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| 2. |
- Becker, M, et al.
(författare)
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Presynaptic dysfunction in CASK-related neurodevelopmental disorders
- 2020
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1, s. 312-
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Tidskriftsartikel (refereegranskat)abstract
- CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory–inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.
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| 5. |
- Jensen, Lasse, et al.
(författare)
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Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of beta-Catenin Signaling
- 2019
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : LIPPINCOTT WILLIAMS & WILKINS. - 1079-5642 .- 1524-4636. ; 39:7, s. 1432-1447
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Tidskriftsartikel (refereegranskat)abstract
- Objective- The Wnt/beta-catenin pathway orchestrates development of the blood-brain barrier, but the downstream mechanisms involved at different developmental windows and in different central nervous system (CNS) tissues have remained elusive. Approach and Results- Here, we create a new mouse model allowing spatiotemporal investigations of Wnt/beta-catenin signaling by induced overexpression of Axin1, an inhibitor of beta-catenin signaling, specifically in endothelial cells (Axin1(iEC)-(OE)). AOE (Axin1 overexpression) in Axin1(iEC)-(OE) mice at stages following the initial vascular invasion of the CNS did not impair angiogenesis but led to premature vascular regression followed by progressive dilation and inhibition of vascular maturation resulting in forebrain-specific hemorrhage 4 days post-AOE. Analysis of the temporal Wnt/beta-catenin driven CNS vascular development in zebrafish also suggested that Axin1(iEC)-(OE) led to CNS vascular regression and impaired maturation but not inhibition of ongoing angiogenesis within the CNS. Transcriptomic profiling of isolated, beta-catenin signaling-deficient endothelial cells during early blood-brain barrier-development (E11.5) revealed ECM (extracellular matrix) proteins as one of the most severely deregulated clusters. Among the 20 genes constituting the forebrain endothelial cell-specific response signature, 8 (Adamtsl2, Apod, Ctsw, Htra3, Pglyrp1, Spock2, Ttyh2, and Wfdc1) encoded bona fide ECM proteins. This specific beta-catenin-responsive ECM signature was also repressed in Axin1(iEC)-(OE) and endothelial cell-specific beta-catenin-knockout mice (Ctnnb1-KOiEC) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/beta-catenin signaling in orchestrating the development of the forebrain vascular ECM. Conclusions- These results suggest a novel mechanism of establishing a CNS endothelium-specific ECM signature downstream of Wnt-beta-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development.
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| 7. |
- Osman, Ahmed M., et al.
(författare)
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Radiation Triggers a Dynamic Sequence of Transient Microglial Alterations in Juvenile Brain
- 2020
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Ingår i: Cell Reports. - : CELL PRESS. - 2211-1247. ; 31:9
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Tidskriftsartikel (refereegranskat)abstract
- Cranial irradiation (IR), an effective tool to treat malignant brain tumors, triggers a chronic pro-inflammatory microglial response, at least in the adult brain. Using single-cell and bulk RNA sequencing, combined with histology, we show that the microglial response in the juvenile mouse hippocampus is rapid but returns toward normal within 1 week. The response is characterized by a series of temporally distinct homeostasis-, sensome-, and inflammation-related molecular signatures. We find that a single microglial cell simultaneously upregulates transcripts associated with pro- and anti-inflammatory microglial phenotypes. Finally, we show that juvenile and adult irradiated microglia are already transcriptionally distinct in the early phase after IR. Our results indicate that microglia are involved in the initial stages but may not be responsible for driving long-term inflammation in the juvenile brain.
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| 9. |
- Di Martino, Elena, et al.
(författare)
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Inflammatory, metabolic, and sex-dependent gene-regulatory dynamics of microglia and macrophages in neonatal hippocampus after hypoxia-ischemia
- 2024
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Ingår i: iScience. - : CELL PRESS. - 2589-0042. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- Neonatal hypoxia-ischemia (HI) is a major cause of perinatal death and long-term disabilities worldwide. in the hippocampi of mice subjected to HI at postnatal day 9. Using inflammatory pathway and transcripcells isolated from hippocampi showed a partial convergence. Interestingly, microglia-specific genes in but not in females during the experimental time frame. These results highlight the importance of further investigations on metabolic rewiring to pave the way for future interventions in asphyxiated neonates.
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| 10. |
- Drouin-Ouellet, Janelle, et al.
