Mongersen, an oral SMAD7 antisense oligonucleotide, and crohn's disease

Background Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. Methods In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. Results The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P = 0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease. Conclusions We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo

Restor(y)ing meaning: reading Manoel de Oliveira’s Non ou a Vã Glória de Mandar

Manoel de Oliveira’s Non ou a Vã Glória de Mandar (1990) is a landmark in Lusophone cinema’s revisitation of the history of Portuguese expansion and colonial conflicts. This article aims at analysing the film’s political import by extrapolating from Jacques Rancière’s meditation on the ‘aesthetic regime’ and from Manoel de Oliveira’s references to Derridean deconstruction. Non and Oliveira’s filming praxis both exceed and disrupt the filmmaker’s personal logocentric and teleological theories of history and cinema

Search for CP violation in D+→ϕπ+ and D+s→K0Sπ+ decays

A search for CP violation in D + → ϕπ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fb−1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (−0.04 ± 0.14 ± 0.14)% for candidates with K − K + mass within 20 MeV/c 2 of the ϕ meson mass. A search for a CP -violating asymmetry that varies across the ϕ mass region of the D + → K − K + π + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+s→K0Sπ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%

Bio-physical characteristics of gastrointestinal mucosa of celiac patients: comparison with control subjects and effect of gluten free diet-

<p>Abstract</p> <p>Background</p> <p>Intestinal mucosa is leaky in celiac disease (CD), and this alteration may involve changes in hydrophobicity of the mucus surface barrier in addition to alteration of the epithelial barrier. The aims of our study were i) to compare duodenal hydrophobicity as an index of mucus barrier integrity in CD patients studied before (n = 38) and during gluten- free diet (GFD, n = 68), and in control subjects (n = 90), and ii) to check for regional differences of hydrophobicity in the gastro-intestinal tract.</p> <p>Methods</p> <p>Hydrophobicity was assessed by measurement of contact angle (CA) (Rame Hart 100/10 goniometer) generated by a drop of water placed on intestinal mucosal biopsies.</p> <p>Results</p> <p>CA (mean ± SD) of distal duodenum was significantly lower in CD patients (56° ± 10°)) than in control subjects (69° ± 9°, p < 0.0001), and persisted abnormal in patients studied during gluten free diet (56° ± 9°; p < 0.005). CA was significantly higher (62° ± 9°) in histologically normal duodenal biopsies than in biopsies with Marsh 1-2 (58° ± 10°; p < 0.02) and Marsh 3 lesions (57° ± 10°; p < 0.02) in pooled results of all patients and controls studied. The order of hydrofobicity along the gastrointestinal tract in control subjects follows the pattern: gastric antrum > corpus > rectum > duodenum > oesophagus > ileum.</p> <p>Conclusions</p> <p>We conclude that the hydrophobicity of duodenal mucous layer is reduced in CD patients, and that the resulting decreased capacity to repel luminal contents may contribute to the increased intestinal permeability of CD. This alteration mirrors the severity of the mucosal lesions and is not completely reverted by gluten-free diet. Intestinal hydrophobicity exhibits regional differences in the human intestinal tract.</p

Measurement of the relative rate of prompt χc0, χc1 and χc2 production at √s=7TeV

Prompt production of charmonium χc0, χc1 and χc2 mesons is studied using proton-proton collisions at the LHC at a centre-of-mass energy of √s=7TeV. The χc mesons are identified through their decay to J/ψγ, with J/ψ→μ+mu− using photons that converted in the detector. A data sample, corresponding to an integrated luminosity of 1.0fb−1 collected by the LHCb detector, is used to measure the relative prompt production rate of χc1 and χc2 in the rapidity range 2.0<y<4.5 as a function of the J/ψ transverse momentum from 3 to 20 GeV/c. First evidence for χc0 meson production at a hadron collider is also presented

Study of DJ meson decays to D+π−, D0π+ and D∗+π− final states in pp collisions

A study of D+π−, D0π+ and D∗+π− final states is performed using pp collision data, corresponding to an integrated luminosity of 1.0 fb−1, collected at a centre-of-mass energy of 7 TeV with the LHCb detector. The D1(2420)0 resonance is observed in the D∗+π− final state and the D∗2(2460) resonance is observed in the D+π−, D0π+ and D∗+π− final states. For both resonances, their properties and spin-parity assignments are obtained. In addition, two natural parity and two unnatural parity resonances are observed in the mass region between 2500 and 2800 MeV. Further structures in the region around 3000 MeV are observed in all the D∗+π−, D+π− and D0π+ final states

Searches for B0(s)→J/ψppˉ and B+→J/ψppˉπ+ decays

The results of searches for B0(s)→J/ψ pp¯ and B + → J/ψ p p¯ π+ decays are reported. The analysis is based on a data sample, corresponding to an integrated luminosity of 1.0 fb−1 of pp collisions, collected with the LHCb detector. An excess with 2.8 σ significance is seen for the decay B0s→J/ψ pp¯ and an upper limit on the branching fraction is set at the 90 % confidence level: B(B0s→J/ψ pp¯) < 4.8 × 10−6, which is the first such limit. No significant signals are seen for B0 → J/ψ pp¯ and B+ → J/ψ pp¯ π + decays, for which the corresponding limits are set: B(B0→J/ψ pp¯) < 5.2 × 10−7, which significantly improves the existing limit; and B(B+→J/ψ pp¯π+) < 5.0 × 10−7, which is the first limit on this branching fraction

