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.     

Improvement of Aglycone π-Stacking Yields Nanomolar to Sub-nanomolar FimH Antagonists

Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d -mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar K_D values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as ¹H,¹⁵N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.     

The Tyrosine Gate of the Bacterial Lectin FimH: A Conformational Analysis by NMR Spectroscopy and X‐ray Crystallography

Urinary tract infections caused by uropathogenic E. coli are among the most prevalent infectious diseases. The mannose‐specific lectin FimH mediates the adhesion of the bacteria to the urothelium, thus enabling host cell invasion and recurrent infections. An attractive alternative to antibiotic treatment is the development of FimH antagonists that mimic the physiological ligand. A large variety of candidate drugs have been developed and characterized by means of in vitro studies and animal models. Here we present the X‐ray co‐crystal structures of FimH with members of four antagonist classes. In three of these cases no structural data had previously been available. We used NMR spectroscopy to characterize FimH–antagonist interactions further by chemical shift perturbation. The analysis allowed a clear determination of the conformation of the tyrosine gate motif that is crucial for the interaction with aglycone moieties and was not obvious from X‐ray structural data alone. Finally, ITC experiments provided insight into the thermodynamics of antagonist binding. In conjunction with the structural information from X‐ray and NMR experiments the results provide a mechanism for the often‐observed enthalpy–entropy compensation of FimH antagonists that plays a role in fine‐tuning of the interaction.     

Transport of pollutant in shallow flows: A space–time CE/SE scheme

This paper focuses on implementation of space–time CE/SE scheme for computing the transport of a passive pollutant by a flow. The flow model comprises of the Saint-Venant system of shallow water equations and the pollutant propagation is described by a transport equation. The one-dimensional and two-dimensional flow equations are numerically investigated using the CE/SE scheme. A number of test problems are presented to check the accuracy and efficiency of the proposed scheme. The results of CE/SE scheme are compared with the central scheme. Both the schemes are found to be in close agreement. However, our proposed CE/SE scheme accurately captures shocks and discontinuous profiles.     

Solving a bi-objective cell formation problem with stochastic production quantities by a two-phase fuzzy linear programming approach

We propose a bi-objective cell formation problem with demand of products expressed in a number of probabilistic scenarios. To deal with the uncertain demand of products, a framework of two-stage stochastic programming model is presented. The proposed model considers minimizing the sum of the miscellaneous costs (machine constant cost, expected machine variable cost, cell fixed-charge cost, and expected intercell movement cost) and expected total cell loading variation. Because of conflicting objectives, we develop a two-phase fuzzy linear programming approach for solving bi-objective cell formation problem. To show the effectiveness of the proposed approach, numerical examples are solved and the results are compared with the two existing approaches in the literature. The computational results show that the proposed fuzzy method achieves lower objective functions as well as higher satisfaction degrees.     

Determining parameters of heat exchangers for heat recovery in a Cu–Cl thermochemical hydrogen production cycle

A heat exchanger is a device built for efficient heat transfer from one medium to another. Shell and tube heat exchangers are separated wall heat exchangers and are commonly used in the nuclear and process industry. The CuCl cycle is used to thermally crack water in to H₂ and O₂. The present study presents the heat exchanger thermal design using analysis of variance for heat recovery from oxygen at 500 °C, coming from the molten salt reactor. Polynomial regressions in terms of the amount of chlorine in the oxygen, the mass flow rate on the tube side, and the shell's outlet temperature are estimated for various exchanger parameters and the results are compared with the bell Delaware method. Based on energy and exergy analysis, this study also discusses the best possible path for the recovered heat from oxygen. Optimal heat exchanger parameters are estimated by Design-Expert^® Stat-Ease for most effective heat recovery.     

