The exactness of a general Skoda complex

We show that a Skoda complex with a general plurisubharmonic weight function is exact if its 'degree' is sufficiently large. This answers a question of Lazarsfeld and implies that not every integrally closed ideal is equal to a multiplier ideal even if we allow general plurisubharmonic weights for the multiplier ideal, extending the result of Lazarsfeld and Lee \cite{LL}.Comment: References added, exposition streamlined, to appear in Michigan Mathematical Journa

Cardiosphere-derived cells suppress allogeneic lymphocytes by production of PGE2 acting via the EP4 receptor

derived cells (CDCs) are a cardiac progenitor cell population, which have been shown to possess cardiac regenerative properties and can improve heart function in a variety of cardiac diseases. Studies in large animal models have predominantly focussed on using autologous cells for safety, however allogeneic cell banks would allow for a practical, cost-effective and efficient use in a clinical setting. The aim of this work was to determine the immunomodulatory status of these cells using CDCs and lymphocytes from 5 dogs. CDCs expressed MHC I but not MHC II molecules and in mixed lymphocyte reactions demonstrated a lack of lymphocyte proliferation in response to MHC-mismatched CDCs. Furthermore, MHC-mismatched CDCs suppressed lymphocyte proliferation and activation in response to Concanavalin A. Transwell experiments demonstrated that this was predominantly due to direct cell-cell contact in addition to soluble mediators whereby CDCs produced high levels of PGE2 under inflammatory conditions. This led to down-regulation of CD25 expression on lymphocytes via the EP4 receptor. Blocking prostaglandin synthesis restored both, proliferation and activation (measured via CD25 expression) of stimulated lymphocytes. We demonstrated for the first time in a large animal model that CDCs inhibit proliferation in allo-reactive lymphocytes and have potent immunosuppressive activity mediated via PGE2

Spin and Chirality Effects in Antler-Topology Processes at High Energy e+e−e^+e^- Colliders

We perform a model-independent investigation of spin and chirality correlation effects in the antler-topology processes $e^+e^-\to\mathcal{P}^+\mathcal{P}^-\to (\ell^+ \mathcal{D}^0) (\ell^-\mathcal{\bar{D}}^0)$ at high energy $e^+e^-$ colliders with polarized beams. Generally the production process $e^+e^-\to\mathcal{P}^+\mathcal{P}^-$ can occur not only through the $s$-channel exchange of vector bosons, $\mathcal{V}^0$, including the neutral Standard Model (SM) gauge bosons, $\gamma$ and $Z$, but also through the $s$- and $t$-channel exchanges of new neutral states, $\mathcal{S}^0$ and $\mathcal{T}^0$, and the $u$-channel exchange of new doubly-charged states, $\mathcal{U}^{--}$. The general set of (non-chiral) three-point couplings of the new particles and leptons allowed in a renormalizable quantum field theory is considered. The general spin and chirality analysis is based on the threshold behavior of the excitation curves for $\mathcal{P}^+\mathcal{P}^-$ pair production in $e^+e^-$ collisions with longitudinal and transverse polarized beams, the angular distributions in the production process and also the production-decay angular correlations. In the first step, we present the observables in the helicity formalism. Subsequently, we show how a set of observables can be designed for determining the spins and chiral structures of the new particles without any model assumptions. Finally, taking into account a typical set of approximately chiral invariant scenarios, we demonstrate how the spin and chirality effects can be probed experimentally at a high energy $e^+e^-$ collider.Comment: 50 pages, 14 figures, 6 tables, matches version published in EPJ

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

This is the final version of the article. Available from American Society for Clinical Investigation via the DOI in this record.The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR–selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.ABT, AC, and PMS received funding from a Wellcome Trust Collaborative Award (201529/Z/16/Z). ABT, SJB, AJB, and TMH were funded through a Medical Research Council programme leader grant provided by the MRC Toxicology Unit. CCF, LMB, AJM, and HES were funded by the Eli Lilly Company. JMB received funding through a Lilly Research Award Program (LRAP) grant (Eli Lilly). RP received funding from the Marie Curie grant “Extrabrain” (European Commission). AC is a senior principal research fellow and PMS a principal research fellow of the National Health and Medical Research Council of Australia. Tissue samples were from Randy Woltjer at the Oregon Alzheimer’s Disease Center. The Oregon Alzheimer’s Disease Center is supported by NIH grant P30AG008017

