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Varroa destructor (Anderson and Trueman) is known as a major pest of Apis mellifera L, especially in the Northern Hemisphere where its effects can be deleterious. As an obligate parasite, this mite relies entirely on its host to reproduce and complete its cycle. Studies focusing on isolated organs are needed to better comprehend this organism. To conduct such targeted molecular or physiological studies, the dissection of V. destructor mites is crucial as it allows the extraction of specific organs. Here, we propose a technical article showing detailed steps of females V. destructor dissection, illustrated with pictures and videos. These illustrated guidelines will represent a helpful tool to go further in V. destructor research.

Resume Introduction Au premier juillet 2020, l’epidemie de SARS-CoV2 avait concerne plus de 200 pays, infecte 10 millions de personnes et etait la cause de 508 000 deces dans le monde. Peu de donnees existent concernant les plus de 75 ans, notamment lorsqu’ils ont des troubles cognitifs et du comportement. Objectif Presenter les caracteristiques des symptomes observes dans deux populations de patients hospitalises : les patients en unites protegees « Alzheimer » et les patients « standards » hospitalises en unite dediee COVID, et comparer les taux de mortalite. Materiel et methode Etude retrospective incluant les patients de plus de 65 ans hospitalises a Paul-Brousse du 13 mars au 15 avril 2020 en unite Alzheimer et en unite COVID, et ayant une infection au Sars-CoV2 confirmee par RT-PCR ou serologie. Recueil de donnees a partir des dossiers medicaux concernant le terrain du patient, les traitements pris au long cours, les donnees cliniques et biologiques pendant l’infection. Resultats Cent soixante-dix-huit patients (87 ans [82 ; 91], 67 % de femmes) ont ete inclus dont 60 patients « Alzheimer » (86 ans [81 ; 88,25], 68 % de femmes) et 118 patients « standards » (88 ans [83,25 ; 92], 66 % de femmes). Le groupe standard etait plus âge et avait un score de Charlson plus eleve. Le taux de mortalite n’etait pas significativement different entre les 2 groupes (p = 0,09). Cliniquement, le groupe « standard » presentait une infection plus grave que le groupe « Alzheimer » : le score qSOFA et le debit d’oxygene maximum necessaire etaient plus eleves. De meme, biologiquement, le groupe « standard » presentait une lymphopenie non observee dans le groupe « Alzheimer ». En revanche, les patients du groupe « Alzheimer » consommaient significativement plus de neuroleptiques. Conclusion Le taux de mortalite etait le meme chez les patients en unites Alzheimer et en unite COVID, avec cependant une tendance a y avoir plus de deces dans le groupe « standard » (27 % vs 17 %, p = 0,09). Une etude plus puissante serait necessaire pou evaluer l’eventuel role protecteur des neuroleptiques.

International audience; Background: Varroa destructor is the major ectoparasite of the western honey bee (Apis mellifera). Through both its parasitic life-cycle and its role as a vector of viral pathogens, it can cause major damage to honey bee colonies. The deformed wing virus (DWV) is the most common virus transmitted by this ectoparasite, and the mite is correlated to increased viral prevalence and viral loads in infested colonies. DWV variants A and B (DWV-A and DWV-B, respectively) are the two major DWV variants, and they differ both in their virulence and transmission dynamics. Methods: We studied the transmission of DWV between bees, parasitic mites and their offspring by quantifying DWV loads in bees and mites collected in in vitro and in situ environments. In vitro, we artificially transmitted DWV-A to mites and quantified both DWV-A and DWV-B in mites and bees. In situ, we measured the natural presence of DWV-B in bees, mites and mites' offspring. Results: Bee and mite viral loads were correlated, and mites carrying both variants were associated with higher mortality of the infected host. Mite infestation increased the DWV-B loads and decreased the DWV-A loads in our laboratory conditions. In situ, viral quantification in the mite offspring showed that, after an initially non-infected egg stage, the DWV-B loads were more closely correlated with the foundress (mother) mites than with the bee hosts. Conclusions: The association between mites and DWV-B was highlighted in this study. The parasitic history of a mite directly impacts its DWV infection potential during the rest of its life-cycle (in terms of variant and viral loads). Regarding the mite's progeny, we hypothesize that the route of contamination is likely through the feeding site rather than by vertical transmission, although further studies are needed to confirm this hypothesis.

Dendritic cells (DCs) encompass several cell subsets that collaborate to initiate and regulate immune responses. Proper DC localization determines their function and requires the tightly controlled action of chemokine receptors. All DC subsets express CXCR4, but the genuine contribution of this receptor to their biology has been overlooked. We addressed this question using natural CXCR4 mutants resistant to CXCL12-induced desensitization and harboring a gain of function that cause the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS), a rare immunodeficiency associated with high susceptibility to the pathogenesis of human papillomavirus (HPV). We report a reduction in the number of circulating plasmacytoid DCs (pDCs) in WHIM patients, whereas that of conventional DCs is preserved. This pattern was reproduced in an original mouse model of WS, enabling us to show that the circulating pDC defect can be corrected upon CXCR4 blockade and that pDC differentiation and function are preserved, despite CXCR4 dysfunction. We further identified proper CXCR4 signaling as a critical checkpoint for Langerhans cell and DC migration from the skin to lymph nodes, with corollary alterations of their activation state and tissue inflammation in a model of HPV-induced dysplasia. Beyond providing new hypotheses to explain the susceptibility of WHIM patients to HPV pathogenesis, this study shows that proper CXCR4 signaling establishes a migration threshold that controls DC egress from CXCL12-containing environments and highlights the critical and subset-specific contribution of CXCR4 signal termination to DC biology.