Preparation, Characterization and Photocatalytic Properties of Ba-Cd-Sr-Ti Doped Fe3O4 Nanohollow Spheres on Removal of Congo Red Under Visible-Light Irradiation

In this study, Ba-Cd-Sr-Ti doped Fe₃O₄ nanohollow spheres were successfully prepared via a simple solvothermal method. The crystal size, structure, morphology and elemental analysis of the as-prepared sample were investigated in detail by X-ray diffraction (XRD), FT-IR, scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) spectroscopy, respectively. Magnetic hysteresis measurement was carried out on a vibrant sample magnetometer (VSM) showing the soft ferromagnetic property at room temperature. The synthesized nanohollow spheres were employed as a photocatalyst to study the photocatalytic degradation of dye contaminations. The UV-Vis results showed that the specimen could well catalyze the decolorizing of congo red (CR) solution and a removal efficiency of 99.5 % was obtained at pH 6. The optical characteristic of the products was studied by estimating the band-gap energy based on diffuse-reflectance spectroscopy (DRS) which represented the doped magnetite with semiconductor metals to be more prone in the visible region as compared to UV region. Some factors such as initial dye concentration, pH, and contact time influencing the decomposition of CR were evaluated.     

Sensitivity Analysis to Operational Parameters of the Offset Well During Fast-SAGD Process in Naturally Fractured Reservoir

Few studies were done to investigate performance of the Fast steam-assisted gravity damage (SAGD) recovery method especially in naturally fractured reservoirs (NFR). The authors studied some cyclic steam stimulated operational parameters effects on the Fast-SAGD performance in NFR. A synthetic 2D homogenous model was constructed by Computer Modelling Group's (CMG) and simulated using the STARS module. Comparison between SAGD and Fast-SAGD recovery methods in this model shows great increase in the oil production but small increase of thermal efficiency in the Fast-SAGD recovery method. Simulation outcomes represent 17% increment in ultimate recovery factor but small reduction in steam-oil ratio. Results show that increasing the number of offset cycles and injection period yield increment in the oil production. Increasing the offset injection rate causes growth in the oil production, but has an optimal value. By increasing the distance between the offset well and SAGD well pairs up to a certain value, oil production increases but decreases after that point. This is due to the ability of the fractures in making connection between the steam chambers in higher distances. When production bottom-hole pressure decreases, the heated oil in near well region is subjected to more pressure drop and causes more oil to be produced. More offset wells result in higher production but simultaneously lower recovery factors. Increasing and decreasing soak time as the last investigated parameter did not affect the trend of production anyway.     

Efficiency assessment of a photo electrochemical chloralkali process for hydrogen and sodium hydroxide production

In present study, a new reactor configuration is developed which integrates photochemical hydrogen production with an electrochemical chloralkali process. The effects of different parameters on rate of hydrogen, chlorine and sodium hydroxide production are experimentally examined and discussed. The parameters include applied voltage, varied from 4 V to 5 V, amount of catalyst, varied from 1 g/425 mL to 4 g/425 mL, and light intensity, varied from 20 W/m² to 55 W/m². Factorial design of experiments is applied and an analysis of variance (ANOVA) is used to analyze the experimental results. Energy and exergy efficiencies are also examined. An optimization study is performed to find the optimal catalyst concentration. An optimized catalyst concentration in salty water is used to examine its effect on the rate of hydrogen production.     

SOURCE ROCK EVALUATION AND PETROLEUM GEOCHEMISTRY, OFFSHORE SW IRAN

Mesozoic and Tertiary source rocks and crude oils from six oilfields in the Persian (Arabian) Gulf (Hendijan, Bahrgansar, Abouzar, Nowruz, Dorood and Foroozan) were studied using a variety of organic-geochemical techniques. Biomarker characteristics were combined with other geochemical data to identify the source rocks which generated the oil in these fields and to reconstruct their depositional environments, and also to characterize the diagenetic and catagenic processes which have occurred. The analyzed oils show a wide range of densities (19 to 39° API) and high sulphur contents. They were generated by Type II-S organic matter; they are not biodegraded and their maturity level is generally low.
Two main oil groups were identified from statistical analysis and can be correlated with different source rocks using age-specific biomarkers and isotope data. Group 1 oils include those from the Hendijan, Bahrgansar and Abouzar fields and were probably generated by a mid-Cretaceous argillaceous source rock. Group 2 oils include those from the Nowruz, Dorood and Foroozan fields, and originated from Jurassic to Early Cretaceous carbonate-rich source rocks.