Development of an Objective Structured Clinical Examination (OSCE) to evaluate the diagnosis announcement of chronic neurological disease by residents in neurology.

BACKGROUND: There is little consensus on how to make a diagnosis announcement of severe chronic disease in neurology. Other medical specialties, such as oncology, have developed assessment methods similar to the Objective Structured Clinical Examination (OSCE) to address this issue. Here we report the implementation of an OSCE focused on the diagnosis announcement of chronic disease in neurology by residents. OBJECTIVE: We aimed to evaluate the acceptability, feasibility and validity in routine practice of an OSCE combined with a theoretical course focused on diagnosis announcement in neurology. METHOD: Eighteen neurology residents were prospectively included between 2019 and 2022. First, they answered a questionnaire on their previous level of training in diagnosis announcement. Second, in a practical session with a simulated patient, they made a 15-min diagnosis announcement and then had 5mins of immediate feedback with an expert observer, present in the room. The OSCE consisted of 4 different stations, with standardized scenarios dedicated to the announcement of multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Third, in a theory session, expert observers covered the essential theoretical points. All residents and expert observers completed an evaluation of the "practical session" and the "theory session". RESULTS: Residents estimated their previous level of diagnosis announcement training at 3.1/5. The most feared announcements were AD and ALS. The "practical session" was rated at a mean of 4.1/5 by the residents and 4.8/5 by the expert observers, and the "theory session" at a mean of 4.7/5 by the residents and 5/5 by the expert observers. After the OSCEs, 11 residents felt more confident about making an announcement. CONCLUSION: This study has shown a benefit of using an OSCE to learn how to make a diagnosis announcement of severe chronic disease in neurology. OSCEs could be used in many departments in routine practice and seem adapted to residents.

RNP granules in ALS and neurodegeneration: From multifunctional membraneless organelles to therapeutic opportunities.

Amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases are characterised by dysfunction of a host of RNA-binding proteins (RBPs) and a severely disrupted RNA metabolism. Recently, RBP-harbouring phase-separated complexes, ribonucleoprotein (RNP) granules, have come into the limelight as "crucibles" of neuronal pathology in ALS. RNP granules are indispensable for the multitude of regulatory processes underlying cellular RNA metabolism and serve as critical organisers of cellular biochemistry. Neurons, highly specialised cells, heavily rely on RNP granules for efficient trafficking, signalling and stress responses. Multiple RNP granule components, primarily RBPs such as TDP-43 and FUS, are affected by ALS mutations. However, even in the absence of mutations, RBP proteinopathies represent pathophysiological hallmarks of ALS. Given the high local concentrations of RBPs and RNAs, their weakened or enhanced interactions within RNP granules disrupt their homeostasis. Thus, the physiological process of phase separation and RNP granule formation, vital for maintaining the high-functioning state of neuronal cells, becomes their Achilles heel. Here, we will review the recent literature on the causes and consequences of abnormal RNP granule functioning in ALS and related disorders. In particular, we will summarise the evidence for the network-level dysfunction of RNP granules in these conditions and discuss considerations for therapeutic interventions to target RBPs, RNP granules and their network as a whole.

Allergens grouping names on packaging: Are the substances similar enough to ensure safety? The worst case scenarios question this.

OBJECTIVE: European Commission Regulation (EU) n°2023/1545 introduced the concept of grouping names in the cosmetics sector in July 2023. These groups bring together allergenic substances with the same level of skin sensitization. Their purpose is to lighten the list of ingredients on cosmetic packaging, by grouping together substances deemed to be similar under the same name. As this classification is based on a single toxic effect - skin sensitization - the present study aims to analyse the relevance of these groupings with regard to other toxic effects of substances in the same group. METHODS: This study was carried out by consulting an available database, various reports from 5 committees, 2 books and 5 articles in order to complete the toxicological profile of each substance. Then, in order to highlight any discrepancies within the classification, the worst cases were identified. For this purpose, the data for each substance in a group were compared, and in the event of greater criticality for a toxic effect, this was qualified as a worst case. In addition, similar toxic effects between several substances within the same group were also recorded. The aim of this additional research was to validate the definition of the grouping name and the similarities between substances in the same group. RESULTS: From the 17 grouping names, 5 presented worst cases. Two groups had 2 worst cases and the others only one. In total, from the 7 worst cases detected, 3 were due to the toxic effect "skin irritation". In most cases, the substances in the groupings shared the presence or absence of risk. Only the degree of risk criticality varied. CONCLUSION: Classification by grouping names appears justified regarding the similarities between substances, particularly in terms of skin sensitization. However, the presence of worst cases qualifies it and highlights the importance of being vigilant when assessing the risk of cosmetic products including these grouping names in their list of ingredients.