Goldstone Bosons in Effective Theories with Spontaneously Broken Flavour Symmetry

The Flavour Symmetry of the Standard Model (SM) gauge sector is broken by the fermion Yukawa couplings. Promoting the Yukawa matrices to scalar spurion fields, one can break the flavour symmetry spontaneously by giving appropriate vacuum expectation values (VEVs) to the spurion fields, and one encounters Goldstone modes for every broken flavour symmetry generator. In this paper, we point out various aspects related to the possible dynamical interpretation of the Goldstone bosons: (i) In an effective-theory framework with local flavour symmetry, the Goldstone fields represent the longitudinal modes for massive gauge bosons. The spectrum of the latter follows the sequence of flavour-symmetry breaking related to the hierarchies in Yukawa couplings and flavour mixing angles. (ii) Gauge anomalies can be consistently treated by adding higher-dimensional operators. (iii) Leaving the U(1) factors of the flavour symmetry group as global symmetries, the respective Goldstone modes behave as axions which can be used to resolve the strong CP problem by a modified Peccei-Quinn mechanism. (iv) The dynamical picture of flavour symmetry breaking implies new sources of flavour-changing neutral currents, which arise from integrating out heavy scalar spurion fields and heavy gauge bosons. The coefficients of the effective operators follow the minimal-flavour violation principle.Comment: 27 pages, abstract and introduction extended, more detailed discussion of heavy gauge boson spectrum and auxiliary heavy fermions, outline restructured. Matches version to be published in JHE

Activation of the SPHK/S1P signalling pathway is coupled to muscarinic receptor-dependent regulation of peripheral airways

BACKGROUND: In peripheral airways, acetylcholine induces contraction via activation of muscarinic M2-and M3-receptor subtypes (M(2)R and M(3)R). Cholinergic hypersensitivity is associated with chronic obstructive pulmonary disease and asthma, and therefore the identification of muscarinic signaling pathways are of great therapeutic interest. A pathway that has been shown to be activated via MR and to increase [Ca(2+)](i )includes the activation of sphingosine kinases (SPHK) and the generation of the bioactive sphingolipid sphingosine 1-phosphate (S1P). Whether the SPHK/S1P signaling pathway is integrated in the muscarinic control of peripheral airways is not known. METHODS: To address this issue, we studied precision cut lung slices derived from FVB and M(2)R-KO and M(3)R-KO mice. RESULTS: In peripheral airways of FVB, wild-type, and MR-deficient mice, SPHK1 was mainly localized to smooth muscle. Muscarine induced a constriction in all investigated mouse strains which was reduced by inhibition of SPHK using D, L-threo-dihydrosphingosine (DHS) and N, N-dimethyl-sphingosine (DMS) but not by N-acetylsphingosine (N-AcS), a structurally related agent that does not affect SPHK function. The initial phase of constriction was nearly absent in peripheral airways of M(3)R-KO mice when SPHK was inhibited by DHS and DMS but was unaffected in M(2)R-KO mice. Quantitative RT-PCR revealed that the disruption of the M(2)R and M(3)R genes had no significant effect on the expression levels of the SPHK1-isoform in peripheral airways. CONCLUSION: These results demonstrate that the SPHK/S1P signaling pathway contributes to cholinergic constriction of murine peripheral airways. In addition, our data strongly suggest that SPHK is activated via the M(2)R. Given the important role of muscarinic mechanisms in pulmonary disease, these findings should be of considerable therapeutic relevance

