| 1. |
- Decout, A, et al.
(author)
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Deciphering the molecular basis of mycobacteria and lipoglycan recognition by the C-type lectin Dectin-2
- 2018
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 16840-
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Journal article (peer-reviewed)abstract
- Dectin-2 is a C-type lectin involved in the recognition of several pathogens such as Aspergillus fumigatus, Candida albicans, Schistosoma mansonii, and Mycobacterium tuberculosis that triggers Th17 immune responses. Identifying pathogen ligands and understanding the molecular basis of their recognition is one of the current challenges. Purified M. tuberculosis mannose-capped lipoarabinomannan (ManLAM) was shown to induce signaling via Dectin-2, an activity that requires the (α1 → 2)-linked mannosides forming the caps. Here, using isogenic M. tuberculosis mutant strains, we demonstrate that ManLAM is a bona fide and actually the sole ligand mediating bacilli recognition by Dectin-2, although M. tuberculosis produces a variety of cell envelope mannoconjugates, such as phosphatidyl-myo-inositol hexamannosides, lipomannan or manno(lipo)proteins, that bear (α1 → 2)-linked mannosides. In addition, we found that Dectin-2 can recognize lipoglycans from other bacterial species, such as Saccharotrix aerocolonigenes or the human opportunistic pathogen Tsukamurella paurometabola, suggesting that lipoglycans are prototypical Dectin-2 ligands. Finally, from a structure/function relationship perspective, we show, using lipoglycan variants and synthetic mannodendrimers, that dimannoside caps and multivalent interaction are required for ligand binding to and signaling via Dectin-2. Better understanding of the molecular basis of ligand recognition by Dectin-2 will pave the way for the rational design of potent adjuvants targeting this receptor.
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| 2. |
- Guerster, M., et al.
(author)
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Permanent crewed Mars base by 2030 - Outcomes of an interdisciplinary, multinational student workshop
- 2018
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In: Proceedings of the International Astronautical Congress, IAC 2018. - : International Astronautical Federation, IAF.
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Conference paper (peer-reviewed)abstract
- Indisputably, we live at the dawn of a novel space exploration era, with the space sector undergoing significant changes. The International Space Station (ISS) is nearing the end of its lifespan and a competitive space industry is emerging. It is characterised by an ongoing redistribution of responsibilities between government agencies and private enterprise, with all stakeholders setting ambitious goals for future missions. Recently, interest in the next crewed space exploration mission has grown continuously. Driven by these developments, the Space Station Design Workshop (SSDW) 2017 in Stuttgart, Germany, posed the challenge to conduct the preliminary analysis and develop a viable proposal for the establishment of a permanent crewed space station in the vicinity of Mars by the year 2030. Two multinational, interdisciplinary teams of twenty students each were given one week to develop their own solutions and present them to experts from industry and academia. The authors, Team Blue, have outlined a design for a Mars surface station, called HUMANS2MARS. This proposal requires the development of mission-specific modules, while the launchers to be used include the foreseen state-of-the-art at the late 2020s, such as the Space Launch System from NASA and Falcon Heavy from SpaceX. Designing such a mission from scratch in one week posed great challenges, either innate in the technical and programmatic difficulties of the mission, or resulting from the time constraints and group dynamics of the project. The main technical challenges can be grouped into two sets. The first includes those related to mass and payload limitations of the mission and launching costs. The second consists of those related to the human element of the mission. Due to the hostile Martian environment, like the extreme radiation levels during transit and unexplored psychological pressure on the crew, the complexities associated with humans introduce significant uncertainties. Potential solutions to the problems discovered have been proposed and are presented in this paper - within the framework of a multicultural and interdisciplinary workshop. The major risks of the proposed mission are identified and possible mitigation strategies and backup scenarios are discussed, thus providing a starting point for future research and detailed studies. The complexity of the mission and nature of the SSDW require addressing a great variety of challenges under severe time constraints. A crucial factor in the success of this effort has been the multidisciplinary and diverse academic background of the participants. This enabled the team to overcome these numerous obstacles in often unconventional ways.
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| 3. |
- Torrino, S., et al.
(author)
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UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling
- 2021
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In: Elife. - 2050-084X. ; 10
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Journal article (peer-reviewed)abstract
- To adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that ubiquitin domain-containing protein 1 (UBTD1) plays a crucial role in both the epidermal growth factor receptor (EGFR) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through N-acylsphingosine amidohydrolase 1 (ASAH1) ubiquitination, UBTD1 controls the ligand-independent phosphorylation of EGFR. On the other hand, UBTD1, via the ubiquitination of Sequestosome 1 (SQSTM1/p62) by RNF26 and endolysosome positioning, participates in the lysosomal degradation of EGFR. The coordination of these two ubiquitin-dependent processes contributes to the control of the duration of the EGFR signal. Moreover, we showed that UBTD1 depletion exacerbates EGFR signaling and induces cell proliferation emphasizing a hitherto unknown function of UBTD1 in EGFR-driven human cell proliferation.
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| 4. |
- Nava, C, et al.
(author)
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Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.
- 2012
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 2
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Journal article (peer-reviewed)abstract
- The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.
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