SUMMARY Metabolites in the kynurenine pathway of tryptophan degradation are thought to play an important role in neurodegenerative disorders such as Alzheimer’s disease and Huntington’s disease. Metabolites that cause glutamate receptor-mediated excitotoxicity and free radical formation are elevated in the blood and vulnerable brain regions in these diseases, while levels of the neuroprotective metabolite kynurenic acid are often decreased. Here we describe the synthesis and characterization of JM6, a novel small-molecule pro-drug inhibitor of kynurenine 3-monooxygenase (KMO). JM6 raises kynurenic acid and reduces extracellular glutamate in the brain after chronic oral administration by inhibiting KMO in blood. In a transgenic mouse model of Alzheimer’s disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extended life span, prevented synaptic loss, and decreased microglial activation in a mouse model of Huntington’s disease. These findings support a critical link between blood cells and neurodegeneration that is mediated by KMO and the kynurenine pathway.

Highlights d Acetylation suppresses cGAS activity d Aspirin directly acetylates cGAS d Aspirin inhibits cGAS-mediated interferon production d Aspirin alleviates DNA-induced autoimmunity in AGS mouse models and patient cells

River morphology and dynamics are strongly infl uenced by active tectonics. We report channel dynamics for the Peikang River, which fl ows through the Hsuehshan Range in central Taiwan. Using a digital elevation model and fi eld surveys, we constrain channel morphology for an ~90 km stretch of river to calculate unit stream power and boundary shear stress along the river path. Incision rates are estimated with optically stimulated luminescence dating of sand deposited on strath terraces. We fi nd a strong correlation between unit stream power/ shear stress and incision rate, but only if variation in channel width is considered. A calibrated river incision rule implies river incision rates of ~9-13.5 mm/yr upstream of the Meiyuan and Tili faults and suggests that one or both of these structures are presently active. Our results indicate that the Shuilikeng fault is also actively deforming, as incision rates increase to ~6-10 mm/yr across it, compared to 1-4 mm/yr in adjacent reaches. Prominent narrowing across the Shuilikeng fault, and the absence of signifi cant gradient variation indicate that channel width is a fi rst-order morphological adjustment to differential incision. Only when the channel width-to-depth ratio reaches a minimum does the channel slope signifi cantly adjust to local changes in base level, as is the case upstream of the Meiyuan and Tili faults.

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