Epithelial NAD+ depletion drives mitochondrial dysfunction and contributes to intestinal inflammation

IntroductionWe have previously demonstrated that a pathologic downregulation of peroxisome proliferator-activated receptor–gamma coactivator 1-alpha (PGC1α) within the intestinal epithelium contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism underlying downregulation of PGC1α expression and activity during IBD is not yet clear.MethodsMice (male; C57Bl/6, Villincre/+;Pgc1afl/fl mice, and Pgc1afl/fl) were subjected to experimental colitis and treated with nicotinamide riboside. Western blot, high-resolution respirometry, nicotinamide adenine dinucleotide (NAD+) quantification, and immunoprecipitation were used to in this study.ResultsWe demonstrate a significant depletion in the NAD+ levels within the intestinal epithelium of mice undergoing experimental colitis, as well as humans with ulcerative colitis. While we found no decrease in the levels of NAD+-synthesizing enzymes within the intestinal epithelium of mice undergoing experimental colitis, we did find an increase in the mRNA level, as well as the enzymatic activity, of the NAD+-consuming enzyme poly(ADP-ribose) polymerase-1 (PARP1). Treatment of mice undergoing experimental colitis with an NAD+ precursor reduced the severity of colitis, restored mitochondrial function, and increased active PGC1α levels; however, NAD+ repletion did not benefit transgenic mice that lack PGC1α within the intestinal epithelium, suggesting that the therapeutic effects require an intact PGC1α axis.DiscussionOur results emphasize the importance of PGC1α expression to both mitochondrial health and homeostasis within the intestinal epithelium and suggest a novel therapeutic approach for disease management. These findings also provide a mechanistic basis for clinical trials of nicotinamide riboside in IBD patients

Mathematical Properties of a New Levin-Type Sequence Transformation Introduced by \v{C}\'{\i}\v{z}ek, Zamastil, and Sk\'{a}la. I. Algebraic Theory

\v{C}\'{\i}\v{z}ek, Zamastil, and Sk\'{a}la [J. Math. Phys. \textbf{44}, 962 - 968 (2003)] introduced in connection with the summation of the divergent perturbation expansion of the hydrogen atom in an external magnetic field a new sequence transformation which uses as input data not only the elements of a sequence $\{s_n \}_{n=0}^{\infty}$ of partial sums, but also explicit estimates $\{\omega_n \}_{n=0}^{\infty}$ for the truncation errors. The explicit incorporation of the information contained in the truncation error estimates makes this and related transformations potentially much more powerful than for instance Pad\'{e} approximants. Special cases of the new transformation are sequence transformations introduced by Levin [Int. J. Comput. Math. B \textbf{3}, 371 - 388 (1973)] and Weniger [Comput. Phys. Rep. \textbf{10}, 189 - 371 (1989), Sections 7 -9; Numer. Algor. \textbf{3}, 477 - 486 (1992)] and also a variant of Richardson extrapolation [Phil. Trans. Roy. Soc. London A \textbf{226}, 299 - 349 (1927)]. The algebraic theory of these transformations - explicit expressions, recurrence formulas, explicit expressions in the case of special remainder estimates, and asymptotic order estimates satisfied by rational approximants to power series - is formulated in terms of hitherto unknown mathematical properties of the new transformation introduced by \v{C}\'{\i}\v{z}ek, Zamastil, and Sk\'{a}la. This leads to a considerable formal simplification and unification.Comment: 41 + ii pages, LaTeX2e, 0 figures. Submitted to Journal of Mathematical Physic

An Odd Assortment of Foreigners in Greenland: Towards the Political Implications of Arctic Travel during the Late Interwar Years

The interwar years, 1918-1939, saw an increase in both the number and variety of travelers headed to the Arctic. Employing new technologies that allowed the region to become more accessible, knowable, and visible to the globe, these ventures to the North both reflected and contributed to the widespread geopolitical, social, and economic shifts occurring during this period, laying the foundation for how the Arctic is understood and framed today. However, many of these travelers remain marginal or completely overlooked in discussions of the region. This paper argues that greater attention to the increasingly odd assortment of foreigners traveling to the Arctic between World War I and World War II can offer a more nuanced understanding of both the geopolitical transitions underway in the region during this period and the broader political implications of travel. As an initial investigation of this ongoing research topic, this paper concentrates on three of the slowly increasing number of travelers with direct or close ties to the United States who ventured to Greenland in the late interwar years. It focuses on the travels of American artist Rockwell Kent, wealthy California socialite and amateur scientist Louise A. Boyd, and the Hollywood-sponsored filming expedition of German filmmaker Arnold Fanck, who all traveled to Greenland between 1931-1932. Approached not as singular endeavors but as part of the changing complex of Arctic expedition and travel, this paper argues that attention to these travelers provides greater insight into shifts in colonial policy, increasing cooperation between states, and the upsurge in global interest in the island, as well as the shifting relations between Denmark, the US, and Greenland. It also raises issues about the changing relationship between politics, science, and art

Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74

The presenilin homologue signal peptide peptidase-like 2a (SPPL2a) is an intramembrane protease of lysosomes/late endosomes which cleaves type II transmembrane proteins. We recently identified CD74, the invariant chain of the MHCII complex, as the first in vivo validated substrate of this protease. In endosomal compartments, CD74 undergoes sequential proteolysis leading to the generation of a membrane-bound N-terminal fragment (NTF) that requires cleavage by SPPL2a for its turnover. In SPPL2a−/− mice, this fragment accumulates in B-cells and significantly disturbs their maturation and functionality. To date, the substrate requirements of the protease SPPL2a have not been investigated. In the present study, we systematically analysed the molecular determinants of CD74 with regard to the intramembrane cleavage by SPPL2a. Using domain-exchange experiments, we demonstrate that the intracellular domain (ICD) of CD74 can be substituted without affecting cleavability by SPPL2a. Based on IP-MS analysis of the cleavage product, we report identification of the primary SPPL2a cleavage site between Y52 and F53 within the CD74 transmembrane segment. Furthermore, systematic alanine-scanning mutagenesis of the transmembrane and membrane-proximal parts of the CD74 NTF has been performed. We show that none of the analysed determinants within the CD74 NTF including the residues flanking the primary cleavage site are absolutely essential for SPPL2a cleavage. Importantly, we found that alanine substitution of helix-destabilizing glycines within the transmembrane segment and distinct residues within the luminal membrane-proximal segment led to a reduced efficiency of SPPL2a-mediated processing. Therefore we propose that elements within the transmembrane segment and the luminal juxtamembrane domain facilitate intramembrane proteolysis of CD74 by SPPL2a.</jats:p