OBJECTIF: Le règlement (UE) n°2023/1545 de la Commission européenne a introduit la notion de « grouping names ¼ dans le domaine des cosmétiques en juillet 2023. Ces groupes rassemblent des substances allergènes ayant le même niveau de sensibilisation cutanée. Ils ont pour objectif d'alléger la liste des ingrédients figurant sur les emballages des produits cosmétiques, en regroupant sous un même nom des substances jugées similaires. Cette classification étant fondée sur un seul effet toxique ­ la sensibilisation cutanée ­ la présente étude vise à analyser la pertinence de ces regroupements au regard des autres effets toxiques des substances d'un même groupe. MÉTHODES: Cette étude a été réalisée en consultant une base de données disponible, différents rapports de 5 comités, 2 livres et 5 articles afin de compléter le profil toxicologique de chaque substance. Ensuite, afin de mettre en évidence les divergences au sein de la classification, les cas de criticité plus importante ont été identifiés. Pour ce faire, les données de chaque substance d'un groupe ont été comparées, et en cas de criticité supérieure d'un effet toxique, celui­ci a été qualifié de « worst case ¼. En outre, les effets toxiques similaires entre plusieurs substances d'un même groupe ont également été enregistrés. L'objectif de cette recherche complémentaire était de valider la définition du « grouping name ¼ et les similitudes entre les substances d'un même groupe. RÉSULTATS: Sur les 17 « grouping names ¼, 5 présentaient des « worst cases ¼. Deux groupes présentaient deux « worst cases ¼ et les autres un seul. Au total, sur les 7 « worst cases ¼ détectés, 3 étaient dus à l'effet toxique "irritation cutanée". Dans la plupart des cas, les substances des groupes partagent la présence ou l'absence de risque. Seul le degré de criticité du risque variait. CONCLUSION: La classification par « grouping names ¼ semble justifiée au regard des similitudes entre les substances, notamment en termes de sensibilisation cutanée. Cependant, la présence de « worst cases ¼ la nuance et souligne l'importance d'être vigilant lors de l'évaluation du risque des produits cosmétiques incluant ces « grouping names ¼ dans leur liste d'ingrédients.

Cross-talk and mutual shaping between the immune system and the microbiota during an oyster's life.

The Pacific oyster Crassostrea gigas lives in microbe-rich marine coastal systems subjected to rapid environmental changes. It harbours a diversified and fluctuating microbiota that cohabits with immune cells expressing a diversified immune gene repertoire. In the early stages of oyster development, just after fertilization, the microbiota plays a key role in educating the immune system. Exposure to a rich microbial environment at the larval stage leads to an increase in immune competence throughout the life of the oyster, conferring a better protection against pathogenic infections at later juvenile/adult stages. This beneficial effect, which is intergenerational, is associated with epigenetic remodelling. At juvenile stages, the educated immune system participates in the control of the homeostasis. In particular, the microbiota is fine-tuned by oyster antimicrobial peptides acting through specific and synergistic effects. However, this balance is fragile, as illustrated by the Pacific Oyster Mortality Syndrome, a disease causing mass mortalities in oysters worldwide. In this disease, the weakening of oyster immune defences by OsHV-1 µVar virus induces a dysbiosis leading to fatal sepsis. This review illustrates the continuous interaction between the highly diversified oyster immune system and its dynamic microbiota throughout its life, and the importance of this cross-talk for oyster health. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.

The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function.

PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and an RNA recognition motif, however the RNA-processing function(s) were poorly investigated over the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that its RNA/NXF1-binding activity is required for the nuclear export of some canonical mitochondrial-related mRNAs and mitochondrial homeostasis. Genome-wide investigations reveal that the nuclear export function is not strictly linked to promoter-binding, identifying in turn novel regulatory targets of PGC-1α in non-homologous end-joining and nucleocytoplasmic transport. These findings provide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, aging and neurodegeneration.

Cooperation and cheating orchestrate Vibrio assemblages and polymicrobial synergy in oysters infected with OsHV-1 virus.

