97 research outputs found
Etude de FOXA1 dans les cellules épithéliales mammaires humaines
Les cancers du sein sont divisĂ©s en sous types dĂ©finis par leur histologie, leur prolifĂ©ration et l expression du rĂ©cepteur aux ĆstrogĂšnes ER. Notre Ă©tude porte sur le gĂšne FOXA1 dans le sous-type luminal caractĂ©risĂ© par des cellules bien diffĂ©renciĂ©es, peu prolifĂ©ratives et exprimant fortement les protĂ©ines FOXA1 et ER. Des Ă©tudes suggĂšrent que FOXA1 est impliquĂ© dans le dĂ©veloppement de la glande mammaire, dans la diffĂ©renciation et la prolifĂ©ration des cellules mammaires. Dans ce cadre, mon projet de thĂšse s articulait autour de trois points ; dĂ©velopper un Knock-In au niveau du gĂšne FOXA1, identifier le rĂŽle de FOXA1 dans la diffĂ©renciation mammaire et enfin rechercher le rĂŽle des facteurs ER et FOXA1 dans la rĂ©sistance Ă l hormonothĂ©rapie. De nombreux tests d intĂ©gration ciblĂ©e ont Ă©tĂ© rĂ©alisĂ©s Ă l aide de diffĂ©rentes matrices de recombinaison et de nuclĂ©ases spĂ©cifiques, les ZFNs. Aucune intĂ©gration ciblĂ©e n a finalement Ă©tĂ© observĂ©e. Nous avons montrĂ© qu en fonction du contexte cellulaire, FOXA1 jouait diffĂ©rents rĂŽles dans la diffĂ©renciation cellulaire et l expression de la molĂ©cule d adhĂ©rence E-CadhĂ©rine. Ces rĂ©sultats suggĂšrent que FOXA1 influence l agressivitĂ© tumorale suivant le contexte cellulaire. Nous avons Ă©galement identifiĂ© une amplification d ER et de FOXA1 dans les cellules tumorales rĂ©sistantes Ă l hormonothĂ©rapie par une Ă©tude gĂ©nomique. Les tests in vitro ont montrĂ© que la surexpression de FOXA1 augmenterait bien la rĂ©sistance au fulvestrant mais la surexpression d ER aurait l effet inverse, suggĂ©rant l implication d autres facteurs. De futures recherches nous permettront d identifier ces facteurs et de prĂ©ciser les rĂŽles de FOXA1 et d ER dans la diffĂ©renciation luminale, l agressivitĂ© tumorale et dans la rĂ©ponse cellulaire Ă l hormonothĂ©rapieBreast cancers are divided into subtypes defined by their histology, proliferation and expression of estrogen receptor ER. Our study focuses on the FOXA1 gene in the luminal subtype characterized by well-differentiated cells, low proliferative and strongly expressing FOXA1 protein and ER. Studies suggest that FOXA1 is involved in the mammary gland development and in the differentiation and proliferation of mammary cells. In this context, my thesis project was structured around three points, develop a knock-in at the FOXA1 gene, identify the role of FOXA1 in mammary differentiation and finally explore the role of ER and FOXA1 in resistance to hormone therapy. Many targeted integration tests were performed using different matrix of recombination and specific nucleases, the ZFNs. No direct integration was finally observed. We showed that depending on the cell context, FOXA1 played different roles in cell differentiation and expression of E-cadherin, an adhesion molecule. These results suggest that FOXA1 influence tumor aggressiveness depending on the cell context. We also identified amplification of ER and FOXA1 in tumor cell resistant to hormone therapy by a genomic study. Surprisingly, in vitro tests showed that overexpression of FOXA1 increased resistance to fulvestrant whereas overexpression of ER would have the opposite effect, suggesting the involvement of other factors. Future research will allow us to identify these factors and to clarify the roles of ER and FOXA1 in luminal differentiation, tumor aggressiveness and response to hormone therapy.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF
The time course of facial expression recognition using spatial frequency information: comparing pain and core emotions
Characterization of auxin transporter PIN6 plasma membrane targeting reveals a function for PIN6 in plant bolting
