Evolution of specialized microbial cooperation in dynamic fluids

Here, we study the evolution of specialization using realistic computer simulations of bacteria that secrete two public goods in a dynamic fluid. Through this first‐principles approach, we find physical factors such as diffusion, flow patterns and decay rates are as influential as fitness economics in governing the evolution of community structure, to the extent that when mechanical factors are taken into account, (a) generalist communities can resist becoming specialists despite the invasion fitness of specialization; (b) generalist and specialists can both resist cheaters despite the invasion fitness of free‐riding; and (c) multiple community structures can coexist despite the opposing force of competitive exclusion. Our results emphasize the role of spatial assortment and physical forces on niche partitioning and the evolution of diverse community structures.     

Acid-base effects on intestinal Na(+) absorption and vesicular trafficking

We examined for vesicular traffickingof the Na⁺/H⁺ exchanger (NHE) in pH-stimulatedileal and CO₂-stimulated colonic Na⁺absorption. Subapical vesicles in rat distal ileum were quantified bytransmission electron microscopy at ×27,500 magnification. Internalization of ileal apical membranes labeled withFITC-phytohemagglutinin was assessed using confocal microscopy, andpH-stimulated ileal Na⁺ absorption was measured afterexposure to wortmannin. Apical membrane protein biotinylation of ilealand colonic segments and Western blots of recovered proteins wereperformed. In ileal epithelial cells incubated inHCO/Ringer or HEPES/Ringer solution, the number ofsubapical vesicles, the relative quantity of apical membrane NHEisoforms 2 and 3 (NHE2 and NHE3, respectively), and apical membranefluorescence under the confocal microscope were not affected by pHvalues between 7.1 and 7.6. Wortmannin did not inhibit pH-stimulatedileal Na⁺ absorption. In colonic epithelial apicalmembranes, NHE3 protein content was greater at aPCO₂ value of 70 than 21 mmHg, was internalized when PCO₂ was reduced, and was exocytosed whenPCO₂ was increased. We conclude that vesicletrafficking plays no part in pH-stimulated ileal Na⁺absorption but is important in CO₂-stimulated colonicNa⁺ absorption.

     

A solid-phase approach towards the synthesis of PDE5 inhibitors

PDE5 inhibitors based upon the xanthine scaffold 8 have been expediently synthesized using a solid-phase route. Attachment of the xanthine scaffold 8 using the Rink chloride linker 4 and N-1 functionalization using Mitsunobu chemistry is described. A library of compounds was produced in multi-milligram quantities with excellent purities and acceptable yields. The compounds were tested for their PDE5 inhibitory activity.     

Cdk5 is essential for synaptic vesicle endocytosis

Synaptic vesicle endocytosis (SVE) is triggered by calcineurin-mediated dephosphorylation of the dephosphin proteins. SVE is maintained by the subsequent rephosphorylation of the dephosphins by unidentified protein kinases. Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE. Thus Cdk5 has an essential role in SVE and is the first dephosphin kinase identified in nerve terminals.     

A combinatorial approach to the synthesis of cystine based organogelators.

A solid-phase approach was used to prepare 20 cystine amide derivatives with disulfide bond formation resulting from an intra-site reaction between neighbouring cysteine residues. Library members were screened as potential organogelators in a range of solvent mixtures and resulted in the identification of a potent gelator able to rigidify water/DMSO mixtures at concentrations as low as 1.3 mM.     

8-Aryl xanthines potent inhibitors of phosphodiesterase 5

In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.     

Acid-base effects on intestinal Cl- absorption and vesicular trafficking

In rat ileum and colon, apical membrane exchange and net Cl^- absorption are stimulated by increases in PCO₂ or . Because changes in PCO₂ stimulate colonic Na⁺ absorption, in part, by modulating vesicular trafficking of the Na⁺/H⁺ exchanger type 3 isoform to and from the apical membrane, we examined whether changes in PCO₂ affect net Cl^- absorption by modulating vesicular trafficking of the exchanger anion exchanger (AE)1. Cl^- transport across rat distal ileum and colon was measured in the Ussing chamber, and apical membrane protein biotinylation of these segments and Western blots of recovered proteins were performed. In colonic epithelial apical membranes, AE1 protein content was greater at PCO₂ 70 mmHg than at PCO₂ 21 mmHg but was not affected by pH changes in the absence of CO₂. AE1 was internalized when PCO₂ was reduced and exocytosed when PCO₂ was increased, and both mucosal wortmannin and methazolamide inhibited exocytosis. Wortmannin also inhibited the increase in colonic Cl^- absorption caused by an increase in PCO₂. Increases in PCO₂ stimulated ileal Cl^- absorption, but wortmannin was without effect. Ileal epithelial apical membrane AE1 content was not affected by PCO₂. We conclude that CO₂ modulation of colonic, but not ileal, Cl^- absorption involves effects on vesicular trafficking of AE1. PCO₂; ileum; colon; anion exchanger 1; Na⁺/H⁺ exchanger type 3     

Preparation, X-ray crystallography and thermal decomposition of transition metal perchlorate complexes with perchlorate and 2,2′-bipyridyl ligands

Three transition metal perchlorate complexes of 2,2′-bipyridyl such as [Mn(bipy)₂(H₂O)(ClO₄)]ClO₄, [Cu(bipy)(ClO₄)₂(H₂O)₂], [Zn(bipy)₂(H₂O)](ClO₄)₂ have been prepared, and characterized by X-ray crystallography. Their thermal decomposition has been studied using iso and non-isothermal thermogravimetry (TG); differential scanning calorimetry (DSC). Kinetics parameters were evaluated by model-fitting and isoconversional methods. Their thermolytic pathways have also been suggested which involves decomposition followed by explosion. The Mn and Cu complexes decompose in single step whereas Zn complex decomposes in two steps. The coordination number of Mn and Cu atoms is found to be six and that of Zn is five. In order to evaluate the response of rapid heating, explosion delay (D_E) measurements were undertaken. The explosion delay and activation energy were found to decrease in the order: Zn > Cu > Mn.