Polymicrobial infections threaten the health of humans and animals but remain understudied in natural systems. We recently described the Pacific Oyster Mortality Syndrome (POMS), a polymicrobial disease affecting oyster production worldwide. In the French Atlantic coast, the disease involves coinfection with ostreid herpesvirus 1 (OsHV-1) and virulent Vibrio. However, it is unknown whether consistent Vibrio populations are associated with POMS in different regions, how Vibrio contribute to POMS, and how they interact with OsHV-1 during pathogenesis. By connecting field-based approaches in a Mediterranean ecosystem, laboratory infection assays and functional genomics, we uncovered a web of interdependencies that shape the structure and function of the POMS pathobiota. We show that Vibrio harveyi and Vibrio rotiferianus are predominant in OsHV-1-diseased oysters and that OsHV-1 drives the partition of the Vibrio community observed in the field. However only V. harveyi synergizes with OsHV-1 by promoting mutual growth and accelerating oyster death. V. harveyi shows high-virulence potential and dampens oyster cellular defenses through a type 3 secretion system, making oysters a more favorable niche for microbe colonization. In addition, V. harveyi produces a key siderophore called vibrioferrin. This important resource promotes the growth of V. rotiferianus, which cooccurs with V. harveyi in diseased oysters, and behaves as a cheater by benefiting from V. harveyi metabolite sharing. Our data show that cooperative behaviors contribute to synergy between bacterial and viral coinfecting partners. Additional cheating behaviors further shape the polymicrobial consortium. Controlling cooperative behaviors or countering their effects opens avenues for mitigating polymicrobial diseases.

Human Th17- and IgG3-associated autoimmunity induced by a translocating gut pathobiont.

Extraintestinal autoimmune diseases are multifactorial with translocating gut pathobionts implicated as instigators and perpetuators in mice. However, the microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. We show here that the translocating pathobiont Enterococcus gallinarum induces human IFNγ + Th17 differentiation and IgG3 subclass switch of anti- E. gallinarum RNA and correlating anti-human RNA autoantibody responses in patients with systemic lupus erythematosus and autoimmune hepatitis. Human Th17 induction by E. gallinarum is cell-contact dependent and involves TLR8-mediated human monocyte activation. In murine gnotobiotic lupus models, E. gallinarum translocation triggers IgG3 anti-RNA autoantibody titers that correlate with renal autoimmune pathophysiology and with disease activity in patients. Overall, we define cellular mechanisms of how a translocating pathobiont induces human T- and B-cell-dependent autoimmune responses, providing a framework for developing host- and microbiota-derived biomarkers and targeted therapies in extraintestinal autoimmune diseases. One Sentence Summary: Translocating pathobiont Enterococcus gallinarum promotes human Th17 and IgG3 autoantibody responses linked to disease activity in autoimmune patients.

A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations.

A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.

Emergence and clonal expansion of Vibrio aestuarianus lineages pathogenic for oysters in Europe.

Crassostrea gigas oysters represent a significant global food source with 4.7 million tons harvested per year. In 2001, the bacterium Vibrio aestuarianus subsp. francensis emerged as a pathogen that causes adult oyster mortality in France and Ireland. Its impact on oyster aquaculture has increased in Europe since its re-emergence in 2012. To better understand the evolutionary mechanisms leading to the emergence and persistence over time of this pathogen, we conducted a survey of mollusc diseases through national reference laboratories across Europe. We analysed 54 new genomes of Vibrio aestuarianus (Va) isolated from multiple environmental compartments since 2001, in areas with and without bivalve mortalities. We used a combination of comparative genomics and population genetics approaches and show that Va has a classical epidemic population structure from which the pathogenic Va francensis subspecies emerged and clonally expanded. Furthermore, we identified a specific cus-cop-containing island conferring copper resistance to Va francensis whose acquisition may have favoured the emergence of pathogenic lineages adapted and specialized to oysters.

A cell-penetrant peptide blocking C9ORF72-repeat RNA nuclear export reduces the neurotoxic effects of dipeptide repeat proteins.