Auxin gradients are sustained by series of influx and efflux carriers whose subcellular localization is sensitive to both exogenous and endogenous factors. Recently the localization of the Arabidopsis thaliana auxin efflux carrier PIN-FORMED (PIN) 6 was reported to be tissue-specific and regulated through unknown mechanisms. Here, we used genetic, molecular and pharmacological approaches to characterize the molecular mechanism(s) controlling the subcellular localization of PIN6. PIN6 localizes to endomembrane domains in tissues with low PIN6 expression levels such as roots, but localizes at the plasma membrane (PM) in tissues with increased PIN6 expression such as the inflorescence stem and nectary glands. We provide evidence that this dual localization is controlled by PIN6 phosphorylation and demonstrate that PIN6 is phosphorylated by mitogen-activated protein kinases (MAPKs) MPK4 and MPK6. The analysis of transgenic plants expressing PIN6 at PM or in endomembrane domains reveals that PIN6 subcellular localization is critical for Arabidopsis inflorescence stem elongation post-flowering (bolting). In line with a role for PIN6 in plant bolting, inflorescence stems elongate faster in pin6 mutant plants than in wild-type plants. We propose that PIN6 subcellular localization is under the control of developmental signals acting on tissue-specific determinants controlling PIN6-expression levels and PIN6 phosphorylation
The financial crisis and health care systems in Europe: universal care under threat? Trends in health sector reforms in Germany, the United Kingdom, and Spain
Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.
RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 â„60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)
FOXA1 study in human mammary epithelial cells
Les cancers du sein sont divisĂ©s en sous types dĂ©finis par leur histologie, leur prolifĂ©ration et lâexpression du rĂ©cepteur aux ĆstrogĂšnes ER. Notre Ă©tude porte sur le gĂšne FOXA1 dans le sous-type luminal caractĂ©risĂ© par des cellules bien diffĂ©renciĂ©es, peu prolifĂ©ratives et exprimant fortement les protĂ©ines FOXA1 et ER. Des Ă©tudes suggĂšrent que FOXA1 est impliquĂ© dans le dĂ©veloppement de la glande mammaire, dans la diffĂ©renciation et la prolifĂ©ration des cellules mammaires. Dans ce cadre, mon projet de thĂšse sâarticulait autour de trois points ; dĂ©velopper un Knock-In au niveau du gĂšne FOXA1, identifier le rĂŽle de FOXA1 dans la diffĂ©renciation mammaire et enfin rechercher le rĂŽle des facteurs ER et FOXA1 dans la rĂ©sistance Ă lâhormonothĂ©rapie. De nombreux tests dâintĂ©gration ciblĂ©e ont Ă©tĂ© rĂ©alisĂ©s Ă lâaide de diffĂ©rentes matrices de recombinaison et de nuclĂ©ases spĂ©cifiques, les ZFNs. Aucune intĂ©gration ciblĂ©e nâa finalement Ă©tĂ© observĂ©e. Nous avons montrĂ© quâen fonction du contexte cellulaire, FOXA1 jouait diffĂ©rents rĂŽles dans la diffĂ©renciation cellulaire et lâexpression de la molĂ©cule dâadhĂ©rence E-CadhĂ©rine. Ces rĂ©sultats suggĂšrent que FOXA1 influence lâagressivitĂ© tumorale suivant le contexte cellulaire. Nous avons Ă©galement identifiĂ© une amplification dâER et de FOXA1 dans les cellules tumorales rĂ©sistantes Ă lâhormonothĂ©rapie par une Ă©tude gĂ©nomique. Les tests in vitro ont montrĂ© que la surexpression de FOXA1 augmenterait bien la rĂ©sistance au fulvestrant mais la surexpression dâER aurait lâeffet inverse, suggĂ©rant lâimplication dâautres facteurs. De futures recherches nous permettront dâidentifier ces facteurs et de prĂ©ciser les rĂŽles de FOXA1 et dâER dans la diffĂ©renciation luminale, lâagressivitĂ© tumorale et dans la rĂ©ponse cellulaire Ă lâhormonothĂ©rapieBreast cancers are divided into subtypes defined by their