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It was widely believed that these oligomers are intermediates along the fibril formation pathway (on-pathway).
Both approaches work on the pathway by pathway basis.
The aggregator approach does not perform any unification of the underlying pathways--viz., if n source databases each contains information on a particular pathway, that pathway is presented by the aggregator as n separate pathways.
If a knockout or parameter set depends on a pathway, this pathway also must be selected.
A cytotoxic effect may plausibly occur through pazopanib's effect on the VEGF pathway, a pathway known to promote proliferation and resistance to apoptosis.
Both the on-pathway and off-pathway I120Q intermediates show structure in β1-β3, whish is also strikingly consistent with kinetic folding experiments of αTS.
Global kinetic analysis revealed that the unfolded state partitions between an off-pathway refolding intermediate and the on-pathway equilibrium intermediate early in folding.
The use of both thermodynamic and kinetic information from native-state HX enabled us to construct a folding landscape of this 28 kDa protein, including local minima and maxima, and to discriminate on-pathway and off-pathway intermediates.
These competing hypotheses are not mutually exclusive given the growing diversity in "on-pathway" and "off-pathway" protein folding conformations observed during amyloidogenesis [15].
The work suggests that oligomer dissociation rates are similar to association rates and that oligomers serve as both on-pathway and off-pathway intermediates in fibril formation.
Note that the on-pathway and off-pathway model above cannot be distinguished, as both models fit the data equally well.
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