Hexanucleotide repeat expansions in C9ORF72 are the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies have shown that the hexanucleotide expansions cause the noncanonical translation of C9ORF72 transcripts into neurotoxic dipeptide repeat proteins (DPRs) that contribute to neurodegeneration. We show that a cell-penetrant peptide blocked the nuclear export of C9ORF72-repeat transcripts in HEK293T cells by competing with the interaction between SR-rich splicing factor 1 (SRSF1) and nuclear export factor 1 (NXF1). The cell-penetrant peptide also blocked the translation of toxic DPRs in neurons differentiated from induced neural progenitor cells (iNPCs), which were derived from individuals carrying C9ORF72-linked ALS mutations. This peptide also increased survival of iNPC-differentiated C9ORF72-ALS motor neurons cocultured with astrocytes. Oral administration of the cell-penetrant peptide reduced DPR translation and rescued locomotor deficits in a Drosophila model of mutant C9ORF72-mediated ALS/FTD. Intrathecal injection of this peptide into the brains of ALS/FTD mice carrying a C9ORF72 mutation resulted in reduced expression of DPRs in mouse brains. These findings demonstrate that disrupting the production of DPRs in cellular and animal models of ALS/FTD might be a strategy to ameliorate neurodegeneration in these diseases.

Atypical TDP-43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP.

We describe an autosomal dominant, multi-generational, amyotrophic lateral sclerosis (ALS) pedigree in which disease co-segregates with a heterozygous p.Y374X nonsense mutation within TDP-43. Mislocalization of TDP-43 and formation of insoluble TDP-43-positive neuronal cytoplasmic inclusions is the hallmark pathology in >95% of ALS patients. Neuropathological examination of the single case for which CNS tissue was available indicated typical TDP-43 pathology within lower motor neurons, but classical TDP-43-positive inclusions were absent from motor cortex. The mutated allele is transcribed and translated in patient fibroblasts and motor cortex tissue, but overall TDP-43 protein expression is reduced compared to wild-type controls. Despite absence of TDP-43-positive inclusions we confirmed deficient TDP-43 splicing function within motor cortex tissue. Furthermore, urea fractionation and mass spectrometry of motor cortex tissue carrying the mutation revealed atypical TDP-43 protein species but not typical C-terminal fragments. We conclude that the p.Y374X mutation underpins a monogenic, fully penetrant form of ALS. Reduced expression of TDP-43 combined with atypical TDP-43 protein species and absent C-terminal fragments extends the molecular phenotypes associated with TDP-43 mutations and with ALS more broadly. Future work will need to include the findings from this pedigree in dissecting the mechanisms of TDP-43-mediated toxicity.

Functional Diversification of Oyster Big Defensins Generates Antimicrobial Specificity and Synergy against Members of the Microbiota.

Big defensins are two-domain antimicrobial peptides (AMPs) that have highly diversified in mollusks. Cg-BigDefs are expressed by immune cells in the oyster Crassostrea gigas, and their expression is dampened during the Pacific Oyster Mortality Syndrome (POMS), which evolves toward fatal bacteremia. We evaluated whether Cg-BigDefs contribute to the control of oyster-associated microbial communities. Two Cg-BigDefs that are representative of molecular diversity within the peptide family, namely Cg-BigDef1 and Cg-BigDef5, were characterized by gene cloning and synthesized by solid-phase peptide synthesis and native chemical ligation. Synthetic peptides were tested for antibacterial activity against a collection of culturable bacteria belonging to the oyster microbiota, characterized by 16S sequencing and MALDI Biotyping. We first tested the potential of Cg-BigDefs to control the oyster microbiota by injecting synthetic Cg-BigDef1 into oyster tissues and analyzing microbiota dynamics over 24 h by 16S metabarcoding. Cg-BigDef1 induced a significant shift in oyster microbiota ß-diversity after 6 h and 24 h, prompting us to investigate antimicrobial activities in vitro against members of the oyster microbiota. Both Cg-BigDef1 and Cg-BigDef5 were active at a high salt concentration (400 mM NaCl) and showed broad spectra of activity against bacteria associated with C. gigas pathologies. Antimicrobial specificity was observed for both molecules at an intra- and inter-genera level. Remarkably, antimicrobial spectra of Cg-BigDef1 and Cg-BigDef5 were complementary, and peptides acted synergistically. Overall, we found that primary sequence diversification of Cg-BigDefs has generated specificity and synergy and extended the spectrum of activity of this peptide family.

RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration.