Varroa destructor is the major ectoparasite of the western honey bee (Apis mellifera). Through both its parasitic life-cycle and its role as a vector of viral pathogens, it can cause major damage to honey bee colonies. The deformed wing virus (DWV) is the most common virus transmitted by this ectoparasite, and the mite is correlated to increased viral prevalence and viral loads in infested colonies. DWV variants A and B (DWV-A and DWV-B, respectively) are the two major DWV variants, and they differ both in their virulence and transmission dynamics.We studied the transmission of DWV between bees, parasitic mites and their offspring by quantifying DWV loads in bees and mites collected in in vitro and in situ environments. In vitro, we artificially transmitted DWV-A to mites and quantified both DWV-A and DWV-B in mites and bees. In situ, we measured the natural presence of DWV-B in bees, mites and mites' offspring.Bee and mite viral loads were correlated, and mites carrying both variants were associated with higher mortality of the infected host. Mite infestation increased the DWV-B loads and decreased the DWV-A loads in our laboratory conditions. In situ, viral quantification in the mite offspring showed that, after an initially non-infected egg stage, the DWV-B loads were more closely correlated with the foundress (mother) mites than with the bee hosts.The association between mites and DWV-B was highlighted in this study. The parasitic history of a mite directly impacts its DWV infection potential during the rest of its life-cycle (in terms of variant and viral loads). Regarding the mite's progeny, we hypothesize that the route of contamination is likely through the feeding site rather than by vertical transmission, although further studies are needed to confirm this hypothesis.

International audience; The ecology of the young stages of allis shad Alosa alosa is poorly documented, although they can be exposed to many pressures during their freshwater phase and their downstream migration. When passing through systems such as the Gironde-Garonne-Dordogne watershed (GGD, SW France), they can be subjected to high temperatures and low levels of oxygen (hypoxia). The aim of this work is to assess the tolerance of young Alosa alosa at four ages (c. 10, 30, 60 and 85 days old) by challenging them to different temperatures (18, 22, 26 and 28C) together with decreasing oxygen saturation levels (from 100% to 30%). Survival of the 10-day-old individuals was not influenced by oxy-thermic conditions, but high stress levels were detected and perhaps this age class was too fragile regarding the constraint of the experimental design. Survival at 30 and at 60 days old was negatively influenced by the highest temperatures tested alone (from 26C and from 28C, respectively) but no effect was detected at 85 days old up to 28C. A combined effect of temperature and oxygen level was highlighted, with heat accelerating survival decrease when associated with oxygen level depletion: essentially, survival was critical (

Simple Summary Varroa destructor (Anderson and Trueman) is known as a major pest of Apis mellifera L. Research about this parasite is very active and dynamic, yet only a few studies focus on an organ in particular. These targeted works are very important as they can enhance our comprehension of the mite, as they did for its host. Dissection is unavoidable when trying to isolate a specific organ. This technical article aims to give illustrated guidelines to conduct female V. destructor dissection. Thanks to photos and videos, this work will constitute a helpful tool to anyone interested in V. destructor dissection, anatomy, or organ function. Abstract Varroa destructor (Anderson and Trueman) is known as a major pest of Apis mellifera L, especially in the Northern Hemisphere where its effects can be deleterious. As an obligate parasite, this mite relies entirely on its host to reproduce and complete its cycle. Studies focusing on isolated organs are needed to better comprehend this organism. To conduct such targeted molecular or physiological studies, the dissection of V. destructor mites is crucial as it allows the extraction of specific organs. Here, we propose a technical article showing detailed steps of females V. destructor dissection, illustrated with pictures and videos. These illustrated guidelines will represent a helpful tool to go further in V. destructor research.

Simple Summary Varroa destructor is a parasitic organism feeding and living among honeybees. It transmits viruses like the Deformed Wing Virus which can lead to the decline and death of the colony. Many treatments have been developed over the years like formamidine amitraz, pyrethroid tau-fluvalinate, organophosphate coumaphos or even acids like formic and oxalic to control the spread of the mite. However, none of this solution provides long-term sustainability for honeybees and no resistance from V. destructor. Therefore, the development of alternative tools remains open. This will require the combination of both laboratory and field results through an integrative approach based on the identification of V. destructor health biomarkers. Here we review what has been done and what can be done from the laboratory to the field against the parasitic pressure held on honeybees. Abstract Varroa destructor is a real challenger for beekeepers and scientists: fragile out of the hive, tenacious inside a bee colony. From all the research done on the topic, we have learned that a better understanding of this organism in its relationship with the bee but also for itself is necessary. Its biology relies mostly on semiochemicals for reproduction, nutrition, or orientation. Many treatments have been developed over the years based on hard or soft acaricides or even on biocontrol techniques. To date, no real sustainable solution exists to reduce the pressure of the mite without creating resistances or harming honeybees. Consequently, the development of alternative disruptive tools against the parasitic life cycle remains open. It requires the combination of both laboratory and field results through a holistic approach based on health biomarkers. Here, we advocate for a more integrative vision of V. destructor research, where in vitro and field studies are more systematically compared and compiled. Therefore, after a brief state-of-the-art about the mite’s life cycle, we discuss what has been done and what can be done from the laboratory to the field against V. destructor through an integrative approach.

