Моделирование лондонского текста в повести Е. И. Замятина "Островитяне"

Статья посвящена анализу лондонского текста русской культуры первой половины ХХ в. на материале повести Е. И. Замятина "Островитяне". Впервые образ города рассматривается сквозь призму модернистской поэтики. Лондон как центр научного, рационалистического метода познания становится воплощением идеологии модернизма. Это дает возможность говорить о многоуровневой структуре восприятия города в рамках русской ментальности. В статье показывается, как образ столицы западной цивилизации усваивается русским сознанием и включается в общерусский литературный и культурный контекст

Осуществление налогового планирования на различных этапах деятельности предприятия

Проанализированы основные условия реализации налогового планирования на разных стадиях жизненного цикла хозяйствующего субъекта. Показана возможность влияния налогов на принятие предпринимательских и управленческих решений внутри предприятия

A POWHEG generator for deep inelastic scattering

We present a new event generator for the simulation of both neutral- and charged-current deep inelastic scattering (DIS) at next-to-leading order in QCD matched to parton showers using the POWHEG method. Our implementation builds on the existing POWHEG BOX framework originally designed for hadron-hadron collisions, supplemented by considerable extensions to account for the genuinely different kinematics inherent to lepton-hadron collisions. In particular, we present new momentum mappings that conserve the special kinematics found in DIS, which we use to modify the POWHEG BOX implementation of the Frixione-Kunszt-Signer subtraction mechanism. We compare our predictions to fixed-order and resummed predictions, as well as to data from the HERA ep collider. Finally we study a few representative distributions for the upcoming Electron Ion Collider.Comment: 54 pages, 25 figures, code obtainable from svn://powhegbox.mib.infn.it/trunk/User-Processes-RES/DI

Economic implications in inflammatory bowel disease: results from a retrospective analysis in an Italian Centre

BACKGROUND: Inflammatory bowel disease (IBD) represents a group of chronic conditions characterized by elevated costs. Over the last years, also a considerable healthcare burden associated with IBD has emerged, due to an increasing use of biological drugs and hospitalization costs. Despite the creation of local or regional databases, data regarding healthcare expenditure are lacking in Italy.AIM: To evaluate the treatment cost (biological drugs and hospitalizations) for patients with ulcerative colitis (UC) or Crohn’s disease (CD) treated with biological drugs.METHODS: Disease severity was evaluated by clinical scores (partial Mayo score and Harvey Bradshaw Index). We analyzed retrospectively patients treated with biologics referred to our IBD Unit between May 2015-April 2016 who underwent at least six months of follow-up (last visit October 2016). We calculated a mean cost per month of treatment for each patient. We also investigated the presence of any correlation between the monthly cost of treatment and demographic or clinical variables.RESULTS: We enrolled 142 patients (52 UC, mean age 44.3 years, male 40.4%; 90 CD, mean age 38.8 years, male 56.7%). About half of CD patients (48.9%) underwent previous intestinal surgery. The disease severity was higher in UC group vs CD group. In UC group infliximab was the most prescribed biologic (51.9%), followed by golimumab (26.9%) and adalimumab (21.2%). While CD patients were treated with adalimumab in 54.4% and infliximab in 45.6%. The mean monthly cost of treatment was € 1,235.41 ± 358.38 for UC and € 1,148.92 ± 337.36 for CD (p = 0.16). In both groups expenditure due to biologics amounts for more than 80%. We found a correlation between costs and disease activity (UC: p < 0.01; CD: p < 0.01).CONCLUSION: The main cost is due to biological drugs, but patients enrolled were the most severe in comparison to the whole IBD population under conventional therapy. As no cost differences were found between biologic drugs and the way of administration (intravenous or subcutaneous), the therapeutic choice should be driven by clinical reasons and not only economic ones

Cost per NNT for upadacitinib in the treatment of patients with moderate-severe atopic dermatitis in Italy

Background: Targeted systemic therapies, including abrocitinib, baricitinib, dupilumab, tralokinumab and upadacitinib, are new treatments for moderate to severe atopic dermatitis (AD). We evaluated the efficacy and the costs of these targeted systemic therapies in the treatment of adult patients with moderate to severe AD. Methods: The clinical efficacy was assessed considering the results of a previous network meta-analysis (NMA). The analysis involved five therapies approved in Italy for the treatment of moderate to severe AD: abrocitinib (ABR), baricitinib (BAR), dupilumab (DUP), tralokinumab (TRA) and upadacitinib (UPA). According to the NMA, the cost of the treatment was based on the number of administrations dispensed at 16 weeks and the clinical efficacy was measured by the number needed to treat (NNT) compared to placebo using the improvement ≥ 75% (EASI-75) or ≥ 90 (EASI-90) from baseline of the eczema area and severity index (EASI). Only the ex-factory price of the targeted systemic therapies was considered. The cost per NNT was adopted as a cost-effectiveness indicator. Results: At 16 weeks, the cost per NNT based on EASI-75 was lower for UPA 15 mg (€ 6,384.00) compared to BAR 4 mg (€ 11,619.73) and 2 mg (€ 14,524.66), ABR 100 mg (€ 16,265.22), DUP 300 mg (€ 16,115.04) and TRA 300 mg (€ 31,710.24). UPA 15 (€ 8,512.00) also showed the lower cost per NNT based on EASI-90 at 16 weeks compared to BAR 4 mg (€ 14,788.75) and 2 mg (€ 20,862.70), ABR 100 mg (€ 25,922.69), DUP 300 mg (€ 25,992.00) and TRA 300 mg (€ 41,067.36). Conclusions: The findings show that upadacitinib is the most cost-effective option (cost per NNT) for the treatment of moderate to severe atopic dermatitis