Short repeated sequences of 3-6 nucleotides are causing a growing number of over 50 microsatellite expansion disorders, which mainly present with neurodegenerative features. Although considered rare diseases in relation to the relatively low number of cases, these primarily adult-onset conditions, often debilitating and fatal in absence of a cure, collectively pose a large burden on healthcare systems in an ageing world population. The pathological mechanisms driving disease onset are complex implicating several non-exclusive mechanisms of neuronal injury linked to RNA and protein toxic gain- and loss- of functions. Adding to the complexity of pathogenesis, microsatellite repeat expansions are polymorphic and found in coding as well as in non-coding regions of genes. They form secondary and tertiary structures involving G-quadruplexes and atypical helices in repeated GC-rich sequences. Unwinding of these structures by RNA helicases plays multiple roles in the expression of genes including repeat-associated non-AUG (RAN) translation of polymeric-repeat proteins with aggregating and cytotoxic properties. Here, we will briefly review the pathogenic mechanisms mediated by microsatellite repeat expansions prior to focus on the RNA helicases eIF4A, DDX3X and DHX36 which act as modifiers of RAN translation in C9ORF72-linked amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72-ALS/FTD) and Fragile X-associated tremor/ataxia syndrome (FXTAS). We will further review the RNA helicases DDX5/17, DHX9, Dicer and UPF1 which play additional roles in the dysregulation of RNA metabolism in repeat expansion disorders. In addition, we will contrast these with the roles of other RNA helicases such as DDX19/20, senataxin and others which have been associated with neurodegeneration independently of microsatellite repeat expansions. Finally, we will discuss the challenges and potential opportunities that are associated with the targeting of RNA helicases for the development of future therapeutic approaches.

C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons.

Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic ß-sheet fibrils in vitro. To dissect the process of cell-to-cell DPR transmission, we closely follow the fate of poly-GA DPRs in either their oligomeric or fibrillized form after administration in the cell culture medium. We observe that poly-GA DPRs are taken up via dynamin-dependent and -independent endocytosis, eventually converging at the lysosomal compartment and leading to axonal swellings in neurons. We then use a co-culture system to demonstrate astrocyte-to-motor neuron DPR propagation, showing that astrocytes may internalise and release aberrant peptides in disease pathogenesis. Overall, our results shed light on the mechanisms of poly-GA cellular uptake and propagation, suggesting lysosomal impairment as a possible feature underlying the cellular pathogenicity of these DPR species.

SMN-deficient cells exhibit increased ribosomal DNA damage.

Spinal muscular atrophy, the leading genetic cause of infant mortality, is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. SMN is a multifunctional protein that is implicated in numerous cytoplasmic and nuclear processes. Recently, increasing attention is being paid to the role of SMN in the maintenance of DNA integrity. DNA damage and genome instability have been linked to a range of neurodegenerative diseases. The ribosomal DNA (rDNA) represents a particularly unstable locus undergoing frequent breakage. Instability in rDNA has been associated with cancer, premature ageing syndromes, and a number of neurodegenerative disorders. Here, we report that SMN-deficient cells exhibit increased rDNA damage leading to impaired ribosomal RNA synthesis and translation. We also unravel an interaction between SMN and RNA polymerase I. Moreover, we uncover an spinal muscular atrophy motor neuron-specific deficiency of DDX21 protein, which is required for resolving R-loops in the nucleolus. Taken together, our findings suggest a new role of SMN in rDNA integrity.

[Learnings from the use of CEdRIC strategy in the context of COVID-19 pandemic]. / Face à la COVID-19. Utilisation de la stratégie CEdRIC dans le contexte de la pandémie à coronavirus : retour d'expérience.

This article relates the experience of mobilisation of the CEdRIC strategy by health promotion staff of the Province of Liège, Belgium between June and September 2020. The perception of the beneficiaries is also approached. Four key messages are discussed in the article: the adjustment of a brief educational intervention strategy to the context of the pandemic and integration into primary care; the need for the citizen to be heard and accompanied in times of crisis; the need to go beyond information to health education embedded in a health promotion approach; the role that a structure such as the Province of Liège can play in the health promotion landscape. This article relates the experience of mobilisation of the CEdRIC strategy by health promotion staff of the Province of Liège, through the eyes of the beneficiaries (citizen) contacted by telephone in the days following the intervention. The results indicate an over-information concerning the rules to be respected and a good knowledge of preventive measures. The participants consider these measures useful, easy to apply and declare that they have a role to play in the fight against the pandemic. Nevertheless, not all of the recommendations made by the government are implemented by all participants. Future research should focus on adherence to preventive measures and the factors that can influence this adherence so that future and sustainable actions can be put in place.

