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Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14–16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3–1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered.
BACKGROUND
Neuronal migration is a crucial process that allows neurons to reach their correct target location to allow the nervous system to function properly. AP-2alpha is a transcription factor essential for neural crest cell migration and its mutation results in apoptosis within this cell population, as demonstrated by genetic models.
RESULTS
We down-modulated AP-2alpha expression in GN-11 neurons by RNA interference and observe reduced neuron migration following the activation of a specific genetic programme including the Adhesion Related Kinase (Axl) gene. We prove that Axl is able to coordinate migration per se and by ChIP and promoter analysis we observe that its transcription is directly driven by AP-2alpha via the binding to one or more functional AP-2alpha binding sites present in its regulatory region. Analysis of migration in AP-2alpha null mouse embryo fibroblasts also reveals an essential role for AP-2alpha in cell movement via the activation of a distinct genetic programme.
CONCLUSION
We show that AP-2alpha plays an essential role in cell movement via the activation of cell-specific genetic programmes. Moreover, we demonstrate that the AP-2alpha regulated gene Axl is an essential player in GN-11 neuron migration.
In this paper, residual sinks are used in bond graph model-based quantitative fault detection for the coupling of a model of a faultless process engineering system to a bond graph model of the faulty system. By this way, integral causality can be used as the preferred computational causality in both models. There is no need for numerical differentiation. Furthermore, unknown variables do not need to be eliminated from power continuity equations in order to obtain analytical redundancy relations (ARRs) in symbolic form. Residuals indicating faults are computed numerically as components of a descriptor vector of a differential algebraic equation system derived from the coupled bond graphs. The presented bond graph approach especially aims at models with non-linearities that make it cumbersome or even impossible to derive ARRs from model equations by elimination of unknown variables. For illustration, the approach is applied to a non-controlled as well as to a controlled hydraulic two-tank system. Finally, it is shown that not only the numerical computation of residuals but also the simultaneous numerical computation of their sensitivities with respect to a parameter can be supported by bond graph modelling.
Carbon Monoxide Rapidly Impairs Alveolar Fluid Clearance by Inhibiting Epithelial Sodium Channels
(2009)
Die Jahresabschlussanalyse
(2009)