Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE-and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.

SAM domain and HD domain-containing protein 1 (SAMHD1) is a dGTP-dependent triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs) thereby limiting the intracellular dNTP pool. Mutations in SAMHD1 cause Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy that mimics congenital viral infection and that phenotypically overlaps with the autoimmune disease systemic lupus erythematosus. Both disorders are characterized by activation of the antiviral cytokine interferon-α initiated by immune recognition of self nucleic acids. Here we provide first direct evidence that SAMHD1 associates with endogenous nucleic acids in situ. Using fluorescence cross-correlation spectroscopy, we demonstrate that SAMHD1 specifically interacts with ssRNA and ssDNA and establish that nucleic acid-binding and formation of SAMHD1 complexes are mutually dependent. Interaction with nucleic acids and complex formation do not require the SAM domain, but are dependent on the HD domain and the C-terminal region of SAMHD1. We finally demonstrate that mutations associated with AGS exhibit both impaired nucleic acid-binding and complex formation implicating that interaction with nucleic acids is an integral aspect of SAMHD1 function.

[1] The past decade witnessed rapid developments in remote sensing methods that now permit an unprecedented description of the spatial variations in water levels (H w ), canopy height (h c ), and leaf area density distribution (a) at large spatial scales. These developments are now renewing interest in effective resistance formulations for water flow within and above vegetated surfaces so that they can be incorporated into simplified water routing models driven by such remote sensing products. The first generation of such water routing models linked the bulk velocity to gradients in H w via a constant diffusion velocity that cannot be inferred from canopy properties (a and h c ). The next generation of such hydrologic models must preserve the nonlinear relationship between the resistance value, canopy attributes (e.g., a and h c ), and H w without compromising model simplicity. Using a simplified scaling analysis on the depth-integrated mean momentum balance and a two-layer model for the bulk velocity, the Darcy-Weisbach friction factor (f) was shown to vary with three canonical length scales that can be either measured or possibly inferred from remote sensing products H w , h c , and the adjustment length scale L c = (C d a) À1 , where C d is the drag coefficient (of order unity). The scaling analysis proposed here reveals that these length scales can be combined in two dimensionless groups, H w /h c and L c /h c . The dependence of f on these two functional groups was then explored using a combination of first-order closure modeling and 130 experimental runs derived from a large number of flume experiments carried out for rigid and flexible vegetation. The results from the data and the model show a nonlinear decrease in f with increasing H w /h c at a given L c /h c and the nonlinear increase in f with decreasing L c /h c . Furthermore, both model and data results did not exhibit any dependence on the bulk Reynolds number.Citation: Poggi, D., C. Krug, and G. G. Katul (2009), Hydraulic resistance of submerged rigid vegetation derived from first-order closure models, Water Resour. Res.,

The notion of authorship is a core element in antipiracy campaigns accompanying an emerging copyright regime, worldwide. These campaigns are built on discourses that aim to ‘problematize’ the issues of ‘legality’ of content downloading practices, ‘protection’ for content creators and the alleged damage caused to creators’ livelihood by piracy. Under these tensions, fandom both subverts such discourses, through sharing and production practices, and legitimizes industry’s mythology of an ‘original’ author. However, how is the notion of authorship constructed in the cooperative spaces of fandom? The article explores the most popular fandom sites of A Song of Ice and Fire, the book series that inspires the TV-show Game of Thrones and argues that the notion of authorship is not one-dimensional, but rather consists of attributes that develop across three processes: community building, the creative and the industrial/production process. Here, fandom constructs a figure of the ‘author’ which, although more complex than the one presented by the industry in its copyright/anti-piracy campaigns, maintains the status quo of regulatory frameworks based on the idea of a ‘primary’ creator.

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