Boosting Autobiographical Memory and the Sense of Identity of Alzheimer Patients Through Repeated Reminiscence Workshops?

peer reviewedDespite severe amnesia, some studies showed that Alzheimer Disease (AD) patients with moderate to severe dementia keep a consistent, but impoverished representation of themselves, showing preservation of the sense of identity even at severe stages of the illness. Some studies suggest that listening to music can facilitate the reminiscence of autobiographical memories and that stimulating autobiographical memory would be relevant to support the self of these patients. Consequently, we hypothesized that repeated participation to reminiscence workshops, using excerpts of familiar songs as prompts would participate to the enrichment of autobiographical memories, self-representation and sense of identity. We included a group of 20 AD patients with severe dementia residing in nursing homes. Their performances were compared to a control group of 20 matched (age, education, mood) healthy residents living in the same institutions. The experiment was conducted in three phases over a 2-week period. On phase 1, an individual assessment of sense of identity was proposed to each participant. On phase 2, participants joined musical reminiscence workshops (six sessions over 2 weeks for AD patients and 3 sessions over a week for controls). During the third phase (12 days after the first assessment), individual evaluation of autobiographical memory and a second assessment of sense of identity were proposed. Our results showed that, despite their massive amnesia syndrome, autobiographical memories of AD reached at the end of the 2 weeks the number and quality of those of matched controls. Moreover, we confirmed a continuity of self-representation in AD patients with a stable profile of the answers between the first and second individual assessments of sense of identity. However, the increase in number and episodic quality of autobiographical memories was not accompanied by an enrichment of the sense of identity. In a complementary study, new patients participated in the same paradigm, but using movie extracts as prompts, and showed very similar effects. We discuss all of these results with regard to the literature showing the significant impact of repetition on the reactivation of memory traces even in very amnestic AD patients at severe stages of the disease

Musical training modulates the early but not the late stage of rhythmic syntactic processing

Syntactic processing is essential for musical understanding. Although the processing of harmonic syntax has been well studied, very little is known about the neural mechanisms underlying rhythmic syntactic processing. The present study investigated the neural processing of rhythmic syntax and whether and to what extent long-term musical training impacts such processing. Fourteen musicians and 14 nonmusicians listened to syntactic-regular or -irregular rhythmic sequences and judged the completeness of these sequences. Musicians, as well as nonmusicians, showed a P600 effect to syntactic-irregular endings, indicating that musical exposure and perceptual learning of music are sufficient to enable nonmusicians to process rhythmic syntax at the late stage. However, musicians, but not nonmusicians, also exhibited an ERAN response to syntactic-irregular endings, which suggests that musical training only modulates the early but not the late stage of rhythmic syntactic processing. These findings revealed for the first time the neural mechanisms underlying the processing of rhythmic syntax in music, which has important implications for theories of hierarchically-organized music cognition and comparative studies of syntactic processing in music and language

Evidence for the Contribution of the Hemozoin Synthesis Pathway of the Murine Plasmodium yoelii to the Resistance to Artemisinin-Related Drugs

Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia

Regulation of the spatio-temporal replication program during early Xenopus development