histology, proliferation and expression of estrogen receptor ER. Our study focuses on the FOXA1 gene in the luminal subtype characterized by well-differentiated cells, low proliferative and strongly expressing FOXA1 protein and ER. Studies suggest that FOXA1 is involved in the mammary gland development and in the differentiation and proliferation of mammary cells. In this context, my thesis project was structured around three points, develop a knock-in at the FOXA1 gene, identify the role of FOXA1 in mammary differentiation and finally explore the role of ER and FOXA1 in resistance to hormone therapy. Many targeted integration tests were performed using different matrix of recombination and specific nucleases, the ZFNs. No direct integration was finally observed. We showed that depending on the cell context, FOXA1 played different roles in cell differentiation and expression of E-cadherin, an adhesion molecule. These results suggest that FOXA1 influence tumor aggressiveness depending on the cell context. We also identified amplification of ER and FOXA1 in tumor cell resistant to hormone therapy by a genomic study. Surprisingly, in vitro tests showed that overexpression of FOXA1 increased resistance to fulvestrant whereas overexpression of ER would have the opposite effect, suggesting the involvement of other factors. Future research will allow us to identify these factors and to clarify the roles of ER and FOXA1 in luminal differentiation, tumor aggressiveness and response to hormone therapy
Ătude de la spĂ©ciation de l'uranium d'origine anthropique dans un sol naturel par approche multitechnique
The thesis work presented in this manuscript focused on the study of the speciation and behavior of anthropogenic uranium dispersed on natural soil. A multi-technique approach combining analytical techniques carried out at the SOLEIL synchrotron, such as EXAFS (Extended X-rays Absorption Fine Structure), XANES (X-rays Absorption Nearl Edge Structure), XRF (X-Ray Fluorescence) mapping, or more conventional techniques such as SLRT (Laser Spectrofluorimetry at Temporal Resolution), has made it possible to highlight the evolution of the chemical form of uranium as it migrates through the subsoil of the site studied. The use of the linear combination of EXAFS spectra obtained on samples taken at different depths has proven to be a powerful tool for data processing. Thus, a strong correlation was established between the evolution of uranium speciation, its concentration profile, and the chemical and mineralogical composition of the soil and substrate at the site, suggesting the relevance of the analytical approach chosen.In parallel with the study of the site, experiments were carried out in the laboratory to improve our knowledge of the dynamic behavior of uranium. To do this, model columns composed of a uranium source term and a stationary phase were leached for several months in order to study the migration and evolution of the speciation of uranium. The results obtained show the impact of humic acids on the behavior of uranium. Indeed, the presence of organic matter leads to observations never before made. When it is present in the leaching water, it sorbs and migrates to the heart of the uranium source term used. When it is present in the matrix that makes up the column, significant diffusion phenomena are observed, correlated with a reduction of the uranium.This work was also used to develop the X-ray fluorescence mapping technique on the MARS line of the SOLEIL synchrotron, which, as the various analysis sessions and the inherent trials and errors were carried out, made the analysis routine and reliable. Moreover, some approaches, notably XANES mapping, open many possibilities of study, especially on systems presenting phase