The Cyclophilin-Binding Agent Sanglifehrin A Is a Dendritic Cell Chemokine and Migration Inhibitor

Sanglifehrin A (SFA) is a cyclophilin-binding immunosuppressant but the immunobiology of action is poorly understood. We and others have reported that SFA inhibits IL-12 production and antigen uptake in dendritic cells (DC) and exhibits lower activity against lymphocytes. Here we show that SFA suppresses DC chemokine production and migration. Gene expression analysis and subsequent protein level confirmation revealed that SFA suppressed CCL5, CCL17, CCL19, CXCL9 and CXCL10 expression in human monocyte-derived DC (moDC). A systems biology analysis, Onto Express, confirmed that SFA interferes with chemokine-chemokine receptor gene expression with the highest impact. Direct comparison with the related agent cyclosporine A (CsA) and dexamethasone indicated that SFA uniquely suppresses moDC chemokine expression. Competitive experiments with a 100-fold molar excess of CsA and with N-Methyl-Val-4-cyclosporin, representing a nonimmunosuppressive derivative of CsA indicated chemokine suppression through a cyclophilin-A independent pathway. Functional assays confirmed reduced migration of CD4+ Tcells and moDCs to supernatant of SFA-exposed moDCs. Vice versa, SFA-exposed moDC exhibited reduced migration against CCL19. Moreover, SFA suppressed expression of the ectoenzyme CD38 that was reported to regulate DC migration and cytokine production. These results identify SFA as a DC chemokine and migration inhibitor and provide novel insight into the immunobiology of SFA

VBFNLO: A parton level Monte Carlo for processes with electroweak bosons -- Manual for Version 2.7.0

VBFNLO is a flexible parton level Monte Carlo program for the simulation of vector boson fusion (VBF), QCD induced single and double vector boson production plus two jets, and double and triple vector boson production (plus jet) in hadronic collisions at next-to-leading order (NLO) in the strong coupling constant, as well as Higgs boson plus two jet production via gluon fusion at the one-loop level. For the new version -- Version 2.7.0 -- several major enhancements have been included into VBFNLO. The following new production processes have been added: $W\gamma jj$ in VBF, $HHjj$ in VBF, $W$, $Wj$, $WH$, $WHj$, $pp\to \text{Spin-2}jj$ in VBF (with $\text{Spin-2}\to WW/ZZ\to\text{leptons}$) and the QCD induced processes $WZjj$, $W\gamma jj$, $W^\pm W^\pm jj$ and $Wjj$ production. The implementation of anomalous gauge boson couplings has been extended to all triboson and VBF $VVjj$ processes, with an enlarged set of operators yielding anomalous couplings. Finally, semileptonic decay modes of the vector bosons are now available for many processes, including $VVjj$ in VBF, $VVV$ and $VV\gamma$ production.Comment: 83 pages, 23 tables; new code available at http://www.itp.kit.edu/vbfnlo/; v3: update to version 2.7.

Jet Substructure Without Trees

We present an alternative approach to identifying and characterizing jet substructure. An angular correlation function is introduced that can be used to extract angular and mass scales within a jet without reference to a clustering algorithm. This procedure gives rise to a number of useful jet observables. As an application, we construct a top quark tagging algorithm that is competitive with existing methods.Comment: 22 pages, 16 figures, version accepted by JHE

Localization-associated immune phenotypes of clonally expanded tumor-infiltrating T cells and distribution of their target antigens in rectal cancer

The degree and type of T cell infiltration influence rectal cancer prognosis regardless of classical tumor staging. We asked whether clonal expansion and tumor infiltration are restricted to selected-phenotype T cells; which clones are accessible in peripheral blood; and what the spatial distribution of their target antigens is. From five rectal cancer patients, we isolated paired tumor-infiltrating T cells (TILs) and T cells from unaffected rectum mucosa (T(UM)) using 13-parameter FACS single cell index sorting. TCRαβ sequences, cytokine, and transcription factor expression were determined with single cell sequencing. TILs and T(UM) occupied distinct phenotype compartments and clonal expansion predominantly occurred within CD8(+) T cells. Expanded TIL clones identified by paired TCRαβ sequencing and exclusively detectable in the tumor showed characteristic PD-1 and TIM-3 expression. TCRβ repertoire sequencing identified 49 out of 149 expanded TIL clones circulating in peripheral blood and 41 (84%) of these were PD-1(-) TIM-3(-). To determine whether clonal expansion of predominantly tumor-infiltrating T cell clones was driven by antigens uniquely presented in tumor tissue, selected TCRs were reconstructed and incubated with cells isolated from corresponding tumor or unaffected mucosa. The majority of clones exclusively detected in the tumor recognized antigen at both sites. In summary, rectal cancer is infiltrated with expanded distinct-phenotype T cell clones that either i) predominantly infiltrate the tumor, ii) predominantly infiltrate the unaffected mucosa, or iii) overlap between tumor, unaffected mucosa, and peripheral blood. However, the target antigens of predominantly tumor-infiltrating TIL clones do not appear to be restricted to tumor tissue

