Inhibition of Biofilm Formation, Quorum Sensing and Infection in Pseudomonas aeruginosa by Natural Products-Inspired Organosulfur Compounds

Using a microplate-based screening assay, the effects on Pseudomonas aeruginosa PAO1 biofilm formation of several S-substituted cysteine sulfoxides and their corresponding disulfide derivatives were evaluated. From our library of compounds, S-phenyl-L-cysteine sulfoxide and its breakdown product, diphenyl disulfide, significantly reduced the amount of biofilm formation by P. aeruginosa at levels equivalent to the active concentration of 4-nitropyridine-N-oxide (NPO) (1 mM). Unlike NPO, which is an established inhibitor of bacterial biofilms, our active compounds did not reduce planktonic cell growth and only affected biofilm formation. When used in a Drosophila-based infection model, both S-phenyl-L-cysteine sulfoxide and diphenyl disulfide significantly reduced the P. aeruginosa recovered 18 h post infection (relative to the control), and were non-lethal to the fly hosts. The possibility that the observed biofilm inhibitory effects were related to quorum sensing inhibition (QSI) was investigated using Escherichia coli-based reporters expressing P. aeruginosa lasR or rhIR response proteins, as well as an endogenous P. aeruginosa reporter from the lasI/lasR QS system. Inhibition of quorum sensing by S-phenyl-L-cysteine sulfoxide was observed in all of the reporter systems tested, whereas diphenyl disulfide did not exhibit QSI in either of the E. coli reporters, and showed very limited inhibition in the P. aeruginosa reporter. Since both compounds inhibit biofilm formation but do not show similar QSI activity, it is concluded that they may be functioning by different pathways. The hypothesis that biofilm inhibition by the two active compounds discovered in this work occurs through QSI is discussed

Variability of diagnostic criteria and treatment of idiopathic nephrotic syndrome across European countries

The aim of the surveys conducted by the Idiopathic Nephrotic Syndrome Working Group of the ESPN was to study the possible variability of treatment in Europe at different stages of the disease by means of questionnaires sent to members of the Working Group. Four surveys have been completed: treatment of the first flare, treatment of the first relapse and the issue of steroid dependency, use of rituximab, and the management of steroid-resistant patients. A uniform treatment of the first flare was applied in only three countries, and ten additional centers have adopted one of the three main protocols. Reported treatment of the first relapse was relatively uniform, whereas the use of additional immunosuppressants in steroid dependency was widely variable. Rituximab had already been used in hundreds of patients, although the formal evidence of efficiency in steroid dependency was relatively recent at the time of the survey. The definition of steroid resistance was variable in the European centers, but strikingly, the first-line treatment was uniform throughout the centers and included the combination of prednisone plus calcineurin antagonists. Conclusion: The variability in the approach of idiopathic nephrotic syndrome is unexpectedly large and affects treatment of the first flare, strategies in the case of steroid dependency, as well as the definitions of steroid resistance.What is Known:• Steroids and immunosuppressants are the universal treatment of idiopathic nephrotic syndrome.What is New:• The variability of treatments and strategy of treatment in European centers of pediatric nephrology

Effect of headgroup size, charge, and solvent structure on polymer−micelle interactions, studied by molecular dynamics simulations

We performed atomistic molecular dynamics simulations of anionic and cationic micelles in the presence of poly(ethylene oxide) (PEO) to understand why nonionic water-soluble polymers such as PEO interact strongly with anionic micelles but only weakly with cationic micelles. Our micelles include sodium n-dodecyl sulfate (SDS), n-dodecyl trimethylammonium chloride (DTAC), n-dodecyl ammonium chloride (DAC), and micelles in which we artificially reverse the sign of partial charges in SDS and DTAC. We observe that the polymer interacts hydrophobically with anionic SDS but only weakly with cationic DTAC and DAC, in agreement with experiment. However, the polymer also interacts with the artificial anionic DTAC but fails to interact hydrophobically with the artificial cationic SDS, illustrating that large headgroup size does not explain the weak polymer interaction with cationic micelles. In addition, we observe through simulation that this preference for interaction with anionic micelles still exists in a dipolar "dumbbell" solvent, indicating that water structure and hydrogen bonding alone cannot explain this preferential interaction. Our simulations suggest that direct electrostatic interactions between the micelle and polymer explain the preference for interaction with anionic micelles, even though the polymer overall carries no net charge. This is possible given the asymmetric distribution of negative charges on smaller atoms and positive charges oil larger units in the polymer chain

Alfred Russel Wallace: Self-educated genius and polymath

Alfred Russel Wallace was a Colossus: courageous, heroic, radical, modest, and above all, a man of insatiable curiosity. One hundred years on one can propose that his prescience anticipated many modern scientific developments and that despite relative neglect his far-ranging insight continues to inspire even now. His earliest memories take us to Usk in South Wales, where he was born in 1823, and many experiences there are fondly recounted as formative influences. Adolescent interest in natural history during apprenticeship to his elder brother, a land-surveyor at the dawn of the railway era in Mid Wales and the Neath valley, blossomed into a lifelong fascination with the living world. The depth and reach of his thinking on the diversity and distribution of species outpaced his contemporaries, and he became the undisputed father of biogeography. Interaction with the ‘poor farmers’ of South Wales and exposure to their humble conditions inculcated a concern for the deprivation of the underclasses, and were influential in the shaping of his societal concerns and later activism. After proposing the basic principles of speciation and of selection and arriving at a novel and original concept of evolutionary mechanisms, Wallace daringly pursued several non-scientific interests: phrenology, mesmerism, spiritualism, and the great question of whether we are alone in the cosmos. Honoured late in a long life, Wallace became regarded as one of the greatest scientists in the world, despite his enthusiasms for supernatural phenomena. Eclipsed after his passing in 1913, a gradual realisation of the depth of his mainstream science as well as premature dismissal of some of his more arcane insights continues beyond his centenary year