A westward extension of the warm pool leads to a westward extension of the Walker circulation, drying eastern Africa

Observations and simulations link anthropogenic greenhouse and aerosol emissions with rapidly increasing Indian Ocean sea surface temperatures (SSTs). Over the past 60 years, the Indian Ocean warmed two to three times faster than the central tropical Pacific, extending the tropical warm pool to the west by ~40° longitude (><4,000 km). This propensity toward rapid warming in the Indian Ocean has been the dominant mode of interannual variability among SSTs throughout the tropical Indian and Pacific Oceans (55°E–140°W) since at least 1948, explaining more variance than anomalies associated with the El Niño-Southern Oscillation (ENSO). In the atmosphere, the primary mode of variability has been a corresponding trend toward greatly increased convection and precipitation over the tropical Indian Ocean. The temperature and rainfall increases in this region have produced a westward extension of the western, ascending branch of the atmospheric Walker circulation. Diabatic heating due to increased mid-tropospheric water vapor condensation elicits a westward atmospheric response that sends an easterly flow of dry air aloft toward eastern Africa. In recent decades (1980–2009), this response has suppressed convection over tropical eastern Africa, decreasing precipitation during the ‘long-rains’ season of March–June. This trend toward drought contrasts with projections of increased rainfall in eastern Africa and more ‘El Niño-like’ conditions globally by the Intergovernmental Panel on Climate Change. Increased Indian Ocean SSTs appear likely to continue to strongly modulate the Warm Pool circulation, reducing precipitation in eastern Africa, regardless of whether the projected trend in ENSO is realized. These results have important food security implications, informing agricultural development, environmental conservation, and water resource planning

Tunable Chemokine Production by Antigen Presenting Dendritic Cells in Response to Changes in Regulatory T Cell Frequency in Mouse Reactive Lymph Nodes

BACKGROUND: Although evidence exists that regulatory T cells (Tregs) can suppress the effector phase of immune responses, it is clear that their major role is in suppressing T cell priming in secondary lymphoid organs. Recent experiments using two photon laser microscopy indicate that dendritic cells (DCs) are central to Treg cell function and that the in vivo mechanisms of T cell regulation are more complex than those described in vitro. PRINCIPAL FINDINGS: Here we have sought to determine whether and how modulation of Treg numbers modifies the lymph node (LN) microenvironment. We found that pro-inflammatory chemokines -- CCL2 (MCP-1) and CCL3 (MIP-la) -- are secreted in the LN early (24 h) after T cell activation, that this secretion is dependent on antigen-specific DC-T cell interactions, and that it was inversely related to the frequency of Tregs specific for the same antigen. Furthermore, we demonstrate that Tregs modify the chemoattractant properties of antigen-presenting DCs, which, as the frequency of Tregs increases, fail to produce CCL2 and CCL3 and to attract antigen-specific T cells. CONCLUSIONS: These results substantiate a major role of Tregs in LN patterning during antigen-specific immune responses

Low CCR7-Mediated Migration of Human Monocyte Derived Dendritic Cells in Response to Human Respiratory Syncytial Virus and Human Metapneumovirus

Human respiratory syncytial virus (HRSV) and, to a lesser extent, human metapneumovirus (HMPV) and human parainfluenza virus type 3 (HPIV3), can re-infect symptomatically throughout life without significant antigenic change, suggestive of incomplete or short-lived immunity. In contrast, re-infection by influenza A virus (IAV) largely depends on antigenic change, suggestive of more complete immunity. Antigen presentation by dendritic cells (DC) is critical in initiating the adaptive immune response. Antigen uptake by DC induces maturational changes that include decreased expression of the chemokine receptors CCR1, CCR2, and CCR5 that maintain DC residence in peripheral tissues, and increased expression of CCR7 that mediates the migration of antigen-bearing DC to lymphatic tissue. We stimulated human monocyte-derived DC (MDDC) with virus and found that, in contrast to HPIV3 and IAV, HMPV and HRSV did not efficiently decrease CCR1, 2, and 5 expression, and did not efficiently increase CCR7 expression. Consistent with the differences in CCR7 mRNA and protein expression, MDDC stimulated with HRSV or HMPV migrated less efficiently to the CCR7 ligand CCL19 than did IAV-stimulated MDDC. Using GFP-expressing recombinant virus, we showed that the subpopulation of MDDC that was robustly infected with HRSV was particularly inefficient in chemokine receptor modulation. HMPV- or HRSV-stimulated MDDC responded to secondary stimulation with bacterial lipopolysaccharide or with a cocktail of proinflammatory cytokines by increasing CCR7 and decreasing CCR1, 2 and 5 expression, and by more efficient migration to CCL19, suggesting that HMPV and HRSV suboptimally stimulate rather than irreversibly inhibit MDDC migration. This also suggests that the low concentration of proinflammatory cytokines released from HRSV- and HMPV-stimulated MDDC is partly responsible for the low CCR7-mediated migration. We propose that inefficient migration of HRSV- and HMPV-stimulated DC to lymphatic tissue contributes to reduced adaptive responses to these viruses