Regulation of eosinophilia and allergic airway inflammation by the glycan-binding protein galectin-1

Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflammatory activities, functions as a proresolving mediator in autoimmune and chronic inflammatory disorders. However, its role in allergic airway inflammation has not yet been elucidated. We evaluated the effects of Gal-1 on eosinophil function and its role in a mouse model of allergic asthma. Allergen exposure resulted in airway recruitment of Gal-1-expressing inflammatory cells, including eosinophils, as well as increased Gal-1 in extracellular spaces in the lungs. In vitro, extracellular Gal-1 exerted divergent effects on eosinophils that were N-glycan- And dose-dependent. At concentrations ≤0.25 μM, Gal-1 increased eosinophil adhesion to vascular cell adhesion molecule-1, caused redistribution of integrin CD49d to the periphery and cell clustering, but inhibited ERK(1/2) activation and eotaxin-1-induced migration. Exposure to concentrations ≥1 μM resulted in ERK(1/2)- dependent apoptosis and disruption of the F- Actin cytoskeleton. At lower concentrations, Gal-1 did not alter expression of adhesion molecules (CD49d, CD18, CD11a, CD11b, L-selectin) or of the chemokine receptor CCR3, but decreased CD49d and CCR3 was observed in eosinophils treated with higher concentrations of this lectin. In vivo, allergen-challenged Gal-1-deficient mice exhibited increased recruitment of eosinophils and CD3+ T lymphocytes in the airways as well as elevated peripheral blood and bone marrow eosinophils relative to corresponding WT mice. Further, these mice had an increased propensity to develop airway hyperresponsiveness and displayed significantly elevated levels of TNF-α in lung tissue. This study suggests that Gal-1 can limit eosinophil recruitment to allergic airways and suppresses airway inflammation by inhibiting cell migration and promoting eosinophil apoptosis.Fil: Ge, Xiao Na. University of Minnesota; Estados UnidosFil: Ha, Sung Gil. University of Minnesota; Estados UnidosFil: Greenberg, Yana G.. University of Minnesota; Estados UnidosFil: Rao, Amrita. University of Minnesota; Estados UnidosFil: Bastan, Idil. University of Minnesota; Estados UnidosFil: Blidner, Ada Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rao, Savita P.. University of Minnesota; Estados UnidosFil: Rabinovich, Gabriel Adrián. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sriramarao, P.. University of Minnesota; Estados Unido

Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (ktr) in a length-dependent fashion

Force and power in cardiac muscle have a known dependence on phosphorylation of the myosin-associated regulatory light chain (RLC). We explore the effect of RLC phosphorylation on the ability of cardiac preparations to redevelop force (ktr ) in maximally activating [Ca2+ ]. Activation was achieved by rapidly increasing the temperature (temperature-jump of 0.5-20ºC) of permeabilized trabeculae over a physiological range of sarcomere lengths (1.85-1.94 μm). The trabeculae were subjected to shortening ramps over a range of velocities and the extent of RLC phosphorylation was varied. The latter was achieved using an RLC-exchange technique, which avoids changes in the phosphorylation level of other proteins. The results show that increasing RLC phosphorylation by 50% accelerates ktr by ∼50%, irrespective of the sarcomere length, whereas decreasing phosphorylation by 30% slows ktr by ∼50%, relative to the ktr obtained for in vivo phosphorylation. Clearly, phosphorylation affects the magnitude of ktr following step shortening or ramp shortening. Using a two-state model, we explore the effect of RLC phosphorylation on the kinetics of force development, which proposes that phosphorylation affects the kinetics of both attachment and detachment of cross-bridges. In summary, RLC phosphorylation affects the rate and extent of force redevelopment. These findings were obtained in maximally activated muscle at saturating [Ca2+ ] and are not explained by changes in the Ca2+ -sensitivity of acto-myosin interactions. The length-dependence of the rate of force redevelopment, together with the modulation by the state of RLC phosphorylation, suggests that these effects play a role in the Frank-Starling law of the heart.Published versio

CP violation in a multi-Higgs doublet model with flavor changing neutral current

We study CP violation in a multi-Higgs doublet model based on a $S_3 \times Z_3$ horizontal symmetry where CKM phase is not the principal source of CP violation. We consider two mechanisms for CP violation in this model: a) CP violation due to complex Yukawa couplings; and b) CP violation due to scalar-pseudoscalar Higgs boson mixings. Both mechanisms can explain the observed CP violation in the neutral Kaon system. $\epsilon'/\epsilon$ due to neutral Higgs boson exchange is small in both mechanisms, but charged Higgs boson con- tributions can be as large as $10^{-3}$ for a), and $10^{-4}$ for b). CP violation in the neutral B system is, however, quite different from the Minimal Standard Model. The neutron Electric Dipole Moment can be as large as the present ex- perimental bound, and can be used to constrain charged Higgs boson masses. The electron EDM is one order of magnitude below the experimental bound in case b) and smaller in case a).Comment: 22 pages, Revtex, OITS-52

Non-unitarity of CKM matrix from the vector singlet quark mixing and neutron electric dipole moment

