Refinement
Dotaz
Zobrazit nápovědu
Laboratory animals ; Vol.37, S.1
51 s.
Developments in Animal and Veterinary Sciences ; 31
First edition 2 svazky (A, B) : ilustrace ; 25 cm
- MeSH
- alternativy výzkumu na zvířatech MeSH
- laboratorní zvířata MeSH
- modely u zvířat MeSH
- Publikační typ
- kongresy MeSH
- souborné dílo MeSH
- zprávy MeSH
- Konspekt
- Veterinární lékařství
- NLK Obory
- experimentální medicína
- veterinární lékařství
- MeSH
- akutní lymfatická leukemie genetika patologie MeSH
- delece genu * MeSH
- dítě MeSH
- filadelfský chromozom * MeSH
- jednonukleotidový polymorfismus genetika MeSH
- kohortové studie MeSH
- lidé MeSH
- mutace genetika MeSH
- nádorové biomarkery genetika MeSH
- prognóza MeSH
- sekvenční analýza DNA MeSH
- transkripční faktor Ikaros genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- dopisy MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
Prediction methods have become an integral part of biomedical and biotechnological research. However, their clinical interpretations are largely based on biochemical or molecular data, but not clinical data. Here, we focus on improving the reliability and clinical applicability of prediction algorithms. We assembled and curated two large non-overlapping large databases of clinical phenotypes. These phenotypes were caused by missense variations in 44 and 63 genes associated with Mendelian diseases. We used these databases to establish and validate the model, allowing us to improve the predictions obtained from EVmutation, SNAP2 and PoPMuSiC 2.1. The predictions of clinical effects suffered from a lack of specificity, which appears to be the common constraint of all recently used prediction methods, although predictions mediated by these methods are associated with nearly absolute sensitivity. We introduced evidence-based tailoring of the default settings of the prediction methods; this tailoring substantially improved the prediction outcomes. Additionally, the comparisons of the clinically observed and theoretical variations led to the identification of large previously unreported pools of variations that were under negative selection during molecular evolution. The evolutionary variation analysis approach described here is the first to enable the highly specific identification of likely disease-causing missense variations that have not yet been associated with any clinical phenotype.
- MeSH
- algoritmy MeSH
- ektodysplasiny genetika MeSH
- fenotyp MeSH
- genetická variace MeSH
- genetické nemoci vrozené genetika MeSH
- genomika MeSH
- glukosa-6-fosfátdehydrogenasa genetika MeSH
- hemoglobiny genetika MeSH
- hepatocytární jaderný faktor 4 genetika MeSH
- lidé MeSH
- missense mutace MeSH
- modely genetické * MeSH
- molekulární evoluce MeSH
- mutace * MeSH
- pravděpodobnostní funkce MeSH
- proteomika MeSH
- tyrosinfosfatasa nereceptorového typu 11 genetika MeSH
- výpočetní biologie metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Theoretically, crystals with supercells exist at a unique crossroads where they can be considered as either a large unit cell with closely spaced reflections in reciprocal space or a higher dimensional superspace with a modulation that is commensurate with the supercell. In the latter case, the structure would be defined as an average structure with functions representing a modulation to determine the atomic location in 3D space. Here, a model protein structure and simulated diffraction data were used to investigate the possibility of solving a real incommensurately modulated protein crystal using a supercell approximation. In this way, the answer was known and the refinement method could be tested. Firstly, an average structure was solved by using the `main' reflections, which represent the subset of the reflections that belong to the subcell and in general are more intense than the `satellite' reflections. The average structure was then expanded to create a supercell and refined using all of the reflections. Surprisingly, the refined solution did not match the expected solution, even though the statistics were excellent. Interestingly, the corresponding superspace group had multiple 3D daughter supercell space groups as possibilities, and it was one of the alternate daughter space groups that the refinement locked in on. The lessons learned here will be applied to a real incommensurately modulated profilin-actin crystal that has the same superspace group.
