Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority ...being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines derived from blood or patient-specific induced pluripotent stem cells (iPSCS). Therefore, the transcriptional and regulatory architecture of the nervous system, particularly during early developmental periods, remains highly incomplete. To access the critical disturbances that may have occurred during pregnancy or early childhood, we recently isolated stem cells from the nasal cavity of anesthetized patients diagnosed for ASD and compared them to stem cells from gender-matched control individuals without neuropsychiatric disorders. This allowed us to discover MOCOS, a non-mutated molybdenum cofactor sulfurase-coding gene that was under-expressed in the stem cells of most ASD patients of our cohort, disturbing redox homeostasis and synaptogenesis. We now report that a divergent transcription upstream of MOCOS generates an antisense long noncoding RNA, to which we coined the name COSMOC. Surprisingly, COSMOC is strongly under-expressed in all ASD patients of our cohort with the exception of a patient affected by Asperger syndrome. Knockdown studies indicate that loss of COSMOC reduces MOCOS expression, destabilizes lipid and energy metabolisms of stem cells, but also affects neuronal maturation and splicing of synaptic genes. Impaired expression of the COSMOC/MOCOS bidirectional unit might shed new lights on the origins of ASD that could be of importance for future translational studies.
We developed a new approach to prepare DNA probes for electrophoretic mobility gel shift assays that presents a number of advantages compared with the classical approach. The method relies on two ...complementary oligonucleotides containing the desired transcription factor binding sequence, one of them being extended at its 3′ end with a universal tail that complements a third, short oligonucleotide labeled with a fluorophore or any other label. The use of this third "universal" oligonucleotide allows labeling many different probes with minimal time, effort and cost. We show that probes prepared this way are as effective and reliable as probes prepared by conventional methods. We refer to this short oligonucleotide as LUEGO for labeled universal electrophoretic gel shift oligonucleotide.
This article studies the building of a successful open source project for the public sector, named CommunesPlones. It proposes an original institutional arrangement to onboard different users as an ...alternative to the classic free/libre and open source software (FLOSS) projects.
Twitter vient d’être racheté par Elon Musk, pour 44 milliards de dollars. Cela illustre la valeur économique énorme de cette plateforme, et de façon plus général, notre dépendance à de grandes ...plateformes privées quand il s’agit de la diffusion d’informations, et notamment d’informations entre individus. C’est dire si l’ouvrage de Godefroy Dang Nguyen, paru cet été aux Presses universitaires de Rennes, est précieux : il se propose justement d’expliquer le fonctionnement de ces plateformes nu...
LHX4 is a LIM homeodomain transcription factor involved in the early steps of pituitary ontogenesis. To date, 8 heterozygous LHX4 mutations have been reported as responsible of combined pituitary ...hormone deficiency (CPHD) in Humans. We identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. Our objective was to determine the role of LHX4 variants in patients' phenotypes. Heterologous HEK293T cells were transfected with plasmids encoding for wild-type or mutant LHX4. Protein expression was analysed by Western Blot, and DNA binding by electro-mobility shift assay experiments. Target promoters of LHX4 were cotransfected with wild type or mutant LHX4 to test the transactivating abilities of each variant. Our results show that the W204X mutation was associated with early GH and TSH deficiencies and later onset ACTH deficiency. It led to a truncated protein unable to bind to alpha-Gsu promoter binding consensus sequence. W204X was not able to activate target promoters in vitro. Cotransfection experiments did not favour a dominant negative effect. In contrast, all other mutants were able to bind the promoters and led to an activation similar as that observed with wild type LHX4, suggesting that they were likely polymorphisms. To conclude, our study underlines the need for functional in vitro studies to ascertain the role of rare allelic variants of LHX4 in disease phenotypes. It supports the causative role of the W204X mutation in CPHD and adds up childhood onset ACTH deficiency to the clinical spectrum of the various phenotypes related to LHX4 mutations.
L’économie de la science et des revues scientifiques est complexe. Pour mieux comprendre les trajectoires de basculement vers les publications ouvertes, cet article propose de décrire leur « modèle ...économique » et ce qu’Internet a changé. Après un rapide rappel des questions soulevées par l’accès ouvert, nous proposons d’étudier la revue scientifique comme un « commun de connaissance ». Cela nous fournit un cadre afin de structurer les enjeux pour chaque acteur de la revue, et ainsi de décrire les différents types de revues scientifiques existantes, autour de l’adéquation format-lectorat d’une part et système de validation scientifique d’autre part. Selon les modèles, le format d’accès ouvert peut varier, mais l’enjeu global est plus au niveau de l’accès aux bases de données d’articles (comme données ouvertes), que sur l’évolution du fonctionnement des revues scientifiques.
To test the role of wtPIT-1 (PITWT) or PIT-1 (R271W) (PIT271) in somatolactotroph cells, we established, using inducible lentiviral vectors, sublines of GH4C1 somatotroph cells that allow the ...blockade of the expression of endogenous PIT-1 and/or the expression of PITWT or PIT271, a dominant negative mutant of PIT-1 responsible for Combined Pituitary Hormone Deficiency in patients. Blocking expression of endogenous PIT-1 induced a marked decrease of cell proliferation. Overexpressing PITWT twofold led also to a dose-dependent decrease of cell proliferation that was accompanied by cell death. Expression of PIT271 induced a strong dose-dependent decrease of cell proliferation accompanied by a very pronounced cell death. These actions of PIT271 are independent of its interaction/competition with endogenous PIT-1, as they were unchanged when expression of endogenous PIT-1 was blocked. All these actions are specific for somatolactotroph cells, and could not be observed in heterologous cells. Cell death induced by PITWT or by PIT271 was accompanied by DNA fragmentation, but was not inhibited by inhibitors of caspases, autophagy or necrosis, suggesting that this cell death is a caspase-independent apoptosis. Altogether, our results indicate that under normal conditions PIT-1 is important for the maintenance of cell proliferation, while when expressed at supra-normal levels it induces cell death. Through this dual action, PIT-1 may play a role in the expansion/regression cycles of pituitary lactotroph population during and after lactation. Our results also demonstrate that the so-called "dominant-negative" action of PIT271 is independent of its competition with PIT-1 or a blockade of the actions of the latter, and are actions specific to this mutant variant of PIT-1.
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