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Reviewer 2 notes that one of the main findings presented is that Hairy interacts with many "off target" sites, with relatively few linked to transcriptional function.
These studies show that mutagenesis and selection lead to many off target genetic changes, and some of these may be undesired.
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On top of this, Dr Huang found that there were many "off-target" mutations in other parts of HBB, or in other, similar genes, which would have caused serious damage if expressed in an actual human being.On the face of things, then, the experiment did not work.
He says one reason the researchers got so many off-target effects is because they did not use the latest version of the gene-editing technology.
The study revealed many off-target effects (random introduction of mutations) and low efficiency levels for introduction of the corrective gene they were using.
ASA has many off-target effects that influence the inflammatory response including inhibition of NFκB [32], augmentation of SOCS-2 and decrease of TRAF6 expression [33], [34].
Sunitinib is a relatively selective receptor tyrosine kinase inhibitor at nanomolar concentrations [ 1, 41, 46], but at micromolar doses it is likely to exert many off-target effects.
Indeed, hydroxamate activity-based MMP probes related to marimastat bound many off-target metalloproteinases that were not MMPs (Saghatelian et al, 2004).
Additionally, as Hsp90 is involved in many diseases and is ubiquitously expressed, striving for one specific result through global Hsp90 inhibition may lead to many off-target effects.
As a caveat, mechanistic understanding of this strategy is highly challenging as the drugs could have many off-target effects and even at the epigenetic level, the integrated response of multiple histone sites might be needed to mediate anti-aging effects.
Because Chx elicits many off-target effects and does not enable us to discriminate between the secondary targets of GR and those jointly controlled by GR and a GR-regulated TF, we performed dynamic modeling of expression data in an attempt to discern specific regulatory patterns.
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