_updated: 2023-08-25T08:02:51Z day: '04' department: - _id: GaNo doi: 10.1021/acs.molpharmaceut.8b01217 external_id: isi: - '000460600400031' pmid: - '30694684' intvolume: ' 16' isi: 1 issue: '3' language: - iso: eng month: '03' oa_version: None page: 1282-1293 pmid: 1 publication: Molecular Pharmaceutics publication_status: published publisher: American Chemical Society quality_controlled: '1' scopus_import: '1' status: public title: Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 16 year: '2019' ... --- _id: '6470' abstract: - lang: eng text: 'Investigating neuronal activity using genetically encoded Ca2+ indicators in behaving animals is hampered by inaccuracies in spike inference from fluorescent tracers. Here we combine two‐photon [Ca2+] imaging with cell‐attached recordings, followed by post hoc determination of the expression level of GCaMP6f, to explore how it affects the amplitude, kinetics and temporal summation of somatic [Ca2+] transients in mouse hippocampal pyramidal cells (PCs). The amplitude of unitary [Ca2+] transients (evoked by a single action potential) negatively correlates with GCaMP6f expression, but displays large variability even among PCs with similarly low expression levels. The summation of fluorescence signals is frequency‐dependent, supralinear and also shows remarkable cell‐to‐cell variability. We performed experimental data‐based simulations and found that spike inference error rates using MLspike depend strongly on unitary peak amplitudes and GCaMP6f expression levels. We provide simple methods for estimating the unitary [Ca2+] transients in individual weakly GCaMP6f‐expressing PCs, with which we achieve spike inference error rates of ∼5%. ' article_processing_charge: No article_type: original author: - first_name: Tímea full_name: Éltes, Tímea last_name: Éltes - first_name: Miklos full_name: Szoboszlay, Miklos last_name: Szoboszlay - first_name: Margit Katalin full_name: Szigeti, Margit Katalin id: 44F4BDC0-F248-11E8-B48F-1D18A9856A87 last_name: Szigeti orcid: 0000-0001-9500-8758 - first_name: Zoltan full_name: Nusser, Zoltan last_name: Nusser citation: ama: Éltes T, Szoboszlay M, Szigeti MK, Nusser Z. Improved spike inference accuracy by estimating the peak amplitude of unitary [Ca2+] transients in weakly GCaMP6f-expressing hippocampal pyramidal cells. Journal of Physiology. 2019;597(11):2925–2947. doi:10.1113/JP277681 apa: Éltes, T., Szoboszlay, M., Szigeti, M. K., & Nusser, Z. (2019). Improved spike inference accuracy by estimating the peak amplitude of unitary [Ca2+] transients in weakly GCaMP6f-expressing hippocampal pyramidal cells. Journal of Physiology. Wiley. https://doi.org/10.1113/JP277681 chicago: Éltes, Tímea, Miklos Szoboszlay, Margit Katalin Szigeti, and Zoltan Nusser. “Improved Spike Inference Accuracy by Estimating the Peak Amplitude of Unitary [Ca2+] Transients in Weakly GCaMP6f-Expressing Hippocampal Pyramidal Cells.” Journal of Physiology. Wiley, 2019. https://doi.org/10.1113/JP277681. ieee: T. Éltes, M. Szoboszlay, M. K. Szigeti, and Z. Nusser, “Improved spike inference accuracy by estimating the peak amplitude of unitary [Ca2+] transients in weakly GCaMP6f-expressing hippocampal pyramidal cells,” Journal of Physiology, vol. 597, no. 11. Wiley, pp. 2925–2947, 2019. ista: Éltes T, Szoboszlay M, Szigeti MK, Nusser Z. 2019. Improved spike inference accuracy by estimating the peak amplitude of unitary [Ca2+] transients in weakly GCaMP6f-expressing hippocampal pyramidal cells. Journal of Physiology. 