PHASE, a Monte Carlo event generator for six-fermion physics at the LHC

PHASE is a new event generator dedicated to the study of Standard Model processes with six fermions in the final state at the LHC. The code is intended for analyses of vector boson scattering, Higgs search, three gauge boson production, and top physics. This first version of the program describes final states characterized by the presence of one neutrino, $pp\to 4q +l\nu_l$, at O($\alpha^6$). PHASE is based on a new iterative-adaptive multichannel technique, and employs exact leading order matrix elements. The code can generate unweighted events for any subset of all available final states. The produced parton-level events carry full information on their colour and flavour structure, enabling the evolution of the partons into fully hadronised final states. An interface to hadronization packages is provided via the Les Houches Protocol.Comment: 27 pages, Latex, 6 figure

e+e−→H+H−e^+e^-\to H^+H^- signals at LEP2 energies in the Minimal Supersymmetric Standard Model

In this paper we compare $H^+H^-$ and $W^+W^-$ into four-fermion production at centre-of-mass energies typical of LEP2 and somewhat larger. The theoretical framework considered is the Minimal Supersymmetric Standard Model. The interest in exploiting the $e^+e^-$ CERN collider at values of $\sqrt s$ greater than 192 GeV could come from the discovery of Supersymmetric signals during runs at lower energy. If these indicate that a charged Higgs boson exists in the mass range \MH\approx95-105 GeV, then a few years of running at $\sqrt s=205-215$ GeV and nominal luminosity could make the detection of such scalars feasible, in the purely leptonic channel $\tau\nu_\tau\tau\nu_\tau$ and, for small \tb's, also in the semi-hadronic(leptonic) one ${jj}\tau\nu_\tau$. Charged Higgs bosons of the above nature cannot be produced by the beam energies approved at present for LEP2. However, if runs beyond the so-called `192 GeV cryogenic limit' will be approved by the CERN Council, our selection procedure will enable us to establish the presence, or otherwise, of charged Higgs bosons in the mentioned mass rangeComment: 30 pages, latex, epsfig, 12 postscript figures, complete paper available at ftp://axpa.hep.phy.cam.ac.uk/stefano/cavendish_9615 and at http://www.hep.phy.cam.ac.uk/theory/papers

Cross-Sample Validation Provides Enhanced Proteome Coverage in Rat Vocal Fold Mucosa

The vocal fold mucosa is a biomechanically unique tissue comprised of a densely cellular epithelium, superficial to an extracellular matrix (ECM)-rich lamina propria. Such ECM-rich tissues are challenging to analyze using proteomic assays, primarily due to extensive crosslinking and glycosylation of the majority of high Mr ECM proteins. In this study, we implemented an LC-MS/MS-based strategy to characterize the rat vocal fold mucosa proteome. Our sample preparation protocol successfully solubilized both proteins and certain high Mr glycoconjugates and resulted in the identification of hundreds of mucosal proteins. A straightforward approach to the treatment of protein identifications attributed to single peptide hits allowed the retention of potentially important low abundance identifications (validated by a cross-sample match and de novo interpretation of relevant spectra) while still eliminating potentially spurious identifications (global single peptide hits with no cross-sample match). The resulting vocal fold mucosa proteome was characterized by a wide range of cellular and extracellular proteins spanning 12 functional categories

