The chemokine receptor CCR6 is an important component of the innate immune response

In our initial studies we found that naÏve CCR6-deficient (CCR6 –/– ) C57BL/6 mice possessed significantly lower number of both F4/80 + macrophages and dendritic cells (DC), but higher number of B cells in the peritoneal cavity, as compared to naÏve wild type (WT) controls. Furthermore, peritoneal macrophages isolated from CCR6 –/– mice expressed significantly lower levels of inflammatory cytokines and nitric oxide following lipopolysaccharide (LPS)stimulation, as compared to WT macrophages. In a severe experimental peritonitis model induced by cecal ligation and puncture (CLP), CCR6 –/– mice were protected when compared with WT controls. At 24 h following the induction of peritonitis, CCR6 –/– mice exhibited significantly lower levels of inflammatory cytokines/chemokines in both the peritoneal cavity and blood. Interestingly, DC recruitment into the peritoneal cavity was impaired in CCR6 –/– mice during the evolution of CLP-induced peritonitis. Peritoneal macrophages isolated from surviving CCR6 –/– mice 3 days after CLP-induced peritonitis exhibited an enhanced LPS response compared with similarly treated WT peritoneal macrophages. These data illustrate that CCR6 deficiency alters the innate response via attenuating the hyperactive local and systemic inflammatory response during CLP-induced peritonitis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56112/1/2487_ftp.pd

Cell‐to‐cell and cell‐to‐matrix interactions mediate chemokine expression: an important component of the inflammatory lesion

Although many studies have characterized soluble factors that stimulate or inhibit chemokine secretion, in this review we focus on the event of cellular adhesion as a novel mechanism for stimulating chemokine expression. Recent work has demonstrated chemokine expression following cell‐to‐cell and cell‐to‐matrix adhesion. The specificity of this finding was demonstrated utilizing various techniques that illustrate that adhesion, and not a soluble stimulus, is in some cases responsible for initiating or augmenting chemokine expression. For example, co‐cultures of peripheral blood monocytes and endothelial cells secreted elevated levels of IL‐8 and MCP‐1 compared with either cell type alone. When co‐cultured in transwells, this effect was significantly attenuated. In other experiments, neutralizing monoclonal antibodies to various adhesion molecules inhibited chemokine expression. The effects of adhesion were not limited to leukocytes. Both immune and non‐immune cell types were evaluated as potential sources of adhesion‐mediated chemokine expression. Not suprisingly, expression of some chemokines was associated with adhesion, whereas others were not, supporting the notion that adhesion differentially signals chemokine secretion during the inflammatory response. We hypothesize that as a recruited leukocyte encounters different adhesion substrates such as endothelial cells, basement membrane, extracellular matrix, and fibroblasts, the expression of chemokines from both the leukocyte and the substrate may be initiated, inhibited, or augmented. Careful characterization of the contribution of adhesion to regulation of chemokine expression will provide insight into the pathogenesis of many human diseases where chemokines have a central role. J. Leukoc. Biol.62: 612–619; 1997.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142209/1/jlb0612.pd

The Balance between Plasmacytoid DC versus Conventional DC Determines Pulmonary Immunity to Virus Infections

Background: Respiratory syncytial virus (RSV) infects nearly all infants by age 2 and is a leading cause of broncialitis. RSV may employ several mechanisms to induce immune dysregulation, including dentritic cell (DC) modulation during the immune response to RSV. Methods and Findings: Expansion of cDC and pDC by Flt3L treatment promoted an anti-viral response with reduced pathophysiology characterized by decreased airway hyperreactivity, reduced Th2 cytokines, increased Th1 cytokines, and a reduction in airway inflammation and mucus overexpression. These protective aspects of DC expansion could be completely reversed by depleting pDCs during the RSV infections. Expansion of DCs by Flt3L treatment enhanced in CD8+ T cell responses, which was reversed by depletion of pDC. Conclusions: These results indicate that a balance between cDC and pDC in the lung and its lymph nodes is crucial for the outcome of a pulmonary infection. Increased pDC numbers induced by Flt3L treatment have a protective impact on the nature of the overall immune environment

Birth and death processes and quantum spin chains

This papers underscores the intimate connection between the quantum walks generated by certain spin chain Hamiltonians and classical birth and death processes. It is observed that transition amplitudes between single excitation states of the spin chains have an expression in terms of orthogonal polynomials which is analogous to the Karlin-McGregor representation formula of the transition probability functions for classes of birth and death processes. As an application, we present a characterization of spin systems for which the probability to return to the point of origin at some time is 1 or almost 1.Comment: 14 page

Differential regulation of C-C chemokines during fibroblast-monocyte interactions: adhesion vs. inflammatory cytokine pathways.