Understanding the mechanisms by which dendritic cells (DC) regulate immunity is essential. DC reside in peripheral tissues, including the skin. Within their tissue of residence, immature DC alternate non-oriented migration phases with antigen capture (AG) phases. In this context, migration is in competition for actin stocks with AG capture processes, such as macropinocytosis. Once activated in response to danger signals, macropinocytosis is inhibited and DC become able to migrate rapidly and in a chemokine-dependent way (e.g. toward CXCL12/CCL21) to lymphoid organs (LO). During my thesis, I characterized the contribution of the Glucocorticoid Induced Leucine Zipper (GILZ) protein and the chemokine receptor CXCR4 to the control of DC migration, the mechanisms associated with this control and the pathophysiological consequences of a deregulation of the expression or function of these factors. I have used two mouse models: 1- A model of Glucocorticoid-Induced Leucine Zipper Protein (GILZ) deletion in DC (GILZko). The previous work of my team has shown that the level of GILZ expression in DC controls their macropinocytosis. 2- A murine model of gain of function for the chemokine receptor of CXCL12: CXCR4. Therefore, I wondered if the GILZko DC and the CXCR4 gain of function DC (CXCR4+/1013) showed an alteration in their in vivo migration capacity. In FITC painting experiments, I demonstrated that GILZko DC and CXCR4+/1013 DC migrate less efficiently than Control DC (CTRL) to the LO. This observation is associated with a constitutive defect in the number of migrating DC in LO in CXCR4+/1013 mice, but not in GILZko mice. To better characterize the impact of GILZ deletion, I studied the migration speed and the ability of GILZko DC to respond to chemokine gradients in vitro. I demonstrated that immature GILZko DC migrate slower than their controls, in direct correlation with increased macropinocytosis. In addition, GILZko DC respond less well to CXCL12 (immature DC) and CCL21 (activated DC) chemokines than CTRL DC. As cytosolic calcium entry into DC is a central process in the regulation of chemotaxis and cell motricity, I the investigated the role of GILZ in controlling the cytosolic calcium entry into these cells. I have shown, for the first time in DC, that GILZ deletion reduces cytosolic calcium concentration and influx. This phenotype is reproducible in CTRL DC by pharmacological inhibition of a glucocorticoid-induced kinase. Finally, the analysis of the consequences of reduced migration from skin DC to LO in our models revealed a worsening of skin inflammation in models of delayed hypersensitivity or chronic inflammation. In conclusion, my work provides new insights on a key process in the establishment of tolerance and immune responses. It demonstrates on the one hand the importance of desensitization of CXCR4 in cutaneous DC to allow them to leave the skin, and on the other hand the involvement of GILZ in regulating the speed and direction of DC migration, according to a mechanism that might depend on the control of calcium responses. Thus, the decrease in GILZ expression in DC, particularly during inflammation, might inhibit their calcium-dependent function. The increased expression of GILZ in DC is known to promote the accumulation of regulatory T cells at the expense of effector T cells. My work suggests that decreasing GILZ expression in DC may not be sufficient to make them efficient in activating T cells in vivo.; Comprendre par quels mécanismes les cellules dendritiques (DC) régulent l’immunité est essentiel. Les DC résident dans les tissus périphériques et notamment la peau. Au sein de leur tissu de résidence, les DC immatures alternent des phases de migration non orientée avec des phases de capture des antigènes (AG). Dans ce contexte, la migration est en compétition pour les stocks d’actine avec les processus de capture des AG, comme la macropinocytose. Une fois activées en réponse à des signaux de danger, la macropinocytose est inhibée et les DC deviennent capables de migrer rapidement et de manière orientée, dépendante de chimiokines (e.g. CXCL12/CCL21), vers les organes lymphoïdes (OL). Au cours de ma thèse, j’ai caractérisé la contribution la protéine Glucocorticoid Induced Leucine Zipper (GILZ) et du récepteur de chimiokine CXCR4 au contrôle de la migration des DC, les mécanismes associés et les conséquences physiopathologiques d’une dérégulation de l’expression ou de la fonction de ces facteurs. J’ai utilisé deux modèles murins : 1- Un modèle de délétion de la protéine Glucocorticoid-Induced Leucine Zipper (GILZ) dans les DC (GILZko). Les travaux de mon équipe avaient précédemment démontré que le niveau d’expression de GILZ dans les DC contrôle leur macropinocytose. 2- Un modèle murin de gain de fonction du chimiorécepteur à CXCL12 : CXCR4. Ainsi, j’ai cherché à savoir si les DC GILZko et les DC CXCR4 gain de fonction (CXCR4+/1013) présentaient une altération de leur capacité de migration in vivo. Dans des expériences de FITC painting j’ai démontré que les DC GILZko et CXCR4+/1013 migrent moins efficacement que les DC contrôles (CTRL) aux OL. Cette observation est associée à un défaut constitutif du nombre de DC migrantes dans les OL des souris CXCR4+/1013 mais pas ceux des souris GILZko. Pour mieux caractériser l’impact de la délétion de GILZ, j’ai étudié d’une part la vitesse de migration et d’autre part la capacité à répondre aux gradients de chimiokines des DC GILZko. J’ai démontré que les DC GILZko immatures migrent moins vite que leurs contrôles, en corrélation directe avec une macropinocytose accrue. De plus, les DC GILZko répondent moins bien aux chimiokines CXCL12 (DC immatures) et CCL21 (DC activées) que les DC CTRL. L’entrée calcique cytosolique dans les DC étant un processus central pour la chimiotaxie et la motricité des cellules, j’ai ensuite étudié le rôle de GILZ dans le contrôle de l’influx calcique cytosolique de ces cellules. J’ai montré, pour la première fois dans les DC, que la délétion de GILZ réduit les concentration et influx calciques cytosoliques, selon un mécanisme pharmacologiquement reproductible dans les DC CTRL par l’inhibition d’une kinase induite par les glucocorticoïdes. Finalement, l’analyse des conséquences de la réduction de la migration des DC vers les OL dans nos modèles a révélé une aggravation de l’inflammation cutanée dans des modèles d’hypersensibilité retardée ou d’inflammation chronique. En conclusion, mes travaux apportent de nouvelles connaissances sur un processus clé dans la mise en place de la tolérance et des réponses immunitaires. Ils démontrent d’une part l’importance de la désensibilisation de CXCR4 dans les DC cutanée pour leur permettre de quitter la peau et d’autre part l’implication de GILZ dans la régulation de la vitesse et de l’orientation de la migration des DC, selon un mécanisme qui pourrait dépendre du contrôle des flux calciques. Ainsi, la diminution de l’expression de GILZ dans les DC, notamment aux cours d’inflammation, pourrait inhiber leur fonction dépendante du calcium. L’expression accrue de GILZ dans les DC est connue pour favoriser l’accumulation de lymphocytes T régulateurs au détriment des effecteurs. Mes travaux tendent à montrer que faire diminuer l’expression de GILZ dans les DC pourrait ne pas suffire à les rendre efficaces pour activer les lymphocytes T in vivo.

