However, these analyses may be already biased by secondary effects of pathogenesis and may therefore obscure the causative process for disease occurring earlier in development.
Thus, the peripheral T cell phenotype in the Foxn1Δ/Δ mutants is the result of both direct effects of abnormal selection within the thymus, compounded by secondary effects of low T cell output and a hypocellular peripheral environment.
Attempts to rescue the efflux defects of the UTI89 mutants by expressing the deleted secretin in trans from expression plasmids were not successful, and thus we cannot rule out that the observed defects were caused by secondary effects of the deletion mutations.
Hypercoagulable maternal conditions such as thrombophilia and antiphospholipid antibody syndrome also inhibit growth either by placental thrombosis formation or by secondary effects of maternal disease.
NAFLD may be triggered by secondary effects of medications (e.g., corticosteroids, tamoxifen), nutritional causes (e.g., rapid weight loss) or metabolic disorders (e.g., lipodystrophy or dysbetalipoproteinemia) [ 86, 87].
However, we speculate that fgf22 expression in the posterior midbrain is reduced by a secondary effect of dorsalization of the midbrain in embryos with blocked Hh signaling, because the phenotype of fgf22 morphants was opposite to that of embryos with blocked Hh signaling.
The tau accumulation might be caused by a secondary effect of αsyn accumulation, such as dysfunction of cellular activity [ 43, 44] or abnormality in protein degradation machinery [ 45]. Biochemical analysis clearly showed that accumulated αsyn was phosphorylated and ubiquitinated similarly to that in DLB brain, regardless of injection site.
Moreover it seems likely that in absence of the priming phosphorylation of HSF1 by ERK1/2, the secondary effect of the activated Gsk3β failed to inhibit HSF1 activity.
Therefore, it seems that the induction of autophagy by EMB is a secondary effect of the impaired autophagic flux.
Downregulated genes tend to be less constrained in this way, either because the genes are suppressed by the upregulated genes (secondary effect of the core cancerous gene expression) or because the suppressed genes are overwhelmed by circumvention from the alternate or compensatory pathway that induces the upregulation of the cancerous genes.
