Sialylation on O-linked glycans protects von Willebrand factor from macrophage galactose lectin mediated clearance

Terminal sialylation determines the plasma half-life of von Willebrand factor (VWF). A role for macrophage galactose lectin (MGL) in regulating hyposialylated VWF clearance has recently been proposed. In this study, we showed that MGL influences physiological plasma VWF clearance. MGL inhibition was associated with a significantly extended mean residence time and 3-fold increase in endogenous plasma VWF antigen levels (P<0.05). Using a series of VWF truncations, we further demonstrated that the A1 domain of VWF is predominantly responsible for enabling the MGL interaction. Binding of both full-length and VWF-A1-A2-A3 to MGL was significantly enhanced in the presence of ristocetin (P<0.05), suggesting that the MGL-binding site in A1 is not fully accessible in globular VWF. Additional studies using different VWF glycoforms demonstrated that VWF O-linked glycans, clustered at either end of the A1 domain, play a key role in protecting VWF against MGLmediated clearance. Reduced sialylation has been associated with pathological, increased clearance of VWF in patients with von Willebrand disease. Herein, we demonstrate that specific loss of α2-3 linked sialylation from O-glycans results in markedly increased MGL-binding in vitro, and markedly enhanced MGL-mediated clearance of VWF in vivo. Our data further show that the asialoglycoprotein receptor (ASGPR) does not have a significant role in mediating the increased clearance of VWF following loss of O-sialylation. Conversely however, we observed that loss of N-linked sialylation from VWF drives enhanced circulatory clearance predominantly via the ASGPR. Collectively, our data support the hypothesis that in addition to regulating physiological VWF clearance, the MGL receptor works in tandem with ASGPR to modulate enhanced clearance of aberrantly sialylated VWF in the pathogenesis of von Willebrand disease

Development of policies and practices of social responsibility in Portuguese companies: implications of the SA8000 standard

Series: Management and Industrial EngineeringThis study aims to explore the implications of the SA8000 standard in the implementation of Corporate Social Responsibility (CSR) policies and practices in Portuguese companies. Although this is not a recent issue, it is a subject that has motivated a growing interest on the part of the business and academic community. CSR should be seen as a new business management model, which includes universal human values as well as ethical decisions that ensure the satisfaction of the interests and needs of all stakeholders and the community in general. Regarding the empirical aspect of this research, a qualitative approach was followed through the application of a semi-structured interview to certified and not certified companies by SA8000 standard, in order to understand possible disparities with regard to the implementation of CSR policies and practices. Although the certification is the guarantee of the commitment of the companies with the CSR, the truth is that this is seen by the companies as a form of differentiation in the market. In general terms, it can be concluded that the policies and practices of CSR do not differ in relation to certification, which means that all companies have the possibility of making a difference by being socially responsible.Delfina Gomes acknowledges that this study was conducted at the Research Center in Political Science (UID/CPO/0758/2019), University of Minho/University of Évora, and was supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Education and Science through national funds

Pathophysiology of acute experimental pancreatitis: Lessons from genetically engineered animal models and new molecular approaches

The incidence of acute pancreatitis is growing and worldwide population-based studies report a doubling or tripling since the 1970s. 25% of acute pancreatitis are severe and associated with histological changes of necrotizing pancreatitis. There is still no specific medical treatment for acute pancreatitis. The average mortality resides around 10%. In order to develop new specific medical treatment strategies for acute pancreatitis, a better understanding of the pathophysiology during the onset of acute pancreatitis is necessary. Since it is difficult to study the early acinar events in human pancreatitis, several animal models of acute pancreatitis have been developed. By this, it is hoped that clues into human pathophysiology become possible. In the last decade, while employing molecular biology techniques, a major progress has been made. The genome of the mouse was recently sequenced. Various strategies are possible to prove a causal effect of a single gene or protein, using either gain-of-function (i.e., overexpression of the protein of interest) or loss-of-function studies (i.e., genetic deletion of the gene of interest). The availability of transgenic mouse models and gene deletion studies has clearly increased our knowledge about the pathophysiology of acute pancreatitis and enables us to study and confirm in vitro findings in animal models. In addition, transgenic models with specific genetic deletion or overexpression of genes help in understanding the role of one specific protein in a cascade of inflammatory processes such as pancreatitis where different proteins interact and co-react. This review summarizes the recent progress in this field. Copyright (c) 2005 S. Karger AG, Basel

