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A 30-min permeability test for SF and EBA markers performed after the 24-h nanocarrier permeability assays confirmed that the integrity of the BBB models was preserved and the nanocarriers had no barrier damaging effect (Table S2)

To meet the diagnostic criteria for aEDS, a person must meet: Major criterion 1 AND major criterion 3 OR Major criterion 1 AND major criterion 2 and at least two minor criteria Major Criteria Congenital bilateral hip dislocation Severe generalized joint hypermobility, with multiple dislocations/subluxations Skin hyperextensibility Minor Criteria Muscle hypotonia Kyphoscoliosis Radiologically mild osteopenia Tissue fragility, including atrophic scars Easily bruisable skin Diagnostic Criteria To meet the diagnostic criteria for BCS, a person must meet: Major criterion 1 AND at least one other major criterion OR Major criterion 1 AND at least three minor criteria Major Criteria Thin cornea, with or without rupture (central corneal thickness often +2 Feature B: Positive family history (one or more first-degree relatives independently meet the current diagnostic criteria for hEDS) Feature C: Musculoskeletal complications (must have at least one of the following): Musculoskeletal pain in two or more limbs, recurring daily for at least three (3) months Chronic, widespread pain for at least three (3) months Recurrent joint dislocations or frank joint instability, in the absence of trauma (a or b) Three (3) or more atraumatic dislocations in the same joint or two (2) or more atraumatic dislocations in two (2) different joints occurring at different times OR Medical confirmation of joint instability at two (2) or more sites not related to trauma Criterion 3: ALL of the following prerequisites must be met: Absence of unusual skin fragility, which should prompt consideration of other types of EDS Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions In patients with an acquired connective tissue disorder (e.g., lupus, rheumatoid arthritis, etc.), additional diagnosis of hEDS requires meeting both Features A and B of Criterion 2

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76 Conditional knockout of GPX4 causes death of mouse embryonic fibroblasts in a lipid peroxide-dependent, non-apoptotic form and causes neurodegenerative disease in the cortical regions and hippocampus of the mouse brain