The Notch Delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of Haematopoietic Progenitor Cells through activation of a key gene network: Delta-4/Notch pathway retains the HPCs potential

International audienceUnderstanding the role of Notch and its ligands within the different bone marrow niches could shed light on the mechanisms regulating haematopoietic progenitor cells (HPCs) maintenance and self renewal. Here, we report that murine bone marrow HPCs activation by the vascular Notch Delta4 ligand maintains a significant proportion of cells specifically in the G0 state. Furthermore, Delta4/Notch pathway limits significantly the loss of the in vivo short-term reconstitutive potential upon transplantation of Delta-4 activated HPCs into lethally irradiated recipient mice. Both effects are directly correlated with the decrease of cell cycle genes transcription such as CYCLIN-D1, − D2, and -D3, and the upregulation of stemness related genes transcription such as BMI1, GATA2, HOXB4 and C-MYC. In addition, the transcriptional screening also highlights new downstream post-transcriptional factors, named PUMILIO1 and − 2, as part of the stem signature associated with the Delta4/Notch signalling pathway

Genetic Admixture and Flavor Preferences: Androstenone Sensitivity in Malagasy Populations

The genetic basis of androstenone anosmia has been well-studied due to androstenone’s putative role as a human sex pheromone and its presence in pork meat. Polymorphisms have been identified on the olfactory receptor gene OR7D4, which significantly affect perception of androstenone pleasantness and intensity in several western populations. This study aims to investigate androstenone sensitivity and the influence of OR7D4 polymorphisms in non-western populations. Androstenone perception was tested in 132 individuals from Madagascar using a double 3-Alternative Choice test with two concentrations of androstenone (0.17 μg/ml and 1.7 μg/ml). We found that Malagasy populations described this molecule in a similar way to European populations, and 21% of the sample was not able to smell androstenone. In contrast to previous studies, there was no significant evidence of the influence of rs61729907: C\u3eT (R88W) and rs5020278: C\u3eT polymorphisms (T133M) on androstenone sensitivity in Malagasy populations. We found, however, a significant effect of the polymorphism rs61732668 (P79L), and a significant difference in androstenone perception between populations in different locations across Madagascar. This study indicates the existence of population specific factors to androstenone sensitivity, suggesting that population history has a role in shaping an individual’s smell and flavor preferences, and food preferences in general

NAP1L1-MLLT10 is a rare recurrent translocation that is associated with HOXA activation and poor treatment response in T-cell acute lymphoblastic leukaemia

International audienceno abstrac

Clinical Study Characteristics and Determinants of Partial Remission in Children with Type 1 Diabetes Using the Insulin-Dose-Adjusted A1C Definition

To evaluate the characteristics and determinants of partial remission (PR) in Belgian children with type 1 diabetes (T1D), we analyzed records of 242 children from our center. Clinical and biological features were collected at diagnosis and during follow-up. PR was defined using the insulin-dose-adjusted A1C definition. PR occurred in 56.2% of patients and lasted 9.2 months (0.5 to 56.6). 25.6% of patients entered T1D with DKA, which correlated with lower PR incidence (17.6% versus 82.3% when no DKA). In our population, lower A1C levels at diagnosis were associated with higher PR incidence and in young children (0-4 years) initial A1C levels negatively correlated with longer PR. Early A1C levels were predictive of PR duration since 34% of patients had long PRs (>1 year) when A1C levels were ≤6% after 3 months whereas incidence of long PR decreased with higher A1Cs. C-peptide levels were higher in patients entering PR and remained higher until 3 years after diagnosis. Initial antibody titers did not influence PR except for anti-IA2 titers that correlated with A1C levels after 2 years. Presence of 2 versus 1 anti-islet antibodies correlated with shorter PR. PR duration did not influence occurrence of severe hypoglycemia or diabetes-related complications but was associated with lower A1C levels after 18 months. We show that, at diagnosis of T1D, parameters associated with -cell mass reserve (A1C, C-peptide, and DKA) correlate with the occurrence of PR, which affects post-PR A1C levels. Further research is needed to determine the long-term significance of PR

Un ensemble funéraire du Haut-Empire le long de la voie de l’Océan (Lyon 9e)