Chez les eucaryotes supérieurs, la réplication de l'ADN est initiée à partir de plusieurs milliers d'origines. Mais la régulation spatio-temporelle de leur activation reste mal caractérisée. Une voie de contrôle (checkpoint) de la phase S est activée lorsque les fourches de réplication sont bloquées, inhibant ainsi l'activation d'origines tardives. L'objectif de ma thèse consistait à étudier deux facteurs essentiels dans le programme spatio-temporel de la réplication, dans le système du xénope : la protéine « checkpoint » Chk1, qui est un facteur inhibiteur de l'activation des origines, et les désoxyribonucléotides (dNTPs), précurseurs de la synthèse de l'ADN. Chez le xénope, après douze divisions embryonnaires, a lieu la transition mid-blastuléenne (MBT). A cette étape, une augmentation du ratio nucléo-cytosolique va entrainer la titration des facteurs de réplication, ce qui active le point de contrôle et ralentit la phase S. Il est possible de mimer in vitro les phases S rapides des embryons pendant le développement précoce en augmentant la concentration en noyaux dans l'extrait d'œufs.Nous avons pu voir par l'inhibition, la déplétion ou la surexpression de Chk1 que cette protéine régulait l'activation des origines lors d'un stress, mais également dans une phase S non perturbée, grâce à la technique du peignage moléculaire. Ce résultat montre que le niveau de Chk1 doit être finement régulé pour permettre une réplication correcte dans une phase S non perturbée, chez les eucaryotes supérieurs. Nous avons ensuite cherché à savoir si la concentration en dNTPs pouvait être limitante pendant le développement et comment elle modulait le programme de réplication. Nous avons comparé l'effet de l'ajout de dNTPs sur la réplication en mimant plusieurs stades précoces du développement pré-MBT. La variation de la concentration en dNTPs agit sur la réplication en augmentant à la fois l'activation des origines et, en fonction de la concentration en noyaux, aussi la vitesse des fourches. Cet effet est indépendant du checkpoint de la réplication dans ce système et d'autres études sont nécessaires pour comprendre les mécanismes moléculaires.DNA replication in higher eukaryotes initiates at thousands of origins according to a spatio-temporal regulation program which is not well characterized. The S phase checkpoint is activated when replication forks are blocked which inhibits the firing of late origins. The aim of my thesis consisted to study two essentials factors in spatio-temporal replication program in Xenopus system: the checkpoint protein Chk1, inhibitor of origin activation, and the deoxyribonucleotides (dNTPs), DNA synthesis precursors. In Xenopus, the mid-blastula transition (MBT) occurs after twelve embryonic divisions. An increase of the nucleo-cytosolic ratio induces a titration of replication factors, that activates the checkpoint and slows down the S phase. It is possible to mimic in vitro the rapid S phases of early Xenopus development stages by increasing the nuclei concentration. By DNA combing combined with Chk1 inhibition, depletion and overexpression experiments, we show that Chk1 controls origins activation in perturbed but also unperturbed S phase. My results show that Chk1 levels needs to be tightly regulated in order to properly control the replication program during normal S phase in higher eukaryotes. In order to determine whether the concentration of dNTPs could be another limiting replication factor, we compared the effect of dNTPs addition on replication by mimicking in vitro several early stages of pre-MBT development. Addition of dNTPs affects DNA replication, by increasing origin activation and, dependent on nuclei concentration, also the fork speed. This effect is independent of the S phase checkpoint and further studies are needed in order to understand the molecular mechanisms behind

Genome wide decrease of DNA replication eye density at the midblastula transition of Xenopus laevis

International audienceDuring the first rapid divisions of early development in many species, the DNA:cytoplasm ratio increases until the midblastula transition (MBT) when transcription resumes and cell cycles lengthen. S phase is very rapid in early embryos, about 20-30 times faster than in differentiated cells. Using a combination of DNA fiber studies and a Xenopus laevis embryonic in vitro replication system, we show that S phase slows down shortly after the MBT owing to a genome wide decrease of replication eye density. Increasing the dNTP pool did not accelerate S phase or increase replication eye density implying that dNTPs are not rate limiting for DNA replication at the Xenopus MBT. Increasing the ratio of DNA:cytoplasm in egg extracts faithfully recapitulates changes in the spatial replication program in embryos, supporting the hypothesis that titration of soluble limiting factors could explain the observed changes in the DNA replication program at the MBT in Xenopus laevis

Effects of sensory deprivation on glomerular interneurons in the mouse olfactory bulb: differences in mortality and phenotypic adjustment of dopaminergic neurons

International audienceNeurogenesis persists in the mammalian subventricular zone after birth, producing various populations of olfactory bulb (OB) interneurons, including GABAergic and mixed dopaminergic/GABAergic (DA) neurons for the glomerular layer. While olfactory sensory activity is a major factor controlling the integration of new neurons, its impact on specific subtypes is not well understood. In this study we used genetic labeling of defined neuron subsets, in combination with reversible unilateral sensory deprivation and longitudinal in vivo imaging, to examine the behavior of postnatally born glomerular neurons. We find that a small fraction of GABAergic and of DA neurons die after 4 weeks of sensory deprivation while surviving DA-neurons exhibit a substantial decrease in tyrosine hydroxylase (TH) expression levels. Importantly, after reopening of the naris, cell death is arrested and TH levels go back to normal levels, indicating a specific adaptation to the level of sensory activity. We conclude that sensory deprivation induces adjustments in the population of glomerular neurons, involving both, cell death and adaptation of neurotransmitter use in specific neuron types. Our study highlights the dynamic nature of glomerular neurons in response to sensory deprivation and provide valuable insights into the plasticity and adaptability of the olfactory system