597(11), 2925–2947. mla: Éltes, Tímea, et al. “Improved Spike Inference Accuracy by Estimating the Peak Amplitude of Unitary [Ca2+] Transients in Weakly GCaMP6f-Expressing Hippocampal Pyramidal Cells.” Journal of Physiology, vol. 597, no. 11, Wiley, 2019, pp. 2925–2947, doi:10.1113/JP277681. short: T. Éltes, M. Szoboszlay, M.K. Szigeti, Z. Nusser, Journal of Physiology 597 (2019) 2925–2947. date_created: 2019-05-19T21:59:17Z date_published: 2019-06-01T00:00:00Z date_updated: 2023-08-25T10:34:15Z day: '01' department: - _id: GaNo doi: 10.1113/JP277681 external_id: isi: - '000470780400013' pmid: - '31006863' intvolume: ' 597' isi: 1 issue: '11' language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1113/JP277681 month: '06' oa: 1 oa_version: Published Version page: 2925–2947 pmid: 1 publication: Journal of Physiology publication_identifier: eissn: - '14697793' issn: - '00223751' publication_status: published publisher: Wiley quality_controlled: '1' scopus_import: '1' status: public title: Improved spike inference accuracy by estimating the peak amplitude of unitary [Ca2+] transients in weakly GCaMP6f-expressing hippocampal pyramidal cells type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 597 year: '2019' ... --- _id: '6896' abstract: - lang: eng text: "Until recently, a great amount of brain studies have been conducted in human post mortem tissues, cell lines and model organisms. These researches provided useful insights regarding cell-cell interactions occurring in the brain. However, such approaches suffer from technical limitations and inaccurate modeling of the tissue 3D cytoarchitecture. Importantly, they might lack a human genetic background essential for disease modeling. With the development of protocols to generate human cerebral organoids, we are now closer to reproducing the early stages of human brain development in vitro. As a result, more relevant cell-cell interaction studies can be conducted.\r\n\r\nIn this review, we discuss the advantages of 3D cultures over 2D in modulating brain cell-cell interactions during physiological and pathological development, as well as the progress made in developing organoids in which neurons, macroglia, microglia and vascularization are present. Finally, we debate the limitations of those models and possible future directions." article_number: '146458' article_processing_charge: No article_type: original author: - first_name: Bárbara full_name: Oliveira, Bárbara id: 3B03AA1A-F248-11E8-B48F-1D18A9856A87 last_name: Oliveira - first_name: Aysan Çerağ full_name: Yahya, Aysan Çerağ id: 365A65F8-F248-11E8-B48F-1D18A9856A87 last_name: Yahya - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: Oliveira B, Yahya AÇ, Novarino G. Modeling cell-cell interactions in the brain using cerebral organoids. Brain Research. 2019;1724. doi:10.1016/j.brainres.2019.146458 apa: Oliveira, B., Yahya, A. Ç., & Novarino, G. (2019). Modeling cell-cell interactions in the brain using cerebral organoids. Brain Research. Elsevier. https://doi.org/10.1016/j.brainres.2019.146458 chicago: Oliveira, Bárbara, Aysan Çerağ Yahya, and Gaia Novarino. “Modeling Cell-Cell Interactions in the Brain Using Cerebral Organoids.” Brain Research. Elsevier, 2019. https://doi.org/10.1016/j.brainres.2019.146458. ieee: B. Oliveira, A. Ç. Yahya, and G. Novarino, “Modeling cell-cell interactions in the brain using cerebral organoids,” Brain Research, vol. 1724. Elsevier, 2019. ista: Oliveira B, Yahya AÇ, Novarino G. 2019. Modeling cell-cell interactions in the brain using cerebral organoids. Brain Research. 1724, 146458. mla: Oliveira, Bárbara, et al. “Modeling Cell-Cell Interactions in the Brain Using Cerebral Organoids.” Brain Research, vol. 1724, 146458, Elsevier, 2019, doi:10.1016/j.brainres.2019.146458. short: B. Oliveira, A.