In the standard model (SM) the lowest order contribution to the quark electric dipole moment (EDM) occurs at the three loop level. We show that the non-unitarity of the CKM matrix in models with an extended quark sector typically gives rise to a quark EDM at the two loop level which has no GIM-like suppression factors except the external quark mass. The induced neutron EDM is of order 10^{-29} e cm and can be well within the reach of the next generation of experiments if it is further enhanced by long distance physics as happens in the SM.Comment: Some typos are corrected. References are updated. Discussion on FCNC contributions is adde

P-odd and CP-odd Four-Quark Contributions to Neutron EDM

In a class of beyond-standard-model theories, CP-odd observables, such as the neutron electric dipole moment, receive significant contributions from flavor-neutral P-odd and CP-odd four-quark operators. However, considerable uncertainties exist in the hadronic matrix elements of these operators strongly affecting the experimental constraints on CP-violating parameters in the theories. Here we study their hadronic matrix elements in combined chiral perturbation theory and nucleon models. We first classify the operators in chiral representations and present the leading-order QCD evolutions. We then match the four-quark operators to the corresponding ones in chiral hadronic theory, finding symmetry relations among the matrix elements. Although this makes lattice QCD calculations feasible, we choose to estimate the non-perturbative matching coefficients in simple quark models. We finally compare the results for the neutron electric dipole moment and P-odd and CP-odd pion-nucleon couplings with the previous studies using naive factorization and QCD sum rules. Our study shall provide valuable insights on the present hadronic physics uncertainties in these observables.Comment: 40 pages, 7 figures. This is the final version. A discussion of the uncertainty of the calculation is adde

Examining the Dynamic Association of BMI and Mortality in the Framingham Heart Study

Based on the 40-year follow-up of the Framingham Heart Study (FHS), we used logistic regression models to demonstrate that different designs of an observational study may lead to different results about the association between BMI and all-cause mortality. We also used dynamic survival models to capture the time-varying relationships between BMI and mortality in FHS. The results consistently show that the association between BMI and mortality is dynamic, especially for men. Our analysis suggests that the dynamic property may explain part of the heterogeneity observed in the literature about the association of BMI and mortality

Barotropic tides on the southeast New England shelf : a view from a hybrid data assimilative modeling approach

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 111 (2006): C08002, doi:10.1029/2005JC003254.A high-resolution hybrid data assimilative (DA) modeling system is used to study barotropic tides and tidal dynamics on the southeast New England shelf. In situ observations include tidal harmonics of 5 major tidal constituents [M2, S2, N2, O1, and K1] analyzed from coastal sea level and bottom pressure gauges. The DA system consists of both forward and inverse models. The former is the three-dimensional, finite difference, nonlinear Regional Ocean Modeling System (ROMS). The latter is a three-dimensional linearized, frequency domain, finite element model TRUXTON. The DA system assimilates in situ observations via the inversion for the barotropic tidal open boundary conditions (OBCs). Model skill is evaluated by comparing the misfits between the observed and modeled tidal harmonics. The assimilation scheme is found effective and efficient in correcting the tidal OBCs, which in turn improve ROMS tidal solutions. Up to 50% decreases of model/data misfits are achieved after inverse data assimilation. Co-amplitude and co-phase maps and tidal current ellipses for each of 5 tidal constituents are generated, revealing complex tidal variability in this transition region between the tidally amplified Gulf of Maine in the northeast and the tidally much less energetic Middle Atlantic Bight in the southwest. Detailed examinations on the residual circulation, energetics, and momentum balances of the M2 tide reveal the key roles of the unique bottom bathymetry of Nantucket Shoals and the complex coastal geometry in affecting the regional tidal dynamics.This work was supported by WHOI Coastal Ocean Institute Research Award. J.W. acknowledges support of the Office of Naval Research

Mitochondrial membrane biogenesis: phospholipids and proteins go hand in hand

Mitochondrial membrane biogenesis requires the import and synthesis of proteins as well as phospholipids. How the mitochondrion regulates phospholipid levels and maintains a tight protein-to-phospholipid ratio is not well understood. Two recent papers (Kutik, S., M. Rissler, X.L. Guan, B. Guiard, G. Shui, N. Gebert, P.N. Heacock, P. Rehling, W. Dowhan, M.R. Wenk, et al. 2008. J. Cell Biol. 183:1213–1221; Osman, C., M. Haag, C. Potting, J. Rodenfels, P.V. Dip, F.T. Wieland, B. Brügger, B. Westermann, and T. Langer. 2009. J. Cell Biol. 184:583–596) identify novel regulators of mitochondrial phospholipid biosynthesis. The biochemical approach of Kutik et al. (2008) uncovered an unexpected role of the mitochondrial translocator assembly and maintenance protein, Tam41, in the biosynthesis of cardiolipin (CL), the signature phospholipid of mitochondria. The genetic analyses of Osman et al. (2009) led to the discovery of a new class of mitochondrial proteins that coordinately regulate CL and phosphatidylethanolamine, another key mitochondrial phospholipid. These elegant studies highlight overlapping functions and interdependent roles of mitochondrial phospholipid biosynthesis and protein import and assembly