HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development

In both mouse and human, Notch1 activation is the main initial driver to induce T-cell development in hematopoietic progenitor cells. The initiation of this developmental process coincides with Notch1-dependent repression of differentiation towards other hematopoietic lineages. Although well described in mice, the role of the individual Notch1 target genes during these hematopoietic developmental choices is still unclear in human, particularly for HES4 since no orthologous gene is present in the mouse. Here, we investigated the functional capacity of the Notch1 target genes HES1 and HES4 to modulate human Notch1-dependent hematopoietic lineage decisions and their requirement during early T-cell development. We show that both genes are upregulated in a Notch-dependent manner during early T-cell development and that HES1 acts as a repressor of differentiation by maintaining a quiescent stem cell signature in CD34(+) hematopoietic progenitor cells. While HES4 can also inhibit natural killer and myeloid cell development like HES1, it acts differently on the T- versus B-cell lineage choice. Surprisingly, HES4 is incapable of repressing B-cell development, the most sensitive hematopoietic lineage with respect to Notch-mediated repression. In contrast to HES1, HES4 promotes initiation of early T-cell development, but ectopic expression of HES4, or HES1 and HES4 combined, is insufficient to induce T-lineage differentiation. Importantly, knockdown of HES1 or HES4 significantly reduces human T-cell development. Overall, we show that the Notch1 target genes HES1 and HES4 have non-redundant roles during early human T-cell development which may relate to differences in mediating Notch-dependent human hematopoietic lineage decisions

Comparison of uniportal robotic-assisted thoracic surgery pulmonary anatomic resections with multiport robotic-assisted thoracic surgery: a multicenter study of the European experience

Background: Robotic-assisted thoracic surgery (RATS) has seen increasing interest in the last few years, with most procedures primarily being performed in the conventional multiport manner. Our team has developed a new approach that has the potential to convert surgeons from uniportal video-assisted thoracic surgery (VATS) or open surgery to robotic-assisted surgery, uniportal-RATS (U-RATS). We aimed to evaluate the outcomes of one single incision, uniportal robotic-assisted thoracic surgery (U-RATS) against standard multiport RATS (M-RATS) with regards to safety, feasibility, surgical technique, immediate oncological result, postoperative recovery, and 30-day follow-up morbidity and mortality. Methods: We performed a large retrospective multi-institutional review of our prospectively curated database, including 101 consecutive U-RATS procedures performed from September 2021 to October 2022, in the European centers that our main surgeon operates in. We compared these cases to 101 consecutive M-RATS cases done by our colleagues in Barcelona between 2019 to 2022. Results: Both patient groups were similar with respect to demographics, smoking status and tumor size, but were significantly younger in the U-RATS group [M-RATS =69 (range, 39-81) years; U-RATS =63 years (range, 19-82) years; P<0.0001]. Most patients in both operative groups underwent resection of a primary non-small cell lung cancer (NSCLC) [M-RATS 96/101 (95%); U-RATS =60/101 (59%); P<0.0001]. The main type of anatomic resection was lobectomy for the multiport group, and segmentectomy for the U-RATS group. In the M-RATS group, only one anatomical segmentectomy was performed, while the U-RATS group had twenty-four (24%) segmentectomies (P=0.0006). All M-RATS and U-RATS surgical specimens had negative resection margins (R0) and contained an equivalent median number of lymph nodes available for pathologic analysis [M-RATS =11 (range, 5-54); U-RATS =15 (range, 0-41); P=0.87]. Conversion rate to thoracotomy was zero in the U-RATS group and low in M-RATS [M-RATS =2/101 (2%); U-RATS =0/101; P=0.19]. Median operative time was also statistically different [M-RATS =150 (range, 60-300) minutes; U-RATS =136 (range, 30-308) minutes; P=0.0001]. Median length of stay was significantly lower in U-RATS group at four days [M-RATS =5 (range, 2-31) days; U-RATS =4 (range, 1-18) days; P<0.0001]. Rate of complications and 30-day mortality was low in both groups. Conclusions: U-RATS is feasible and safe for anatomic lung resections and comparable to the multiport conventional approach regarding surgical outcomes. Given the similarity of the technique to uniportal VATS, it presents the potential to convert minimally invasive thoracic surgeons to a robotic-assisted approach

A new astrometric reduction of photographic plates using the DAMIAN digitizer: improving the dynamics of the Jovian system

International audienceThe astrometric monitoring of the natural planetary satellites is an important step to assess the formation and the evolution of these systems. However, in order to quantify relevant gravitational effects such as tidal forces, it is necessary to have very accurate observations over a long time interval. Unfortunately, the accuracy is decreasing as one considers older observations. To solve this issue, digitizing of old photographic plates is an attractive method, but a high accuracy in the measurement and the reduction of those plates is absolutely necessary.We have developed methods and algorithms adapted to specific plates provided by USNO, using the DAMIAN digitizer of ROB. From a set of 35 plates taken in 1974, we have been able to produce measurements with an accuracy better than 0.08 μm and after reduction using the UCAC2 catalogue, rms residuals of 35 mas (1.7 μm) for intersatellite positions (when the original reduction provided 100 mas) and of 65 mas for equatorial RA and Dec. positions (which were not possible to get with the original reduction). First results on the dynamics of the satellites and of the planet Jupiter are provided

Distinct and temporary-restricted epigenetic mechanisms regulate human αβ and γδ T cell development

The epigenetic landscape of human alpha beta and gamma delta T cell development has remained unexplored thus far. Taghon and colleagues provide a resource of RNA-seq and ATAC-seq profiles examining human thymocyte development. The development of TCR alpha beta and TCR gamma delta T cells comprises a step-wise process in which regulatory events control differentiation and lineage outcome. To clarify these mechanisms, we employed RNA-sequencing, ATAC-sequencing and ChIPmentation on well-defined thymocyte subsets that represent the continuum of human T cell development. The chromatin accessibility dynamics show clear stage specificity and reveal that human T cell-lineage commitment is marked byGATA3- andBCL11B-dependent closing of PU.1 sites. A temporary increase in H3K27me3 without open chromatin modifications is unique for beta-selection, whereas emerging gamma delta T cells, which originate from common precursors of beta-selected cells, show large chromatin accessibility changes due to strong T cell receptor (TCR) signaling. Furthermore, we unravel distinct chromatin landscapes between CD4(+)and CD8(+)alpha beta-lineage cells that support their effector functions and reveal gene-specific mechanisms that define mature T cells. This resource provides a framework for studying gene regulatory mechanisms that drive normal and malignant human T cell development

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Comité scientifique Mathieu Avanzi, Université de Neuchâtel Christophe Benzitoun, Université de Lorraine Philippe Blache, Aix-Marseille Université, CNRS, LPL UMR 7309 José Deulofeu, Aix-Marseille Université Jean-Marc Dewaele, Birkbeck University of London Anne Dister, Université de Louvain Martine Faraco, Aix-Marseille Université, CNRS, LPL UMR 7309 Tsuyoshi Kida, Tsukuba University Thierry Legou, Aix-Marseille Université, CNRS, LPL UMR 7309 Marie-Noëlle Roubaud, Aix-Marseille Université Frédéric Sabio, Aix-Marseille Université, CNRS, LPL UMR 7309 Marion Tellier, Aix-Marseille Université, CNRS, LPL UMR 7309 Sylvie Wharton, Aix-Marseille Université, CNRS, LPL UMR 730