Ç. Yahya, G. Novarino, Brain Research 1724 (2019). date_created: 2019-09-22T22:00:35Z date_published: 2019-12-01T00:00:00Z date_updated: 2023-08-30T06:19:49Z day: '01' department: - _id: GaNo doi: 10.1016/j.brainres.2019.146458 external_id: isi: - '000491646600033' pmid: - '31521639' intvolume: ' 1724' isi: 1 language: - iso: eng month: '12' oa_version: None pmid: 1 publication: Brain Research publication_identifier: eissn: - '18726240' issn: - '00068993' publication_status: published publisher: Elsevier quality_controlled: '1' scopus_import: '1' status: public title: Modeling cell-cell interactions in the brain using cerebral organoids type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 1724 year: '2019' ... --- _id: '7415' article_processing_charge: No article_type: original author: - first_name: Jasmin full_name: Morandell, Jasmin id: 4739D480-F248-11E8-B48F-1D18A9856A87 last_name: Morandell - first_name: Armel full_name: Nicolas, Armel id: 2A103192-F248-11E8-B48F-1D18A9856A87 last_name: Nicolas - first_name: Lena A full_name: Schwarz, Lena A id: 29A8453C-F248-11E8-B48F-1D18A9856A87 last_name: Schwarz - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: Morandell J, Nicolas A, Schwarz LA, Novarino G. S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism. European Neuropsychopharmacology. 2019;29(Supplement 6):S11-S12. doi:10.1016/j.euroneuro.2019.09.040 apa: Morandell, J., Nicolas, A., Schwarz, L. A., & Novarino, G. (2019). S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism. European Neuropsychopharmacology. Elsevier. https://doi.org/10.1016/j.euroneuro.2019.09.040 chicago: Morandell, Jasmin, Armel Nicolas, Lena A Schwarz, and Gaia Novarino. “S.16.05 Illuminating the Role of the E3 Ubiquitin Ligase Cullin3 in Brain Development and Autism.” European Neuropsychopharmacology. Elsevier, 2019. https://doi.org/10.1016/j.euroneuro.2019.09.040. ieee: J. Morandell, A. Nicolas, L. A. Schwarz, and G. Novarino, “S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism,” European Neuropsychopharmacology, vol. 29, no. Supplement 6. Elsevier, pp. S11–S12, 2019. ista: Morandell J, Nicolas A, Schwarz LA, Novarino G. 2019. S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism. European Neuropsychopharmacology. 29(Supplement 6), S11–S12. mla: Morandell, Jasmin, et al. “S.16.05 Illuminating the Role of the E3 Ubiquitin Ligase Cullin3 in Brain Development and Autism.” European Neuropsychopharmacology, vol. 29, no. Supplement 6, Elsevier, 2019, pp. S11–12, doi:10.1016/j.euroneuro.2019.09.040. short: J. Morandell, A. Nicolas, L.A. Schwarz, G. Novarino, European Neuropsychopharmacology 29 (2019) S11–S12. date_created: 2020-01-30T10:07:41Z date_published: 2019-12-13T00:00:00Z date_updated: 2023-09-07T14:56:17Z day: '13' department: - _id: GaNo - _id: LifeSc doi: 10.1016/j.euroneuro.2019.09.040 external_id: isi: - '000502657500021' intvolume: ' 29' isi: 1 issue: Supplement 6 language: - iso: eng month: '12' oa_version: None page: S11-S12 publication: European Neuropsychopharmacology publication_identifier: issn: - 0924-977X publication_status: published publisher: Elsevier quality_controlled: '1' status: public title: S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 29 year: '2019' ... --- _id: '7414' article_processing_charge: No article_type: original author: - first_name: Lisa full_name: Knaus, Lisa id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 last_name: Knaus - first_name: Dora-Clara full_name: Tarlungeanu, Dora-Clara id: 2ABCE612-F248-11E8-B48F-1D18A9856A87 last_name: Tarlungeanu - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: Knaus L, Tarlungeanu D-C, Novarino G. S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. European Neuropsychopharmacology. 2019;29(Supplement 6):S11. doi:10.1016/j.euroneuro.2019.09.039 apa: Knaus, L., Tarlungeanu, D.