Understanding the mechanisms by which dendritic cells (DC) regulate immunity is essential. DC reside in peripheral tissues, including the skin. Within their tissue of residence, immature DC alternate non-oriented migration phases with antigen capture (AG) phases. In this context, migration is in competition for actin stocks with AG capture processes, such as macropinocytosis. Once activated in response to danger signals, macropinocytosis is inhibited and DC become able to migrate rapidly and in a chemokine-dependent way (e.g. toward CXCL12/CCL21) to lymphoid organs (LO). During my thesis, I characterized the contribution of the Glucocorticoid Induced Leucine Zipper (GILZ) protein and the chemokine receptor CXCR4 to the control of DC migration, the mechanisms associated with this control and the pathophysiological consequences of a deregulation of the expression or function of these factors. I have used two mouse models: 1- A model of Glucocorticoid-Induced Leucine Zipper Protein (GILZ) deletion in DC (GILZko). The previous work of my team has shown that the level of GILZ expression in DC controls their macropinocytosis. 2- A murine model of gain of function for the chemokine receptor of CXCL12: CXCR4. Therefore, I wondered if the GILZko DC and the CXCR4 gain of function DC (CXCR4+/1013) showed an alteration in their in vivo migration capacity. In FITC painting experiments, I demonstrated that GILZko DC and CXCR4+/1013 DC migrate less efficiently than Control DC (CTRL) to the LO. This observation is associated with a constitutive defect in the number of migrating DC in LO in CXCR4+/1013 mice, but not in GILZko mice. To better characterize the impact of GILZ deletion, I studied the migration speed and the ability of GILZko DC to respond to chemokine gradients in vitro. I demonstrated that immature GILZko DC migrate slower than their controls, in direct correlation with increased macropinocytosis. In addition, GILZko DC respond less well to CXCL12 (immature DC) and CCL21 (activated DC) chemokines than CTRL DC. As cytosolic calcium entry into DC is a central process in the regulation of chemotaxis and cell motricity, I the investigated the role of GILZ in controlling the cytosolic calcium entry into these cells. I have shown, for the first time in DC, that GILZ deletion reduces cytosolic calcium concentration and influx. This phenotype is reproducible in CTRL DC by pharmacological inhibition of a glucocorticoid-induced kinase. Finally, the analysis of the consequences of reduced migration from skin DC to LO in our models revealed a worsening of skin inflammation in models of delayed hypersensitivity or chronic inflammation. In conclusion, my work provides new insights on a key process in the establishment of tolerance and immune responses. It demonstrates on the one hand the importance of desensitization of CXCR4 in cutaneous DC to allow them to leave the skin, and on the other hand the involvement of GILZ in regulating the speed and direction of DC migration, according to a mechanism that might depend on the control of calcium responses. Thus, the decrease in GILZ expression in DC, particularly during inflammation, might inhibit their calcium-dependent function. The increased expression of GILZ in DC is known to promote the accumulation of regulatory T cells at the expense of effector T cells. My work suggests that decreasing GILZ expression in DC may not be sufficient to make them efficient in activating T cells in vivo., Comprendre par quels mécanismes les cellules dendritiques (DC) régulent l’immunité est essentiel. Les DC résident dans les tissus périphériques et notamment la peau. Au sein de leur tissu de résidence, les DC immatures alternent des phases de migration non orientée avec des phases de capture des antigènes (AG). Dans ce contexte, la migration est en compétition pour les stocks d’actine avec les processus de capture des AG, comme la macropinocytose. Une fois activées en réponse à des signaux de danger, la macropinocytose est inhibée et les DC deviennent capables de migrer rapidement et de manière orientée, dépendante de chimiokines (e.g. CXCL12/CCL21), vers les organes lymphoïdes (OL). Au cours de ma thèse, j’ai caractérisé la contribution la protéine Glucocorticoid Induced Leucine Zipper (GILZ) et du récepteur de chimiokine CXCR4 au contrôle de la migration des DC, les mécanismes associés et les conséquences physiopathologiques d’une dérégulation de l’expression ou de la fonction de ces facteurs. J’ai utilisé deux modèles murins : 1- Un modèle de délétion de la protéine Glucocorticoid-Induced Leucine Zipper (GILZ) dans les DC (GILZko). Les travaux de mon équipe avaient précédemment démontré que le niveau d’expression de GILZ dans les DC contrôle leur macropinocytose. 2- Un modèle murin de gain de fonction du chimiorécepteur à CXCL12 : CXCR4. Ainsi, j’ai cherché à savoir si les DC GILZko et les DC CXCR4 gain de fonction (CXCR4+/1013) présentaient une altération de leur capacité de migration in vivo. Dans des expériences de FITC painting j’ai démontré que les DC GILZko et CXCR4+/1013 migrent moins efficacement que les DC contrôles (CTRL) aux OL. Cette observation est associée à un défaut constitutif du nombre de DC migrantes dans les OL des souris CXCR4+/1013 mais pas ceux des souris GILZko. Pour mieux caractériser l’impact de la délétion de GILZ, j’ai étudié d’une part la vitesse de migration et d’autre part la capacité à répondre aux gradients de chimiokines des DC GILZko. J’ai démontré que les DC GILZko immatures migrent moins vite que leurs contrôles, en corrélation directe avec une macropinocytose accrue. De plus, les DC GILZko répondent moins bien aux chimiokines CXCL12 (DC immatures) et CCL21 (DC activées) que les DC CTRL. L’entrée calcique cytosolique dans les DC étant un processus central pour la chimiotaxie et la motricité des cellules, j’ai ensuite étudié le rôle de GILZ dans le contrôle de l’influx calcique cytosolique de ces cellules. J’ai montré, pour la première fois dans les DC, que la délétion de GILZ réduit les concentration et influx calciques cytosoliques, selon un mécanisme pharmacologiquement reproductible dans les DC CTRL par l’inhibition d’une kinase induite par les glucocorticoïdes. Finalement, l’analyse des conséquences de la réduction de la migration des DC vers les OL dans nos modèles a révélé une aggravation de l’inflammation cutanée dans des modèles d’hypersensibilité retardée ou d’inflammation chronique. En conclusion, mes travaux apportent de nouvelles connaissances sur un processus clé dans la mise en place de la tolérance et des réponses immunitaires. Ils démontrent d’une part l’importance de la désensibilisation de CXCR4 dans les DC cutanée pour leur permettre de quitter la peau et d’autre part l’implication de GILZ dans la régulation de la vitesse et de l’orientation de la migration des DC, selon un mécanisme qui pourrait dépendre du contrôle des flux calciques. Ainsi, la diminution de l’expression de GILZ dans les DC, notamment aux cours d’inflammation, pourrait inhiber leur fonction dépendante du calcium. L’expression accrue de GILZ dans les DC est connue pour favoriser l’accumulation de lymphocytes T régulateurs au détriment des effecteurs. Mes travaux tendent à montrer que faire diminuer l’expression de GILZ dans les DC pourrait ne pas suffire à les rendre efficaces pour activer les lymphocytes T in vivo.

