AAV-NRF2 protects retinal and choroidal vasculature in a GDF15-dependent manner in an oxidative damage model of AMD.

August 18, 2026| Source: Proceedings of the National Academy of Sciences of the United States of America

Oxidative stress is proposed to be a driver of age-related diseases. Age-related macular degeneration (AMD) is one such disease, where the retinal pigment epithelium (RPE) is affected early in the disease. Vasculature damage also occurs, sometimes preceding RPE damage. To model some aspects of dry AMD, we used the NaIO 3 mouse model of oxidative damage. Disruption of the deep retinal vascular plexus, disorganization and death of capillaries within the choriocapillaris, and marked electroretinographic decline were observed. Adeno-associated virus (AAV) overexpressing the transcription factor, NRF2, which induces antioxidation enzymes and represses inflammation, was tested for protection of damage. The BEST1 promoter limited expression to the RPE. The RPE, photoreceptors, and vascular architecture in both retinal and choroidal compartments were protected. Conditioned medium from RPE-choroid explants, infected by AAV8/BEST1-NRF2, was sufficient to transfer partial protection in vivo, suggesting that NRF2 induces a protective secreted factor(s). Analysis of RNA-seq data nominated growth differentiation factor 15 (GDF15) as a candidate secreted mediator. Injection of recombinant GDF15 reproduced key protective phenotypes in vivo, whereas Gdf15 deficiency attenuated NRF2-mediated rescue. Pharmacologic inhibition of TGF-β receptor signaling diminished NRF2-induced protection, supporting involvement of this signaling pathway. In a laser-induced choroidal neovascularization model, intravitreal GDF15 injection reduced fluorescein leakage and lesion size. These findings support a model in which NRF2 activation in the RPE induces expression of GDF15, which is capable of protecting the RPE, photoreceptors, and the retinal and choroidal vasculature. NRF2 and GDF15 have therapeutic potential for ocular diseases, as well as for other diseases with vascular pathology.

Read the original source →

Extensive glacier loss in the coterminous United States.

Glaciers populate the mountain ranges of the western conterminous United States and despite their importance to alpine hydrology, their area and volume change have never been comprehensively evaluated. Our study shows that since the mid-twentieth century about one-quarter of the glaciers have disappeared and the overall area and volume are reduced by one-third. The pattern of glacier shrinkage suggests most glaciers in the conterminous United States are largely maintained by local topographic in

Physical/TechOctober 20, 2026

Reaction-based cryo-EM resolves the continuous conformational spectrum of CTP synthase catalysis.

Capturing enzymes under native turnover conditions remains a grand challenge in structural biology. Here, we develop a reaction-based cryo-electron microscopy (cryo-EM) strategy that directly samples Drosophila melanogaster cytidine triphosphate synthase (CTPS) from actively catalyzing mixtures containing only natural substrates and allosteric effectors. By integrating reaction-based sampling with three-dimensional variability analysis, we resolve a continuous conformational spectrum of CTPS dur

Physical/TechOctober 20, 2026

GTP orchestrates CTP synthase via an allosteric effector-cycling mechanism.

Cytidine triphosphate (CTP), a fundamental building block of RNA, plays vital roles in diverse biological processes. CTP synthase (CTPS) is the only known enzyme for de novo synthesis of CTP. Efficient CTPS catalysis requires guanosine triphosphate (GTP) in a dose-dependent, nonconsumptive manner; however, the precise mechanism by which GTP drives CTP formation remains unclear. Here, we integrate a series of cryo-EM structures of Drosophila melanogaster CTPS captured from actively catalyzing sam

Physical/TechOctober 20, 2026

Antiferromagnetism and tightly bound Cooper pairs induced by kinetic frustration.

Antiferromagnetism and superconductivity are often viewed as competing orders in correlated electron systems. Here, we demonstrate that kinetic frustration in hole motion facilitates their coexistence within the square-lattice repulsive Hubbard model. Combining exact analytical solutions on tailored geometries with large-scale numerical simulations, we reveal a robust pairing mechanism: Holes on opposite sublattices behave as if they carry opposite effective charges due to spin singlet formation

Physical/TechOctober 20, 2026

Coordinated transformations of the labyrinth and occiput during the dinosaur-bird transition.

Evolutionary shape changes of the vertebrate semicircular canals (SCCs) are often ascribed to evolutionary transitions in locomotion, including the origin of flight during the dinosaur-bird transition. However, the potential for transformations of braincase architecture to influence SCC shape independent of sensory-functional adaptation has generally been overlooked. We evaluate the influence of both factors using a large dataset of 146 living and recently extinct crown birds, including taxa rep