-C., & Novarino, G. (2019). S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. European Neuropsychopharmacology. Elsevier. https://doi.org/10.1016/j.euroneuro.2019.09.039 chicago: Knaus, Lisa, Dora-Clara Tarlungeanu, and Gaia Novarino. “S.16.03 A Homozygous Missense Mutation in SLC7A5 Leads to Autism Spectrum Disorder and Microcephaly.” European Neuropsychopharmacology. Elsevier, 2019. https://doi.org/10.1016/j.euroneuro.2019.09.039. ieee: L. Knaus, D.-C. Tarlungeanu, and G. Novarino, “S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly,” European Neuropsychopharmacology, vol. 29, no. Supplement 6. Elsevier, p. S11, 2019. ista: Knaus L, Tarlungeanu D-C, Novarino G. 2019. S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. European Neuropsychopharmacology. 29(Supplement 6), S11. mla: Knaus, Lisa, et al. “S.16.03 A Homozygous Missense Mutation in SLC7A5 Leads to Autism Spectrum Disorder and Microcephaly.” European Neuropsychopharmacology, vol. 29, no. Supplement 6, Elsevier, 2019, p. S11, doi:10.1016/j.euroneuro.2019.09.039. short: L. Knaus, D.-C. Tarlungeanu, G. Novarino, European Neuropsychopharmacology 29 (2019) S11. date_created: 2020-01-30T10:06:15Z date_published: 2019-12-13T00:00:00Z date_updated: 2023-09-07T14:55:23Z day: '13' department: - _id: GaNo doi: 10.1016/j.euroneuro.2019.09.039 external_id: isi: - '000502657500020' intvolume: ' 29' isi: 1 issue: Supplement 6 language: - iso: eng month: '12' oa_version: None page: S11 publication: European Neuropsychopharmacology publication_identifier: issn: - 0924-977X publication_status: published publisher: Elsevier quality_controlled: '1' status: public title: S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 29 year: '2019' ... --- _id: '456' abstract: - lang: eng text: 'Inhibition of the endoplasmic reticulum stress pathway may hold the key to Zika virus-associated microcephaly treatment. ' article_number: eaar7514 author: - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: 'Novarino G. Zika-associated microcephaly: Reduce the stress and race for the treatment. Science Translational Medicine. 2018;10(423). doi:10.1126/scitranslmed.aar7514' apa: 'Novarino, G. (2018). Zika-associated microcephaly: Reduce the stress and race for the treatment. Science Translational Medicine. American Association for the Advancement of Science. https://doi.org/10.1126/scitranslmed.aar7514' chicago: 'Novarino, Gaia. “Zika-Associated Microcephaly: Reduce the Stress and Race for the Treatment.” Science Translational Medicine. American Association for the Advancement of Science, 2018. https://doi.org/10.1126/scitranslmed.aar7514.' ieee: 'G. Novarino, “Zika-associated microcephaly: Reduce the stress and race for the treatment,” Science Translational Medicine, vol. 10, no. 423. American Association for the Advancement of Science, 2018.' ista: 'Novarino G. 2018. Zika-associated microcephaly: Reduce the stress and race for the treatment. Science Translational Medicine. 10(423), eaar7514.' mla: 'Novarino, Gaia. “Zika-Associated Microcephaly: Reduce the Stress and Race for the Treatment.” Science Translational Medicine, vol. 10, no. 423, eaar7514, American Association for the Advancement of Science, 2018, doi:10.1126/scitranslmed.aar7514.' short: G. Novarino, Science Translational Medicine 10 (2018). date_created: 2018-12-11T11:46:34Z date_published: 2018-01-10T00:00:00Z date_updated: 2021-01-12T07:59:42Z day: '10' department: - _id: GaNo doi: 10.1126/scitranslmed.aar7514 intvolume: ' 10' issue: '423' language: - iso: eng month: '01' oa_version: None publication: Science Translational Medicine publication_status: published publisher: American Association for the Advancement of Science publist_id: '7365' quality_controlled: '1' scopus_import: 