L’aire funéraire découverte au 30-32 rue de Bourgogne, dans la plaine de Vaise à Lyon, a été implantée le long de la voie de l’Océan, dont un tronçon a été mis au jour. La durée de l’occupation funéraire s’étend sur une période relativement courte : du début du Ier siècle ap. J.-C. jusqu’au début du IIe siècle. Cent quarante-cinq structures liées aux rituels funéraires ont été fouillées : dix-neuf bûchers en fosse avec ou sans vestiges osseux humains, soixante-dix-neuf dépôts de crémation mixte ou non, vingt-trois dépôts de résidus, vingt et une inhumations, une aire de crémation, un dépôt de céramique et un four.L’étude de la gestion des tombes dans l’espace démontre un désir de rapprocher certains défunts et exclut un phénomène d’éventuel empiétement induit par l’étroitesse de l’occupation par rapport à la voie. Au cours de son utilisation, l’accès à cet espace funéraire s’est restreint aux adultes et certains gestes se sont modifiés. Le prélèvement des restes osseux crémés sur le bûcher est de plus en plus faible au fil des années. Ce changement dans la collecte des restes du défunt est contemporain du développement du bûcher en fosse. La gestion de l’espace, les structures, les gestes et les rituels auxquels ils sont liés sont conformes à ceux observés sur les sites lyonnais contemporains. L’implantation de l’aire funéraire dans un contexte environnemental plutôt défavorable, probablement responsable de son abandon, est peut-être l’indice que l’installation des tombes dans ce secteur de Lyon était liée à une contrainte financière.The cemetery discovered at 30-32 rue de Bourgogne in the Vaise plain at Lyon was in fact located along the “Ocean” Roman Road, part of which has also been discovered. The funerary activity of the site lasted a relatively short period from the beginning of the 1st to the beginning of the 2nd century AD. 145 funerary structures were unearthed, including nineteen pyres in pits with or without human remains, seventy-nine cremation deposits (mixed or not), twenty-three deposits of cremation residues, twenty-one inhumations, a cremation area, a pottery deposit and an oven.This study reveals how the site was managed by the grouping of tombs, whilst avoiding any encroachment inferred by the narrowness of the site in relation to the road. During the site’s use, its access was restricted to adults and certain practices were progressively modified. The taking of bone remains from the funerary pyres becomes less prominent with time and this change coincides with the development of pit pyres. The site’s management, its structures, funerary practices and rituals are typical of what has been already observed on other sites in the Lyon area. The cemetery’s location in a somewhat unfavourable context is probably why it was abandoned and could also indicate that funerary sites in Lyon were subjected to some kind of tax.Das 30-32, rue de Bourgogne in der Ebene von Vaise in Lyon entdeckte Grabareal zog sich entlang der auf einem Teilstück freigelegten Ozean-Straße. Die Belegung des Grabareals erstreckt sich über eine relativ kurze Zeitspanne, d.h. vom Beginn des 1. bis zum Beginn des 2. Jh. n. Chr. 140 Strukturen, die einen Zusammenhang mit den Grabriten aufweisen, wurden ergraben: 19 Grubenscheiterhaufen mit oder ohne Leichenbrand, 79 gemischte oder ungemischte Aschedepots, 23 Depots von Verbrennungsresten, 21 Körpergräber, ein Verbrennungsareal, ein Keramikdepot und ein Ofen.Die Untersuchung der räumlichen Verteilung der Gräber zeugt von dem Wunsch, einige Verstorbene unweit voneinander zu begraben, sie schließt jedoch aus, dass eine mögliche Überschneidung auf die Eingeengtheit der Nekropole im Vergleich zur Straße zurückzuführen ist. Im Laufe seiner Benutzung beschränkt sich die Belegung des Grabbereichs auf Erwachsene, einige Riten unterliegen einer Wandlung. Mit der Zeit verliert der Brauch, den Leichenbrand auf dem Scheiterhaufen auszulesen, an Bedeutung. Diese Wandlung bezüglich des Auslesens der Überreste des Verstorbenen vollzieht sich gleichzeitig mit der Herausbildung des Grubenscheiterhaufens. Die räumliche Organisation, die Strukturen, die mit diesen verknüpften Gesten und Rituale entsprechen denen der zeitgenössischen Fundstätten Lyons. Die Lage des Grabareals in einer eher ungünstigen Umgebung, die wahrscheinlich zu seiner Aufgabe geführt hat, mag ein Hinweis dafür sein, dass die Anlegung der Gräber in diesem Sektor Lyons finanziell bedingt war

The m 6 A pathway protects the transcriptome integrity by restricting RNA chimera formation in plants

