A Potent Mimetic of the Siglec-8 Ligand 6’-Sulfo-Sialyl Lewisx

Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewis^x has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewis^x and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.     

Influence of two-step process and of different stoichiometric ratios on morphologies generated in castor oil epoxy resins

Phase separation during polymerization was studied in a model system consisting of a diepoxide based on diglycidyl ether of bisphenol A (DGEBA), variable amounts of ethylenediamine (EDA) and the mass of castor oil (CO) necessary to obtain a mass fraction equal to 0-15 in a final system where the stoichiometric ratio of amine to epoxy equivalents, r, was equal to 1. A two-step polymerization process was performed by curing first a system with r = 0-5, during variable times before phase separation, and then carrying the system to r = 1. Thermodynamic analysis of samples with different r values led to a linear relationship between the Flory-Huggins interaction parameter and r. The concentration (P) and average size (D?) of dispersed-phase particles followed opposite trends, i.e. P increased while D? decreased, when either r was increased or the time of curing in the first step of a two-step process was decreased. This was explained by assuming that the competition between nucleation and growth was determined by the viscosity at the cloud point, η_cp. Low values of η_cp favoured growth over nucleation and led to fewer but larger particles.     

Evidence for a Negative Correlation between Human Reactive Enamine-Imine Intermediate Deaminase A (RIDA) Activity and Cell Proliferation Rate: Role of Lysine Succinylation of RIDA

Reactive intermediate deaminase (Rid) proteins are enzymes conserved in all domains of life. UK114, a mammalian member of RidA subfamily, has been firstly identified as a component of liver perchloric acid-soluble proteins (L-PSP). Although still poorly defined, several functions have been attributed to the mammalian protein UK114/RIDA, including the reactive intermediate deamination activity. The expression of UK114/RIDA has been observed in some tumors, arousing interest in this protein as an evaluable tumor marker. However, other studies reported a negative correlation between UK114/RIDA expression, tumor differentiation degree and cell proliferation. This work addressed the question of UK114/RIDA expression in human non-tumor HEK293 cell lines and in some human tumor cell lines. Here we reported that human RIDA (hRIDA) was expressed in all the analyzed cell line and subjected to lysine (K-)succinylation. In HEK293, hRIDA K-succinylation was negatively correlated to the cell proliferation rate and was under the control of SIRT5. Moreover, K-succinylation clearly altered hRIDA quantification by immunoblotting, explaining, at least in part, some discrepancies about RIDA expression reported in previous studies. We found that hRIDA was able to deaminate reactive enamine-imine intermediates and that K-succinylation drastically reduced deaminase activity. As predicted by in silico analysis, the observed reduction of deaminase activity has been related to the drastic alterations of hRIDA structure inferred by K-succinylation. The role of hRIDA and the importance of its K-succinylation in cell metabolism, especially in cancer biology, have been discussed.     

Cure kinetics and shrinkage model for epoxy-amine systems

Manufacture of most of epoxy resins implies that cure needs to be carried out under pressure. Due to the significance of knowing the influence of the pressure factor in cure kinetics, cure shrinkage of a stoichiometric epoxy-amine system was measured using a pressure-volume-temperature (PVT) analyzer. Recording the specific volume change in the range of temperature from 100 to 180 °C and a pressure of 200 bar we could model the cure kinetics. The Runge-Kutta method was applied to obtain the kinetic constants of the cure reaction. In addition, using the differential scanning calorimeter (DSC) for measurements of 1 bar and the PVT analyzer for pressures of 200, 400, and 600 bar, we also model the kinetic constants as a function of pressure. The results obtained show that the effect of the temperature on the kinetic constants is higher than the effect of pressure. Therefore, both PVT and DSC are complementary techniques to describe the full range of cure kinetic process of epoxy mixtures.     