Estimation of PM10-bound As, Cd, Ni and Pb levels by means of statistical modelling: PLSR and ANN approaches

Air quality assessment regarding metals and metalloids using experimental measurements is expensive and time consuming due to the cost and time required for the analytical determination of the levels of these pollutants. According to the European Union (EU) Air Quality Framework Directive (Directive 2008/50/EC), other alternatives, such as objective estimation techniques, can be considered for ambient air quality assessment in zones and agglomerations where the level of pollutants is below a certain concentration value known as the lower assessment threshold. These conditions occur in urban areas in Cantabria (northern Spain). This work aims to estimate the levels of As, Cd, Ni and Pb in airborne PM10 at two urban sites in the Cantabria region (Castro Urdiales and Reinosa) using statistical models as objective estimation techniques. These models were developed based on three different approaches: partial least squares regression (PLSR), artificial neural networks (ANNs) and an alternative approach consisting of principal component analysis (PCA) coupled with ANNs (PCA-ANN). Additionally, these models were externally validated using previously unseen data. The results show that the models developed in this work based on PLSR and ANNs fulfil the EU uncertainty requirements for objective estimation techniques and provide an acceptable estimation of the mean values. As a consequence, they could be considered as an alternative to experimental measurements for air quality assessment regarding the aforementioned pollutants in the study areas while saving time and resources.The authors gratefully acknowledge the financial support from the Spanish Ministry of Economy and Competitiveness through the Project CMT2010-16068. The authors also thank the Regional Environment Ministry of the Cantabria Government for providing the PM10 samples at the Castro Urdiales and Reinosa sites

Long-Time Asymptotics for the Korteweg-de Vries Equation via Nonlinear Steepest Descent

We apply the method of nonlinear steepest descent to compute the long-time asymptotics of the Korteweg-de Vries equation for decaying initial data in the soliton and similarity region. This paper can be viewed as an expository introduction to this method.Comment: 31 page

Mining biological information from 3D short time-series gene expression data: the OPTricluster algorithm

<p>Abstract</p> <p>Background</p> <p>Nowadays, it is possible to collect expression levels of a set of genes from a set of biological samples during a series of time points. Such data have three dimensions: gene-sample-time (GST). Thus they are called 3D microarray gene expression data. To take advantage of the 3D data collected, and to fully understand the biological knowledge hidden in the GST data, novel subspace clustering algorithms have to be developed to effectively address the biological problem in the corresponding space.</p> <p>Results</p> <p>We developed a subspace clustering algorithm called Order Preserving Triclustering (OPTricluster), for 3D short time-series data mining. OPTricluster is able to identify 3D clusters with coherent evolution from a given 3D dataset using a combinatorial approach on the sample dimension, and the order preserving (OP) concept on the time dimension. The fusion of the two methodologies allows one to study similarities and differences between samples in terms of their temporal expression profile. OPTricluster has been successfully applied to four case studies: immune response in mice infected by malaria (<it>Plasmodium chabaudi</it>), systemic acquired resistance in <it>Arabidopsis thaliana</it>, similarities and differences between inner and outer cotyledon in <it>Brassica napus </it>during seed development, and to <it>Brassica napus </it>whole seed development. These studies showed that OPTricluster is robust to noise and is able to detect the similarities and differences between biological samples.</p> <p>Conclusions</p> <p>Our analysis showed that OPTricluster generally outperforms other well known clustering algorithms such as the TRICLUSTER, gTRICLUSTER and K-means; it is robust to noise and can effectively mine the biological knowledge hidden in the 3D short time-series gene expression data.</p

Honey bee foraging distance depends on month and forage type

To investigate the distances at which honey bee foragers collect nectar and pollen, we analysed 5,484 decoded waggle dances made to natural forage sites to determine monthly foraging distance for each forage type. Firstly, we found significantly fewer overall dances made for pollen (16.8 %) than for non-pollen, presumably nectar (83.2 %; P < 2.2 × 10−23). When we analysed distance against month and forage type, there was a significant interaction between the two factors, which demonstrates that in some months, one forage type is collected at farther distances, but this would reverse in other months. Overall, these data suggest that distance, as a proxy for forage availability, is not significantly and consistently driven by need for one type of forage over the other

A literature review of the predictive validity of European dental school selection methods

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.Non peer reviewedPostprin

Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism

Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery