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1 januari 2012, Item does not contain fulltext, OBJECTIVE: Prostaglandin D2 (PGD2) may exert proinflammatory or antiinflammatory effects in different biologic systems. Although this prostanoid and the enzymes responsible for its synthesis are up-regulated by interleukin-1beta (IL-1beta) in human chondrocytes in vitro, the role of PGD2 in arthritis remains unclear. This study was undertaken to investigate the role of PGD2 in the inflammatory response and in joint destruction during the development of collagen-induced arthritis (CIA) in mice. METHODS: PGD2 and cytokine levels in mice with CIA were determined by enzyme-linked immunosorbent assay. Expression of hematopoietic PGD synthase (h-PGDS), lipocalin-type PGD synthase (l-PGDS), and DP1 and DP2 receptors was analyzed by immunohistochemical methods. PGE2 levels were determined by radioimmunoassay. RESULTS: The arthritic process up-regulated the expression of h-PGDS, l-PGDS, DP1, and DP2 in articular tissue. PGD2 was produced in the joint during the early phase of arthritis, and serum PGD2 levels increased progressively throughout the arthritic process, reaching a maximum during the late stages of CIA. Treatment of arthritic mice with the DP1 antagonist MK0524 soon after the onset of disease increased the incidence and severity of CIA as well as the local levels of IL-1beta, CXCL-1, and PGE2, whereas IL-10 levels were reduced. The administration of the DP2 antagonist CAY10595 did not modify the severity of arthritis. The injection of PGD2 into the paw, as well as the administration of the DP1 agonist BW245C, significantly lowered the incidence of CIA, the inflammatory response, and joint damage. CONCLUSION: Our findings indicate that PGD2 is produced in articular tissue during the development of CIA and plays an antiinflammatory role, acting through the DP1 receptor.

Contains fulltext : 97785.pdf (publisher's version ) (Open Access), AIMS: Although oxidative stress participates in the etiopathogenesis of rheumatoid arthritis, its importance in this inflammatory disease has not been fully elucidated. In this study, we analyzed the relevance of the transcription factor Nrf2, master regulator of redox homeostasis, in the effector phase of an animal model of rheumatoid arthritis, using the transfer of serum from K/BxN transgenic mice to Nrf2(-/-) mice. RESULTS: Nrf2 deficiency accelerated the incidence of arthritis, and animals showed a widespread disease affecting both front and hind paws. Therefore, the inflammatory response was enhanced, with increased migration of leukocytes and joint destruction in front paws. We observed an increased production of tumor necrosis factor-alpha, interleukin-6, and CXCL-1 in the joint, with small changes in eicosanoid levels. Serum levels of CXCL-1 and receptor activator for nuclear factor kappaB ligand were enhanced and osteocalcin decreased in arthritic Nrf2(-/-) mice. The expression of cyclooxygenase-2, inducible nitric oxide synthase, and peroxynitrite in the joints was higher in Nrf2 deficiency, whereas heme oxygenase-1 was downregulated. Innovation: Nrf2 may be a therapeutic target for arthritis. CONCLUSION: Our results support a protective role of Nrf2 against joint inflammation and degeneration in arthritis.

Genetic analysis of diffusion tensor images (DTI) shows great promise in revealing specific genetic variants that affect brain integrity and connectivity. Most genetic studies of DTI analyze voxel-based diffusivity indices in the image space (such as 3D maps of fractional anisotropy) and overlook tract geometry. Here we propose an automated workflow to cluster fibers using a white matter probabilistic atlas and perform genetic analysis on the shape characteristics of fiber tracts. We apply our approach to large study of 4-Tesla high angular resolution diffusion imaging (HARDI) data from 198 healthy, young adult twins (age: 20-30). Illustrative results show heritability for the shapes of several major tracts, as color-coded maps.

01 december 2011, Contains fulltext : 97492.pdf (publisher's version ) (Closed access), We have studied the influence of ovariectomy on the inflammatory response and bone metabolism on CIA as a model of postmenopausal arthritis as well as the effects of tin protoporphyrin IX (SnPP), a heme oxygenase inhibitor. Ovariectomy in non-arthritic mice produced increased serum PGD(2) levels and up-regulated the expression of COX-2, h-PGDS, l-PGDS, and HO-1 in the joints. In CIA, ovariectomy potentiated the inflammatory response with higher levels of serum IL-6 and MMP-3, local PGD(2) and MMP-3 as well as trabecular bone erosion. In OVX-CIA, SnPP decreased the serum levels of IL-6, MMP-3, and PGD(2); down-regulated TNFalpha, COX-2, hPGDS, PGD(2), PGE(2), and MMP-3 in joint tissues; and also decreased focal bone loss in the inflamed joint. Ovariectomy up-regulates inflammatory mediators in non-arthritic and in arthritic animals. In the OVX-CIA model, SnPP exerts anti-inflammatory effects which are not associated with the prevention of systemic bone loss.

