SUMMARY Age related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. While recent studies have demonstrated strong genetic associations of single nucleotide polymorphisms within a number of genes and AMD, other modes of regulation are also likely to play a role in its etiology. We identified a significantly decreased level of methylation on the IL17RC promoter in AMD patients. Further, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and mRNA in peripheral blood as well as in the affected retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis.

Correspondence jian@mskcc.org (N.J.), pateld@mskcc.org (D.J.P.) In BriefCryo-EM structures of type III-A Csm crRNA in the absence or presence of target RNA define the role of the 5 0 -repeat tag and kinks in positioning of 6-nt periodic RNA cleavage sites, the contribution of a Glurich loop to DNase activity regulation, and pairing capacity at À2 to À5 within 5 0 -repeat dictating autoimmunity. anti-tag ternary complexes in the 3.1 Å range. The topological features of the crRNA 5 0 -repeat tag explains the 5 0 -ruler mechanism for defining target cleavage sites, with accessibility of positions -2 to -5 within the 5 0 -repeat serving as sensors for avoidance of autoimmunity. The Csm3 thumb elements introduce periodic kinks in the crRNA-target RNA duplex, facilitating cleavage of the target RNA with 6-nt periodicity. Key Glu residues within a Csm1 loop segment of Csm crRNA adopt a proposed autoinhibitory conformation suggestive of DNase activity regulation. These structural findings, complemented by mutational studies of key intermolecular contacts, provide insights into Csm crRNA complex assembly, mechanisms underlying RNA targeting and site-specific periodic cleavage, regulation of DNase cleavage activity, and autoimmunity suppression.

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Highlights d Csm6 is a CARF domain ring nuclease regulating HEPN domain RNase cleavage activity d Two-step sequential cleavage of cA 4 by the CARF domain to ApApApA>p and ApA>p d Csm6 CARF domain His132 plays an autoinhibitory role in controlling RNase activity d RNA cleavage by Csm6 CARF and HEPN domains yield products with A>p 3 0 ends

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We present techniques for scaling Swin Transformer [35] up to 3 billion parameters and making it capable of training with images of up to 1,536×1,536 resolution. By scaling up capacity and resolution, Swin Transformer sets new records on four representative vision benchmarks: 84.0% top-1 accuracy on ImageNet-V2 image classification, 63.1 / 54.4 box / mask mAP on COCO object detection, 59.9 mIoU on ADE20K semantic segmentation, and 86.8% top-1 accuracy on Kinetics-400 video action classification. Our techniques are generally applicable for scaling up vision models, which * Equal. † Project lead. Ze, Yutong, Zhuliang, Zhenda, Yixuan, Jia are long-term interns at MSRA.