Arts Syndrome

At autopsy, African American decedents often have mixed Alzheimer's and cerebrovascular brain pathologies including arteriolosclerosis. We applied a novel in-vivo classifier of ARTerioloSclerosis (ARTS) in 167 older African Americans (∼75y of age) with > 2 biennial 3 T MRI scans and > 3 years of associated cognitive follow-up to determine if ARTS scores (higher score=higher likelihood of arteriolosclerosis) changed over time and if this change associated with changes in cognition in the same individuals. Mixed effects regression models tested whether ARTS scores increased over time, while simultaneous mixed effects regression models estimated the simultaneous rates of change in both ARTS and cognition and the correlation of these changes. ARTS scores increased over time (estimate=0.030, SE=0.002, p < 0.0001). Faster increases in ARTS were associated with faster rates of global cognitive decline (r = -0.447, p = 0.006) and domain-specific cognitive functions. Applying an in-vivo marker of arteriolosclerosis in an African American cohort revealed that the likelihood of arteriolosclerosis increases over time, and participants whose ARTS scores increased more rapidly tended to have faster than average rates of cognitive decline.

Here we report on the reproductive morphology and histology of three gobiidae species (the Caspian monkey goby, Neogobius pallasi, the Caspian goby, Neogobius caspius and the round goby, Neogobius melanostomus) from the Iranian coastline of the Caspian Sea. Based on aging, reproductive histology, internal and external morphological measures, it appears that all three of these goby species have two types of reproductive males, a large courting, territorial, male type and a small cuckolding parasitic male type, a phenomenon known as alternative reproductive tactics (ARTs). Although ARTs have been reported previously for one of these species, the round goby, all reports stem from its invasive range; ARTs have never been reported before in any fish species in the Caspian Sea. In all three goby species there was a large, older male type, with a wide head, dark body colouration and a large investment in accessory glands, an organ important for female attraction and parental care. But there was also as a small, light, younger male type, with a narrow head, longer urogenital papilla and little investment in accessory glands. The Caspian monkey goby were the largest of the three species, and in this species the smaller, lighter, presumably cuckolding male morph was quite rare (only ~5% of the reproductive male population). In contrast, many of the round goby and monkey goby males were the small, lighter parasitic type, making up nearly half the population of reproductive males (48% and 40% respectively). Round goby and Caspian goby males had a prominent mesorchial gland, a fibrous sheath of pheromone releasing connective tissue that attaches the testes to the dorsal body wall, but the monkey goby specimens examined all lacked this structure. Although ARTs are well documented across fish species and appear to be particularly common in gobies, our study provides the first evidence for ARTs in goby fishes from the Caspian Sea. This article is protected by copyright. All rights reserved.

O-linked β-N-acetyl glucosamine (O-GlcNAc) is at the crossroads of cellular metabolism, including glucose and glutamine; its dysregulation leads to molecular and pathological alterations that cause diseases. Here we report that O-GlcNAc directly regulates de novo nucleotide synthesis and nicotinamide adenine dinucleotide (NAD) production upon abnormal metabolic states. Phosphoribosyl pyrophosphate synthetase 1 (PRPS1), the key enzyme of the de novo nucleotide synthesis pathway, is O-GlcNAcylated by O-GlcNAc transferase (OGT), which triggers PRPS1 hexamer formation and relieves nucleotide product-mediated feedback inhibition, thereby boosting PRPS1 activity. PRPS1 O-GlcNAcylation blocked AMPK binding and inhibited AMPK-mediated PRPS1 phosphorylation. OGT still regulates PRPS1 activity in AMPK-deficient cells. Elevated PRPS1 O-GlcNAcylation promotes tumorigenesis and confers resistance to chemoradiotherapy in lung cancer. Furthermore, Arts-syndrome-associated PRPS1 R196W mutant exhibits decreased PRPS1 O-GlcNAcylation and activity. Together, our findings establish a direct connection among O-GlcNAc signals, de novo nucleotide synthesis and human diseases, including cancer and Arts syndrome.