(författare)
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Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson's disease
- 2022
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 17:10, s. 2203-2219
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Tidskriftsartikel (refereegranskat)abstract
- We have developed an efficient approach to generate functional induced dopaminergic (DA) neurons from adult human dermal fibroblasts. When performing DA neuronal conversion of patient fibroblasts with idiopathic Parkinson's disease (PD), we could specifically detect disease-relevant pathology in these cells. We show that the patient-derived neurons maintain age-related properties of the donor and exhibit lower basal chaperone-mediated autophagy compared with healthy donors. Furthermore, stress-induced autophagy resulted in an age-dependent accumulation of macroautophagic structures. Finally, we show that these impairments in patient-derived DA neurons leads to an accumulation of phosphorylated alpha-synuclein, the classical hallmark of PD pathology. This pathological phenotype is absent in neurons generated from induced pluripotent stem cells from the same patients. Taken together, our results show that direct neural reprogramming can be used for obtaining patient-derived DA neurons, which uniquely function as a cellular model to study age-related pathology relevant to idiopathic PD.
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| 12. |
- Friederici, Anke, 1994-, et al.
(författare)
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A lagrangian method for extracting eddy boundaries in the red sea and the gulf of aden
- 2018
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Ingår i: 2018 IEEE Scientific Visualization Conference, SciVis 2018 - Proceedings. - : Institute of Electrical and Electronics Engineers (IEEE). - 9781538668825 ; , s. 52-56
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Konferensbidrag (refereegranskat)abstract
- Mesoscale ocean eddies play a major role for both the intermixing of water and the transport of biological mass. This makes the identification and tracking of their shape, location and deformation over time highly important for a number of applications. While eddies maintain a roughly circular shape in the free ocean, the narrow basins of the Red Sea and Gulf of Aden lead to the formation of irregular eddy shapes that existing methods struggle to identify. We propose the following model: Inside an eddy, particles rotate around a common core and thereby remain at a constant distance under a certain parametrization. The transition to the more unpredictable flow on the outside can thus be identified as the eddy boundary. We apply this algorithm on a realistic simulation of the Red Sea circulation, where we are able to identify the shape of irregular eddies robustly and more coherently than previous methods. We visualize the eddies as tubes in space-time to enable the analysis of their movement and deformation over several weeks.
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| 13. |
- Kele-Olovsson, Julianna M V
(författare)
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Regulation of midbrain dopaminergic neuron development by Wnts, sFRPs and bHLH proteins
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) is a chronic neurodegenerative disorder. The main pathology is characterized by progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra leading to loss of striatal dopamine innervation. The knowledge about the fundamental mechanisms behind the degenerative process has been limited. During recent years a promising approach is evolving based on DA cell replacement therapy. However, in order to find a cure for PD an increased understanding is required about the intrinsic and extrinsic signals involved in the development of DA progenitor cells during embryogenesis. This thesis identifies novel players in midbrain development and investigates the mechanisms by which three major signaling modulators, Wnts, soluble Frizzled Related Proteins (sFRPs) and basic-Helix-Loop-Helix (bHLH) family of proteins, regulate DA neuron development. Proneural genes belong to the bHLH family of transcription factors and are crucial regulators of neurogenesis and subtype specification in many areas of the nervous system. Their function in DA neuron development has been unknown. In this thesis it is reported that the proneural genes Neurogenin2 (Ngn2) and Mash1 have an intricate pattern of expression in the ventricular zone (VZ) of the ventral midbrain (vMB), where DA neurons are generated. To examine the function of these genes, mice were analyzed in which one or two of these genes were deleted (Ngn1,Ngn2 and Mash1) or substituted (Mash1 in the Ngn2 locus). Our results demonstrate that Ngn2 is required for the differentiation of Sox2+ VZ progenitors into Nurr1+ postmitotic DA neuron precursors in the intermediate zone (ImZ), and that it is also required for their subsequent differentiation into DA neurons in the marginal zone (MZ). Although Mash1 normally has no detectable function in DA neuron development, it could partially rescue the generation of DA neuron precursors in the absence of Ngn2. These results demonstrate that Ngn2 is uniquely required for the development of vMB DA neurons. The Wnt signaling pathway regulates several developmental processes in the mammalian CNS; neural patterning, cell fate determination, proliferation, differentiation, neuronal maturation, cell migration and axon guidance. Our results present evidence that Wnt-1, -3a, and -5a expression is differentially regulated during vMB development. Wnt-3a promoted the proliferation of precursor cells expressing the orphan nuclear receptor-related factor 1 (Nurr1) but did not increase the number of DA neurons. Conversely, Wnt-1 and -5a increased the number of rat vMB DA neurons in rat embryonic day 14.5 precursor cultures by two distinct mechanisms. Wnt-1 predominantly increased the proliferation of Nurr1-precursors. In contrast, Wnt-5a primarily increased the proportion of Nurr1 precursors that acquired a neuronal DA