Notice bibliographique
Résumé
Gel-forming mucins are large glycoproteins constituting the main structural component of themucus layer protecting epithelial surfaces of the body. This thesis aims to a deeper understandingof how gel-forming mucins are synthesized and assembled, and how they may interact with othermolecules. This knowledge is fundamental for understanding the physiology of the mucus barrierin health and disease.That mucins are large, heterogeneously glycosylated and forms polymeric structures,make them hard to study by conventional methods. Our approach has been to express parts of theproteins separately in different cells allowing biochemical analyses.When expressing the N-terminal part of the human MUC2 mucin the protein formeddisulfide-linked oligomers late in the secretory pathway. The secreted oligomers were heldtogether in a trimeric trypsin-resistant core fragment. That the protein formed trimers wasconfirmed by electron microscopy. Expression of the C-terminal region of the mucin showed thatthis part formed disulfide-linked dimers in the endoplasmic reticulum. The dimeric nature wasconfirmed by electron microscopy.When studying the C-terminal part of MUC2, a cleavage between an aspartate and aproline located in a GDPH sequence was observed. This cleavage was shown to be a slow, nonenzymaticprocess occurring at a pH below 6. The cleavage could occur in the later more acidicparts of the secretory pathway as neutralization of these compartments inhibited the cleavage.In vitro studies showed that the cleavage generated a new reactive C-terminus that could link theprotein to other molecules. The human MUC5AC mucin also contains a GDPH sequence andshows high sequence similarities to MUC2 in the area surrounding this sequence. That thecleavage also occurred in MUC5AC was shown after expressing its C-terminal part. Although thecleavage occurred already in the neutral endoplasmic reticulum further cleavage was observed atan acidic pH. Also after this cleavage a reactive C-terminus was formed. The generation of thereactive ends of these mucins can have implications in diseases such as cystic fibrosis andasthma, both states characterized by mucus pluggings and lower pH in the mucus of the airways.The lower pH could lead to increased cleavage causing cross-links between the mucins or tomolecules found on the epithelial surface thereby adding to the mucus retention seen in thesediseases.For parasites to reach the epithelial surfaces they have to penetrate the mucus gel.Entamoeba histolytica, the parasite causing amoebiasis secretes cysteine proteases that aresuggested to degrade the colonic mucus, mainly composed of MUC2. To test this hypothesis, therecombinant parts of MUC2 and insoluble mucins prepared from LS 174T cells were treated withproteases secreted by the amoeba. The results showed that the cysteine proteases degraded themucus gel by targeting the C-terminal part of MUC2. This is, to our knowledge, the firstidentification of a specific cleavage mechanism, used by an enteric pathogen, to disrupt thepolymeric nature of the mucin gel.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».