Inhibition of cellular protein secretion by norwalk virus nonstructural protein p22 requires a mimic of an endoplasmic reticulum export signal.

Protein trafficking between the endoplasmic reticulum (ER) and Golgi apparatus is central to cellular homeostasis. ER export signals are utilized by a subset of proteins to rapidly exit the ER by direct uptake into COPII vesicles for transport to the Golgi. Norwalk virus nonstructural protein p22 contains a YXΦESDG motif that mimics a di-acidic ER export signal in both sequence and function. However, unlike normal ER export signals, the ER export signal mimic of p22 is necessary for apparent inhibition of normal COPII vesicle trafficking, which leads to Golgi disassembly and antagonism of Golgi-dependent cellular protein secretion. This is the first reported function for p22. Disassembly of the Golgi apparatus was also observed in cells replicating Norwalk virus, which may contribute to pathogenesis by interfering with cellular processes that are dependent on an intact secretory pathway. These results indicate that the ER export signal mimic is critical to the antagonistic function of p22, shown herein to be a novel antagonist of ER/Golgi trafficking. This unique and well-conserved human norovirus motif is therefore an appealing target for antiviral drug development

Acrylic resins in wet white

Content: The purpose of this paper is to study the influence of acrylic resins on the properties of the hide when added in the pickling-tanning stage of a wet white process. Among retanning products, acrylic resins are very frequently used because they lend very good properties to the hide on account of their high affinity for chromium. When applied during chrome tanning, these resins provide the hides with high fullness, due to the strong interaction of the carboxylate groups with chromium. Extensive bibliography is available on the application of acrylic resins in wet blue, where it is observed that the properties they provide to the hides depend basically on the type of monomers and molecular weight. However, less information is found when these products are applied in wet white tanning. In this study, 9 resins with different molecular weights and different monomer compositions were selected. Resins were applied to pelt leathers of Spanish origin split at 3.5 mm. Hides were cut along the backbone. A standard process was applied to the left halves and the same process adding the resin was applied to the right halves. The resin was added after adjusting the salt of the bath and before adding the pickling acids. The COD was measured before and after adding formic and sulfuric acid, and the shrinkage temperature and the degree of whiteness of the tanned hide were assessed. Hides were retanned and fatliquored with a standard process, and degree of softness, thickness, color intensity and organoleptic properties (fluffiness, compactness and grain tightness) were assessed. Leather shrinkage under temperature was also assessed, and images of leather sections were obtained by scanning electron microscopy (SEM). While acrylic resins did not increase shrinkage temperature, they did fix and/or deposit themselves in the interfibrillary spaces of the hide; indeed, highly reduced COD values after acidification in the pickling stage were observed. This study shows that homopolymeric acrylic resins provided fuller and fluffier hides, while the rest of resins practically did not improve the physical and organoleptic properties of the hides. Take-Away: Homopolymeric acrylic resins provided full er and fluffier hides, while the rest of resins practically did not improve the physical and organoleptic properties of the hides Wet white tanning improvemen

Corporate social responsibility in cruising: Using materiality analysis to create shared value

© 2015 Elsevier Ltd. Creating Shared Value hinges on the interdependence between a company's success and social welfare, and also the identification and expansion of connections between that company and society. Because critics say the concept is counterproductive, in that it focuses too narrowly on the company's economic value creation, we take a materiality analysis approach of corporate social responsibility (CSR). This approach provides evidence of what is important to stakeholders and promotes meaningful corporate disclosure, central to the Global Reporting Initiative. This study reports on a materiality analysis of the cruise industry, comparing stakeholder concerns/demands with both the relevant literature and existing CSR reports to determine to what extent the current industry definition of its social responsibility matches the expectations of its stakeholders, and subsequently, to theorise reasons for the patterns found. Results evidence that cruise companies tend to both over-report immaterial issues and under-report material issues, without responding to stakeholders' requests

Inhibition of Cellular Protein Secretion by Norwalk Virus Nonstructural Protein p22 Requires a Mimic of an Endoplasmic Reticulum Export Signal

Protein trafficking between the endoplasmic reticulum (ER) and Golgi apparatus is central to cellular homeostasis. ER export signals are utilized by a subset of proteins to rapidly exit the ER by direct uptake into COPII vesicles for transport to the Golgi. Norwalk virus nonstructural protein p22 contains a YXΦESDG motif that mimics a di-acidic ER export signal in both sequence and function. However, unlike normal ER export signals, the ER export signal mimic of p22 is necessary for apparent inhibition of normal COPII vesicle trafficking, which leads to Golgi disassembly and antagonism of Golgi-dependent cellular protein secretion. This is the first reported function for p22. Disassembly of the Golgi apparatus was also observed in cells replicating Norwalk virus, which may contribute to pathogenesis by interfering with cellular processes that are dependent on an intact secretory pathway. These results indicate that the ER export signal mimic is critical to the antagonistic function of p22, shown herein to be a novel antagonist of ER/Golgi trafficking. This unique and well-conserved human norovirus motif is therefore an appealing target for antiviral drug development

Pathogenicity and virulence of Hepatitis A virus.

