In my view, the underlying principle behind all of this is that everything we claim to know relies on stuff we can't know (axioms). It is because "we", or our minds, are not connected to the universe except through fallible senses. Thus arises the assertion that it is not possible to determine whether the universe really exists, or if I am simply a participant in an elaborate simulation in which my senses are provided input by some sufficiently-advanced computing device.
Richard Feynman expressed it this way: "The best a scientist can ever say is 'I'm not wrong yet'."
I always fall back on the reality that we are constantly finding out that past scientific "proof" are found to not be true after all. Scientists from 50 years ago based their hypotheses / theories / proofs on what they could observe with the instruments of their time and have since proven to be incomplete at best and down-right false in many cases. I personally expect that trend to continue. I would hope we can be humble enough to know that, just because something is unexplainable by us doesn't mean it's unexplainable.
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