International audienceGlobal, segmental, and gene duplication-related processes are driving genome size and complexity in plants. Despite their evolutionary potentials, those processes can also have adverse effects on genome regulation, thus implying the existence of specialized corrective mechanisms. Here, we report that an N6-methyladenosine (m 6 A)-assisted polyadenylation (m-ASP) pathway ensures tran-scriptome integrity in Arabidopsis thaliana. Efficient m-ASP pathway activity requires the m 6 A methyltransferase-associated factor FIP37 and CPSF30L, an m 6 A reader corresponding to an YT512-B Homology Domain-containing protein (YTHDC)-type domain containing isoform of the 30-kD subunit of cleavage and polyadenylation specificity factor. Targets of the m-ASP pathway are enriched in recently rearranged gene pairs, displayed an atypical chromatin signature, and showed transcriptional readthrough and mRNA chimera formation in FIP37-and CPSF30L-deficient plants. Furthermore, we showed that the m-ASP pathway can also restrict the formation of chimeric gene/transposable-element transcript, suggesting a possible implication of this pathway in the control of transposable elements at specific locus. Taken together, our results point to selective recognition of 39-UTR m 6 A as a safeguard mechanism ensuring transcriptome integrity at rearranged genomic loci in plants

Development and application of a next-generation-sequencing (NGS) approach to detect known and novel gene defects underlying retinal diseases

<p>Abstract</p> <p>Background</p> <p>Inherited retinal disorders are clinically and genetically heterogeneous with more than 150 gene defects accounting for the diversity of disease phenotypes. So far, mutation detection was mainly performed by APEX technology and direct Sanger sequencing of known genes. However, these methods are time consuming, expensive and unable to provide a result if the patient carries a new gene mutation. In addition, multiplicity of phenotypes associated with the same gene defect may be overlooked.</p> <p>Methods</p> <p>To overcome these challenges, we designed an exon sequencing array to target 254 known and candidate genes using Agilent capture. Subsequently, 20 DNA samples from 17 different families, including four patients with known mutations were sequenced using Illumina Genome Analyzer IIx next-generation-sequencing (NGS) platform. Different filtering approaches were applied to identify the genetic defect. The most likely disease causing variants were analyzed by Sanger sequencing. Co-segregation and sequencing analysis of control samples validated the pathogenicity of the observed variants.</p> <p>Results</p> <p>The phenotype of the patients included retinitis pigmentosa, congenital stationary night blindness, Best disease, early-onset cone dystrophy and Stargardt disease. In three of four control samples with known genotypes NGS detected the expected mutations. Three known and five novel mutations were identified in <it>NR2E3, PRPF3, EYS, PRPF8, CRB1, TRPM1 </it>and <it>CACNA1F</it>. One of the control samples with a known genotype belongs to a family with two clinical phenotypes (Best and CSNB), where a novel mutation was identified for CSNB. In six families the disease associated mutations were not found, indicating that novel gene defects remain to be identified.</p> <p>Conclusions</p> <p>In summary, this unbiased and time-efficient NGS approach allowed mutation detection in 75% of control cases and in 57% of test cases. Furthermore, it has the possibility of associating known gene defects with novel phenotypes and mode of inheritance.</p

Isatuximab plus pomalidomide and dexamethasone in frail patients with relapsed/refractory multiple myeloma: ICARIA-MM subgroup analysis.

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Similar at-sea behaviour but different habitat use between failed and successful breeding albatrosses

Breeding failure is expected to induce behavioural changes in central place foragers. Indeed, after a failed reproductive attempt, breeding individuals are relieved from having to return to their breeding site for reproductive duties and thus are less constrained than successful breeders in their movements during the remainder of the breeding season. Accordingly, they are expected to adjust their behaviour, travelling longer in distance and/or time to reach foraging grounds. They are also expected to use different foraging areas to decrease local intra-specific competition with successful breeders. We compared the at-sea behaviour and habitat use of successful and failed Indian yellow-nosed albatrosses nesting in Amsterdam Island, Southern Indian Ocean, during 2 chick-rearing seasons. Failed breeders exhibited the same at-sea foraging behaviour, travelling as far and as long as successful breeders. They also spent the same amount of time on their nest between at-sea trips. Nevertheless, habitat models revealed partial spatial segregation of failed breeders, which used specific foraging areas characterized by deeper and colder waters in addition to the areas they shared with successful breeders. Our study shows the importance of combining a range of analytical methods (spatial analysis, behavioural inferences with advanced movement models and habitat models) to infer the at-sea behaviour and habitat use of seabirds. It also stresses the importance of considering individual breeding status when aiming to understand the spatial distribution of individuals, especially when this information may have conservation implications