Observation of isotonic symmetry for enhanced quadrupole collectivity in neutron-rich 62,64,66Fe isotopes at N=40

The transition rates for the 2_{1}^{+} states in 62,64,66Fe were studied using the Recoil Distance Doppler-Shift technique applied to projectile Coulomb excitation reactions. The deduced E2 strengths illustrate the enhanced collectivity of the neutron-rich Fe isotopes up to N=40. The results are interpreted by the generalized concept of valence proton symmetry which describes the evolution of nuclear structure around N=40 as governed by the number of valence protons with respect to Z~30. The deformation suggested by the experimental data is reproduced by state-of-the-art shell calculations with a new effective interaction developed for the fpgd valence space.Comment: 4 pages, 2 figure

Identifying Boosted Objects with N-subjettiness

We introduce a new jet shape -- N-subjettiness -- designed to identify boosted hadronically-decaying objects like electroweak bosons and top quarks. Combined with a jet invariant mass cut, N-subjettiness is an effective discriminating variable for tagging boosted objects and rejecting the background of QCD jets with large invariant mass. In efficiency studies of boosted W bosons and top quarks, we find tagging efficiencies of 30% are achievable with fake rates of 1%. We also consider the discovery potential for new heavy resonances that decay to pairs of boosted objects, and find significant improvements are possible using N-subjettiness. In this way, N-subjettiness combines the advantages of jet shapes with the discriminating power seen in previous jet substructure algorithms.Comment: 26 pages, 26 figures, 2 tables; v2: references added; v3: discussion of results extende

Diboson-Jets and the Search for Resonant Zh Production

New particles at the TeV-scale may have sizeable decay rates into boosted Higgs bosons or other heavy scalars. Here, we investigate the possibility of identifying such processes when the Higgs/scalar subsequently decays into a pair of W bosons, constituting a highly distinctive "diboson-jet." These can appear as a simple dilepton (plus MET) configuration, as a two-prong jet with an embedded lepton, or as a four-prong jet. We study jet substructure methods to discriminate these objects from their dominant backgrounds. We then demonstrate the use of these techniques in the search for a heavy spin-one Z' boson, such as may arise from strong dynamics or an extended gauge sector, utilizing the decay chain Z' -> Zh -> Z(WW^(*)). We find that modes with multiple boosted hadronic Zs and Ws tend to offer the best prospects for the highest accessible masses. For 100/fb luminosity at the 14 TeV LHC, Z' decays into a standard 125 GeV Higgs can be observed with 5-sigma significance for masses of 1.5-2.5 TeV for a range of models. For a 200 GeV Higgs (requiring nonstandard couplings, such as fermiophobic), the reach may improve to up to 2.5-3.0 TeV.Comment: 23 pages plus appendices, 9 figure

Heavy Squarks at the LHC

The LHC, with its seven-fold increase in energy over the Tevatron, is capable of probing regions of SUSY parameter space exhibiting qualitatively new collider phenomenology. Here we investigate one such region in which first generation squarks are very heavy compared to the other superpartners. We find that the production of these squarks, which is dominantly associative, only becomes rate-limited at mSquark > 4(5) TeV for L~10(100) fb-1. However, discovery of this scenario is complicated because heavy squarks decay primarily into a jet and boosted gluino, yielding a dijet-like topology with missing energy (MET) pointing along the direction of the second hardest jet. The result is that many signal events are removed by standard jet/MET anti-alignment cuts designed to guard against jet mismeasurement errors. We suggest replacing these anti-alignment cuts with a measurement of jet substructure that can significantly extend the reach of this channel while still removing much of the background. We study a selection of benchmark points in detail, demonstrating that mSquark= 4(5) TeV first generation squarks can be discovered at the LHC with L~10(100)fb-1