Cell Swelling Stimulates Cytosol to Membrane Transposition of ICln

ICln is a multifunctional protein that is essential for cell volume regulation. It can be found in the cytosol and is associated with the cell membrane. Besides its role in the splicing process, ICln is critically involved in the generation of ion currents activated during regulatory volume decrease after cell swelling (RVDC). If reconstituted in artificial bilayers, ICln can form ion channels with biophysical properties related to RVDC. We investigated (i) the cytosol versus cell membrane distribution of ICln in rat kidney tubules, NIH 3T3 fibroblasts, Madin-Darby canine kidney (MDCK) cells, and LLC-PK1 epithelial cells, (ii) fluorescence resonance energy transfer (FRET) in living fibroblasts between fluorescently tagged ICln and fluorochromes in the cell membrane, and (iii) possible functional consequences of an enhanced ICln presence at the cell membrane. We demonstrate that ICln distribution in rat kidneys depends on the parenchymal localization and functional state of the tubules and that cell swelling causes ICln redistribution from the cytosol to the cell membrane in NIH 3T3 fibroblasts and LLC-PK1 cells. The addition of purified ICln protein to the extracellular solution or overexpression of farnesylated ICln leads to an increased anion permeability in NIH 3T3 fibroblasts. The swelling-induced redistribution of ICln correlates to altered kinetics of RVDC in NIH 3T3 fibroblasts, LLC-PK1 cells, and MDCK cells. In these cells, RVDC develops more rapidly, and in MDCK cells the rate of swelling-induced depolarization is accelerated if cells are swollen for a second time. This coincides with an enhanced ICln association with the cell membrane

A bright megaelectronvolt emission line in γ\gamma-ray burst GRB 221009A

The highly variable and energetic pulsed emission of a long gamma-ray burst (GRB) is thought to originate from local, rapid dissipation of kinetic or magnetic energy within an ultra-relativistic jet launched by a newborn compact object, formed during the collapse of a massive star. The spectra of GRB pulses are best modelled by power-law segments, indicating the dominance of non-thermal radiation processes. Spectral lines in the X-ray and soft $\gamma$-ray regime for the afterglow have been searched for intensively, but never confirmed. No line features ever been identified in the high energy prompt emission. Here we report the discovery of a highly significant ($> 6 \sigma$) narrow emission feature at around $10$ MeV in the brightest ever GRB 221009A. By modelling its profile with a Gaussian, we find a roughly constant width $\sigma \sim 1$ MeV and temporal evolution both in energy ($\sim 12$ MeV to $\sim 6$ MeV) and luminosity ($\sim 10^{50}$ erg/s to $\sim 2 \times 10^{49}$ erg/s) over 80 seconds. We interpret this feature as a blue-shifted annihilation line of relatively cold ($k_\mathrm{B}T\ll m_\mathrm{e}c^2$) electron-positron pairs, which could have formed within the jet region where the brightest pulses of the GRB were produced. A detailed understanding of the conditions that can give rise to such a feature could shed light on the so far poorly understood GRB jet properties and energy dissipation mechanism.Comment: Submitte

Alternative molecular mechanisms for force transmission at adherens junctions via β-catenin-vinculin interaction

Force transmission through adherens junctions (AJs) is crucial for multicellular organization, wound healing and tissue regeneration. Recent studies shed light on the molecular mechanisms of mechanotransduction at the AJs. However, the canonical model fails to explain force transmission when essential proteins of the mechanotransduction module are mutated or missing. Here, we demonstrate that, in absence of α-catenin, β-catenin can directly and functionally interact with vinculin in its open conformation, bearing physiological forces. Furthermore, we found that β-catenin can prevent vinculin autoinhibition in the presence of α-catenin by occupying vinculin´s head-tail interaction site, thus preserving force transmission capability. Taken together, our findings suggest a multi-step force transmission process at AJs, where α-catenin and β-catenin can alternatively and cooperatively interact with vinculin. This can explain the graded responses needed to maintain tissue mechanical homeostasis and, importantly, unveils a force-bearing mechanism involving β-catenin and extended vinculin that can potentially explain the underlying process enabling collective invasion of metastatic cells lacking α-catenin