Titans’ revenge: Detecting Zeus via its own flaws

Malware is one of the main threats to the Internet security in general, and to commercial transactions in particular. However, given the high level of sophistication reached by malware (e.g. usage of encrypted payload and obfuscation techniques), malware detection tools and techniques still call for effective and efficient solutions. In this paper, we address a specific, dreadful, and widely diffused financial malware: Zeus.The contributions of this paper are manifold: first, we propose a technique to break the encrypted malware communications, extracting the keystream used to encrypt such communications; second, we provide a generalization of the proposed keystream extraction technique. Further, we propose Cronus, an IDS that specifically targets Zeus malware. The implementation of Cronus has been experimentally tested on a production network, and its high quality performance and effectiveness are discussed. Finally, we highlight some principles underlying malware—and Zeus in particular—that could pave the way for further investigation in this field.     

Geographical characterisation of honeys according to their mineral content and antioxidant activity using a chemometric approach

In this article, discrimination models are presented, relating the origin of honey samples to several variables, being the concentrations of different cations and anions in the honey samples measured by ion chromatography, and parameters that measure/reflect the antioxidant activity of the honey samples. The unsupervised method, principal component analysis, and supervised discrimination methods, such as linear and quadratic discriminant analysis, and classification and regression trees (CART), were applied to evaluate the existence of data patterns and the relationship between geographical origin and the measured parameters. The model with the best predictive ability (%CCR_TEST = 66.67%), the best overall % specificity (80%) and the best overall % sensitivity (67%) was found to be CART. It was proven that the mineral content and parameters analysed can provide enough information for the geographical characterisation and discrimination of honey.     

Eco-efficiency of the world cement industry: A data envelopment analysis

Chemical reactions and the combustion of dirty fuels, such as coal and petroleum coke (petcoke), that are used in cement production processes generate a significant amount of CO₂ emissions. In this paper, we provide an eco-efficiency measure for 21 prototypes of cement industries operating in many countries by applying both a data envelopment analysis (DEA) and a directional distance function approach, which are particularly suitable for models where several production inputs and desirable and undesirable outputs are taken into account. To understand whether this eco-efficiency is due to a rational utilization of inputs or to a real carbon dioxide reduction as a consequence of environmental regulation, we analyze the cases where CO₂ emissions can either be considered as an input or as an undesirable output. Empirical results show that countries where cement industries invest in technologically advanced kilns and adopt alternative fuels and raw materials in their production processes are eco-efficient. This gives a comparative advantage to emerging countries, such as India and China, which are incentivized to modernize their production processes.     

Cure of epoxy resins containing epoxidized polyols

A commercial epoxy resin, consisting of a mixture of diepoxides based on diglycidyl ether of bisphenol-A (DGEBA) and containing an epoxidized polypropylene glycol as reactive diluent, was characterized by ¹HNMR, FTIR, SEC, and chemical analysis. The kinetics of the cure with ethylenediamine (EDA) was catalyzed by the (OH) groups present in a large amount in the commercial formulation. A second order kinetic behavior gave an accurate fitting of results obtained by different experimental techniques (DSC in dynamic and isothermal modes and SEC in the pregel stage). The activation energy was E = 59.1 kJ/mol (14.1 kcal/mol), in very close agreement with values reported for the catalytic mechanism of the DGEBA-EDA polymerization. From the gel conversion and the critical stoichiometric ratio for samples containing an epoxy excess it was found that the average functionality of epoxidized species was f = 1.58.     

Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relationships between the Immune System and Diseases

Over the last 10 years, the evaluation of the neutrophil-to-lymphocyte ratio (NLR) as an emerging marker of diseases has become a compelling field of bio-medical research. Although a precise and unique cut-off value has not been yet found, its role as a flag of immune system homeostasis is well established. NLR has a well-known prognostic value and independently correlates with mortality in the general population and in several specific subsets of disease (sepsis, pneumonia, COVID-19, cancer, etc.). Moreover, NLR was recently considered as part of the decision-making processes concerning the admission/recovery of patients with COVID-19 pneumonia. This review aims to provide an overview of the main use of this biomarker, focusing on the pathophysiology and the molecular basis underlying its central role as a reliable mirror of inflammatory status and adaptive immunity.