Prolonged quiescence delays somatic stem cell-like divisions in Caenorhabditis elegans and is controlled by insulin signaling

Cells can enter quiescence in adverse conditions and resume proliferation when the environment becomes favorable. Prolonged quiescence comes with a cost, reducing the subsequent speed and potential to return to proliferation. Here, we show that a similar process happens during Caenorhabditis elegans development, providing an in vivo model to study proliferative capacity after quiescence. Hatching under starvation provokes the arrest of blast cell divisions that normally take place during the first larval stage (L1). We have used a novel method to precisely quantify each stage of postembryonic development to analyze the consequences of prolonged L1 quiescence. We report that prolonged L1 quiescence delays the reactivation of blast cell divisions in C. elegans, leading to a delay in the initiation of postembryonic development. The transcription factor DAF‐16/FOXO is necessary for rapid recovery after extended arrest, and this effect is independent from its role as a suppressor of cell proliferation. Instead, the activation of DAF‐16 by decreased insulin signaling reduces the rate of L1 aging, increasing proliferative potential. We also show that yolk provisioning affects the proliferative potential after L1 arrest modulating the rate of L1 aging, providing a possible mechanistic link between insulin signaling and the maintenance of proliferative potential. Furthermore, variable yolk provisioning in embryos is one of the sources of interindividual variability in recovery after quiescence of genetically identical animals. Our results support the relevance of L1 arrest as an in vivo model to study stem cell‐like aging and the mechanisms for maintenance of proliferation potential after quiescence.Spanish Ministerio de Economía y Competitividad (BFU2016-74949-P and BFU2012- 35509)European Research Council (ERC-2011-StG-281691)Marie-Curie Intra-European Fellowship (FP7-PEOPLE-2013- IEF/GA Nr: 627263

Preferences for neuromyelitis optica spectrum disorder treatments: A conjoint analysis with neurologists in Spain

Conjoint analysis; Disability; Neuromyelitis optica spectrum disorderAnàlisi conjunta; Discapacitat; Trastorn de l'espectre de la neuromielitis òpticaAnálisis conjunto; Discapacidad; Trastorno del espectro de la neuromielitis ópticaBackground The treatment landscape for neuromyelitis optica spectrum disorder (NMOSD) has changed in recent years with the approval of therapies with different efficacy, safety and administration profiles. Objective The aim of this study was to assess neurologists’ preferences for different NMOSD treatment attributes using conjoint analysis (CA). Methods We conducted an online, non-interventional, cross-sectional study in collaboration with the Spanish Society of Neurology. Our CA assessed five drugs’ attributes: prevention of relapse, prevention of disability accumulation, safety risk, management during pregnancy, and route and frequency of administration. Participants were presented with eight hypothetical treatment scenarios to rank based on their preferences from the most preferred to the least. An ordinary least squares method was selected to estimate weighted preferences. Results A total of 104 neurologists were included. Mean age (standard deviation-SD) was 37.7 (10.3) years, 52.9 % were male, and median time (interquartile range) of experience managing NMOSD was 5.0 (2.9, 10.8) years. Neurologists placed the greatest importance on efficacy attributes, time to relapse (44.1 %) being the most important, followed by preventing disability accumulation (36.8 %). In contrast, route and frequency of administration (4.6 %) was the least important characteristic. Participants who prioritised efficacy attributes felt more comfortable in decision-making, had fewer past experiences of care-related regret and a lower attitude to risk taking than their counterparts. Conclusion Neurologists’ treatment preferences in NMOSD were mainly driven by efficacy attributes. These results may be useful to design policy decisions and treatment guidelines for this condition.The study was funded by Roche Medical Department, Spain (SL43671). The funding source had no role in the design, analysis and interpretation of the data, review or approval of the manuscript, and decision to submit for publication

Insulin signaling and the age of the mothers modulate L1 arrest and recovery

Trabajo presentado en EMBO Workshop C. elegans development, cell biology and gene expression and European Worm Meeting, celebrado en Barcelona (España) del 13 al 17 de junio de 2018

Regulation of L1 quiescence by insulin signalling and population density

Trabajo presentado en Virtual European Worm Meeting, celebrado en modalidad virtual del 22 al 23 de junio de 2020

The Rabl chromosome configuration masks a kinetochore reassembly mechanism in yeast mitosis

During cell cycle progression in metazoans, the kinetochore is assembled at mitotic onset and disassembled during mitotic exit. Once assembled, the kinetochore complex attached to centromeres interacts directly with the spindle microtubules, the vehicle of chromosome segregation. This reassembly program is assumed to be absent in budding and fission yeast, because most kinetochore proteins are stably maintained at the centromeres throughout the entire cell cycle. Here, we show that the reassembly program of the outer kinetochore at mitotic onset is unexpectedly conserved in the fission yeast Schizosaccharomyces pombe. We identified this behavior by removing the Rabl chromosome configuration, in which centromeres are permanently associated with the nuclear envelope beneath the spindle pole body during interphase. In addition to having evolutionary implications for kinetochore reassembly, our results aid the understanding of the molecular processes responsible for kinetochore disassembly and assembly during mitotic entry.This work was supported by the Spanish government, Plan Nacional project PGC2018-098118-A-I00, Ramon y Cajal program, RyC-2016-19659 to A.F.-A. and the program “Escalera de Excelencia” of the Junta de Castilla y León Ref. CLU-2017-03, co-funded by the P.O. FEDER of Castilla y León 14-20 and by the Pablo de Olavide University “Ayuda Puente Predoctoral” fellowship (PPI1803) to A.P.-S., and by the Spanish Education and Professional Formation Ministry, Research Collaboration Grant to D.L.-P

Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55-IL6ST Gene Region in Immature Dendritic Cells

Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4(+) T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-gamma and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4(+) T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4(+) T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo-DC) differentiation as a process potentially influenced by MS risk SNPs