transitions and speciation changes at the interface between two media.Les travaux de thĂšse prĂ©sentĂ©s dans le prĂ©sent manuscrit ont portĂ© sur l'Ă©tude de la spĂ©ciation et du comportement de l'uranium d'origine anthropique ayant Ă©tĂ© dispersĂ© sur un sol naturel. Une approche multitechnique groupant des techniques d'analyse rĂ©alisĂ©e au synchrotron SOLEIL tel que l'EXAFS (Extended X-raies Absorption Fine Structure), le XANES (X-raies Absorption Nearl Edge Structure), la cartographie XRF (X-Raie Fluorescence) ou plus conventionnelle tels que la SLRT (SpectrofluorimĂ©trie Laser Ă RĂ©solution Temporelle) Ă permis de mettre en Ă©vidence l'Ă©volution de la forme chimique de l'uranium au fur et Ă mesure de sa migration dans le sous-sol du site Ă©tudiĂ©. L'utilisation de la combinaison linĂ©aire des spectres EXAFS obtenus sur des Ă©chantillons prĂ©levĂ©s Ă diffĂ©rentes profondeurs s'est avĂ©rĂ© ĂȘtre un outil puissant des traitements de donnĂ©es. Ainsi, une forte corrĂ©lation a pu ĂȘtre Ă©tablie entre l'Ă©volution de la spĂ©ciation de l'uranium, son profil de concentration, et la composition chimique et minĂ©ralogique du sol et du substrat du site, suggĂ©rant dĂšs lors de la pertinence de l'approche analytique choisie.En parallĂšle de l'Ă©tude du site, des expĂ©rimentations ont Ă©tĂ© rĂ©alisĂ©es en laboratoire afin d'amĂ©liorer nos connaissances sur le comportement dynamique de l'uranium. Pour ce faire, des colonnes modĂšles composĂ©es d'un terme source en uranium et d'une phase stationnaire ont Ă©tĂ© lixiviĂ©es durant plusieurs mois afin d'Ă©tudier la migration et l'Ă©volution de la spĂ©ciation de l'uranium. Les rĂ©sultats obtenus montrent l'impact des acides humiques sur le comportement de l'uranium. En effet, la prĂ©sence de matiĂšre organique engendre des observations jusqu'ici jamais rĂ©alisĂ©es. Lorsqu'elle est prĂ©sente dans l'eau de lixiviation, celle-ci se sorbe et migre au cĆur du terme source d'uranium utilisĂ©. Lorsqu'elle est prĂ©sente dans la matrice composant la colonne, des phĂ©nomĂšnes de diffusion importants sont observĂ©s, corrĂ©lĂ©s avec une rĂ©duction de l'uranium.Ces travaux auront Ă©galement servi Ă dĂ©velopper la technique de cartographie de la fluorescence X sur la ligne MARS du synchrotron SOLEIL, qui, au fur et Ă mesure des diffĂ©rentes sessions d'analyses et des essais/erreurs inhĂ©rents, a permis de rendre l'analyse routiniĂšre et fiable. De plus, certaines approches, notamment celle de la cartographie XANES, ouvrent de nombreuses possibilitĂ©s d'Ă©tude, notamment sur les systĂšmes prĂ©sentant des transitions de phases et des changements de spĂ©ciation Ă l'interface entre deux milieux
FOXA1 study in human mammary epithelial cells
Les cancers du sein sont divisĂ©s en sous types dĂ©finis par leur histologie, leur prolifĂ©ration et lâexpression du rĂ©cepteur aux ĆstrogĂšnes ER. Notre Ă©tude porte sur le gĂšne FOXA1 dans le sous-type luminal caractĂ©risĂ© par des cellules bien diffĂ©renciĂ©es, peu prolifĂ©ratives et exprimant fortement les protĂ©ines FOXA1 et ER. Des Ă©tudes suggĂšrent que FOXA1 est impliquĂ© dans le dĂ©veloppement de la glande mammaire, dans la diffĂ©renciation et la prolifĂ©ration des cellules mammaires. Dans ce cadre, mon projet de thĂšse sâarticulait autour de trois points ; dĂ©velopper un Knock-In au niveau du gĂšne FOXA1, identifier le rĂŽle de FOXA1 dans la diffĂ©renciation mammaire et enfin rechercher le rĂŽle des facteurs ER et FOXA1 dans la rĂ©sistance Ă lâhormonothĂ©rapie. De nombreux tests dâintĂ©gration ciblĂ©e ont Ă©tĂ© rĂ©alisĂ©s Ă lâaide de diffĂ©rentes matrices de recombinaison et de nuclĂ©ases spĂ©cifiques, les ZFNs. Aucune intĂ©gration ciblĂ©e nâa finalement Ă©tĂ© observĂ©e. Nous avons montrĂ© quâen fonction du contexte cellulaire, FOXA1 jouait diffĂ©rents