pH-Potentiometric Investigation towards Chelating Tendencies of p-Hydroquinone and Phenol Iminodiacetate Copper(II) Complexes

Copper ions in the active sites of several proteins/enzymes interact with phenols and quinones, and this interaction is associated to the reactivity of the enzymes. In this study the speciation of the Cu2+ with iminodiacetic phenolate/hydroquinonate ligands has been examined by pH-potentiometry. The results reveal that the iminodiacetic phenol ligand forms mononuclear complexes with Cu2+ at acidic and alkaline pHs, and a binuclear Ophenolate-bridged complex at pH range from 7 to 8.5. The binucleating hydroquinone ligand forms only 2 : 1 metal to ligand complexes in solution. The pK values of the protonation of the phenolate oxygen of the two ligands are reduced about 2 units after complexation with the metal ion and are close to the pK values for the copper-interacting tyrosine phenol oxygen in copper enzymes

The goals of EU competition law: a comprehensive empirical investigation

For any field of law, the goal it was designed to achieve permeates every aspect of its application and interpretation. This is particularly true when the black letter of the law is cryptic and silent on most aspects of how it should be interpreted and applied, as is the case with competition law, which for the most part revolves around a small number of highly abstract provisions. It is only natural then that ample scholarly work has been devoted to identifying the goals and purposes of competition law. By and large these attempts have been textual, historical, and teleological. We introduce here instead a quantitative analysis of the case law and present the results of the first empirical study into the goals and purposes of EU competition law as they emerge from the entirety of the case law of the European Court of Justice, opinions of the Advocate Generals, Commission decisions, and speeches of Commissioners for Competition. This body of almost 4,000 sources paints a comprehensive picture of the underlying goals of EU competition law, and helps conclusively confirm some previous insights while debunking others, thereby helping to advance the present application and future evolution of competition law

Synthesis, Solution, and Structural Characterization of Tetrahydrofuranyl-2,2-Bisphosphonic Acid Disodium Salt

Bisphosphonates are biologically relevant therapeutics for bone disorders and cancer. Reaction of γ-chlorobutyric acid, phosphorus acid, and phosphorus trichloride without the use of solvent gave the tetrahydrofuranyl-2,2-bisphosphonate sodium salt (Na2H2L). The Na2H2L was isolated, characterized in solution by 1H, 13C, and 31P NMR spectroscopy and in solid state by single X-Ray crystallography. The crystal structure showed that the Na2H2L forms in the crystal infinite two-dimensional sheets stacked one parallel to the other. A comparison of the chelating properties of H2L2− with similar hydroxyl bisphosphonate ligands shows that the strength of the Na–O(furanyl/hydroxyl) bond is directly related to the total charge of the ligand anion

Phenol-Soluble Modulin α Peptide Toxins from Aggressive Staphylococcus aureus Induce Rapid Formation of Neutrophil Extracellular Traps through a Reactive Oxygen Species-Independent Pathway

Neutrophils have the ability to capture and kill microbes extracellularly through the formation of neutrophil extracellular traps (NETs). These are DNA and protein structures that neutrophils release extracellularly and are believed to function as a defense mechanism against microbes. The classic NET formation process, triggered by, e.g., bacteria, fungi, or by direct stimulation of protein kinase C through phorbol myristate acetate, is an active process that takes several hours and relies on the production of reactive oxygen species (ROS) that are further modified by myeloperoxidase (MPO). We show here that NET-like structures can also be formed by neutrophils after interaction with phenol-soluble modulin α (PSMα) that are cytotoxic membrane-disturbing peptides, secreted from community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The PSMα-induced NETs contained the typical protein markers and were able to capture microbes. The PSMα-induced NET structures were disintegrated upon prolonged exposure to DNase-positive S. aureus but not on exposure to DNase-negative Candida albicans. Opposed to classic NETosis, PSMα-triggered NET formation occurred very rapidly, independently of ROS or MPO, and was also manifest at 4°C. These data indicate that rapid NETs release may result from cytotoxic membrane disturbance by PSMα peptides, a process that may be of importance for CA-MRSA virulence

