Human intestinal epithelial and smooth muscle cells are potent producers of IL-6.

BACKGROUND: Interleukin-6 (IL-6), a pluripotent cytokine, has traditionally been considered the product of proinflammatory cells. However, many other cell types have been shown to produce IL-6. Since intestinal inflammation is commonly associated with a vigorous systemic inflammatory response, we hypothesized that intestinal epithelial and smooth muscle cells might contribute to that response by producing IL-6. We therefore studied the capacity of differentiated human intestinal epithelial and smooth muscle cell lines to produce IL-6 in response to various proinflammatory stimuli. MATERIALS AND METHODS: CCL-241, a human intestinal epithelial cell line, and HISM, a human intestinal muscle cell line, were grown to confluency and then treated for 24 h with various concentrations of lipopolysaccharide, Clostridium difficile culture extract containing both toxin A and toxin B, recombinant human tumor necrosis factor-alpha (TNF-alpha), or recombinant human interleukin-1 beta (IL-1beta). Supernatants were then collected for IL-6 determination using an enzyme-linked immunosorbent assay. Cell numbers were determined using a Coulter counter. For comparison, parallel studies were performed using phorbol ester-primed U-937 and THP-1 human macrophage cell lines. RESULTS: Both human intestinal epithelial and smooth muscle cells produced IL-6 under basal conditions. In HISM cells, but not in CCL-241 cells, IL-6 release was increased slightly by treatment with C. difficile culture extract containing both toxin A and toxin B and with lipopolysaccharide. In both cell lines, IL-6 production was profoundly stimulated by treatment with IL-1beta and less so with TNF-alpha. Combinations of high-dose TNF-alpha and IL-1beta may have a slightly additive, but not synergistic, effect on IL-6 release. The amount of IL-6 produced by IL-1-stimulated intestinal cell lines was 70-fold higher than that produced by stimulated macrophage cell lines. CONCLUSIONS; Both intestinal epithelial and smooth muscle cells demonstrate the ability to release significant amounts of IL-6. The profound response to IL-1beta and TNF-alpha stimulation by both cell lines suggests that human intestinal parenchymal cells, influenced by paracrine mediators liberated from proinflammatory cells, might significantly contribute to the overall systemic inflammatory response by producing IL-6

Upper and Lower Bounds on Gravitational Entropy

The entropy in the interior of the Universe has many contributions including well understood ones from radiation and relic neutrinos. The gravitational entropy is larger and more subtle. One contribution which provides our lower bound is from supermassive black holes at the centers of galaxies. The remainder is harder to pin down. We suggest an upper bound which is many orders of magnitude below the holographic bound yet above that of the supermassive black holes. We propose that gravitational entropy in dark matter halos is the largest contributor to the present entropy of the universe.Comment: 10 pages LaTeX. Minor correction

Genetic background modifies vulnerability to glaucoma related phenotypes in Lmx1b mutant mice

Variants in the LIM homeobox transcription factor 1-beta (LMX1B) gene predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1Bmutations varies widely between individuals. To better understand the mechanisms underlying LMX1B-related phenotypes and individual differences, we backcrossed the Lmx1bV265D (also known as Lmx1bIcst ) allele onto the C57BL/6J (B6), 129/Sj (129), C3A/BLiA-Pde6b+ /J (C3H) and DBA/2J-Gpnmb+ (D2-G) mouse strain backgrounds. Strain background had a significant effect on the onset and severity of ocular phenotypes in Lmx1bV265D/+ mutant mice. Mice of the B6 background were the most susceptible to developing abnormal IOP distribution, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands and corneal abnormalities) and glaucomatous nerve damage. By contrast, Lmx1bV265D mice of the 129 background were the most resistant to developing anterior segment abnormalities, had less severe IOP elevation than B6 mutants at young ages and showed no detectable nerve damage. To identify genetic modifiers of susceptibility to Lmx1bV265D -induced glaucoma-associated phenotypes, we performed a mapping cross between mice of the B6 (susceptible) and 129 (resistant) backgrounds. We identified a modifier locus on Chromosome 18, with the 129 allele(s) substantially lessening severity of ocular phenotypes, as confirmed by congenic analysis. By demonstrating a clear effect of genetic background in modulating Lmx1b-induced phenotypes, providing a panel of strains with different phenotypic severities and identifying a modifier locus, this study lays a foundation for better understanding the roles of LMX1B in glaucoma with the goal of developing new treatments

Breakdown of the adiabatic limit in low dimensional gapless systems

It is generally believed that a generic system can be reversibly transformed from one state into another by sufficiently slow change of parameters. A standard argument favoring this assertion is based on a possibility to expand the energy or the entropy of the system into the Taylor series in the ramp speed. Here we show that this argumentation is only valid in high enough dimensions and can break down in low-dimensional gapless systems. We identify three generic regimes of a system response to a slow ramp: (A) mean-field, (B) non-analytic, and (C) non-adiabatic. In the last regime the limits of the ramp speed going to zero and the system size going to infinity do not commute and the adiabatic process does not exist in the thermodynamic limit. We support our results by numerical simulations. Our findings can be relevant to condensed-matter, atomic physics, quantum computing, quantum optics, cosmology and others.Comment: 11 pages, 5 figures, to appear in Nature Physics (originally submitted version