1 status: public title: 'Zika-associated microcephaly: Reduce the stress and race for the treatment' type: journal_article user_id: 4435EBFC-F248-11E8-B48F-1D18A9856A87 volume: 10 year: '2018' ... --- _id: '5888' abstract: - lang: eng text: "Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental\r\ndisorders (e.g., autism spectrum disorder, intellectual disability) remains a great challenge. Recent advancements in\r\ngenomics, such as whole-exome or whole-genome sequencing, have enabled scientists to identify numerous\r\nmutations underlying neurodevelopmental disorders. Given the few hundred risk genes that have been discovered,\r\nthe etiological variability and the heterogeneous clinical presentation, the need for genotype — along with phenotype-\r\nbased diagnosis of individual patients has become a requisite. In this review we look at recent advancements in\r\ngenomic analysis and their translation into clinical practice." article_number: '100' article_processing_charge: No author: - first_name: Dora-Clara full_name: Tarlungeanu, Dora-Clara id: 2ABCE612-F248-11E8-B48F-1D18A9856A87 last_name: Tarlungeanu - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: 'Tarlungeanu D-C, Novarino G. Genomics in neurodevelopmental disorders: an avenue to personalized medicine. Experimental & Molecular Medicine. 2018;50(8). doi:10.1038/s12276-018-0129-7' apa: 'Tarlungeanu, D.-C., & Novarino, G. (2018). Genomics in neurodevelopmental disorders: an avenue to personalized medicine. Experimental & Molecular Medicine. Springer Nature. https://doi.org/10.1038/s12276-018-0129-7' chicago: 'Tarlungeanu, Dora-Clara, and Gaia Novarino. “Genomics in Neurodevelopmental Disorders: An Avenue to Personalized Medicine.” Experimental & Molecular Medicine. Springer Nature, 2018. https://doi.org/10.1038/s12276-018-0129-7.' ieee: 'D.-C. Tarlungeanu and G. Novarino, “Genomics in neurodevelopmental disorders: an avenue to personalized medicine,” Experimental & Molecular Medicine, vol. 50, no. 8. Springer Nature, 2018.' ista: 'Tarlungeanu D-C, Novarino G. 2018. Genomics in neurodevelopmental disorders: an avenue to personalized medicine. Experimental & Molecular Medicine. 50(8), 100.' mla: 'Tarlungeanu, Dora-Clara, and Gaia Novarino. “Genomics in Neurodevelopmental Disorders: An Avenue to Personalized Medicine.” Experimental & Molecular Medicine, vol. 50, no. 8, 100, Springer Nature, 2018, doi:10.1038/s12276-018-0129-7.' short: D.-C. Tarlungeanu, G. Novarino, Experimental & Molecular Medicine 50 (2018). date_created: 2019-01-27T22:59:11Z date_published: 2018-08-07T00:00:00Z date_updated: 2023-09-11T14:04:41Z day: '07' ddc: - '570' department: - _id: GaNo doi: 10.1038/s12276-018-0129-7 external_id: isi: - '000441266700006' pmid: - '30089840' file: - access_level: open_access checksum: 4498301c8c53097c9a1a8ef990936eb5 content_type: application/pdf creator: dernst date_created: 2019-01-28T15:18:02Z date_updated: 2020-07-14T12:47:13Z file_id: '5893' file_name: 2018_EMM_Tarlungeanu.pdf file_size: 1237482 relation: main_file file_date_updated: 2020-07-14T12:47:13Z has_accepted_license: '1' intvolume: ' 50' isi: 1 issue: '8' language: - iso: eng license: https://creativecommons.org/licenses/by/4.0/ month: '08' oa: 1 oa_version: Published Version pmid: 1 publication: Experimental & Molecular Medicine publication_identifier: issn: - 2092-6413 publication_status: published publisher: Springer Nature quality_controlled: '1' scopus_import: '1' status: public title: 'Genomics in neurodevelopmental disorders: an avenue to personalized medicine' tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 50 year: '2018' ... --- _id: '546' abstract: - lang: eng text: The precise control of neural stem cell (NSC) proliferation and differentiation is crucial for the development and function of the human brain. Here, we review the emerging links between the alteration of embryonic and adult neurogenesis and the etiology of neuropsychiatric disorders (NPDs) such as autism spectrum disorders (ASDs) and schizophrenia (SCZ), as well as the advances in stem cell-based modeling and the novel therapeutic targets derived from these studies. article_processing_charge: No author: - first_name: Roberto full_name: Sacco, Roberto id: 42C9F57E-F248-11E8-B48F-1D18A9856A87 last_name: Sacco - first_name: Emanuele full_name: Cacci, Emanuele last_name: Cacci - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: Sacco R, Cacci E, Novarino G. Neural stem cells in neuropsychiatric disorders. Current Opinion in Neurobiology. 2018;48(2):131-138. doi:10.1016/j.conb.2017.12.005 apa: Sacco, R., Cacci, E., & Novarino, G. (2018). Neural stem cells in neuropsychiatric disorders. Current Opinion in Neurobiology. Elsevier. https://doi.org/10.1016/j.conb.2017.12.005 chicago: Sacco, Roberto, Emanuele Cacci, and Gaia Novarino. “Neural Stem Cells in Neuropsychiatric Disorders.” Current Opinion in Neurobiology. Elsevier, 2018. https://doi.org/10.1016/j.conb.2017.12.005. ieee: R. Sacco, E. Cacci, and G. Novarino, “Neural stem cells in neuropsychiatric disorders,” Current Opinion in Neurobiology, vol. 48, no. 2. Elsevier, pp. 131–138, 2018. ista: Sacco R, Cacci E, Novarino G. 2018. Neural stem cells in neuropsychiatric disorders. Current Opinion in Neurobiology. 48(2), 131–138. mla: Sacco, Roberto, et al. “Neural Stem Cells in Neuropsychiatric Disorders.” Current Opinion in Neurobiology, vol. 48, no. 2, Elsevier, 2018, pp. 131–38, doi:10.1016/j.conb.2017.12.005. short: R. Sacco, E. Cacci, G. Novarino, Current Opinion in Neurobiology 48 (2018) 131–138. date_created: 2018-12-11T11:47:06Z date_published: 2018-02-01T00:00:00Z date_updated: 2023-09-13T09:01:56Z day: '01' department: - _id: GaNo doi: 10.1016/j.conb.2017.12.005 external_id: isi: - '000427101600018' intvolume: ' 48' isi: 1 issue: '2' language: - iso: eng month: '02' oa_version: None page: 131 - 138 publication: Current Opinion in Neurobiology publication_status: published publisher: Elsevier publist_id: '7268' quality_controlled: '1' scopus_import: '1' status: public title: Neural stem cells in neuropsychiatric disorders type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 48 year: '2018' ... --- _id: '691' abstract: - lang: eng text: "Background: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain.\r\n\r\nObjective: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families.\r\n\r\nMethods: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease.\r\n\r\nResults: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold.\r\n\r\nConclusion: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function." article_processing_charge: No article_type: original author: - first_name: Isaac full_name: Marin Valencia, Isaac last_name: Marin Valencia - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 - first_name: Anide full_name: Johansen, Anide last_name: Johansen - first_name: Başak full_name: Rosti, Başak last_name: Rosti - first_name: Mahmoud full_name: Issa, Mahmoud last_name: Issa - first_name: Damir full_name: Musaev, Damir last_name: Musaev - first_name: Gifty full_name: Bhat, Gifty last_name: Bhat - first_name: Eric full_name: Scott, Eric last_name: Scott - first_name: Jennifer full_name: Silhavy, Jennifer last_name: Silhavy - first_name: Valentina full_name: Stanley, Valentina last_name: Stanley - first_name: Rasim full_name: Rosti, Rasim last_name: Rosti - first_name: Jeremy full_name: Gleeson, Jeremy last_name: Gleeson - first_name: Farhad full_name: Imam, Farhad last_name: Imam - first_name: Maha full_name: Zaki, Maha last_name: Zaki - first_name: Joseph full_name: Gleeson, Joseph last_name: Gleeson citation: ama: Marin Valencia I, Novarino G, Johansen A, et al. A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features. Journal of Medical Genetics. 