Synthesis and AcidBase Properties of an Imidazole-Containing Nucleotide Analog, 1-(2'-Deoxy-β-D-ribofuranosyl)imidazole 5'-Monophosphate (dImMP(2-) )

Deletion of the substituted pyrimidine ring in purine-2'-deoxynucleoside 5'-monophosphates leads to the artificial nucleotide analog dImMP(2-) . This analog can be incorporated into DNA to yield, upon addition of Ag(+) ions, a molecular wire. Here, we measured the acidity constants of H(2) (dImMP)(±) having one proton at N(3) and one at the PO$\rm{{_{3}^{2-}}}$ group by potentiometric pH titrations in aqueous solution. The micro acidity constants show that N(3) is somewhat more basic than PO$\rm{{_{3}^{2-}}}$ and, consequently, the (H??dImMP)(-) tautomer with the proton at N(3) dominates to ca. 75%. The calculated micro acidity constants are confirmed by (31) P- and (1) H-NMR chemical shifts. The assembled data allow many quantitative comparisons, e.g., the N(3)-protonated and thus positively charged imidazole residue facilitates deprotonation of the P(O)(2) (OH)(-) group by 0.3?pK units. Information on the intrinsic site basicities also allows predictions about metal-ion binding; e.g., Mg(2+) and Mn(2+) will primarily coordinate to the phosphate group, whereas Ni(2+) and Cu(2+) will preferably bind to N(3). Macrochelate formation for these metal ions is also predicted. The micro acidity constant for N(3)H(+) deprotonation in the (H???dImMP?H)(±) species (pk(a) 6.46) and the M(n+) -binding properties are of relevance for understanding the behavior of dImMP units present in DNA hairpins and metalated duplexes.     

A new pycnidial fungus with clamped hyphae from Central America

A fungus forming white gelatinous pycnidia on rotting wood was collected in Panama. The presence of hyphal clamps and dolipores with continuous parenthesomes indicates that the fungus belongs to the Basidiomycota, Agaricomycotina. In a phylogenetic hypothesis inferred from DNA sequence analysis, the species shows a close relationship with members of the Auriculariales. A new genus and species is described in order to accommodate this anamorph, being the first taxon of the Auriculariales to be known which forms pycnidia.     

Choline-releasing glycerophosphodiesterase EDI3 links the tumor metabolome to signaling network activities

Recently, EDI3 was identified as a key factor for choline metabolism that controls tumor cell migration and is associated with metastasis in endometrial carcinomas. EDI3 cleaves glycerophosphocholine (GPC) to form choline and glycerol-3-phosphate (G3P). Choline is then further metabolized to phosphatidylcholine (PtdC), the major lipid in membranes and a key player in membrane-mediated cell signaling. The second product, G3P, is a precursor molecule for several lipids with central roles in signaling, for example lysophosphatidic acid (LPA), phosphatidic acid (PA) and diacylglycerol (DAG). LPA activates intracellular signaling pathways by binding to specific LPA receptors, including membrane-bound G protein-coupled receptors and the intracellular nuclear receptor, PPARγ. Conversely, PA and DAG mediate signaling by acting as lipid anchors that bind and activate several signaling proteins. For example, binding of GTPases and PKC to PA and DAG, respectively, increases the activation of signaling networks, mediating processes such as migration, adhesion, proliferation or anti-apoptosis—all relevant for tumor development. We present a concept by which EDI3 either directly generates signaling molecules or provides “membrane anchors” for downstream signaling factors. As a result, EDI3 links choline metabolism to signaling activities resulting in a more malignant phenotype.     

Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go?

In this review we discuss recent progress in the development, testing, and clinical evaluation of new vaccines against tuberculosis (TB). Over the last 20 years, tremendous progress has been made in TB vaccine research and development: from a pipeline virtually empty of new TB candidate vaccines in the early 1990s, to an era in which a dozen novel TB vaccine candidates have been and are being evaluated in human clinical trials. In addition, innovative approaches are being pursued to further improve existing vaccines, as well as discover new ones. Thus, there is good reason for optimism in the field of TB vaccines that it will be possible to develop better vaccines than BCG, which is still the only vaccine available against TB.     

Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation

Smyd3 is a lysine methyltransferase implicated in chromatin and cancer regulation. Here we show that Smyd3 catalyzes histone H4 methylation at lysine 5 (H4K5me). This novel histone methylation mark is detected in diverse cell types and its formation is attenuated by depletion of Smyd3 protein. Further, Smyd3-driven cancer cell phenotypes require its enzymatic activity. Thus, Smyd3, via H4K5 methylation, provides a potential new link between chromatin dynamics and neoplastic disease.     

Shear-induced Crystal Structure Formation in Milk Fat and Blends with Rapeseed Oil

The effect of shear on the rheological properties of anhydrous milk fat (AMF) and blends added 10?C30 w/w% rapeseed oil (RO) was studied. Shear was applied during early crystallization, and the complex modulus |G*| was measured during the final isothermal crystallization. The firmest and most rapidly formed network was achieved when an intermediate shear of 50?s^?1 was applied, and at this shear rate, up to 20?% RO could be added without lowering the final |G*| compared to pure AMF. A similar effect was not obtained at lower or higher shear rates. Solid fat content was unaffected by shear, while fat crystal size decreased upon increasing shear rate. The study indicates that intermediate shear produces a continuous and strong crystal network, while high shear breaks down the microstructure to such an extent that it is difficult to rebuild during subsequent crystallization, thus resulting in lower |G*|.     

Bioavailability of chromium(III)-supplements in rats and humans

Chromium(III) is long regarded as essential trace element but the biochemical function and even basic transport ways in the body are still unclear. For a more rational discussion on beneficial as well as toxic effects of Cr(III), we re-investigated the bioavailability of the most important oral Cr supplements by using radiolabeled compounds and whole-body-counting in rats and in the first time also in humans. The apparent absorption of (51)Cr(III) from Cr-picolinate, Cr-nicotinate, Cr-phenylalaninate, Cr-proprionate, or Cr-chloride was generally low (0.04-0.24?%) in rats with slightly higher values for Cr-chloride and -phenylalaninate. Taking a fast urine excretion into account, the true absorption of (51)Cr was clearly higher for CrPic(3) (0.99?%), probably indicating a different uptake mechanism of this rather stable organic Cr complex. The bioavailability of CrPic(3) and Cr(D: -Phen)(3), the leading compounds in actual investigations, was analysed also in human volunteer by intraindividual comparison. The apparent absorption (=Cr bioavailability) of (51)Cr from both compounds was substantially higher in humans (0.8-1?%) than in rats. Again, most of freshly absorbed CrPic(3) was excreted into the urine resulting in the same low whole-body retention after 7?days for both compounds. In summary, the bioavailability of Cr from pharmaceutical Cr compound is lower than hitherto assumed. Importantly, humans absorb Cr(III) clearly better than rats. The absorption mechanism of CrPic(3) seems to be different from ionic Cr(III) but, as only the same low amount of Cr is retained from this compound, it is also not more bioavailable than other Cr compounds.     

β-Barrel Mobility Underlies Closure of the Voltage-Dependent Anion Channel

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Highlights? The rigid N-terminal helix of VDAC stabilizes the cylindrical β-barrel ? Removal of the helix leads to elliptical, semicollapsed pore shapes ? Semicollapse can quantitatively explain conductance and selectivity of closed VDAC ? The N terminus acts as a switch controlling VDAC entry into the closed state     

Habitat stability affects dispersal and the ability to track climate change

Habitat persistence should influence dispersal ability, selecting for stronger dispersal in habitats of lower temporal stability. As standing (lentic) freshwater habitats are on average less persistent over time than running (lotic) habitats, lentic species should show higher dispersal abilities than lotic species. Assuming that climate is an important determinant of species distributions, we hypothesize that lentic species should have distributions that are closer to equilibrium with current climate, and should more rapidly track climatic changes. We tested these hypotheses using datasets from 1988 and 2006 containing all European dragon- and damselfly species. Bioclimatic envelope models showed that lentic species were closer to climatic equilibrium than lotic species. Furthermore, the models over-predicted lotic species ranges more strongly than lentic species ranges, indicating that lentic species track climatic changes more rapidly than lotic species. These results are consistent with the proposed hypothesis that habitat persistence affects the evolution of dispersal.