Strategy using a combination of physico/chemical analysis and in vitro bioassays for chemical safety of food contact articles

International audienceConducting risk assessments for Non-Intentionally Added Substances (NIAS) in food contact articles (FCA) that may migrate into food presents a significant challenge for food packaging manufacturers, as well as for risk assessors and managers. This challenge becomes even more pronounced in the context of a circular economy where the utilization of bio-based, reusable, and recycled materials is expected to surge in the coming years. The objective of the Packsafe project is to propose a comprehensive strategy for ensuring the chemical safety of FCAs. This strategy involves the combination of analytical tools and in vitro studies, enabling the identification of hazards within complex mixtures.The project involves extracting various FCAs and subjecting them to thorough analysis through analytical chemistry to establish a unique chemical signature or fingerprint. Simultaneously, these extracts will undergo in vitro biotests to assess genotoxicity (Ames test, micronucleus assay, DDR test) and endocrine disruption (employing an Estrogen/Androgen/Thyroid/Steroidogenesis approach). The initial phase of the project entailed extracting forty-one articles, including LDPE, HDPE, PP, PET, PS, and cardboard. The extraction protocol involved a mixture of methanol and dichloromethane (1/3), followed by a concentration step to transfer the substances into a biocompatible solvent (DMSO). These mixtures were then subjected to a battery of in vitro bioassays. Positive results were observed in some cases, suggesting potential genotoxicity and endocrine disruption, which will require further confirmation. For extracts with negative results, additional spiked experiments will be conducted to study the matrix effect of the extract and determine the threshold of biological detection.The subsequent phase of the project involves the preparation of extracts enriched with NIAS, which will be tested using selected biotests. Concurrently, chemical analysis will be carried out to characterize the extracts and attempt to identify their chemical signature.All the collected data will be integrated into an expert system, which will serve as a comprehensive toolbox for risk assessment

Sense of identity in advanced Alzheimer's dementia: a cognitive dissociation between sameness and selfhood?

International audienceWe looked at whether sense of identity persists in patients with Alzheimer's disease (AD) and if its profile remains the same between two examinations. A specifically designed protocol was administered to 16 AD patients in the mild to severe stages of dementia and to 16 matched healthy controls, both living in the same institution. We showed that sense of identity was broadly preserved in AD patients. The patterns of their responses were similar to those of controls, and remained consistent over a two-week period. However, some qualitative characteristics of sense of identity in AD patients differed significantly from those of controls, suggesting that AD patients may not be able to update their self-knowledge, probably because of their episodic memory deficit. These results are discussed in the light of both current models of the self and philosophical concepts such as sameness and selfhood

Stratégie pour une sécurité chimique intégrée des matériaux d’emballage au contact des denrées alimentaires

International audienceRisk assessment of Non-Intentionally Added Substances (NIAS) present in food contact packaging that may migrate into food is a major challenge for food packagers and manufacturers and for risk assessors and managers. A strategy, consisting of combining analytical tools, in silico and in vitro studies, allowing the identification of the hazard in a complex mixture (packaging extract/migrate), is presented in this article. The aim is to avoid the presence of undesirable, chemically uncharacterised or unknown substances in food. This approach appears all the more essential and relevant in a circular economy context, where the share of bio-based, reusable and recycled materials will increase considerably in the coming years. To date, traceability of these new materials is, for the most part, difficult.L’évaluation des risques des Substances Non Intentionnelles (SNI), présentes dans les emballages au contact des denrées alimentaires et susceptibles de migrer dans les aliments, représente un défi majeur pour les conditionneurs, les industriels de l’agroalimentaire, les évaluateurs et les gestionnaires du risque. Une stratégie, consistant à combiner des outils analytiques à des études in silico et in vitro, permettant l’identification du danger dans un mélange complexe (extrait/migrat d’emballage), est présentée dans cet article. L’objectif est d’éviter la présence dans l’aliment de substances indésirables, non caractérisées d’un point de vue chimique, voire inconnues. Cette approche semble d’autant plus indispensable et pertinente dans un contexte d’économie circulaire où la part des matériaux biosourcés, réutilisables et recyclés va considérablement augmenter dans les prochaines années, la traçabilité de ces nouveaux matériaux étant, pour la plupart, à ce jour, difficile