My interest in playing sports in the forest and the growing importance of Lyme disease, caused by Borrelia burgdorferi transmitted by a tick of the genus Ixodes, led me to look for a link between the both. Through a questionnaire, distributed in different sport clubs in the forest, it appeared that the risk of contracting this infectious disease is higher for these athletes (6.3%). Clinical and biological diagnoses are difficult to make because the symptoms are varied and inconsistent and the paraclinical tests are unreliable. Answers obtained, good behavior can reduce the risk of being bitten by a tick, such as wearing long trousers with a long or short sleeve shirt of cold colors, not applying moisturizing lotion, waxing (shaving) legs and arms, practicing sport alone. In addition, sport practices seem more protective than others so during the walk, the athlete risks less being bitten by a tick than during a mountain bike ride which is lower risk than the race walk. However, some biases may exist (selection, classification, diagnosis). Finally, what you need to remember to protect yourself against Lyme disease, in addition to the behaviors explained before, is the check of the body, the rapid removal of the tick and the auscultation of a doctor as soon as the appearance of clinical signs more or less suggestive of this disease.; Mon attrait pour la pratique de sports en milieu forestier et l’importance grandissante de la maladie de Lyme, due à Borrelia burgdorferi transmise par une tique du genre Ixodes, m’ont poussée à rechercher l’existence d’un lien entre les deux. Grâce à un questionnaire, diffusé au sein de différents clubs de sports en forêt, il est apparu que ces sportifs étaient plus à risque de contracter cette maladie infectieuse (6,3%). Les diagnostics tant cliniques que biologiques sont difficiles à poser car les symptômes sont variés et inconstants et que les tests paracliniques sont peu fiables. Des réponses obtenues, certains comportements réduisant le risque de se faire mordre par une tique sont apparus tels que porter un pantalon long avec un haut à manches longues ou courtes de préférence de couleurs froides, ne pas appliquer d’agent hydratant, s’épiler jambes et bras, pratiquer son sport en solitaire. De plus, certaines pratiques sportives semblent plus protectrices que d’autres ainsi durant la marche, le sportif est moins à risque de se faire mordre par une tique que lors d’une sortie VTT qui elle-même est moins à risque que la course à pied. Toutefois, certains biais peuvent exister (sélection, classement, diagnostic). Enfin, ce qu’il faut retenir pour se protéger efficacement contre la maladie de Lyme, en plus des comportements vus plus haut, c’est une observation du corps, le retrait rapide de la tique et la consultation d’un médecin dès l’apparition de signes cliniques plus ou moins évocateurs de cette maladie.

Dendritic cells (DCs) are key antigen-presenting cells that control the induction of both tolerance and immunity. Understanding the molecular mechanisms regulating DCs commitment toward a regulatory- or effector-inducing profile is critical for better designing prophylactic and therapeutic approaches. Initially identified in dexamethasone-treated thymocytes, the glucocorticoid-induced leucine zipper (GILZ) protein has emerged as a critical factor mediating most, but not all, glucocorticoids effects in both non-immune and immune cells. This intracellular protein exerts pleiotropic effects through interactions with transcription factors and signaling proteins, thus modulating signal transduction and gene expression. GILZ has been reported to control the proliferation, survival, and differentiation of lymphocytes, while its expression confers anti-inflammatory phenotype to monocytes and macrophages. In the past twelve years, a growing set of data has also established that GILZ expression in DCs is a molecular switch controlling their T-cell-priming capacity. Here, after a brief presentation of GILZ isoforms and functions, we summarize current knowledge regarding GILZ expression and regulation in DCs, in both health and disease. We further present the functional consequences of GILZ expression on DCs capacity to prime effector or regulatory T-cell responses and highlight recent findings pointing to a broader role of GILZ in the fine tuning of antigen capture, processing, and presentation by DCs. Finally, we discuss future prospects regarding the possible roles for GILZ in the control of DCs function in the steady state and in the context of infections and chronic pathologies.

