Pharmacological chaperone therapies: Can aldehyde dehydrogenase activator make us healthier?

Hom Santolaia, Cint

The plastic cellular states of liver cells: Are EpCAM and Lgr5 fit for purpose?

Adult liver cells have been considered restricted regarding their fate and lineage potential. That is, hepatocytes have been thought able only to generate hepatocytes and duct cells, only duct cells. While this may be the case for the majority of scenarios in a state of quiescence or homeostasis, evidence suggests that liver cells are capable of interconverting between cellular states of distinct phenotypic traits. This interconversion or plasticity had been suggested by classical studies using cellular markers, but recently lineage tracing approaches have proven that cells are highly plastic and retain an extraordinary ability to respond differently to normal tissue homeostasis, to tissue repair, or when challenged to expand ex vivo or to differentiate upon transplantation. Stemness, as "self-renewal and multipotency," seems not to be limited to a particular cell type but rather to a cellular state in which cells exhibit a high degree of plasticity and can move back and forth in different phenotypic states. For instance, upon damage cells can dedifferentiate to acquire stem cell potential that allows them to self-renew, repopulate a damaged tissue, and then undergo differentiation. In this review, we will discuss the evidence on cellular plasticity in the liver, focusing our attention on two markers, epithelial cell adhesion molecule and leucine-rich repeat-containing G protein-coupled receptor 5, which identify cells with stem cell potential. (Hepatology 2016;64:652-662).MH: is a Wellcome Trust Sir Henry Dale Fellow and is jointly funded by the Wellcome Trust and the Royal Society (104151/Z/14/Z); LD: is funded by the Interuniversity Attraction Poles (IAP) - phase VII - contract P7/47 (Federal Science Policy – BELSPO).This is the final version of the article. It first appeared from Wiley via https://doi.org/ 10.1002/hep.2846

High‐quality biobanks : pivotal assets for reproducibility of OMICS‐data in biomedical translational research

Human biospecimen samples (HBS) and associated data stored in biobanks (also called "biotrusts," "biorepositories," or "biodistributors") are very critical resources for translational research. As HBS quality is decisive to the reproducibility of research results, biobanks are also key assets for new developments in precision medicine. Biobanks are more than infrastructures providing HBS and associated data. Biobanks have pioneered in identifying and standardizing sources of preanalytical variations in HBS, thus paving the way for the current biospecimen science. To achieve this milestone, biobankers have successively assumed the role of "detective," and then "architect," to identify new detrimental impact of preanalytical variables on the tissue integrity. While standardized methods in omics are required to be practiced throughout research communities, the accepted best practices and standards on biospecimen handling are generally not known nor applied by researchers. Therefore, it is mandatory to raise the awareness within omics communities regarding not only the basic concepts of collecting, storing, and utilizing HBS today, but also to suggest insights on biobanking in the cancer omics context

Design of a biologically inspired navigation system for the Psikharpax rodent robot

This work presents the development and implementation of a biologically inspired navigation system on the autonomous Psikharpax rodent robot. Our system comprises two independent navigation strategies: a taxon expert and a planning expert. The presented navigation system allows the robot to learn the optimal strategy in each situation, by relying upon a strategy selection mechanism

A biologically inspired meta-control navigation system for the Psikharpax rat robot

A biologically inspired navigation system for the mobile rat-like robot named Psikharpax is presented, allowing for self-localization and autonomous navigation in an initially unknown environment. The ability of parts of the model (e. g. the strategy selection mechanism) to reproduce rat behavioral data in various maze tasks has been validated before in simulations. But the capacity of the model to work on a real robot platform had not been tested. This paper presents our work on the implementation on the Psikharpax robot of two independent navigation strategies (a place-based planning strategy and a cue-guided taxon strategy) and a strategy selection meta-controller. We show how our robot can memorize which was the optimal strategy in each situation, by means of a reinforcement learning algorithm. Moreover, a context detector enables the controller to quickly adapt to changes in the environment-recognized as new contexts-and to restore previously acquired strategy preferences when a previously experienced context is recognized. This produces adaptivity closer to rat behavioral performance and constitutes a computational proposition of the role of the rat prefrontal cortex in strategy shifting. Moreover, such a brain-inspired meta-controller may provide an advancement for learning architectures in robotics

High Throughput Micro-Well Generation of Hepatocyte Micro-Aggregates for Tissue Engineering

The main challenge in hepatic tissue engineering is the fast dedifferentiation of primary hepatocytes in vitro. One successful approach to maintain hepatocyte phenotype on the longer term is the cultivation of cells as aggregates. This paper demonstrates the use of an agarose micro-well chip for the high throughput generation of hepatocyte aggregates, uniform in size. In our study we observed that aggregation of hepatocytes had a beneficial effect on the expression of certain hepatocyte specific markers. Moreover we observed that the beneficial effect was dependent on the aggregate dimensions, indicating that aggregate parameters should be carefully considered. In a second part of the study, the selected aggregates were immobilized by encapsulation in methacrylamide-modified gelatin. Phenotype evaluations revealed that a stable hepatocyte phenotype could be maintained during 21 days when encapsulated in the hydrogel. In conclusion we have demonstrated the beneficial use of micro-well chips for hepatocyte aggregation and the size-dependent effects on hepatocyte phenotype. We also pointed out that methacrylamide-modified gelatin is suitable for the encapsulation of these aggregates

Analyzing interactions between navigation strategies using a computational model of action selection