Hepatitis A is an acute infection of the liver, which is mostly asymptomatic in children and increases the severity with age. Although in most patients the infection resolves completely, in a few of them it may follow a prolonged or relapsed course or even a fulminant form. The reason for these different outcomes is unknown, but it is generally accepted that host factors such as the immunological status, age and the occurrence of underlaying hepatic diseases are the main determinants of the severity. However, it cannot be ruled out that some virus traits may also contribute to the severe clinical outcomes. In this review, we will analyze which genetic determinants of the virus may determine virulence, in the context of a paradigmatic virus in terms of its genomic, molecular, replicative, and evolutionary feature

Evidence for positive selection of hepatitis A virus antigenic variants in vaccinated men-having-sex-with men patients: implications for immunization policies

Background: A huge outbreak in the men-having-sex-with-men (MSM) has hit Europe during the years 2016-2018. Outbreak control has been hampered by vaccine shortages in many countries, and to minimize their impact, reduction of antigen doses has been implemented. However, these measures may have conse-quences on the evolution of hepatitis A virus (HAV), leading to the emergence of antigenic variants. Cases in vac-cinated MSM patients have been detected in Barcelona, opening the possibility to study HAV evolution under immune pressure. Methods: We performed deep-sequencing analysis of ten overlapping fragments covering the complete capsid coding region of HAV. A total of 14578255 reads were obtained and used for the analysis of virus evolution in vaccinated versus non-vaccinated patients. We estimated maximum and minimum mutation frequencies, and Shan-non entropy in the quasispecies of each patient. Non-synonymous (NSyn) mutations affecting residues exposed in the capsid surface were located, with respect to epitopes, using the recently described crystal structure of HAV, as an indication of its potential role in escaping to the effect of vaccines. Findings: HAV evolution at the quasispecies level, in non-vaccinated and vaccinated patients, revealed higher diversity in epitope-coding regions of the vaccinated group. Although amino acid replacements occurring in and around the epitopes were observed in both groups, their abundance was significantly higher in the quasispecies of vaccinated patients, indicating ongoing processes of fixation. Interpretation: Our data suggest positive selection of antigenic variants in some vaccinated patients, raising concerns for new vaccination polices directed to the MSM group

Development of an enhanced health-economic model and cost-effectiveness analysis of tiotropium + olodaterol Respimat® fixed-dose combination for chronic obstructive pulmonary disease patients in Italy

Background: The objective of this study was to compare the cost-effectiveness of the fixed-dose combination (FDC) of tiotropium + olodaterol Respimat® FDC with tiotropium alone for patients with chronic obstructive pulmonary disease (COPD) in the Italian health care setting using a newly developed patient-level Markov model that reflects the current understanding of the disease. Methods: While previously published models have largely been based around a cohort approach using a Markov structure and GOLD stage stratification, an individual-level Markov approach was selected for the new model. Using patient-level data from the twin TOnado trials assessing Tiotropium + olodaterol Respimat® FDC versus tiotropium, outcomes were modelled based on the trough forced expiratory volume (tFEV1) of over 1000 patients in each treatment arm, tracked individually at trial visits through the 52-week trial period, and after the trial period it was assumed to decline at a constant rate based on disease stage. Exacerbation risk was estimated based on a random-effects logistic regression analysis of exacerbations in UPLIFT. Mortality by age and disease stage was estimated from an analysis of TIOSPIR trial data. Cost of bronchodilators and other medications, routine management, and costs of treatment for moderate and severe exacerbations for the Italian setting were included. A cost-effectiveness analysis was conducted over a 15-year time horizon from the perspective of the Italian National Health Service. Results: Aggregating total costs and quality-adjusted life years (QALYs) for each treatment cohort over 15 years and comparing tiotropium + olodaterol Respimat® FDC with tiotropium alone, resulted in mean incremental co