In France, only a third of demented patients have an established diagnostic of dementia. Hospitalization is often an opportunity to perform a diagnostic of dementia. Real benefits for patients of such a diagnostic process are unknown. The objective of the study was to observe prognosis of elderly patients hospitalized in geriatric courses in terms of mortality, hospitalization rate and entry into an institution. This was a monocentric prospective study with a one-year follow-up of 90 patients hospitalized in an acute geriatric ward with either dementia known by general practitioner, either diagnosed during the hospitalization according to DSM IV criteria. A one year follow-up by phone has been conducted. From a consecutive set of 159 inpatients for 18 weeks, we included in this study 49 patients with a known dementia (group 1, mean age 85.7±4.6 years, mean Mini-mental state examination (MMSE) score 12.4±6.2) and 41 patients with dementia diagnosed during hospitalization (group 2, mean age 88.4±6.4 years, mean MMSE score 16.1±6.5). Differences between the two groups were significant for age (p0.03) and MMSE score (p0.02). One-year mortality rate was near 30% in the 2 groups. Rate of institutionalization was 33% in group 1 and 49% in group 2 (not statistically significant). There was a significant difference in number of days spent at home between group 1 and group 2, respectively 190.9±159.9 days vs 111.1±148.1 days (p0.03). Demented patients previously diagnosed lived longer at home at one year than patients newly diagnosed. These results tend to support the diagnosis of dementia in very elderly patients with multiple comorbidities. Conditions of living at home, in particular the quality of life, should be the object of further studies.

Ag sampling is a key process in dendritic cell (DC) biology. DCs use constitutive macropinocytosis, receptor-mediated endocytosis, and phagocytosis to capture exogenous Ags for presentation to T cells. We investigated the mechanisms that regulate Ag uptake by DCs in the steady-state and after a short-term LPS exposure in vitro and in vivo. We show that the glucocorticoid-induced leucine zipper protein (GILZ), already known to regulate effector versus regulatory T cell activation by DCs, selectively limits macropinocytosis, but not receptor-mediated phagocytosis, in immature and recently activated DCs. In vivo, the GILZ-mediated inhibition of Ag uptake is restricted to the CD8α+ DC subset, which expresses the highest GILZ level among splenic DC subsets. In recently activated DCs, we further establish that GILZ limits p38 MAPK phosphorylation, providing a possible mechanism for GILZ-mediated macropinocytosis control. Finally, our results demonstrate that the modulation of Ag uptake by GILZ does not result in altered Ag presentation to CD4 T cells but impacts the efficiency of cross-presentation to CD8 T cells. Altogether, our results identify GILZ as an endogenous inhibitor of macropinocytosis in DCs, the action of which contributes to the fine-tuning of Ag cross-presentation.

Hepatitis E is currently diagnosed after all other causes of hepatitis have been excluded. Moreover, HEV testing is not performed to prevent blood transmission in developed countries. We report here on the case of a patient with acute hepatitis while receiving potentially hepatotoxic medications for autoimmune disorders, with low-level autoimmune markers and negative ‘‘standard’’ viral markers; it was finally determined that he was suffering from transfusion-transmitted hepatitis E. 2012 European Association for the Study of the Liver. Published

Stability and control of noise in a flow duct are discussed in this paper. The flow is assumed to be uniform for the steady state. But an unstationary interaction between acoustic waves and a flexible part of the wall can induce wave amplification up to an instability. This phenomenon is similar to flutter encountered in aeroelasticity of airfoils [H. Dowell, C. Curtiss Jr., R.H. Scanlan, F. Sisto, A Modern Course in Aeroelasticity, Kluwer Academic Publishers, 1989; Y.C. Fung, An Introduction to the Theory of Aeroelasticity, J. Wiley, New York, 1955]. In fact, one can suggest that the flexible wall can act as a trap for acoustic energy and using a smart device located on this structure, one can design an efficient control method for noise. The goal of this paper is to describe a simple model and few numerical tests which partially justify these considerations.

International audience; Mots clés Chimiothérapie Sénescence Apoptose Hétérogénéité Résistance Cancer colorectal Résumé Contrer la résistance tumorale est un enjeu majeur des traitements de chimiothérapie. Plusieurs mécanismes d'arrêt inhibent le cycle cellulaire mais alors que ceux-ci semblaient définitifs, des études récentes décrivent l'adaptation des cellules et soulignent l'importance des contrôles mitotiques et post-mitotiques. L'ensemble de ces évènements doit donc être pris en compte pour comprendre la réponse aux chimiothérapies et identifier des marqueurs prédictifs de résistance. Cependant, pour définir ces capacités d'adaptation, il faut également considérer les réponses suppressives induites par ces points de contrôle, l'apoptose et la sénescence. L'apoptose semble un mécanisme suppresseur plus efficace, si l'on considère qu'obtenir une cellule morte est un objectif plus pertinent que de conserver une cellule tumorale arrêtée mais toujours vivante et influençant son environnement. Cependant, comparer ces mécanismes pourrait supposer que toutes les cellules au sein d'une tumeur choisissent exclusivement l'une ou l'autre des réponses. Illustrée dans le cancer colorectal, l'hétérogénéité intra-tumorale, définie comme la présence de clones et altérations différents, est certainement responsable d'une hétérogénéité de réponse au sein d'une même tumeur. De plus, les notions de cellules souches, de plasticité et de micro-environnement complexifient la théorie des stratégies thérapeutiques. La coexistence de cellules proliférantes ou dédifférenciées, de cellules tumorales ou stromales ainsi que leurs relations assurent en effet des capacités d'adaptation efficaces. Au-delà de la compréhension des méca-nismes de réponse et du choix entre apoptose et sénescence, l'hétérogénéité des cellules à cibler, leur plasticité et leur interdépendance restent donc des défis majeurs pour les futures thérapies anticancéreuses. Reçu le 16 octobre 2015 Accepté le 29 octobre 2015 Disponible sur internet le : 4 janvier 2016 tome 103 > n81 > janvier 2016 http://dx.

Understanding adaptive signaling pathways in response to chemotherapy is one of the main challenges of cancer treatment. Activated in response to DNA damage, cell cycle and mitotic checkpoints activate the p53-p21 and p16-Rb pathways and induce apoptosis or senescence. Since senescent cells survive and produce a secretome that influences neighbouring cells, it is not particularly clear whether these responses are equivalent and if tumor cells escape these two suppressive pathways to the same extent. Predicting escape is also complicated by the fact that cancer cells adapt to treatments by activating the epithelial-mesenchymal transition and by producing clones with cancer-initiating cells features. Dedifferentiation pathways used in stressful conditions reconstitute dividing and sometimes more aggressive populations in response to chemotherapy. These observations illustrate the importance of tumor heterogeneity and the adaptation capacities of different intra-tumoral subclones. Depending on their oncogenic profile, on their localisation within the tumor and on their interaction with stromal cells, these subclones are expected to have different responses and adaptation capacities to chemotherapy. A complete eradication will certainly rely on combination therapies that can kill at the same time the bulk of the sensitive tumor but can also prevent plasticity and the generation of persistent clones.