For animals as well as for humans, the hypothesis of multiple memory systems involved in different navigation strategies is supported by several biological experiments. However, due to technical limitations, it remains difficult for experimentalists to elucidate how these neural systems interact. We present how a computational model of selection between navigation strategies can be used to analyse phenomena that cannot be directly observed in biological experiments. We reproduce an experiment where the rat's behaviour is assumed to be ruled by two different navigation strategies (a cue-guided and a map-based one). Using a modelling approach, we can explain the experimental results in terms of interactions between these systems, either competing or cooperating at specific moments of the experiment. Modelling such systems can help biological investigations to explain and predict the animal behaviour

Next generation of ALDH substrates and their potential to study maturational lineage biology in stem and progenitor cells

High aldehyde dehydrogenase (ALDH) activity is a feature of stem cells from normal and cancerous tissues and a reliable universal marker used to isolate them. There are numerous ALDH isoforms with preferred substrate specificity variably expressed depending on tissue, cell type, and organelle and cell status. On the other hand, a given substrate may be metabolized by several enzyme isoforms. Currently ALDH activity is evidenced by using Aldefluor, a fluorescent substrate likely to be metabolized by numerous ALDH isoforms. Therefore, isolation techniques based on ALDH activity detection select a heterogeneous population of stem or progenitor cells. Despite active research in the field, the precise role(s) of different ALDH isoforms in stem cells remains enigmatic. Understanding the metabolic role of different ALDH isoform in the control of stem cell phenotype and cell fate during development, tissue homeostasis, or repair, as well as carcinogenesis, should open perspectives to significant discoveries in tissue biology. In this perspective, novel ALDH substrates are being developed. Here we describe how new substrates could be instrumental for better isolation of cell population with stemness potential and for defining hierarchy of cell populations in tissue. Finally, we speculate on other potential applications

EpCAM and the biology of hepatic stem/progenitor cells

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which is frequently and highly expressed on carcinomas, tumor-initiating cells, selected tissue progenitors, and embryonic and adult stem cells. During liver development, EpCAM demonstrates a dynamic expression, since it can be detected in fetal liver, including cells of the parenchyma, whereas mature hepatocytes are devoid of EpCAM. Liver regeneration is associated with a population of EpCAM-positive cells within ductular reactions, which gradually lose the expression of EpCAM along with maturation into hepatocytes. EpCAM can be switched on and off through a wide panel of strategies to fine-tune EpCAM-dependent functional and differentiative traits. EpCAM-associated functions relate to cell–cell adhesion, proliferation, maintenance of a pluripotent state, regulation of differentiation, migration, and invasion. These functions can be conferred by the full-length protein and/or EpCAM-derived fragments, which are generated upon regulated intramembrane proteolysis. Control by EpCAM therefore not only depends on the presence of full-length EpCAM at cellular membranes but also on varying rates of the formation of EpCAM-derived fragments that have their own regulatory properties and on changes in the association of EpCAM with interaction partners. Thus spatiotemporal localization of EpCAM in immature liver progenitors, transit-amplifying cells, and mature liver cells will decisively impact the regulation of EpCAM functions and might be one of the triggers that contributes to the adaptive processes in stem/progenitor cell lineages. This review will summarize EpCAM-related molecular events and how they relate to hepatobiliary differentiation and regeneration

Comment opérationnaliser et évaluer la prise en compte du concept ‘FAIR' dans le partage des données: Vers une grille simplifiée d’évaluation du respect des critères FAIR.

National audienceIndexed identifier ? Identification Are each data/dataset identified by an indexed and independant identifier ? Persistent metadata / data link ? Metadata traceability Are the metadata linked to the dataset through a persistent identifier? Metadata & authority linked ? Metadata traceability Are the metadata of each dataset linked to a unique authority (responsible for the datasets at a given time)? Unique, global, persistent ID? Identification Are the data identifiers unique, global and persistent ? Are the data identifiers unique, global and persistent ? Datasets linked to authority ? Metadata traceability Are all datasets linked to an authority (legal entity) through a unique and persistent identifier over time (e.g. institution, association or established body)? In case of a legal reuse restriction (such as personal data, state and public security, national defense secret, confidentiality of external relations, information systems security, secrets in industrial and commercial matters) , is the restriction properly justified?SHARC (SHAring Reward & Credit) est un groupe d’intérêt scientifique interdisciplinaire créé dans le cadre de RDA (Research Data Alliance) dans le but de faciliter le partage des données de recherche (et des ressources) par la valorisation de l’ensemble des activités pré-requises à ce partage, tout au long du cycle de vie des données. Dans ce cadre, un sous-groupe de travail SHARC élabore des grilles d’évaluation des chercheurs afin de mesurer leur niveau de prise en compte des principes FAIR dans la gestion de leurs données.La grille d’évaluation présentée dans ce poster est destinée à être complétée par tout scientifique produisant et / ou utilisant des données. Il s'agit d'un résumé d'une grille d'évaluation plus étendue conçue pour un partage optimal des données (non encore mise en œuvre pour le moment par la plupart des scientifiques).L'évaluation est basée sur les critères de conformité FAIR. Pour remplir cet objectif, la grille affiche le minimum de critères qui doivent absolument être appliqués par les chercheurs pour attester de leur pratique FAIR. Ces critères sont organisés en 5 groupes: «Motivations de partage»; "Trouvable", "Accessible", "Interopérable" et "Réutilisable". Pour chaque critère, 4 degrés d’évaluation sont proposés ("Jamais / Non évaluable"; "Si obligatoire"; "Parfois"; "Toujours"). Au moins un degré mais un seul doit être sélectionné par critère. L'évaluation doit être effectuée pour chaque catégorie F / A / I / R; L'évaluation finale est la somme de chaque degré coché rapportée au nombre total de critères dans chaque catégorie F / A / I / R. Des règles d'interprétation prenant en compte les «motivations du partage» sont proposées