Associations between low birth weight and higher adrenal androgen secretion before puberty have yet only been reported in case-control studies in girls. We examined the influence of birth weight and early postnatal weight gain on overnight-fasting adrenal androgen and cortisol levels in 770 children from a large normal United Kingdom birth cohort at age 8 yr. In univariate analyses, adrenal androgen levels were inversely related to birth weight SD score in each sex [ dehydroepiandrosterone sulfate in boys: regression coefficient (B) = - 2.5 mug/dl/SD; 95% confidence interval (CI), - 4.7 to - 0.2; in girls: B = - 3.8 mug/dl/SD; 95% CI, - 6.2 to - 1.4; androstenedione in boys: B = - 0.15 nmol/liter/SD, 95% CI, - 0.25 to - 0.6; in girls: B = - 0.13 nmol/liter/SD; 95% CI, - 0.24 to - 0.02). In multivariate analyses, both lower birth weight and larger current body weight predicted higher adrenal androgen levels ( P < 0.005 for all comparisons). Allowing for current weight, children who showed rapid postnatal weight gain between 0 and 3 yr had higher dehydroepiandrosterone sulfate ( P = 0.002) and androstenedione ( P = 0.004) levels at 8 yr. In contrast, cortisol levels were unrelated to birth weight or current body size. In summary, the relationship between lower birth weight and higher childhood adrenal androgen levels was continuous throughout the range of normal birth weights, and was similar in boys and girls. Adrenal androgen levels were highest in small infants who gained weight rapidly during early childhood. We suggest that higher adrenal androgen secretion could contribute to links between early growth and adult disease risks, possibly by enhancing insulin resistance and central fat deposition.

Intersecting D-brane models seem to be one of the most promising avenues to embed the Standard Model physics within the string context. We review here different aspects of these models. Topics include the question of SUSY and quasi-SUSY in intersecting brane models, model-building, the brane recombination interpretation of the SM Higgs mechanism, Yukawa couplings, the lowering of the string scale and possible new Z's accessible to accelerators., Comment: 10 pages, Latex file, 7 figures. Contribution to the proceedings of SUSY-02, Hamburg

Generic D-brane string models of particle physics predict the existence of extra U(1) gauge symmetries beyond hypercharge. These symmetries are not of the E_6 class but rather include the gauging of Baryon and Lepton numbers as well as certain Peccei-Quinn-like symmetries. Some of the U(1)'s have triangle anomalies, but they are cancelled by a Green-Schwarz mechanism. The corresponding gauge bosons typically acquire a mass of order the string scale M_S by combining with two-index antisymmetric fields coming from the closed string sector of the theory. We argue that in string models with a low string scale M_S proportional to 1-10 TeV, the presence of these generic U(1)'s may be amenable to experimental test. Present constraints from electroweak precision data already set important bounds on the mass of these extra gauge bosons. In particular, for large classes of models, rho-parameter constraints imply M_S >= 1.5 TeV. In the present scheme some fraction of the experimentally measured Z^0 mass would be due not to the Higgs mechanism, but rather to the mixing with these closed string fields. We give explicit formulae for recently constructed classes of intersecting D6- and D5-brane models yielding the Standard Model (SM) fermion spectrum., Comment: 46 pages, LaTeX, JHEP.cls, 21 Figures. minor corrections

We propose a new solution to the strong-CP problem. It involves the existence of an unbroken gauged $U(1)_X$ symmetry whose gauge boson gets a Stuckelberg mass term by combining with a pseudoscalar field $\eta (x)$. The latter has axion-like couplings to $F_{QCD}\wedge F_{QCD}$ so that the theta parameter may be gauged away by a $U(1)_X$ gauge transformation. This system leads to mixed gauge anomalies and we argue that they are cancelled by the addition of an appropriate Wess-Zumino term, so that no SM fermions need to be charged under $U(1)_X$. We discuss scenarios in which the above set of fields and couplings appear. The mechanism is quite generic, but a natural possibility is that the the $U(1)_X$ symmetry arises from bulk gauge bosons in theories with extra dimensions or string models. We show that in certain D-brane Type-II string models (with antisymmetric tensor field strength fluxes) higher dimensional Chern-Simons couplings give rise to the required D=4 Wess-Zumino terms upon compactification. In one of the possible string realizations of the mechanism the $U(1)_X$ gauge boson comes from the Kaluza-Klein reduction of the eleven-dimensional metric in M-theory., Comment: 21 pages, latex, one eps figure; v2 improved discussion