Pharmaceutical And Immunollogical Challenge Of Fungal Pathogens

Incidences of fungal infections are on the rise in immunosuppressed people. Predominant causative agents for these mycoses are species of the genus Candida, including Candida albicans, Candida glabrata and Candida dublieniensis. Despite a wide range of emerging pathogens, C. albicans remains the leading cause. According to recent epidemiological studies, blood stream infections with C. albicans cause annually ~55% mortality in approximately 300,000 patients from intensive care units worldwide. Furthermore, the percentage of morbidity linked to oral, esophageal and vulvovaginal mycoses cause by C. albicans reach up to 90%. Reasons for these medical concerns are the lack of efficient diagnostics and antifungal therapy. Here, we therefore sought to find novel antifungal strategies inspired by innate immune cells, such as neutrophils. These phagocytes are able to block the fungal pathogenicity. Neutrophils are bloodstream leukocytes serving as the first line of defense against pathogenic microbes. It has been shown that neutrophils have a strong antifungal activity by impairing the conversion of the dimorphic C. albicans from yeast to hyphal form (Y-H). Consequently, we raised the question whether other immune cells, such as mast cells, with less phagocytic cabapilities may have similar activity to neutrophils. Mast cells are tissue-dwelling cells. Mucosal tissue is rich in mast cells and usually constitutes the entry ports for fungal pathogens into the human body. A contribution of mast cells in antifungal defense is, thus, very likely. We human explored mast cell functions upon encounter with fungal pathogens. Interestingly, human mast cells show a transient potential to impair fungal viability. To understand the mechanism behind this impairment we analyzed the human mast cell functions in more detail. We found that human mast cells challenged with C. albicans, immediately degranulate and secrete distinct cytokines and chemokines in an orchestrated manner. The chemokines secreted attract neutrophils. Mast cells moreover are able to internalize fungal cells and to ‘commit suicide’ by releasing extracellular DNA traps that ensnare the pathogen.   The effectiveness of future antifungals is depended on targeting the pathogen virulence with more efficiency. The dimorphism of C. albicans is proven to be essential its virulence. Blockage of this switching ability could render the pathogen avirulent. Consequently, we screened for compounds that mimic the neutrophils anti-dimorphic activity by screening small chemical molecule libraries that block Y-H transition. The screening of big chemical libraries requires a reliable, reproducible and rapid high-throughput screening assay (HTS). We developed an HTS assay based on automated microscopy and image analysis, thereby allowing to distinguish between yeast and filamentous forms. In order to find the ideal Y-H blocker, we also evaluated the cell viability via the count of ATP levels when challenged with the respective small chemical molecules.   Drug development is an elaborate and expensive process. We therefore applied our screening setup to identify antidimorphic/antifungal activity in compounds from two different chemical libraries including FDA-approved drugs. The study disclosed 7 off-patent antifungal drugs that have potent antimycotic activity, including 4 neoplastic agents, 2 antipsychotic drugs and 1 antianemic medication. In a nutshell, we aimed to mimic the anti-dimorphic/antifungal activity of neutrophils with small chemical molecules. Furthermore, we elucidated how immune cells contribute to antifungal defense to exploit these mechanisms for the development of novel antifungal therapies. Thus, this thesis provides novel tools for the discovery of more efficient compounds, identifies previously unknown antifungal aspect of off-patent FDA-approved drugs and highlights the interplay of mast cells with pathogenic fungi with the aim to define new screening strategies

g-Social: Enhancing Integrated e-Science Tools with Social Networking Functionality

During the last decade, the scientific community has witnessed an unprecedented deployment of large-scale, federated e-Infrastructures such as Grid Computing, primarily for supporting data-intensive scientific exploration and coordinated problem solving. However, practical experience and user studies have indicated that the adoption of such e-Infrastructures is lagging behind original expectations, a fact which is mainly attributed to the limited support that available tools provide for user collaboration and information sharing. The goal of this paper is twofold, first to lay down the foundations for building a collaboration environment in the form of abstractions and second to show the effectiveness of these abstractions through g-Social, an Eclipse-based, open-source environment as an extension to g-Eclipse, that provides a powerful, user-friendly, platform-independent toolset for users, application developers and administrators of Grid infrastructures. g-Social enables user collaboration and resource sharing through Online Social Networking services, capitalizing on the success that these services have

NMR characterization and dynamics of vanadium(V) complexes with tripod (hydroquinonate/phenolate) iminodiacetate ligands in aqueous solution

Reaction of NH 4VO 3 with (phenolate/hydroquinonate) iminodiacetate tripod ligands in aqueous solution in the pH range 7-8 results in the isolation of three new dioxido vanadium(V) complexes, one dinuclear (NH 4) 4{(V VO) 2[μ-bicah(6-)-N,O,O, O]}.8H 2O, (H 6bicah, 2,5-bis[N,N'-bis(carboxymethyl) aminomethyl]-hydroquinone), and two mono - nuclear (NH 4) 2{(V VO) 2[Hcah(3-)-N,O,O,O].2H 2O, (H 4cah, 2-[N,N'-bis(carboxy - methyl)aminomethyl]-hydroquinone) and (NH 4) 2{(V VO)[Hcacp(3-)-N,O,O,O]} 4H 2O, (H 4cacp, 2-[N,N'-bis(carboxymethyl)aminomethyl]-4- carboxyphenol). The 51V, 1H, and 13C NMR spectra in D 2O show the coordination environment of vanadium in the above complexes to be octahedral, with four out of six positions to be occupied by the two carboxylate oxygen, one hydroquinonate oxygen, and one amine nitrogen atoms of the tripod ligand. The two acetate arms are in cis position to each other. Variable-temperature 1H and 13C NMR measure ments show that the complexes are kinetically labile. An intramolecular exchange that proceeds through the opening of the phenolate/hydroquinonate chelate ring has been revealed by 2D{ 1H} NMR EXSY (exchange spectroscopy