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The Melding Plague is a nanotech virus that attacks anything that has nanotechnology present within it and does not discriminate between human and machine. It attempts to meld the nanomachines and implants that are commonly present in the bodies of humans, with the structure of their body on a cellular level. This results in horrific, uncontrollable modifications to the body of whoever is infected and almost inevitably leads to death.

The most extreme example of a Plague outbreak is encountered in Chasm City, the capital of Yellowstone, which has been infected by the Plague. Once the centre of Demarchist society, the buildings and even the inhabitants of the city were capable of modifying themselves. The coming of the Plague changed all this and reduced the city and its inhabitants to a level of technology that the Plague could not attack. By the time that the worst of the Plague had passed, the city was almost unrecognisable, its buildings twisted and deformed and the population decimated by the Plague. The only survivors were those that had taken steps to remove their implants or who hadn't had them to begin with, although some extremely wealthy individuals could afford "palanquins"—hermetic devices secure against the plague. Others used "dream fuel"—an alien drug that counteracted the plague. Ilia Volyova develops a virus which can apparently combat it, but the plague she attempted to fight with it was immunised against it before she could use it to any effect.

By the time the events of Redemption Ark took place, the Plague was seen as less of a threat, though it was still considered dangerous. The Conjoiners in particular, being one of the only factions to have been relatively unaffected by the Plague, were adept at dealing with its various strains. This is demonstrated in a scene in Redemption Ark in which Galiana's lighthugger is brought into the Mother Nest. Conjoiner quarantine techniques include large amounts of ceramic armour (amongst other things) which the plague apparently cannot penetrate. Also, Clavain is later shown to be unworried about infection, maintaining his implants even while aboard the plague-infested Nostalgia for Infinity. Other conjoiners hold similar sentiments, including Remontoire and his soldiers (who install advanced weaponry on the Nostalgia for Infinity). The Conjoiners and Ultranauts are the only factions who continue to use their implants during the time of the plague.

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