Discrimination of low missing energy look-alikes at the LHC

The problem of discriminating possible scenarios of TeV scale new physics with large missing energy signature at the Large Hadron Collider (LHC) has received some attention in the recent past. We consider the complementary, and yet unexplored, case of theories predicting much softer missing energy spectra. As there is enough scope for such models to fake each other by having similar final states at the LHC, we have outlined a systematic method based on a combination of different kinematic features which can be used to distinguish among different possibilities. These features often trace back to the underlying mass spectrum and the spins of the new particles present in these models. As examples of "low missing energy look-alikes", we consider Supersymmetry with R-parity violation, Universal Extra Dimensions with both KK-parity conserved and KK-parity violated and the Littlest Higgs model with T-parity violated by the Wess-Zumino-Witten anomaly term. Through detailed Monte Carlo analysis of the four and higher lepton final states predicted by these models, we show that the models in their minimal forms may be distinguished at the LHC, while non-minimal variations can always leave scope for further confusion. We find that, for strongly interacting new particle mass-scale ~600 GeV (1 TeV), the simplest versions of the different theories can be discriminated at the LHC running at sqrt{s}=14 TeV within an integrated luminosity of 5 (30) fb^{-1}.Comment: 40 pages, 10 figures; v2: Further discussions, analysis and one figure added, ordering of certain sections changed, minor modifications in the abstract, version as published in JHE

Chemical Safety Assessment Using Read-Across: Assessing the Use of Novel Testing Methods to Strengthen the Evidence Base for Decision Making

Background: Safety assessment for repeated dose toxicity is one of the largest challenges in the process to replace animal testing. This is also one of the proof of concept ambitions of SEURAT-1, the largest ever European Union research initiative on alternative testing, co-funded by the European Commission and Cosmetics Europe. This review is based on the discussion and outcome of a workshop organized on initiative of the SEURAT-1 consortium joined by a group of international experts with complementary knowledge to further develop traditional read-across and include new approach data. Objectives: The aim of the suggested strategy for chemical read-across is to show how a traditional read-across based on structural similarities between source and target substance can be strengthened with additional evidence from new approach data—for example, information from in vitro molecular screening, “-omics” assays and computational models—to reach regulatory acceptance. Methods: We identified four read-across scenarios that cover typical human health assessment situations. For each such decision context, we suggested several chemical groups as examples to prove when read-across between group members is possible, considering both chemical and biological similarities. Conclusions: We agreed to carry out the complete read-across exercise for at least one chemical category per read-across scenario in the context of SEURAT-1, and the results of this exercise will be completed and presented by the end of the research initiative in December 2015

Gaugino Anomaly Mediated SUSY Breaking: phenomenology and prospects for the LHC

We examine the supersymmetry phenomenology of a novel scenario of supersymmetry (SUSY) breaking which we call Gaugino Anomaly Mediation, or inoAMSB. This is suggested by recent work on the phenomenology of flux compactified type IIB string theory. The essential features of this scenario are that the gaugino masses are of the anomaly-mediated SUSY breaking (AMSB) form, while scalar and trilinear soft SUSY breaking terms are highly suppressed. Renormalization group effects yield an allowable sparticle mass spectrum, while at the same time avoiding charged LSPs; the latter are common in models with negligible soft scalar masses, such as no-scale or gaugino mediation models. Since scalar and trilinear soft terms are highly suppressed, the SUSY induced flavor and CP-violating processes are also suppressed. The lightest SUSY particle is the neutral wino, while the heaviest is the gluino. In this model, there should be a strong multi-jet +etmiss signal from squark pair production at the LHC. We find a 100 fb^{-1} reach of LHC out to m_{3/2}\sim 118 TeV, corresponding to a gluino mass of \sim 2.6 TeV. A double mass edge from the opposite-sign/same flavor dilepton invariant mass distribution should be visible at LHC; this, along with the presence of short-- but visible-- highly ionizing tracks from quasi-stable charginos, should provide a smoking gun signature for inoAMSB.Comment: 30 pages including 14 .eps figure

Quantum Symmetries and Marginal Deformations

We study the symmetries of the N=1 exactly marginal deformations of N=4 Super Yang-Mills theory. For generic values of the parameters, these deformations are known to break the SU(3) part of the R-symmetry group down to a discrete subgroup. However, a closer look from the perspective of quantum groups reveals that the Lagrangian is in fact invariant under a certain Hopf algebra which is a non-standard quantum deformation of the algebra of functions on SU(3). Our discussion is motivated by the desire to better understand why these theories have significant differences from N=4 SYM regarding the planar integrability (or rather lack thereof) of the spin chains encoding their spectrum. However, our construction works at the level of the classical Lagrangian, without relying on the language of spin chains. Our approach might eventually provide a better understanding of the finiteness properties of these theories as well as help in the construction of their AdS/CFT duals.Comment: 1+40 pages. v2: minor clarifications and references added. v3: Added an appendix, fixed minor typo