2018;55(1):48-54. doi:10.1136/jmedgenet-2017-104627 apa: Marin Valencia, I., Novarino, G., Johansen, A., Rosti, B., Issa, M., Musaev, D., … Gleeson, J. (2018). A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features. Journal of Medical Genetics. BMJ Publishing Group. https://doi.org/10.1136/jmedgenet-2017-104627 chicago: Marin Valencia, Isaac, Gaia Novarino, Anide Johansen, Başak Rosti, Mahmoud Issa, Damir Musaev, Gifty Bhat, et al. “A Homozygous Founder Mutation in TRAPPC6B Associates with a Neurodevelopmental Disorder Characterised by Microcephaly Epilepsy and Autistic Features.” Journal of Medical Genetics. BMJ Publishing Group, 2018. https://doi.org/10.1136/jmedgenet-2017-104627. ieee: I. Marin Valencia et al., “A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features,” Journal of Medical Genetics, vol. 55, no. 1. BMJ Publishing Group, pp. 48–54, 2018. ista: Marin Valencia I, Novarino G, Johansen A, Rosti B, Issa M, Musaev D, Bhat G, Scott E, Silhavy J, Stanley V, Rosti R, Gleeson J, Imam F, Zaki M, Gleeson J. 2018. A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features. Journal of Medical Genetics. 55(1), 48–54. mla: Marin Valencia, Isaac, et al. “A Homozygous Founder Mutation in TRAPPC6B Associates with a Neurodevelopmental Disorder Characterised by Microcephaly Epilepsy and Autistic Features.” Journal of Medical Genetics, vol. 55, no. 1, BMJ Publishing Group, 2018, pp. 48–54, doi:10.1136/jmedgenet-2017-104627. short: I. Marin Valencia, G. Novarino, A. Johansen, B. Rosti, M. Issa, D. Musaev, G. Bhat, E. Scott, J. Silhavy, V. Stanley, R. Rosti, J. Gleeson, F. Imam, M. Zaki, J. Gleeson, Journal of Medical Genetics 55 (2018) 48–54. date_created: 2018-12-11T11:47:57Z date_published: 2018-01-01T00:00:00Z date_updated: 2023-10-16T09:55:43Z day: '01' department: - _id: GaNo doi: 10.1136/jmedgenet-2017-104627 external_id: isi: - '000418199800007' pmid: - '28626029' intvolume: ' 55' isi: 1 issue: '1' language: - iso: eng main_file_link: - open_access: '1' url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056005/ month: '01' oa: 1 oa_version: Submitted Version page: 48 - 54 pmid: 1 project: - _id: 254BA948-B435-11E9-9278-68D0E5697425 grant_number: '401299' name: Probing development and reversibility of autism spectrum disorders publication: Journal of Medical Genetics publication_identifier: issn: - 0022-2593 publication_status: published publisher: BMJ Publishing Group publist_id: '7016' quality_controlled: '1' scopus_import: '1' status: public title: A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 55 year: '2018' ... --- _id: '395' abstract: - lang: eng text: 'Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders (e.g. autism spectrum disorder, intellectual disability, epilepsy) remains a great challenge. Recent advancements in geno mics, like whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that were discovered, the etiological variability and the heterogeneous phenotypic outcomes, the need for genotype -along with phenotype- based diagnosis of individual patients becomes a requisite. Driven by this rationale, in a previous study our group described mutations, identified via whole - exome sequencing, in the gene BCKDK – encoding for a key regulator of branched chain amin o acid (BCAA) catabolism - as a cause of ASD. Following up on the role of BCAAs, in the study described