NAD+ recycling is likely key for cell proliferation, because many biosynthetic pathways produce NADH as a byproduct (34). These insights confirm the long-standing hypothesis (26, 29) that pyruvate supplementation rescues proliferation in cells with disrupted ETC by restoring NAD + /NADH balance via the LDH reaction. In the future, LbNOX and engineered or naturally occurring variants may become valuable tools for studying compartmentalization of redox metabolism. These constructs will allow for a dissection of the relative contributions of redox imbalance and ATP insufficiency to mitochondrial disease pathogenesis. If a substantial amount of the organ pathology of mitochondrial disease stems from reductive stress or pseudohypoxia, then expression of this single polypeptide holds promise as a "protein prosthesis" for the large number of disorders characterized by ETC dysfunction.

Summary Anatomically modern humans interbred with Neanderthals and with a related archaic population known as Denisovans. Genomes of several Neanderthals and one Denisovan have been sequenced, and these reference genomes have been used to detect introgressed genetic material in present-day human genomes. Segments of introgression can also be detected without use of reference genomes, which can be advantageous for finding introgressed segments that are less closely related to the sequenced archaic genomes. We apply a new reference-free method for detecting archaic introgression to 5639 whole genome sequences from Eurasia and Oceania. We find Denisovan ancestry in populations from East and South Asia, and in Papuans. The Denisovan ancestry is comprised of two components with differing similarity to the sequenced Altai Denisovan individual. This indicates that at least two distinct instances of Denisovan admixture into modern humans occurred, involving Denisovan populations that had different levels of relatedness to the sequenced Altai Denisovan.

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