Persistent protein seeds make replacement tissue fail sooner
Proteostatic templatingIn models expressing human islet amyloid polypeptide (IAPP), persistent protein seeds would make later endocrine grafts fail sooner at previously affected sites.
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SCOUT: Each replacement episode can establish persistent, self-templating protein aggregates that survive turnover of the introduced cells and seed subsequent replacements. Dispersing tissue across more independently susceptible sites increases the chance of establishing at least one persistent seed reservoir; repeated renewal then shortens nucleation latency instead of resetting tissue age. The maladaptive memory resides in aggregate conformation. Selective seed neutralization stabilizes SPV_10 without changing interface permeability, mechanics, or delivered tissue mass.
In human-IAPP-expressing endocrine replacement models, later graft generations should fail sooner specifically at previously seed-positive sites, even after matching workload, perfusion, and founder composition.
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Validated seed depletion should reset the failure latency, while transfer of cell-free seed-containing material should shorten latency at a previously unused site. Aggregate-depleted matched material should not do so. Absence of transferable seeding activity or failure of selective seed depletion rejects this mechanism.
In an aged-animal endocrine replacement model, independently randomize tissue fraction, dispersion, procedural episode count, and pairing of an arbitrary sensory cue with each procedure.
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After recover
At matched total mass, mean secretion, oxygen delivery, and anatomical dispersion, independently controlled units should require greater measured dissipation to achieve the same per-unit output precis
Apply a blinded, configuration-independent renewal rule requiring sustained loss of aggregate donor-attributable function and equivalent host demand. With fixed baseline denominators, complete growth
Using progenitor-containing replacement units with matched cell number, initial output, and geometry, randomize balanced allocation of independently validated long-term founders versus ordinary aliquo