Characterizing the Role of the E3 Ligase ITCH in Gut Mucosal Homeostasis

The mucosal barrier of the small intestine is highly dynamic, enabling the passage of nutrients that are necessary for the body’s function while simultaneously preventing a breach by harmful microorganisms that are damaging to the host. The effectiveness of the mucosal barrier is dependent on the cohesive relationship established between the luminal mucosal epithelium and the underlying immune compartment in the small intestine. The epithelium provides the first line of defense against pathogens by establishing a physical barrier separating the external environment from the body’s internal milieu, while the immune system secondarily responds to clear bacteria that have breached the epithelial barrier. The HECT E3 ubiquitin ligase ITCH is known to regulate immune responses, and loss of function of ITCH has been associated with gastrointestinal inflammatory disorders. However, the high level of ITCH expression within the intestinal epithelium suggests that it may have an important function(s) in that tissue for maintaining gut homeostasis. Indeed, we identified that global loss of ITCH (Itcha18H/a18H) in young adult animals influenced intestinal architecture characterized by increases in both crypt and villus area that were more prominent in the distal part of the small intestine. Increased crypt area was found to result from expansion of both the proliferating transit amplifying progenitor population and terminally differentiated Paneth cells. Lack of ITCH also resulted in changes in numbers of goblet cells on the villus. Epithelial cell turnover was also accelerated in Itcha18h/a18H animals, as evidenced by increases in both proliferation and apoptosis within the crypt, as well a more rapid cell migration of bromodeoxyuridine-labeled epithelial cells along the crypt-villus axis. Consistent with the observed enhancement of cellular migration, Itcha18H/a18H mice carrying the Min mutation (Itcha18H/a18H; ApcMin/+) displayed a 76% reduction in tumor burden as compared to ApcMin/+ littermates with normal levels of ITCH. To identify which aspects of these changes were cell autonomous, intestinal organoids were generated from the crypts of ITCH sufficient and ITCH deficient animals. Interestingly, epithelial cell proliferation and differentiation were not perturbed in ITCH deficient organoids, in contrast to the in vivo phenotype of the Itcha18H/a18H small intestines. However, increased cell death was observed in organoids lacking ITCH, which was also consistent with increased cleavedcaspase 3 staining in the intestines of mice lacking ITCH exclusively in the intestinal epithelium. The failure to recapitulate the Itcha18H/a18H epithelial phenotype prompted us to investigate how loss of ITCH in immune cells impacts the intestinal epithelium. Animals lacking ITCH within the myeloid cell lineage have similar defects in crypt area, as well as increases goblet and Paneth cell numbers, as compared to the Itcha18H/a18H animals, albeit delayed. These finding highlight a cell autonomous as well as non-cell autonomous function for ITCH in mediating epithelial homeostasis, and emphasize the importance of ITCH in small intestinal barrier function

Time Correlation Functions of Three Classical Heisenberg Spins on an Isosceles Triangle and on a Chain: Strong Effects of Broken Symmetry

At arbitrary temperature $T$, we solve for the dynamics of single molecule magnets composed of three classical Heisenberg spins either on a chain with two equal exchange constants $J_1$, or on an isosceles triangle with a third, different exchange constant $J_2$. As T\rightrarrow\infty, the Fourier transforms and long-time asymptotic behaviors of the two-spin time correlation functions are evaluated exactly. The lack of translational symmetry on a chain or an isosceles triangle yields time correlation functions that differ strikingly from those on an equilateral trinagle with $J_1=J_2$. At low $T$, the Fourier transforms of the two autocorrelation functions with $J_1\ne J_2$ show one and four modes, respectively. For a semi-infinite $J_2/J_1$ range, one mode is a central peak. At the origin of this range, this mode has a novel scaling form.Comment: 9 pages, 14 figures, accepted for publication in Phys. Rev.

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

The GITEWS Tsunami Simulation System based on Multi-Sensor Inversion

The German Indonesian Tsunami Early Warning System (GITEWS) comprises a sophisticated interaction of online sensor data, simulation-based inversion, and modeling result interpretation to provide qualified and accurate tsunami warning within extremely short time. In order to provide accurate inversion capabilities for near-field tsunamis, the simulation system (SIM) within the GITEWS tsunami early warning system relies on simultaneous evaluation of multiple sensors. In order to provide quick situation assessment, it relies on a large number of pre-computed tsunami scenarios. In order to reliably invert and select a reasonable scenario from incoming sensor data the following prerequisites have to be fulfilled: pre-computed scenarios need to be accurate and realistic; different data types need to be related with each other; different data types need to complement each other as to minimize uncertainty and ill-posedness. In order to address these topics, a new tsunami modeling approach has been developed, including an unstructured mesh finite element tsunami inundation and propagation model. A new scenario selection method has been developed, which interprets different types of data (seismic parameters, wave height and wave arrival time, earth crust deformation vectors) simultaneously, using physical modeling and a generalized distance measure to relate these data. It can be shown that this simultaneous evaluation of complementary data leads to reliable and quick inversion results. Equipped with this novel inversion method, a fully automatic simulation system forms the engine of the GITEWS early warning system. Without human interaction, it is capable of performing the matching of incoming data with existing scenarios as well as post-processing and formatting simulation results like mapped data and virtual sensor data

Intestinal epithelial CGAS dampens inflammation by upregulating autophagy

The pathogenesis of intestinal inflammation involves a complex network of cell signaling pathways. CGAS (cyclic GMP-AMP synthase) is a cytoplasmic DNA sensor that is most known for upregulating interferon-mediated inflammation. In this punctum, we discuss our novel finding that in the intestinal epithelium, CGAS binds to BECN1 (beclin 1) to subsequently induce macroautophagy/autophagy and dampen inflammation