Notice bibliographique
Résumé
Cellular function is dependent upon the correct translation of genomic information encoded in DNA into functioning products, usually proteins. Prior to protein translation, DNA is transcribed into messenger RNA (mRNA). In eukaryotes such as human, this process must almost always undergo an intermediate step, termed pre-mRNA splicing, in which non-protein-coding regions (introns) are removed from the mRNA, yielding mature message (exons). Defects in pre-mRNA splicing are responsible for various human disorders including retinitis pigmentosa, spinal muscular atrophy, and myotonic dystrophy. In order to work towards a cure for these diseases, it is necessary to understand how pre-mRNA splicing works normally. One potentially useful tool for this is small molecule inhibitors of splicing, which have previously been shown to inhibit catalytic RNAs the additional benefit of being candidates for therapeutics. Only two papers (Hertweck et al., 2003; Kaida et al. 2007) have explored the effects of small molecules on nuclear splicing. Previous work has investigated inhibition of human splicing. In this work, I have examined the effect of small molecules on yeast splicing in order to make use of the powerful genetic and biochemical tools available for yeast. The main goal of this thesis was to identify small molecule inhibitors of yeast pre-mRNA splicing and to characterize the step at which they exert their inhibitory effects. Thirty-two different small molecules were tested. Ten of them were found to completely inhibit pre-mRNA splicing. IC₅₀ values were measured for each of the inhibitory small molecules, and neomycin was found to be the strongest inhibitor with an IC₅₀ of 80~M, while cefoperazone was the weakest inhibitor with an IC50 of 6.1 mM. Native gel analysis was used to establish the step at which splicing was inhibited. Four of the ten inhibitors showed a complete block in spliceosome assembly with accumulation of spliceosomal complex H; one accumulated spliceosomal complex A; two accumulated both spliceosomal complexes A and B; and three accumulated spliceosomal complexes B and C. I anticipate that these inhibitors will be useful tools for the studying the mechanism of pre-mRNA splicing. By characterizing the splicing complexes that accumulate in the presence of these inhibitors it will be possible to map out the path by which splicing complexes assemble. Furthermore, several of the inhibitors are previously uncharacterized, and consequently have potential to be useful in a variety of other context. In the long term, these inhibitors may lead to novel therapies for splicing related diseases.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| 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 | 0,001 |
| 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 ».