rĂŽles dans la diffĂ©renciation cellulaire et lâexpression de la molĂ©cule dâadhĂ©rence E-CadhĂ©rine. Ces rĂ©sultats suggĂšrent que FOXA1 influence lâagressivitĂ© tumorale suivant le contexte cellulaire. Nous avons Ă©galement identifiĂ© une amplification dâER et de FOXA1 dans les cellules tumorales rĂ©sistantes Ă lâhormonothĂ©rapie par une Ă©tude gĂ©nomique. Les tests in vitro ont montrĂ© que la surexpression de FOXA1 augmenterait bien la rĂ©sistance au fulvestrant mais la surexpression dâER aurait lâeffet inverse, suggĂ©rant lâimplication dâautres facteurs. De futures recherches nous permettront dâidentifier ces facteurs et de prĂ©ciser les rĂŽles de FOXA1 et dâER dans la diffĂ©renciation luminale, lâagressivitĂ© tumorale et dans la rĂ©ponse cellulaire Ă lâhormonothĂ©rapieBreast cancers are divided into subtypes defined by their histology, proliferation and expression of estrogen receptor ER. Our study focuses on the FOXA1 gene in the luminal subtype characterized by well-differentiated cells, low proliferative and strongly expressing FOXA1 protein and ER. Studies suggest that FOXA1 is involved in the mammary gland development and in the differentiation and proliferation of mammary cells. In this context, my thesis project was structured around three points, develop a knock-in at the FOXA1 gene, identify the role of FOXA1 in mammary differentiation and finally explore the role of ER and FOXA1 in resistance to hormone therapy. Many targeted integration tests were performed using different matrix of recombination and specific nucleases, the ZFNs. No direct integration was finally observed. We showed that depending on the cell context, FOXA1 played different roles in cell differentiation and expression of E-cadherin, an adhesion molecule. These results suggest that FOXA1 influence tumor aggressiveness depending on the cell context. We also identified amplification of ER and FOXA1 in tumor cell resistant to hormone therapy by a genomic study. Surprisingly, in vitro tests showed that overexpression of FOXA1 increased resistance to fulvestrant whereas overexpression of ER would have the opposite effect, suggesting the involvement of other factors. Future research will allow us to identify these factors and to clarify the roles of ER and FOXA1 in luminal differentiation, tumor aggressiveness and response to hormone therapy
Study of the speciation of anthropogenic uranium in a natural soil using : a multi-technique approach
Les travaux de thĂšse prĂ©sentĂ©s dans le prĂ©sent manuscrit ont portĂ© sur l'Ă©tude de la spĂ©ciation et du comportement de l'uranium d'origine anthropique ayant Ă©tĂ© dispersĂ© sur un sol naturel. Une approche multitechnique groupant des techniques d'analyse rĂ©alisĂ©e au synchrotron SOLEIL tel que l'EXAFS (Extended X-raies Absorption Fine Structure), le XANES (X-raies Absorption Nearl Edge Structure), la cartographie XRF (X-Raie Fluorescence) ou plus conventionnelle tels que la SLRT (SpectrofluorimĂ©trie Laser Ă RĂ©solution Temporelle) Ă permis de mettre en Ă©vidence l'Ă©volution de la forme chimique de l'uranium au fur et Ă mesure de sa migration dans le sous-sol du site Ă©tudiĂ©. L'utilisation de la combinaison linĂ©aire des spectres EXAFS obtenus sur des Ă©chantillons prĂ©levĂ©s Ă diffĂ©rentes profondeurs s'est avĂ©rĂ© ĂȘtre un outil puissant des traitements de donnĂ©es. Ainsi, une forte corrĂ©lation a pu ĂȘtre Ă©tablie entre l'Ă©volution de la spĂ©ciation de l'uranium, son profil de concentration, et la composition chimique et minĂ©ralogique du sol et du substrat du site, suggĂ©rant dĂšs lors de la pertinence de l'approche analytique choisie.En parallĂšle de l'Ă©tude du site, des expĂ©rimentations ont Ă©tĂ© rĂ©alisĂ©es en laboratoire afin d'amĂ©liorer nos connaissances sur le comportement