phenotype. These findings indicate that Wnts are key regulators of proliferation and differentiation of DA precursors during vMB neurogenesis and that different Wnts have specific and unique activity profiles. Furthermore temporal expression profiles of Wnt components during critical phases of MB development revealed Frizzled (Fz) 9, a Wnt receptor, to be highly expressed in DA progenitors but not in newborn DA neurons. A possible function of Fz9 during early MB development might be to regulate proliferation of DA progenitors and inhibit differentiation, since Fz9 reduced Wnt5a signaling in DA cells in vitro. Finally, we set to examine the function of sFRPs in the developing ventral midbrain. sFRPs are a secreted family of factors that sterically hinder the Wnt ligand-Fz receptor complex to form and thereby block the Wnt signling pathway. sFRP1-3, but not 4 were expressed in the developing vMB, during DA neurogenesis. We therefore examined whether sFRP1-3 could work as Wnt antagonists in a dopaminergic cell line. We found that high doses of sFRP1 and sFRP2, but not sFRP3, acted as competitive antagonists of Wnt signaling. Treatment of vMB precursor cultures with sFRP1 resulted in DA neuron cell death, an effect that is compatible with Wnt1 blocking. However, treatment with sFRP2 lead to increased proliferation of progenitors and increased number of DA neurons, an effect incompatible with a Wnt blocking activity. Analysis of the sFRP2-/- mice also suggested that sFRP2 does not block Wnt function. On the contrary, we found that sFRP2 is partially required for several sequential steps in DA neuron development, including DA neurogenesis, differentiation of DA precursors into neurons and neuritogenesis. Thus, our results unravel several novel functions of sFRPs and identify sFRP2 as a novel player in DA neuron development. In summary, these results presented identify several novel players in midbrain DA neuron development and reveal new functions of proneural bHLHs, Wnts and sFRPs, thereby extending our knowledge and identifying factors that may be used to develop novel DA cell replacement therapies for the treatment of PD.
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| 14. |
- Shen, J. X., et al.
(författare)
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Organotypic and Microphysiological Models of Liver, Gut, and Kidney for Studies of Drug Metabolism, Pharmacokinetics, and Toxicity
- 2020
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 33:1, s. 38-60
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Tidskriftsartikel (refereegranskat)abstract
- Despite extensive breakthroughs in chemistry, molecular biology, and genetics in the last decades, the success rates of drug development projects remain low. To improve predictions of clinical efficacy and safety of new compounds, a plethora of 3D culture methods of human cells have been developed in which the cultured cells retain physiologically and functionally relevant phenotypes for multiple weeks. Here, we critically review current paradigms for organotypic cultures of human liver, gut, and kidney such as perfused microchips, spheroids, and hollow fiber bioreactors and discuss their utility for understanding drug pharmacokinetics, metabolism, and toxicity. Furthermore, bioprinting and the microfluidic integration of different tissue models to mimic systemic drug effects are highlighted as promising technological trends. In the last part of the review, we discuss important considerations regarding the choice of culture substratum material to limit adverse effects such as drug absorption while facilitating the phenotypic maintenance of cultured cells. We conclude that recent advances in organotypic and microphysiological culture models of human tissues can improve drug development and contribute to an amelioration of clinical attrition rates. However, further validation, benchmarking, and consolidation efforts are needed to achieve more widespread dissemination and eventually regulatory acceptance of these novel tools.
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| 15. |
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| 17. |
- Újvári,, Gabor, et al.
(författare)
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Stadial-interstadial temperature variations in East Central Europe preceding the Last Glacial Maximum
- 2021
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Ingår i: Paleoceanography and Paleoclimatology. - : American Geophysical Union (AGU). - 2572-4517 .- 2572-4525. ; 36
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Tidskriftsartikel (refereegranskat)abstract
- Last glacial North Atlantic climate is characterized by abrupt, centennial-millennial scale climate oscillations, called Dansgaard-Oeschger (D-O) events. Understanding the cause and propagation of these D-O events into Eurasia is hampered by the scarcity of quantitative paleotemperature estimates from continental archives with precise, independent age models. Here, we present land snail shell carbonate clumped isotope-based active season paleotemperature estimates and δ13C/δ18O-based aridity reconstructions from Greenland stadial/interstadials (GS/GI) between 31 and 26.5 ka from the 14C-dated Dunaszekcső loess section (Hungary). This reconstruction is complemented with a new 230Th-dated flowstone stable isotope record covering 30-26 ka. Our snail shell clumped isotope (Δ47) data indicate growing season temperatures (GSTs) of 16°C–18°C and 7°C–14°C for the investigated interstadials and stadials, respectively. Stable carbon and oxygen stable isotope compositions of shells and flowstone calcite reveal milder interstadials with drier summers and more available moisture over the winter season, and colder stadials with annually/seasonally (winter) drier conditions, promoting increased loess/dust deposition. We propose that large-scale ocean-atmospheric variability, characterized by NAO phases, may have imparted a major control on transmitting abrupt North Atlantic climate event signals into continental Europe during the last glacial.
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