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| 3. |
- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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| 4. |
- Tabiri, S, et al.
(author)
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- 2021
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swepub:Mat__t
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| 5. |
- Glasbey, JC, et al.
(author)
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- 2021
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swepub:Mat__t
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| 9. |
- Bellavia, D, et al.
(author)
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Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis
- 2002
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 99:6, s. 3788-3793
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Journal article (peer-reviewed)abstract
- Notch receptors are conserved regulators of cell fate and have been implicated in the regulation of T cell differentiation and lymphomagenesis. However, neither the generality of Notch involvement in leukemia, nor the molecules with which Notch may interact have been clarified. Recently, we showed that transgenic mice expressing the constitutively active intracellular domain of Notch3 in thymocytes and T cells developed early and aggressive T cell neoplasias. Although primarily splenic, the tumors sustained features of immature thymocytes, including expression of pTα, a defining component of the pre T cell receptor, known to be a potent signaling complex provoking thymocyte survival, proliferation, and activation. Thus, enforced expression of Notch3, which is ordinarily down-regulated as thymocytes mature, may sustain pre T cell receptor expression, causing dysregulated hyperplasia. This hypothesis has been successfully tested in this article by the observation that deletion of pTα in Notch3 transgenic mice abrogates tumor development, indicating a crucial role for pTα in T cell leukemogenesis. Parallel observations were made in humans, in that all T cell acute lymphoblastic leukemias examined showed expression of Notch3 and of the Notch target gene HES-1, as well as of pTα a and b transcripts, whereas the expression of all these genes was dramatically reduced or absent in remission. Together, these results suggest that the combined expression of Notch3 and pTα sustains T cell leukemogenesis and may represent pathognomonic molecular features of human T-ALL.
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| 12. |
- Frati, G., et al.
(author)
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Human iPSC-based models highlight defective glial and neuronal differentiation from neural progenitor cells in metachromatic leukodystrophy
- 2018
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In: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9
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Journal article (peer-reviewed)abstract
- The pathological cascade leading from primary storage to neural cell dysfunction and death in metachromatic leukodystrophy (MLD) has been poorly elucidated in human-derived neural cell systems. In the present study, we have modeled the progression of pathological events during the differentiation of patient-specific iPSCs to neuroepithelial progenitor cells (iPSC-NPCs) and mature neurons, astrocytes, and oligodendrocytes at the morphological, molecular, and biochemical level. We showed significant sulfatide accumulation and altered sulfatide composition during the differentiation of MLD iPSC-NPCs into neuronal and glial cells. Changes in sulfatide levels and composition were accompanied by the expansion of the lysosomal compartment, oxidative stress, and apoptosis. The neuronal and glial differentiation capacity of MLD iPSC-NPCs was significantly impaired. We showed delayed appearance and/or reduced levels of oligodendroglial and astroglial markers as well as reduced number of neurons and disorganized neuronal network. Restoration of a functional Arylsulfatase A (ARSA) enzyme in MLD cells using lentiviral-mediated gene transfer normalized sulfatide levels and composition, globally rescuing the pathological phenotype. Our study points to MLD iPSC-derived neural progeny as a useful in vitro model to assess the impact of ARSA deficiency along NPC differentiation into neurons and glial cells. In addition, iPSC-derived neural cultures allowed testing the impact of ARSA reconstitution/overexpression on disease correction and, importantly, on the biology and functional features of human NPCs, with important therapeutic implications.
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| 13. |
- Goknil, A., et al.
(author)
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Analysis support for TADL2 timing constraints on EAST-ADL models
- 2013
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In: Lecture Notes in Computer Science, vol. 7957. - Berlin, Heidelberg : Springer. - 9783642390302 ; , s. 89-105
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Book chapter (peer-reviewed)abstract
- It is critical to analyze characteristics of real-time embedded systems, such as timing behavior, early in the development. In the automotive domain, EAST-ADL is a concrete example of the model-based approach for the architectural modeling of real-time systems. The Timing Augmented Description Language v2 (TADL2) allows for the specification of timing constraints on top of EAST-ADL models. In this paper we propose a formal validation & verification methodology for timing behaviors given with TADL2. The formal semantics of the timing constraints is given as a mapping to the Clock Constraint Specification Language (CCSL), a formal language that implements the MARTE Time Model. Based on such a mapping, the validation is carried out by the simulation of TADL2 specifications. The simulation allows for a rapid prototyping of TADL2 specifications. The verification is performed based on a TADL2 mapping to timed automata modeling using the Uppaal model-checker. The whole process is illustrated on a Brake-By-Wire application.
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| 14. |
- Peraldi-Frati, M.-A., et al.
(author)
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A timing model for specifying multi clock automotive systems: The timing augmented description language V2
- 2012
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In: Proceedings - 2012 IEEE 17th International Conference on Engineering of Complex Computer Systems, ICECCS 2012, Paris;18 July 2012 through20 July 2012. ; :Article number 06299218, s. 230-239
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Conference paper (peer-reviewed)abstract
- Precise timing constraint modeling and analysis is a key point for the correct development of automotive electronics. EAST-ADL and AUTOSAR has been adopted as standards in automotive industry. These standards have recently adopted TADL (Time Augmented Description Language), a timing model for expressing timing constraints. Its current use highlighted different issues, mainly concerning the integration of parameterized multi rate and multi-clock systems. This paper presents new extensions, aligned on AUTOSAR and EAST-ADL, to solve these issues: a support for symbolic timing expression including multi time base description and complex timing constraints. These extensions are applicable at different abstraction levels during design and enable precise modeling of the multi clock characteristics of distributed systems together with parameterized timing expressions. This work has been conducted in the ITEA TIMMO-2-USE project.
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| 19. |
- Tykesson, Emil, et al.
(author)
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Dermatan sulfate epimerase 1 and dermatan 4-O-sulfotransferase 1 form complexes that generate long epimerized 4-O-sulfated blocks
- 2018
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In: Journal of Biological Chemistry. - 0021-9258. ; 293:35, s. 13725-13735
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Journal article (peer-reviewed)abstract
- During the biosynthesis of chondroitin/dermatan sulfate (CS/ DS), a variable fraction of glucuronic acid is converted to iduronic acid through the activities of two epimerases, dermatan sulfate epimerases 1 (DS-epi1) and 2 (DS-epi2). Previous in vitro studies indicated that without association with other enzymes, DS-epi1 activity produces structures that have only a few adjacent iduronic acid units. In vivo, concomitant with epimerization, dermatan 4-O-sulfotransferase 1 (D4ST1) sulfates the GalNAc adjacent to iduronic acid. This sulfation facilitates DS-epi1 activity and enables the formation of long blocks of sulfated iduronic acid– containing domains, which can be major components of CS/DS. In this report, we used recombinant enzymes to confirm the concerted action of DS-epi1 and D4ST1. Confocal microscopy revealed that these two enzymes colocalize to the Golgi, and FRET experiments indicated that they physically interact. Furthermore, FRET, immunoprecipitation, and cross-linking experiments also revealed that DS-epi1, DS-epi2, and D4ST1 form homomers and are all part of a hetero-oligomeric complex where D4ST1 directly interacts with DS-epi1, but not with DS-epi2. The cooperation of DS-epi1 with D4ST1 may therefore explain the processive mode of the formation of iduronic acid blocks. In conclusion, the iduronic acid–forming enzymes operate in complexes, similar to other enzymes active in glycosaminoglycan biosynthesis. This knowledge shed light on regulatory mechanisms controlling the biosynthesis of the structurally diverse CS/DS molecule.
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