Diesel Exhaust Particle (DEP)-induced glucose intolerance is driven by an intestinal innate immune response and NLRP3 activation in mice

BACKGROUND We previously found that air pollution particles reaching the gastrointestinal tract elicit gut inflammation as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. This inflammatory response was associated with beta-cell dysfunction and glucose intolerance. So far, it remains unclear whether gut inflammatory changes upon oral air pollution exposure are causally linked to the development of diabetes. Hence, our aim was to assess the role of immune cells in mediating glucose intolerance instigated by orally administered air pollutants. METHODS To assess immune-mediated mechanisms underlying air pollution-induced glucose intolerance, we administered diesel exhaust particles (DEP; NIST 1650b, 12 µg five days/week) or phosphate-buffered saline (PBS) via gavage for up to 10 months to wild-type mice and mice with genetic or pharmacological depletion of innate or adaptive immune cells. We performed unbiased RNA-sequencing of intestinal macrophages to elucidate signaling pathways that could be pharmacologically targeted and applied an in vitro approach to confirm these pathways. RESULTS Oral exposure to air pollution particles induced an interferon and inflammatory signature in colon macrophages together with a decrease of CCR2$^{-}$ anti-inflammatory/resident macrophages. Depletion of macrophages, NLRP3 or IL-1β protected mice from air pollution-induced glucose intolerance. On the contrary, Rag2-/- mice lacking adaptive immune cells developed pronounced gut inflammation and glucose intolerance upon oral DEP exposure. CONCLUSION In mice, oral exposure to air pollution particles triggers an immune-mediated response in intestinal macrophages that contributes to the development of a diabetes-like phenotype. These findings point towards new pharmacologic targets in diabetes instigated by air pollution particles

Fivebranes and 4-manifolds

We describe rules for building 2d theories labeled by 4-manifolds. Using the proposed dictionary between building blocks of 4-manifolds and 2d N=(0,2) theories, we obtain a number of results, which include new 3d N=2 theories T[M_3] associated with rational homology spheres and new results for Vafa-Witten partition functions on 4-manifolds. In particular, we point out that the gluing measure for the latter is precisely the superconformal index of 2d (0,2) vector multiplet and relate the basic building blocks with coset branching functions. We also offer a new look at the fusion of defect lines / walls, and a physical interpretation of the 4d and 3d Kirby calculus as dualities of 2d N=(0,2) theories and 3d N=2 theories, respectivelyComment: 81 pages, 18 figures. v2: misprints corrected, clarifications and references added. v3: additions and corrections about lens space theory, 4-manifold gluing, smooth structure

Gaugino Condensation in M-theory on S^1/Z_2

In the low energy limit of for M-theory on S^1/Z_2, we calculate the gaugino condensate potential in four dimensions using the background solutions due to Horava. We show that this potential is free of delta-function singularities and has the same form as the potential in the weakly coupled heterotic string. A general flux quantization rule for the three-form field of M-theory on S^1/Z_2 is given and checked in certain limiting cases. This rule is used to fix the free parameter in the potential originating from a zero mode of the form field. Finally, we calculate soft supersymmetry breaking terms. We find that corrections to the Kahler potential and the gauge kinetic function, which can be large in the strongly coupled region, contribute significantly to certain soft terms. In particular, for supersymmetry breaking in the T-modulus direction, the small values of gaugino masses and trilinear couplings that occur in the weakly coupled, large radius regime are enhanced to order m_3/2 in M-theory. The scalar soft masses remain small even, in the strong coupling M-theory limit.Comment: 20 pages, LATE

Binary Cosmic Strings

The properties of cosmic strings have been investigated in detail for their implications in early-universe cosmology. Although many variations of the basic structure have been discovered, with implications for both the microscopic and macroscopic properties of cosmic strings, the cylindrical symmetry of the short-distance structure of the string is generally unaffected. In this paper we describe some mechanisms leading to an asymmetric structure of the string core, giving the defects a quasi-two-dimensional character. We also begin to investigate the consequences of this internal structure for the microscopic and macroscopic physics.Comment: 19 pages; uses harvmac (not included

Supersymmetric Electroweak Cosmic Strings

We study the connection between $N=2$ supersymmetry and a topological bound in a two-Higgs-doublet system with an $SU(2)\times U(1)_Y\times U(1)_{Y^{\prime}}$ gauge group. We derive the Bogomol'nyi equations from supersymmetry considerations showing that they hold provided certain conditions on the coupling constants, which are a consequence of the huge symmetry of the theory, are satisfied. Their solutions, which can be interpreted as electroweak cosmic strings breaking one half of the supersymmetries of the theory, are studied. Certain interesting limiting cases of our model which have recently been considered in the literature are finally analyzed.Comment: 20 pages, RevTe

Lung versus gut exposure to air pollution particles differentially affect metabolic health in mice