La pandémie de coronavirus (COVID-19) a mis en évidence l'importance de développer des stratégies de prévention pour éviter la propagation du virus en adoptant des mesures d'autogestion sanitaires. La stratégie CEdRIC consiste en un protocole en 5 étapes visant à aider le personnel soignant des centres de dépistage à structurer leur communication afin d'éduquer brièvement les citoyens sur les conduites à tenir pour préserver leur santé et prévenir la propagation du virus. Dans cet article est relatée l'expérience de mobilisation de la stratégie CEdRIC menée entre juin et septembre 2020 par du personnel de promotion de la Santé de la Province de Liège. La perception des bénéficiaires est également approchée. Quatre messages clés sont discutés dans l'article : l'ajustement d'une stratégie d'intervention éducative brève au contexte de la pandémie et d'intégration en première ligne de soins; le besoin pour le citoyen d'être entendu et accompagné en temps de crise; la nécessité de dépasser l'information pour passer à de l'éducation en santé inscrite dans une approche de promotion de la santé; le rôle qu'une structure comme la Province de Liège peut tenir dans le paysage de la promotion de la Santé.

Prevalence and polymorphism of a mussel transmissible cancer in Europe.

Transmissible cancers are parasitic malignant cell lineages that have acquired the ability to infect new hosts from the same species, or sometimes related species. First described in dogs and Tasmanian devils, transmissible cancers were later discovered in some marine bivalves affected by a leukaemia-like disease. In Mytilus mussels, two lineages of bivalve transmissible neoplasia (BTN) have been described to date (MtrBTN1 and MtrBTN2), both of which emerged in a Mytilus trossulus founder individual. Here, we performed extensive screening of genetic chimerism, a hallmark of transmissible cancer, by genotyping 106 single nucleotide polymorphisms of 5,907 European Mytilus mussels. Genetic analysis allowed us to simultaneously obtain the genotype of hosts - Mytilus edulis, M. galloprovincialis or hybrids - and the genotype of tumours of heavily infected individuals. In addition, a subset of 222 individuals were systematically genotyped and analysed by histology to screen for possible nontransmissible cancers. We detected MtrBTN2 at low prevalence in M. edulis, and also in M. galloprovincialis and hybrids although at a much lower prevalence. No MtrBTN1 or new BTN were found, but eight individuals with nontransmissible neoplasia were observed at a single polluted site on the same sampling date. We observed a diversity of MtrBTN2 genotypes that appeared more introgressed or more ancestral than MtrBTN1 and reference healthy M. trossulus individuals. The observed polymorphism is probably due to somatic null alleles caused by structural variations or point mutations in primer-binding sites leading to enhanced detection of the host alleles. Despite low prevalence, two sublineages divergent by 10% fixed somatic null alleles and one nonsynonymous mtCOI (mitochondrial cytochrome oxidase I) substitution are cospreading in the same geographical area, suggesting a complex diversification of MtrBTN2 since its emergence and host species shift.

Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation.

Disruption to protein homeostasis caused by lysosomal dysfunction and associated impairment of autophagy is a prominent pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The most common genetic cause of ALS/FTD is a G4C2 hexanucleotide repeat expansion in C9orf72 (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 repeat transcripts gives rise to dipeptide repeat (DPR) proteins that have been shown to be toxic and may contribute to disease etiology. Genetic variants in TMEM106B have been associated with frontotemporal lobar degeneration with TDP-43 pathology and disease progression in C9ALS/FTD. TMEM106B encodes a lysosomal transmembrane protein of unknown function that is involved in various aspects of lysosomal biology. How TMEM106B variants affect C9ALS/FTD is not well understood but has been linked to changes in TMEM106B protein levels. Here, we investigated TMEM106B function in the context of C9ALS/FTD DPR pathology. We report that knockdown of TMEM106B expression exacerbates the accumulation of C9ALS/FTD-associated cytotoxic DPR proteins in cell models expressing RAN-translated or AUG-driven DPRs as well as in C9ALS/FTD-derived iAstrocytes with an endogenous G4C2 expansion by impairing autophagy. Loss of TMEM106B caused a block late in autophagy by disrupting autophagosome to autolysosome maturation which coincided with impaired lysosomal acidification, reduced cathepsin activity, and juxtanuclear clustering of lysosomes. Lysosomal clustering required Rab7A and coincided with reduced Arl8b-mediated anterograde transport of lysosomes to the cell periphery. Increasing Arl8b activity in TMEM106B-deficient cells not only restored the distribution of lysosomes, but also fully rescued autophagy and DPR protein accumulation. Thus, we identified a novel function of TMEM106B in autophagosome maturation via Arl8b. Our findings indicate that TMEM106B variants may modify C9ALS/FTD by regulating autophagic clearance of DPR proteins. Caution should therefore be taken when considering modifying TMEM106B expression levels as a therapeutic approach in ALS/FTD.