Let us consider a one dimensional flow in a cylindrical tube, a portion of which is flexible. It can be a shell structure or a membrane equipped with actuators in order to reduce and if possible to cancel the acoustic perturbations transferred by the flow. The goal of this paper is to discuss the efficiency of such a noise insulator in a mathematical framework.

International audience; Identification and monitoring of urban fabric and preservation of existing ecosystems have become major issues to maintain or increase biodiversity in areas under urban influence in most of European cities. While many studies have shown the interest of using optical remotely sensed data for that purpose, a consolidated and reproducible methodological framework was still missing. In this context, a multi-scale methodology has been proposed in the framework of the project VALI-URB to map built-up and vegetated land features in urban and suburban areas based on Pleiades images and existing ancillary data (vector databases or the Open Street Map database). The objective of this paper is to highlight the interest of using land cover/use maps derived from Pleiades images and vector databases to semi-automatically characterize grey and green infrastructures at a scale of 1:10,000. First results are presented on two medium-sized cities with different urban forms: Strasbourg and Rennes (France).

International audience; Induction of senescence by chemotherapy was initially characterized as a suppressive response that prevents tumor cell proliferation. However, in response to treatment, it is not really known how cells can survive senescence and how irreversible this pathway is. In this study, we analyzed cell escape in response to irinotecan, a first line treatment used in colorectal cancer that induced senescence. We detected subpopulations of cells that adapted to chemotherapy and resumed proliferation. Survival led to the emergence of more transformed cells that induced tumor formation in mice and grew in low adhesion conditions. A significant amount of viable polyploid cells was also generated following irinotecan failure. Markers such as lgr5, CD44, CD133 and ALDH were downregulated in persistent clones, indicating that survival was not associated with an increase in cancer initiating cells. Importantly, malignant cells which resisted senescence relied on survival pathways induced by Mcl-1 signaling and to a lesser extent by Bcl-xL. Depletion of Mcl-1 increased irinotecan efficiency, induced the death of polyploid cells, prevented cell emergence and inhibited growth in low-adhesion conditions. We therefore propose that Mcl-1 targeting should be considered in the future to reduce senescence escape and to improve the treatment of irinotecan-refractory colorectal cancers.

International audience; Activated in response to chemotherapy, senescence is a tumor suppressive mechanism that induces a permanent loss of proliferation. However, in response to treatment, it is not really known how cells can escape senescence and how irreversible or incomplete this pathway is. We have recently described that cells that escape senescence are more transformed than non-treated parental cells, they resist anoikis and rely on Mcl-1. In this study, we further characterize this emergence in response to irinotecan, a first line treatment used in colorectal cancer. Our results indicate that Akt was activated as a feedback pathway during the early step of senescence. The inhibition of the kinase prevented cell emergence and improved treatment efficacy, both in vitro and in vivo. This improvement was correlated with senescence inhibition, p21waf1 downregulation and a concomitant activation of apoptosis due to Noxa upregulation and Mcl-1 inactivation. The inactivation of Noxa prevented apoptosis and increased the number of emergent cells. Using either RNA interference or p21waf1-deficient cells, we further confirmed that an intact p53-p21-senescence pathway favored cell emergence and that its downregulation improved treatment efficacy through apoptosis induction. Therefore, although senescence is an efficient suppressive mechanism, it also generates more aggressive cells as a consequence of apoptosis inhibition. We therefore propose that senescence-inducing therapies should be used sequentially with drugs favoring cell death such as Akt inhibitors. This should reduce cell emergence and tumor relapse through a combined induction of senescence and apoptosis.

International audience; Olfactomedin-4 (OLFM4, OLM4) is a 72 kDa secreted glycoprotein belonging to the olfactomedin family. The OLFM4 gene expression is regulated by the transcription factors NF-kappa B and AP-1, and the OLM4 functions are poorly understood. OLM4 has been described as being able to interact with cell surface proteins such as lectins and concanavalin-A suggesting that one function of OLM4 is to regulate cell adhesion and migration. OLM4 is a marker for intestinal stem cells and is expressed at the bottom of the intestinal crypts. Expression of OLM4 during tumor development showed that OLM4 expression is increased in the early stages of tumor initiation. As OLM4 is a secreted protein, it is a prime candidate for biomarker research for tumor detection or progression. Levels of circulating OLM4 were significantly higher in patients with gastric, colorectal, and pancreatic cancers than in healthy subjects.

For people born in France, age is a major risk factor for developing tuberculosis.This curable pathology still has a high mortality rate which increases with age. Diagnosis difficulties, tolerance and compliance with treatment are issues specific to old age. An active policy of prevention, monitoring and training should enable the incidence of this pathology to continue to fall.

L’etude et la restauration de deux sphynges en terre cuite, particulierement degradees par leur installation en exterieur, ont permis d’approfondir la connaissance des techniques d’estampage, de caracteriser les proprietes des terres cuites et les mecanismes de degradation lies au gel. Les differentes techniques mises en oeuvre ont ete l’occasion de reflechir aux limites d’intervention pour des sculptures de jardin.

L’étude et la restauration de deux sphynges en terre cuite, particulièrement dégradées par leur installation en extérieur, ont permis d’approfondir la connaissance des techniques d’estampage, de caractériser les propriétés des terres cuites et les mécanismes de dégradation liés au gel. Les différentes techniques mises en oeuvre ont été l’occasion de réfléchir aux limites d’intervention pour des sculptures de jardin.The study and the restoration of two sphynges in terra-cotta, particularly degraded by their outdoor installation, allowed to deepen the knowledge of stamping techniques, to characterize the properties of terra-cottas and mechanisms of degradation bound to the frost. The different techniques used were the opportunity to think about limits of intervention for garden installed sculptures.