here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized mainly at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation and severe neurolo gical abnormalities. Additionally, deletion of Slc7a5 from the neural progenitor cell population leads to microcephaly. Interestingly, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Furthermore, whole - exome sequencing of patients diagnosed with neurological dis o r ders helped us identify several patients with autistic traits, microcephaly and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. In conclusion, our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for t he BCAA s in human bra in function. Together with r ecent studies (described in chapter two) that have successfully made the transition into clinical practice, our findings on the role of B CAAs might have a crucial impact on the development of novel individualized therapeutic strategies for ASD. ' acknowledged_ssus: - _id: PreCl - _id: EM-Fac - _id: Bio alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Dora-Clara full_name: Tarlungeanu, Dora-Clara id: 2ABCE612-F248-11E8-B48F-1D18A9856A87 last_name: Tarlungeanu citation: ama: Tarlungeanu D-C. The branched chain amino acids in autism spectrum disorders . 2018. doi:10.15479/AT:ISTA:th_992 apa: Tarlungeanu, D.-C. (2018). The branched chain amino acids in autism spectrum disorders . Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:th_992 chicago: Tarlungeanu, Dora-Clara. “The Branched Chain Amino Acids in Autism Spectrum Disorders .” Institute of Science and Technology Austria, 2018. https://doi.org/10.15479/AT:ISTA:th_992. ieee: D.-C. Tarlungeanu, “The branched chain amino acids in autism spectrum disorders ,” Institute of Science and Technology Austria, 2018. ista: Tarlungeanu D-C. 2018. The branched chain amino acids in autism spectrum disorders . Institute of Science and Technology Austria. mla: Tarlungeanu, Dora-Clara. The Branched Chain Amino Acids in Autism Spectrum Disorders . Institute of Science and Technology Austria, 2018, doi:10.15479/AT:ISTA:th_992. short: D.-C. Tarlungeanu, The Branched Chain Amino Acids in Autism Spectrum Disorders , Institute of Science and Technology Austria, 2018. date_created: 2018-12-11T11:46:14Z date_published: 2018-03-01T00:00:00Z date_updated: 2023-09-07T12:38:59Z day: '01' ddc: - '570' - '616' degree_awarded: PhD department: - _id: GaNo doi: 10.15479/AT:ISTA:th_992 file: - access_level: closed checksum: 9f5231c96e0ad945040841a8630232da content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: dernst date_created: 2019-04-05T09:19:17Z date_updated: 2021-02-11T23:30:15Z embargo_to: open_access file_id: '6217' file_name: 2018_Thesis_Tarlungeanu_source.docx file_size: 43684035 relation: source_file - access_level: open_access checksum: 0c33c370aa2010df5c552db57a6d01e9 content_type: application/pdf creator: dernst date_created: 2019-04-05T09:19:17Z date_updated: 2021-02-11T11:17:16Z embargo: 2018-03-15 file_id: '6218' file_name: 2018_Thesis_Tarlungeanu.pdf file_size: 30511532 relation: main_file file_date_updated: 2021-02-11T23:30:15Z has_accepted_license: '1' language: - iso: eng month: '03' oa: 1 oa_version: Published Version page: '88' project: - _id: 25473368-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: F03523 name: Transmembrane Transporters in Health and Disease publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria publist_id: '7434' pubrep_id: '992' related_material: record: - id: '1183' relation: part_of_dissertation status: public status: public supervisor: - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 title: 'The branched chain amino acids in autism spectrum disorders ' tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2018' ...