BACKGROUND Air pollution has emerged as an unexpected risk factor for diabetes. However, the mechanism behind remains ill-defined. So far, the lung has been considered as the main target organ of air pollution. In contrast, the gut has received little scientific attention. Since air pollution particles can reach the gut after mucociliary clearance from the lungs and through contaminated food, our aim was to assess whether exposure deposition of air pollution particles in the lung or the gut drive metabolic dysfunction in mice. METHODS To study the effects of gut versus lung exposure, we exposed mice on standard diet to diesel exhaust particles (DEP; NIST 1650b), particulate matter (PM; NIST 1649b) or phosphate-buffered saline by either intratracheal instillation (30 µg 2 days/week) or gavage (12 µg 5 days/week) over at least 3 months (total dose of 60 µg/week for both administration routes, equivalent to a daily inhalation exposure in humans of 160 µg/m$^{3}$ PM$_{2.5}$) and monitored metabolic parameters and tissue changes. Additionally, we tested the impact of the exposure route in a "prestressed" condition (high-fat diet (HFD) and streptozotocin (STZ)). RESULTS Mice on standard diet exposed to particulate air pollutants by intratracheal instillation developed lung inflammation. While both lung and gut exposure resulted in increased liver lipids, glucose intolerance and impaired insulin secretion was only observed in mice exposed to particles by gavage. Gavage with DEP created an inflammatory milieu in the gut as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. In contrast, liver and adipose inflammation markers were not increased. Beta-cell secretory capacity was impaired on a functional level, most likely induced by the inflammatory milieu in the gut, and not due to beta-cell loss. The differential metabolic effects of lung and gut exposures were confirmed in a "prestressed" HFD/STZ model. CONCLUSIONS We conclude that separate lung and gut exposures to air pollution particles lead to distinct metabolic outcomes in mice. Both exposure routes elevate liver lipids, while gut exposure to particulate air pollutants specifically impairs beta-cell secretory capacity, potentially instigated by an inflammatory milieu in the gut

Closed String Tachyons and Semi-Classical Instabilities

We conjecture that the end point of bulk closed string tachyon decay at any non-zero coupling, is the annihilation of space time by Witten's bubble of nothing, resulting in a topological phase of the theory. In support of this we present a variety of situations in which there is a correspondence between the existence of perturbative tachyons in one regime and the semi-classical annihilation of space-time. Our discussion will include many recently investigated scenarios in string theory including Scherk-Schwarz compactifications, Melvin magnetic backgrounds, and noncompact orbifolds. We use this conjecture to investigate a possible web of dualities relating the eleven-dimensional Fabinger-Horava background with nonsupersymmetric string theories. Along the way we point out where our conjecture resolves some of the puzzles associated with bulk closed string tachyon condensation.Comment: 31 pages, 5 figures 3 figures added, typos corrected and references added. Discussion of Type 0/Heterotic s-duality extended and some other points clarified Revision of discussion on Fabinger-Horava string descendents, section on Scherk-Schwarz compactification of Horava-Witten removed, some references adde

Black Holes and Five-brane Thermodynamics

The phase diagram for Dp-branes in M-theory compactified on $T^4$, $T^4/Z_2$, $T^5$, and $T^6$ is constructed. As for the lower-dimensional tori considered in our previous work (hep-th/9810224), the black brane phase at high entropy connects onto matrix theory at low entropy; we thus recover all known instances of matrix theory as consequences of the Maldacena conjecture. The difficulties that arise for $T^6$ are reviewed. We also analyze the D1-D5 system on $T^5$; we exhibit its relation to matrix models of M5-branes, and use spectral flow as a tool to investigate the dependence of the phase structure on angular momentum.Comment: 57 pages, 6 eps figures, latex. v2: DLCQ limit of 5-brane corrected; typos corrected, references added. v3: reference added, typos corrected v4: comments on DLCQ limit of 5-brane corrected one last time. Final version, to appear in Phys. Rev.

String Universality

If there is a single underlying "theory of everything" which in some limits of its "moduli space" reduces to the five weakly coupled string theories in 10D, and 11D SUGRA, then it is possible that all six of them have some common domain of validity and that they are in the same universality class, in the sense that the 4D low energy physics of the different theories is the same. We call this notion String Universality. This suggests that the true vacuum of string theory is in a region of moduli space equally far (in some sense) from all perturbative theories, most likely around the self-dual point with respect to duality symmetries connecting them. We estimate stringy non-perturbative effects from wrapped brane instantons in each perturbative theory, show how they are related by dualities, and argue that they are likely to lead to moduli stabilization only around the self-dual point. We argue that moduli stabilization should occur near the string scale, and SUSY breaking should occur at a much lower intermediate scale, and that it originates from different sources. We discuss the problems of moduli stabilization and SUSY breaking in currently popular scenarios, explain why these problems are generic, and discuss how our scenario can evade them. We show that String Universality is not inconsistent with phenomenology but that it is in conflict with some popular versions of brane world scenarios.Comment: 48 pages, 1 figure; one reference adde