Contains fulltext : 34517.pdf (author's version ) (Open Access)

We motivate and present an automated validation tool takes as input a Java Card application and a set of rules, and provides as output an analysis of the way in which the Java Card application follows the rules. The applications are usually provided in binary format, as CAP files, which means that the validation occurs on the exact code that will be downloaded in the card. The rules may consist of a standard set of rules, for instance the application portability rules defined by the SIM Alliance. They may also include some rules customized for a specific card issuer, card program, or even for a specific application (for instance, a highly sensitive application may require specific rules that do not apply to other applications). The result of the validation consists of a diagnosis and a report.

In the present study we investigated the effects of various doses of gamma-irradiation, followed by induction of granulocytic differentiation with all-trans-retinoic acid (ATRA), on proliferative rate, differentiation capability and oxidative metabolism of leukaemic cells from two different myeloid leukaemia cell lines, HL-60 and PLB-985. Regarding the effects of such combined treatment on the proliferative capabilities of HL-60 and PLB-985 cell lines, we showed that their growth kinetics were similar after 2 Gy gamma-irradiation combined with ATRA. However, with doses2 Gy, the behaviour of the cell lines differed largely. Indeed, HL-60 appeared to be more radiosensitive than PLB-985 regarding cell viability and proliferation. Besides, whatever dose of irradiation (2, 5 or 10 Gy) was applied, ATRA was still able to induce differentiation of HL-60 and PLB-985 into granulocytes that retained the capacity to produce superoxide anion. The results of these in vitro studies suggest that leukaemia cell lines retain their ability to respond to ATRA, a granulocytic-differentiating inducer following high doses of irradiation. This may have implications for the use of radiation therapy in combination with ATRA for the treatment of extramedullary infiltrations of myeloid leukaemias in humans.

Dendritic cells (DCs) are key players in the control of tolerance and immunity. Glucocorticoids (GCs) are known to regulate DC function by promoting their tolerogenic differentiation through the induction of inhibitory ligands, cytokines, and enzymes. The GC-induced effects in DCs were shown to critically depend on increased expression of the Glucocorticoid-Induced Leucine Zipper protein (GILZ). GILZ expression levels were further shown to control antigen-presenting cell function, as well as T-cell priming capacity of DCs. However, the pattern of GILZ expression in DC subsets across tissues remains poorly described, as well as the modulation of its expression levels in different pathological settings. To fill in this knowledge gap, we conducted an exhaustive analysis of GILZ relative expression levels in DC subsets from various tissues using multiparametric flow cytometry. This study was performed at steady state, in the context of acute as well as chronic skin inflammation, and in a model of cancer. Our results show the heterogeneity of GILZ expression among DC subsets as well as the complexity of its modulation, that varies in a cell subset- and context-specific manner. Considering the contribution of GILZ in the control of DC functions and its potential as an immune checkpoint in cancer settings, these results are of high relevance for optimal GILZ targeting in therapeutic strategies.

Les fossés, structures anthropiques conçues pour répondre aux besoins de l’homme, constituent un compartiment à part entière du bassin versant du SAGE de la Rance, du Frémur et de la baie de Beaussais. La densité de leur réseau et leurs connexions aux cours d’eau affectent la qualité de l’eau. Ils sont pourtant, dans le cadre d’une gestion adaptée, le siège de nombreux processus écologiques leur conférant d’autres effets parmi lesquels la rétention et l’épuration de l’eau. La gestion actuellement appliquée à ces fossés porte essentiellement sur la collecte et l’écoulement des eaux.La Commission Locale de l'Eau souhaite aujourd’hui travailler sur ce compartiment pour savoir comment amorcer des changements dans les modes de gestion des fossés afin de concilier maintien de leurs usages et préservation des cours d’eau qu’ils alimentent.Afin de répondre à cette problématique, la première étape a consisté à faire une synthèse sur l’état actuel des connaissances sur la thématique des fossés. La seconde étape a consisté à réaliser un diagnostic de la gestion menée sur les fossés du territoire et à appréhender les perceptions et les représentations au sujet des fossés et de l’eau auprès des acteurs du territoire. Ainsi 19 entretiens semi-directifs ont été réalisés avec des collectivités et des partenaires techniques ayant la compétence voirie, des élus, des partenaires techniques en charge des milieux aquatiques et bocage, des experts travaillant sur la thématique des fossés.L’analyse de ces résultats a montré que les fossés font partie intégrante du paysage de par les rôles d’intérêts publics qu’ils jouent. Les gestionnaires de voirie rencontrés identifient essentiellement les rôles pratiques des fossés au détriment parfois des rôles écologiques. Ils sont associés à la route et à l’eau, cette association portant sur l’aspect d’évacuation de l’eau et de prévention des inondations et non pas sur la qualité de l’eau. Les pratiques sont le résultat de ces perceptions et d’une rationalité économique, c’est à dire des pratiques d’entretien rentables dans le but de dégager le fossé de toute végétation ou obstacle gênant pour permettre la bonne évacuation de l’eau. Il a également été relevé un attachement aux pratiques d’entretien « traditionnelles » des agents. Enfin l’analyse des entretiens révèle un manque d’échange et de communication entre les différents services et structures.À partir de ces conclusions, des pistes d’actions ont été proposées. D’une part, réaliser une réelle communication et sensibilisation autour des processus environnementaux fournis par les fossés mais aussi autour des enjeux relatifs à la qualité de l’eau via des supports de communication. Et d’autre part, réaliser une journée d’échanges annuelle pour créer du lien et une transversalité entre les acteurs du territoire. Il sera également possible de réaliser des journées de formation pour accompagner les agents d’entretien dans l’évolution de leur métier.