Recently a class of Type IIA orientifold models was constructed yielding just the fermions of the SM at the intersections of D6-branes wrapping a 6-torus. We generalize that construction to the case of Type IIB compactified on an orientifold of T^4 \times (C/Z_N) with D5-branes intersecting at angles on T^4. We construct explicit models in which the massless fermion spectrum is just the one of a three-generation Standard Model. One of the motivations for these new constructions is that in this case there are 2 dimensions which are transverse to the SM D5-brane configuration. By making those two dimensions large enough one can have a low string scale M_s of order 1-10 TeV and still have a large M_{Planck} in agreement with observations. From this point of view, these are the first explicit D-brane string constructions where one can achieve having just the fermionic spectrum and gauge group of the SM embedded in a Low String Scale scenario. The cancellation of U(1) anomalies turns out to be quite analogous to the toroidal D6-brane case and the proton is automatically stable due to the gauging of baryon number. Unlike the D6-brane case, the present class of models has N = 0 SUSY both in the bulk and on the branes and hence the spectrum is simpler., Comment: 46 pages, Latex file, 5 figures. Minor corrections and references updated

We analyze a recently constructed class of D-brane theories with the fermion spectrum of the SM at the intersection of D6-branes wrapping a compact toroidal space. We show how the SM Higgs mechanism appears as a brane recombination effect in which the branes giving rise to U(2)_L \times U(1) recombine into a single brane related to U(1)_{em}. We also show how one can construct D6-brane models which respect some supersymmetry at every intersection. These are quasi-supersymmetric models of the type introduced in hep-th/0201205 which may be depicted in terms of SUSY-quivers and may stabilize the hierarchy between the weak scale and a fundamental scale of order 10-100 TeV present in low string scale models. Several explicit D6-brane models with three generations of quarks and leptons and different SUSY-quiver structure are presented. One can prove on general grounds that if one wants to build a (factorizable) D6-brane configuration with the SM gauge group and N = 1 SUSY (or quasi-SUSY), also a massless (B-L) generator must be initially present in any model. If in addition we insist on lef- and right-handed fermions respecting the same N=1 SUSY, the brane configurations are forced to have intersections giving rise to Higgs multiplets, providing for a rationale for the very existence of the SM Higgs sector., Comment: 58 pages, using JHEP3.cls, 13 figures. Minor corrections and references updated

We present what we believe are the first specific string (D-brane) constructions whose low-energy limit yields just a three generation $SU(3)\times SU(2)\times U(1)$ standard model with no extra fermions nor U(1)'s (without any further effective field theory assumption). In these constructions the number of generations is given by the number of colours. The Baryon, Lepton and Peccei-Quinn symmetries are necessarily gauged and their anomalies cancelled by a generalized Green-Schwarz mechanism. The corresponding gauge bosons become massive but their presence guarantees automatically proton stability. There are necessarily three right-handed neutrinos and neutrino masses can only be of Dirac type. They are naturally small as a consequence of a PQ-like symmetry. There is a Higgs sector which is somewhat similar to that of the MSSM and the scalar potential parameters have a geometric interpretation in terms of brane distances and intersection angles. Some other physical implications of these constructions are discussed., Comment: References added, some typos corrected and a comment about axionic couplings included

I briefly describe the recent construction of the first specific string D-brane models yielding just the SM massless fermion spectrum. One of the most remarkable facts predicted by these constructions is that the global symmetries of the SM like Baryon and Lepton numbers as well as the axial $U(1)_A$ are gauged symmetries whose anomalies are cancelled by a Green-Schwarz mechanism only in the case of three quark-lepton generations. Proton stability and the Dirac nature of neutrino masses are thus a prediction of these theories. This is work done in collaboration with Fernando Marchesano and Raul Rabadan., Comment: 10 pages, Latex file, no figures. Contribution to the proceedings of SUSY-01, Dubna (Russia), June 2001