ALPGEN, a generator for hard multiparton processes in hadronic collisions

This paper presents a new event generator, ALPGEN, dedicated to the study of multiparton hard processes in hadronic collisions. The code performs, at the leading order in QCD and EW interactions, the calculation of the exact matrix elements for a large set of parton-level processes of interest in the study of the Tevatron and LHC data. The current version of the code describes the following final states: (W -> ffbar') QQbar+ N jets (Q being a heavy quark, and f=l,q), with N f fbar)+QQbar+Njets (f=l,nu), with N ffbar') + charm + N jets (f=l,q), N f fbar') + N jets (f=l,q) and (Z/gamma* -> f fbar)+ N jets (f=l,nu), with N<=6; nW+mZ+lH+N jets, with n+m+l+N<=8 and N<=3 including all 2-fermion decay modes of W and Z bosons, with spin correlations; Q Qbar+N jets (N b f fbar' decays and relative spin correlations included if Q=t; Q Qbar Q' Qbar'+N jets, with Q and Q' heavy quarks (possibly equal) and N b f fbar' decays and relative spin correlations included if Q=t; N jets, with N<=6. Parton-level events are generated, providing full information on their colour and flavour structure, enabling the evolution of the partons into fully hadronised final states.Comment: 1+38 pages, uses JHEP.cls. Documents code version 1.2: extended list of processes, updated documentation and bibliograph

Standard Model Large-E_T Processes and Searches for New Physics at HERA

Existing and missing calculations of standard model processes producing large transverse energy in electron-proton interactions at HERA are reviewed. The adequacy of the existing standard model Monte Carlo programs for generic searches of exotic processes is analyzed.Comment: 9 pages, LaTeX, uses iop style files, Contribution to the 3rd UK Phenomenology Workshop on HERA Physics, September 1998, Durha

The Prosensory Function of Sox2 in the Chicken Inner Ear Relies on the Direct Regulation of Atoh1

The proneural gene Atoh1 is crucial for the development of inner ear hair cells and it requires the function of the transcription factor Sox2 through yet unknown mechanisms. In the present work, we used the chicken embryo and HEK293T cells to explore the regulation of Atoh1 by Sox2. The results show that hair cells derive from Sox2-positive otic progenitors and that Sox2 directly activates Atoh1 through a transcriptional activator function that requires the integrity of Sox2 DNA binding domain. Atoh1 activation depends on Sox transcription factor binding sites (SoxTFBS) present in the Atoh1 3′ enhancer where Sox2 directly binds, as shown by site directed mutagenesis and chromatin immunoprecipitation (ChIP). In the inner ear, Atoh1 enhancer activity is detected in the neurosensory domain and it depends on Sox2. Dominant negative competition (Sox2HMG-Engrailed) and mutation of the SoxTFBS abolish the reporter activity in vivo. Moreover, ChIP assay in isolated otic vesicles shows that Sox2 is bound to the Atoh1 enhancer in vivo. However, besides activating Atoh1, Sox2 also promotes the expression of Atoh1 negative regulators and the temporal profile of Atoh1 activation by Sox2 is transient suggesting that Sox2 triggers an incoherent feed-forward loop. These results provide a mechanism for the prosensory function of Sox2 in the inner ear. We suggest that sensory competence is established early in otic development through the activation of Atoh1 by Sox2, however, hair cell differentiation is prevented until later stages by the parallel activation of negative regulators of Atoh1 function

Chemerin regulates β-cell function in mice

Although various function of chemerin have been suggested, its physiological role remains to be elucidated. Here we show that chemerin-deficient mice are glucose intolerant irrespective of exhibiting reduced macrophage accumulation in adipose tissue. The glucose intolerance was mainly due to increased hepatic glucose production and impaired insulin secretion. Chemerin and its receptor ChemR23 were expressed in β-cell. Studies using isolated islets and perfused pancreas revealed impaired glucose-dependent insulin secretion (GSIS) in chemerin-deficient mice. Conversely, chemerin transgenic mice revealed enhanced GSIS and improved glucose tolerance. Expression of MafA, a pivotal transcriptional factor for β-cell function, was downregulated in chemerin-deficient islets and a chemerin-ablated β-cell line and rescue of MafA expression restored GSIS, indicating that chemerin regulates β-cell function via maintaining MafA expression. These results indicate that chemerin regulates β-cell function and plays an important role in glucose homeostasis in a tissue-dependent manner

The histone demethylase LSD1 regulates inner ear progenitor differentiation through interactions with Pax2 and the NuRD repressor complex