The cell-to-cell interactions during chronic inflammatory diseases likely contribute to leukocyte accumulation leading to increased pathology and organ dysfunction. In particular, there is a paucity of information relating to the maintenance of chronic fibrotic diseases. Using a lung fibroblast line and enriched monocyte populations, we have investigated the activational events which contribute to the production of two C-C chemokines, macrophage inflammatory protein-1 alpha (MIP-1alpha) and monocyte chemoattractant protein-1 (MCP-1), during fibroblast-monocyte interactions. Neither the fibroblast cell line (16lu) nor isolated monocytes alone produced significant levels of MIP-1alpha or MCP-1. However, when isolated monocytes were layered onto 16 lu fibroblast monolayers a significant increase in MIP-1alpha and MCP-1 production was observed. The use of fixed cell populations indicated that the MIP-1alpha was derived from monocytes and MCP-1 from both cell populations. To examine the molecules which were required for chemokine production during the interaction, specific antibodies were used in the co-cultures. Blocking beta3-integrin interactions significantly inhibited MIP-1alpha production. In contrast, beta-integrin interactions had no effect on the MCP-1 production, while, neutralization of TNF significantly decreased MCP-1 production during the co-culture. These data indicate that fibroblast-monocyte interactions induce chemokine production through different mechanisms and a combination of these responses may contribute to the maintenance of the mononuclear cell accumulation during disease progression

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154665/1/fsb2fj078653com.pd

Integrated random processes exhibiting long tails, finite moments and 1/f spectra

A dynamical model based on a continuous addition of colored shot noises is presented. The resulting process is colored and non-Gaussian. A general expression for the characteristic function of the process is obtained, which, after a scaling assumption, takes on a form that is the basis of the results derived in the rest of the paper. One of these is an expansion for the cumulants, which are all finite, subject to mild conditions on the functions defining the process. This is in contrast with the Levy distribution -which can be obtained from our model in certain limits- which has no finite moments. The evaluation of the power spectrum and the form of the probability density function in the tails of the distribution shows that the model exhibits a 1/f spectrum and long tails in a natural way. A careful analysis of the characteristic function shows that it may be separated into a part representing a Levy processes together with another part representing the deviation of our model from the Levy process. This allows our process to be viewed as a generalization of the Levy process which has finite moments.Comment: Revtex (aps), 15 pages, no figures. Submitted to Phys. Rev.

BLUF Domain Function Does Not Require a Metastable Radical Intermediate State

BLUF (blue light using flavin) domain proteins are an important family of blue light-sensing proteins which control a wide variety of functions in cells. The primary light-activated step in the BLUF domain is not yet established. A number of experimental and theoretical studies points to a role for photoinduced electron transfer (PET) between a highly conserved tyrosine and the flavin chromophore to form a radical intermediate state. Here we investigate the role of PET in three different BLUF proteins, using ultrafast broadband transient infrared spectroscopy. We characterize and identify infrared active marker modes for excited and ground state species and use them to record photochemical dynamics in the proteins. We also generate mutants which unambiguously show PET and, through isotope labeling of the protein and the chromophore, are able to assign modes characteristic of both flavin and protein radical states. We find that these radical intermediates are not observed in two of the three BLUF domains studied, casting doubt on the importance of the formation of a population of radical intermediates in the BLUF photocycle. Further, unnatural amino acid mutagenesis is used to replace the conserved tyrosine with fluorotyrosines, thus modifying the driving force for the proposed electron transfer reaction; the rate changes observed are also not consistent with a PET mechanism. Thus, while intermediates of PET reactions can be observed in BLUF proteins they are not correlated with photoactivity, suggesting that radical intermediates are not central to their operation. Alternative nonradical pathways including a keto–enol tautomerization induced by electronic excitation of the flavin ring are considered

The Schroedinger Problem, Levy Processes Noise in Relativistic Quantum Mechanics

The main purpose of the paper is an essentially probabilistic analysis of relativistic quantum mechanics. It is based on the assumption that whenever probability distributions arise, there exists a stochastic process that is either responsible for temporal evolution of a given measure or preserves the measure in the stationary case. Our departure point is the so-called Schr\"{o}dinger problem of probabilistic evolution, which provides for a unique Markov stochastic interpolation between any given pair of boundary probability densities for a process covering a fixed, finite duration of time, provided we have decided a priori what kind of primordial dynamical semigroup transition mechanism is involved. In the nonrelativistic theory, including quantum mechanics, Feyman-Kac-like kernels are the building blocks for suitable transition probability densities of the process. In the standard "free" case (Feynman-Kac potential equal to zero) the familiar Wiener noise is recovered. In the framework of the Schr\"{o}dinger problem, the "free noise" can also be extended to any infinitely divisible probability law, as covered by the L\'{e}vy-Khintchine formula. Since the relativistic Hamiltonians $|\nabla |$ and $\sqrt {-\triangle +m^2}-m$ are known to generate such laws, we focus on them for the analysis of probabilistic phenomena, which are shown to be associated with the relativistic wave (D'Alembert) and matter-wave (Klein-Gordon) equations, respectively. We show that such stochastic processes exist and are spatial jump processes. In general, in the presence of external potentials, they do not share the Markov property, except for stationary situations. A concrete example of the pseudodifferential Cauchy-Schr\"{o}dinger evolution is analyzed in detail. The relativistic covariance of related waveComment: Latex fil