Intersecting Dp-branes often give rise to chiral fermions living on their intersections. We study the construction of four-dimensional chiral gauge theories by considering configurations of type II D(3+n)-branes wrapped on non-trivial n-cycles on T^{2n} x(R^{2(3-n)}/Z_N), for n=1,2,3. The gauge theories on the four non-compact dimensions of the brane world-volume are generically chiral and non-supersymmetric. We analyze consistency conditions (RR tadpole cancellation) for these models, and their relation to four-dimensional anomaly cancellation. Cancellation of U(1) gauge anomalies involves a Green-Schwarz mechanism mediated by RR partners of untwisted and/or twisted moduli. This class of models is of potential phenomenological interest, and we construct explicit examples of SU(3) x SU(2) x U(1) three-generation models. The models are non-supersymmetric, but the string scale may be lowered close to the weak scale so that the standard hierarchy problem is avoided. We also comment on the presence of scalar tachyons and possible ways to avoid the associated instabilities. We discuss the existence of (meta)stable configurations of D-branes on 3-cycles in (T^2)^3, free of tachyons for certain ranges of the six-torus moduli., Comment: 35 pages, latex. Minor mistakes in mass formulae corrected

We propose a bottom-up approach to the building of particle physics models from string theory. Our building blocks are Type II D-branes which we combine appropriately to reproduce desirable features of a particle theory model: 1) Chirality ; 2) Standard Model group ; 3) N=1 or N=0 supersymmetry ; 4) Three quark-lepton generations. We start such a program by studying configurations of D=10, Type IIB D3-branes located at singularities. We study in detail the case of Z_N, N=1,0 orbifold singularities leading to the SM group or some left-right symmetricextension. In general, tadpole cancellation conditions require the presence of additional branes, e.g. D7-branes. For the N=1 supersymmetric case the unique twist leading to three quark-lepton generations is Z_3, predicting $\sin^2\theta_W=3/14=0.21$. The models obtained are the simplest semirealistic string models ever built. In the non-supersymmetric case there is a three-generation model for each Z_N, N>4, but the Weinberg angle is in general too small. One can obtain a large class of D=4 compact models by considering the above structure embedded into a Calabi Yau compactification. We explicitly construct examples of such compact models using Z_3 toroidal orbifolds and orientifolds, and discuss their properties. In these examples, global cancellation of RR charge may be achieved by adding anti-branes stuck at the fixed points, leading to models with hidden sector gravity-induced supersymmetry breaking. More general frameworks, like F-theory compactifications, allow completely $\NN=1$ supersymmetric embeddings of our local structures, as we show in an explicit example., Comment: Latex, 75 pages, 8 enclosed figures. Minor corrections, references added

We review recent progress in constructing realistic brane models from type I string vacua. Explicit models with three families of the standard model gauge group and its left-right generalizations are presented with supersymmetry broken at the string scale of order $M_s\sim 10^{10-12}$ GeV, realizing gravity mediated supersymmetry breaking at low energies. Unification of couplings occurs at the string scale due to the particular U(1) normalizations of D-branes, as well as to the existence of a Higgs field per family of quarks and leptons. The proton is naturally stable due to intrinsic discrete symmetries of the corresponding string theory. In particular R-parity appears as a natural stringy symmetry. There are axionic fields with the right couplings as to solve the strong CP problem. Similar realizations are also presented for a string scale of 1 TeV, although without solving the gauge unification problem. Open questions are briefly discussed., Comment: 8 pages, plenary talk by FQ at PASCOS 99

It is known that chiral fermions naturally appear at certain intersections of branes at angles. Motivated by this fact, we propose a string scenario in which different standard model gauge interactions propagate on different (intersecting) brane worlds, partially wrapped in the extra dimensions. Quarks and leptons live at brane intersections, and are thus located at different positions in the extra dimensions. Replication of families follows naturally from the fact that the branes generically intersect at several points. Gauge and Yukawa couplings can be computed in terms of the compactification radii. Hierarchical Yukawa couplings appear naturally, since amplitudes involving three different intersections are proportional to exp{-A_{ijk}}, where A_{ijk} is the area of a string world-sheet extending among the intersections. The models are non-supersymmetric but the string scale may be lowered down to 1-10 TeV. The proton is however stable due to a set of discrete symmetries arising from world-sheet selection rules, exact to all orders in perturbation theory. The scenario has some distinctive features like the presence of KK, winding and other new excited states (`gonions'), with masses below the string scale and accessible to accelerators. The models contain scalar tachyons with the quantum numbers of standard SU(2) x U(1) Higgs doublets, and we propose that they induce electroweak symmetry breaking in a somewhat novel way. Specific string models with D4-branes wrapping on T^2 x (T^2)^2/Z_N, leading to three-family semirealistic spectra, are presented, in which the above properties are exemplified., Comment: 36 pages, 6 figures, (v2) reference added, explicit examples changed; (v3) one figure changed, typos corrected