dynamique de l'uranium. Pour ce faire, des colonnes modĂšles composĂ©es d'un terme source en uranium et d'une phase stationnaire ont Ă©tĂ© lixiviĂ©es durant plusieurs mois afin d'Ă©tudier la migration et l'Ă©volution de la spĂ©ciation de l'uranium. Les rĂ©sultats obtenus montrent l'impact des acides humiques sur le comportement de l'uranium. En effet, la prĂ©sence de matiĂšre organique engendre des observations jusqu'ici jamais rĂ©alisĂ©es. Lorsqu'elle est prĂ©sente dans l'eau de lixiviation, celle-ci se sorbe et migre au cĆur du terme source d'uranium utilisĂ©. Lorsqu'elle est prĂ©sente dans la matrice composant la colonne, des phĂ©nomĂšnes de diffusion importants sont observĂ©s, corrĂ©lĂ©s avec une rĂ©duction de l'uranium.Ces travaux auront Ă©galement servi Ă dĂ©velopper la technique de cartographie de la fluorescence X sur la ligne MARS du synchrotron SOLEIL, qui, au fur et Ă mesure des diffĂ©rentes sessions d'analyses et des essais/erreurs inhĂ©rents, a permis de rendre l'analyse routiniĂšre et fiable. De plus, certaines approches, notamment celle de la cartographie XANES, ouvrent de nombreuses possibilitĂ©s d'Ă©tude, notamment sur les systĂšmes prĂ©sentant des transitions de phases et des changements de spĂ©ciation Ă l'interface entre deux milieux.The thesis work presented in this manuscript focused on the study of the speciation and behavior of anthropogenic uranium dispersed on natural soil. A multi-technique approach combining analytical techniques carried out at the SOLEIL synchrotron, such as EXAFS (Extended X-rays Absorption Fine Structure), XANES (X-rays Absorption Nearl Edge Structure), XRF (X-Ray Fluorescence) mapping, or more conventional techniques such as SLRT (Laser Spectrofluorimetry at Temporal Resolution), has made it possible to highlight the evolution of the chemical form of uranium as it migrates through the subsoil of the site studied. The use of the linear combination of EXAFS spectra obtained on samples taken at different depths has proven to be a powerful tool for data processing. Thus, a strong correlation was established between the evolution of uranium speciation, its concentration profile, and the chemical and mineralogical composition of the soil and substrate at the site, suggesting the relevance of the analytical approach chosen.In parallel with the study of the site, experiments were carried out in the laboratory to improve our knowledge of the dynamic behavior of uranium. To do this, model columns composed of a uranium source term and a stationary phase were leached for several months in order to study the migration and evolution of the speciation of uranium. The results obtained show the impact of humic acids on the behavior of uranium. Indeed, the presence of organic matter leads to observations never before made. When it is present in the leaching water, it sorbs and migrates to the heart of the uranium source term used. When it is present in the matrix that makes up the column, significant diffusion phenomena are observed, correlated with a reduction of the uranium.This work was also used to develop the X-ray fluorescence mapping technique on the MARS line of the SOLEIL synchrotron, which, as the various analysis sessions and the inherent trials and errors were carried out, made the analysis routine and reliable. Moreover, some approaches, notably XANES mapping, open many possibilities of study, especially on systems presenting phase transitions and speciation changes at the interface between two media
Identification de la fraction active des bactéries du microbiote améliorant la résistance à la colonisation intestinale contre les entérocoques résistants à la vancomycine
Communication orale (20 minutes)International audienc
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