Nickel-Catalyzed Allylic Substitution of Simple Alkenes

This report describes a nickel-catalyzed allylic substitution process of simple alkenes whereby an important structural motif, a 1,4-diene, was prepared. The key to success is the use of an appropriate nickel–phosphine complex and a stoichiometric amount of silyl triflate. Reactions of 1-alkyl-substituted alkenes consistently provided 1,1-disubstituted alkenes with high selectivity. Insight into the reaction mechanism as well as miscellaneous application of the developed catalytic process is also documented.National Institute of General Medical Sciences (U.S.) (GM-63755)Japan Society for the Promotion of Science. Postdoctoral Fellowship for Research Abroa

Unimodular bimode gravity and the coherent scalar-graviton field as galaxy dark matter

The explicit violation of the general gauge invariance/relativity is adopted as the origin of dark matter and dark energy of the gravitational nature. The violation of the local scale invariance alone, with the residual unimodular one, is considered. Besides the four-volume preserving deformation mode -- the transverse-tensor graviton -- the metric comprises a compression mode -- the scalar graviton, or the systolon. A unimodular invariant and general covariant metric theory of the bimode/scalar-tensor gravity is consistently worked out. To reduce the primordial ambiguity of the theory a dynamical global symmetry is imposed, with its subsequent spontaneous breaking revealed. The static spherically symmetric case in the empty, but possibly for the origin, space is studied. A three-parameter solution describing a new static space structure -- the dark lacuna -- is constructed. It enjoys the property of gravitational confinement, with the logarithmic potential of gravitational attraction at the periphery, and results in the asymptotically flat rotation curves. Comprising a super-massive dark fracture (a scalar-modified black hole) at the origin surrounded by a cored dark halo, the dark lacunas are proposed as a prototype model of galaxies, implying an ultimate account for the distributed non-gravitational matter and a putative asphericity or rotation.Comment: 38 pages, 10 figures; exposition improved, remarks added, accepted for publicatio

Depolarization of the cosmic microwave background by a primordial magnetic field and its effect upon temperature anisotropy

We estimate the depolarizing effect of a primordial magnetic field upon the cosmic microwave background radiation due to differential Faraday rotation across the last scattering surface. The degree of linear polarization of the CMB is significantly reduced at frequencies around and below 30 GHz $(B_* /10^{-2}{\rm Gauss})^{1/2}$, where $B_*$ is the value of the primordial field at recombination. The depolarizing mechanism reduces the damping of anisotropies due to photon diffusion on small angular scales. The $l\approx 1000$ multipoles of the CMB temperature anisotropy correlation function in a standard cold dark matter cosmology increase by up to 7.5\% at frequencies where depolarization is significant.Comment: Latex, 23 pages, 4 figures. Submitted to Phys. Rev.

Thickness-weighted mean theory for the effect of surface gravity waves on mean flows in the upper ocean

The residual effect of surface gravity waves on mean flows in the upper ocean is investigated using thickness weighted mean (TWM) theory applied in a vertically Lagrangian and horizontally Eulerian coordinate system. Depth-dependent equations for the conservation of volume, momentum, and energy are derived. These equations allow for (i) finite amplitude fluid motions, (ii) the horizontal divergence of currents and (iii) a concise treatment of both the kinematic and viscous boundary conditions at the sea surface. Under the assumptions of steady and monochromatic waves and a uniform turbulent viscosity, the TWM momentum equations are used to illustrate the pressure- and viscosity-induced momentum fluxes through the surface that are implicit in previous studies of the wave-induced modification of the classical Ekman spiral problem. The TWM approach clarifies, in particular, the surface momentum flux associated with the so-called virtual wave stress of Longuet-Higgins. Overall the TWM framework can be regarded as an alternative to the three-dimensional Lagrangian mean framework of Pierson. Moreover the TWM framework can be used to include the residual effect of surface waves in large-scale circulation models. In specific models that carry the TWM velocity appropriate for advecting tracers as their velocity variable, the turbulent viscosity term should be modified so that the viscosity acts only on the Eulerian mean velocity

A Comment or two on Holographic Dark Energy

It has, quite recently, become fashionable to study a certain class of holographic-inspired models for the dark energy. These investigations have, indeed, managed to make some significant advances towards explaining the empirical data. Nonetheless, surprisingly little thought has been given to conceptual issues such as the composition and the very nature of the implicated energy source. In the current discourse, we attempt to fill this gap by the way of some speculative yet logically self-consistent arguments. Our construction takes us along a path that begins with an entanglement entropy and ends up at a Hubble-sized gas of exotic particles. Moreover, our interpretation of the dark energy turns out to be suggestive of a natural resolution to the cosmic-coincidence problem.Comment: 18 pages; (v2) an oversight in Section 2.1 is rectified and a few citations adde