We present an analysis of the low-energy implications of an intermediate scale ~10^{11} GeV string theory. We mainly focus on the evolution of the physical parameters under the renormalisation group equations (RGEs) and find several interesting new features that differ from the standard GUT scale or Planck scale scenarios. We give a general discussion of soft supersymmetry breaking terms in type I theories and then investigate the renormalization group running. In the dilaton domination scenario, we present the sparticle spectra, analyzing constraints from charge and colour breaking, fine tuning and radiative electroweak symmetry breaking. We compare with the allowed regions of parameter space when the RGEs start running at the standard GUT or the intermediate scales, and find quite remarkably that the dilaton dominated supersymmetry breaking scenario, which is essentially ruled out from constraints on charge and colour breaking if the fundamental scale is close to the Planck mass, is allowed in a large region of parameter space if the fundamental scale is intermediate., Comment: 32 pages, 4 figures, v2 has added references and no t-b-tau unification

The success of SU(5)-like gauge coupling unification boundary conditions $g_3^2=g_2^2=5/3 g_1^2$ has biased most attempts to embed the SM interactions into a unified structure. After discussing the limitations of the orthodox approach, we propose an alternative that appears to be quite naturally implied by recent developments based on D-brane physics. In this new alternative: 1) The gauge group, above a scale of order 1 TeV, is the minimal left-right symmetric extension $SU(3)\times SU(2)_L\times SU(2)_R\times U(1)_{B-L}$ of the SM; 2) Quarks, leptons and Higgs fields come in three generations; 3) Couplings unify at an intermediate string scale $M_s= 9\times 10^{11}$ GeV with boundary conditions $g_3^2=g_L^2=g_R^2=32/3 g_{B-L}^2$. This corresponds to the natural embedding of gauge interactions into D-branes and is different from the standard SO(10) embedding which corresponds to $k_{B-L}=8/3$. Unification only works in the case of three generations; 4) Proton stability is automatic due to the presence of $Z_2$ discrete R-parity and lepton parities. A specific Type IIB string orientifold model with the above characteristics is constructed. The existence of three generations is directly related to the existence of three complex extra dimensions. In this model the string scale can be identified with the intermediate scale and SUSY is broken also at that scale due to the presence of anti-branes in the vacuum. We discuss a number of phenomenological issues in this model including Yukawa couplings and a built-in axion solution to the strong-CP problem. The present framework could be tested by future accelerators by finding the left-right symmetric extension of the SM at a scale of order 1 TeV., Comment: 50 pages, 7 figures. References added

Compact Type IIB D=4, N=1 orientifolds have certain U(1) sigma model symmetries at the level of the effective Lagrangian. These symmetries are generically anomalous. We study the particular case of $Z_N$ orientifolds and find that these anomalies may be cancelled by a generalized Green-Schwarz mechanism. This mechanism works by the exchange of twisted RR-fields associated to the orbifold singularities and it requires the mixing between twisted and untwisted moduli of the orbifold. As a consequence, the Fayet-Iliopoulos terms which are present for the gauged anomalous U(1)'s of the models get an additional untwisted modulus dependent piece at the tree level., Comment: 33 pages, Latex, 7 figures

We construct D=4 Type I vacua with massless content remarkably close to that of the standard model of particle physics. They are tachyon-free non-supersymmetric models which are obtained starting with a standard D=4, N=1 compact Type IIB orientifold and adding the same number of Dp-branes and anti-Dp-branes distributed at different points of the underlying orbifold. Supersymmetry-breaking is felt by the observable world either directly, by gravity mediation or gauge mediation, depending on the brane configuration. We construct several simple three generation examples with the gauge group of the standard model or its left-right symmetric extensions. The models contain a number of U(1) gauge groups whose anomalies are cancelled by a generalized Green-Schwarz mechanism. These U(1)'s are broken but may survive as global symmetries providing for a flavour structure to the models. The value of the string scale may be lowered down to the intermediate scale (as required in the gravity mediation case) or down to 1-100 TeV for the non-SUSY models. Thus the present models are the first semirealistic string vacua realizing the possibility of a low string scale. The unbalanced force between the pairs of Dp- and anti-Dp-branes provides for an effect which tends to compactify some of the extra dimensions but no others. This could provide a new mechanism for radius stabilization., Comment: 58 pages, latex (typos corrected and references added)