The histone demethylase LSD1 plays a pivotal role in cellular differentiation, particularly in silencing lineage-specific genes. However, little is known about how LSD1 regulates neurosensory differentiation in the inner ear. Here we show that LSD1 interacts directly with the transcription factor Pax2 to form the NuRD co-repressor complex at the Pax2 target gene loci in a mouse otic neuronal progenitor cell line (VOT-N33). VOT-N33 cells expressing a Pax2-response element reporter were GFP-negative when untreated, but became GFP positive after forced differentiation or treatment with a potent LSD inhibitor. Pharmacological inhibition of LSD1 activity resulted in the enrichment of mono- and di-methylation of H3K4, upregulation of sensory neuronal genes and an increase in the number of sensory neurons in mouse inner ear organoids. Together, these results identify the LSD1/NuRD complex as a previously unrecognized modulator for Pax2-mediated neuronal differentiation in the inner ear

MCP-1 Upregulates Amylin Expression in Murine Pancreatic β Cells through ERK/JNK-AP1 and NF-κB Related Signaling Pathways Independent of CCR2

BACKGROUND: Amylin is the most abundant component of islet amyloid implicated in the development of type 2 diabetes. Plasma amylin levels are elevated in individuals with obesity and insulin resistance. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is involved in insulin resistance of obesity and type 2 diabetes. We investigated the effect of MCP-1 on amylin expression and the underlying mechanisms with murine pancreatic β-cell line MIN6 and pancreatic islets. METHODOLOGY/PRINCIPAL FINDINGS: We found that MCP-1 induced amylin expression at transcriptional level and increased proamylin and intermediate forms of amylin at protein level in MIN6 cells and islets. However, MCP-1 had no effect on the expressions of proinsulin 1 and 2, as well as prohormone convertase (PC) 1/3 and PC2, suggesting that MCP-1 specifically induces amylin expression in β-cells. Mechanistic studies showed that although there is no detectable CCR2 mRNA in MIN6 cells and islets, pretreatment of MIN6 cells with pertussis toxin inhibited MCP-1 induced amylin expression, suggesting that alternative Gi-coupled receptor(s) mediates the inductive effect of MCP-1. MCP-1 rapidly induced ERK1/2 and JNK phosphorylation. Inhibitors for MEK1/2 (PD98059), JNK (SP600125) or AP1 (curcumin) significantly inhibited MCP-1-induced amylin mRNA expression. MCP-1 failed to induce amylin expression in pancreatic islets isolated from Fos knockout mice. EMSA showed that JNK and ERK1/2 were involved in MCP-1-induced AP1 activation. These results suggest that MCP-1 induces murine amylin expression through AP1 activation mediated by ERK1/2 or JNK. Further studies showed that treatment of MIN6 cells with NF-κB inhibitor or overexpression of IκBα dominant-negative construct in MIN6 cells significantly inhibited MCP-1-induced amylin expression, suggesting that NF-κB related signaling also participates in MCP-1-induced murine amylin expression. CONCLUSIONS/SIGNIFICANCE: MCP-1 induces amylin expression through ERK1/2/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. Amylin upregulation by MCP-1 may contribute to elevation of plasma amylin in obesity and insulin resistance

A Patient-Specific in silico Model of Inflammation and Healing Tested in Acute Vocal Fold Injury

The development of personalized medicine is a primary objective of the medical community and increasingly also of funding and registration agencies. Modeling is generally perceived as a key enabling tool to target this goal. Agent-Based Models (ABMs) have previously been used to simulate inflammation at various scales up to the whole-organism level. We extended this approach to the case of a novel, patient-specific ABM that we generated for vocal fold inflammation, with the ultimate goal of identifying individually optimized treatments. ABM simulations reproduced trajectories of inflammatory mediators in laryngeal secretions of individuals subjected to experimental phonotrauma up to 4 hrs post-injury, and predicted the levels of inflammatory mediators 24 hrs post-injury. Subject-specific simulations also predicted different outcomes from behavioral treatment regimens to which subjects had not been exposed. We propose that this translational application of computational modeling could be used to design patient-specific therapies for the larynx, and will serve as a paradigm for future extension to other clinical domains