Co-Transplantation of Barcoded Lymphoid-Primed Multipotent (LMPP) and Common Lymphocyte (CLP) Progenitors Reveals a Major Contribution of LMPP to the Lymphoid Lineage.

T cells have the potential to maintain immunological memory and self-tolerance by recognizing antigens from pathogens or tumors. In pathological situations, failure to generate de novo T cells causes immunodeficiency resulting in acute infections and complications. Hematopoietic stem cells (HSC) transplantation constitutes a valuable option to restore proper immune function. However, delayed T cell reconstitution is observed compared to other lineages. To overcome this difficulty, we developed a new approach to identify populations with efficient lymphoid reconstitution properties. To this end, we use a DNA barcoding strategy based on the insertion into a cell chromosome of a lentivirus (LV) carrying a non-coding DNA fragment named barcode (BC). These will segregate through cell divisions and be present in cells' progeny. The remarkable characteristic of the method is that different cell types can be tracked simultaneously in the same mouse. Thus, we in vivo barcoded LMPP and CLP progenitors to test their ability to reconstitute the lymphoid lineage. Barcoded progenitors were co-grafted in immuno-compromised mice and their fate analyzed by evaluating the BC composition in transplanted mice. The results highlight the predominant role of LMPP progenitors for lymphoid generation and reveal valuable novel insights to be reconsidered in clinical transplantation assays.

Novel landscape of HLA-G isoforms expressed in clear cell renal cell carcinoma patients.

Immune checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. Human leukocyte antigen G (HLA-G), a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor-infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anticancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in-depth the HLA-G isoforms expressed in these tumors. We found that the expression of HLA-G is highly variable among tumors and distinct areas of the same tumor, testifying a marked inter- and intratumor heterogeneity. Moreover, our results generate an inventory of novel HLA-G isoforms which includes spliced forms that have an extended 5'-region and lack the transmembrane and alpha-1 domains. So far, these isoforms could not be detected by any method available and their assessment may improve the procedure by which tumors are analyzed. Collectively, our approach provides the first extensive portrait of HLA-G in ccRCC and reveals data that should prove suitable for the tailoring of future clinical applications.

The Circulation of Scientific Articles in the Sphere of Web-Based Media: Citation Practices, Communities of Interests and Local Ties.

On 5th December 2012, a scientific article reviewing a change in the feeding behaviour of the European catfish, one of the largest freshwater fish, was published in the American scientific journal, PLOS ONE, an open access journal, which also allows the mass publication of pictures and videos. Within a few days following the publication of this article, it was relayed by numerous web sites and generated a media craze. In this paper, we analyse the circulation of this scientific information in the sphere of Web-based media during the two months following its publication, by revealing the citation mechanisms of the original article and the logic of the Internet users participating in its diffusion. In addition, since the circulation of its informational content travelled beyond linguistic and geographical boundaries, we chose to compare the citation modalities and intertextual relationships of documents in the three countries where the article spread the most widely, namely: France, the United States and Great Britain. Even though our study shows that the media circulation of scientific papers operates in a traditional way, the intertextual analysis underlines the grand variety of participants (such as journalists, non-scientists, fishermen, technology enthusiasts and Internet users) involved in the diffusion of this information, each of them mobilizing different intertextual strategies, according to their various targets. They all transformed, reformulated and appropriated the scientific information according to their own, unique interests. This study also emphasizes the importance of journalistic websites as opinion relays. They were the first diffusers involved in spreading the information but this role was rarely acknowledged by the Internet users - through citations, for example. In contrast, we observed that amateurs' communities (communities of practices and communities of interest of fishermen or of buzz fans), which only became involved in a second temporal phase of the spreading, preferred to build up their credibility through citations of the original article. Finally, this research helps to rethink the mechanisms of the circulation of scientific information in the Web-based media, highlighting both the variety and the inventiveness of the interactions between the academic and public spheres.

Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.

OBJECTIVE: The aim of this study was to identify the causal gene in a consanguineous Moroccan family with temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy, previously mapped to the 6q16-q22 region. METHODS: We used exome sequencing and analyzed candidate variants in the 6q16-q22 locus, as well as a rescue assay in Fig4-null mouse fibroblasts and immunohistochemistry of Fig4-null mouse brains. RESULTS: A homozygous missense mutation (p.Asp783Val) in the phosphoinositide phosphatase gene FIG4 was identified. Pathogenicity of the variant was supported by impaired rescue of the enlarged vacuoles in transfected fibroblasts from Fig4-deficient mice. Histologic examination of Fig4-null mouse brain revealed neurodevelopmental impairment in the hippocampus, cortex, and cerebellum as well as impaired cerebellar gyration/foliation reminiscent of human cortical malformations. CONCLUSIONS: This study extends the spectrum of phenotypes associated with FIG4 mutations to include cortical malformation associated with seizures and psychiatric manifestations, in addition to the previously described Charcot-Marie-Tooth disease type 4J and Yunis-Varón syndrome.