A General, Practical Palladium-Catalyzed Cyanation of (Hetero)Aryl Chlorides and Bromides

Playing it safe: The nontoxic cyanide source K[subscript 4][Fe(CN)[subscript 6]⋅3 H[subscript 2]O can be used for the cyanation of (hetero)aryl halides. The application of palladacycle catalysts prevents poisoning during catalyst formation, thereby allowing for low catalyst loadings, fast reaction times, and wide heterocyclic substrate scope.National Institutes of Health (U.S.) (Award GM46059

Force dependent fragility in RNA hairpins

We apply Kramers theory to investigate the dissociation of multiple bonds under mechanical force and interpret experimental results for the unfolding/refolding force distributions of an RNA hairpin pulled at different loading rates using laser tweezers. We identify two different kinetic regimes depending on the range of forces explored during the unfolding and refolding process. The present approach extends the range of validity of the two-states approximation by providing a theoretical framework to reconstruct free-energy landscapes and identify force-induced structural changes in molecular transition states using single molecule pulling experiments. The method should be applicable to RNA hairpins with multiple kinetic barriers.Comment: Latex file, 4 pages+3 figure

Fractional reaction-diffusion equations

In a series of papers, Saxena, Mathai, and Haubold (2002, 2004a, 2004b) derived solutions of a number of fractional kinetic equations in terms of generalized Mittag-Leffler functions which provide the extension of the work of Haubold and Mathai (1995, 2000). The subject of the present paper is to investigate the solution of a fractional reaction-diffusion equation. The results derived are of general nature and include the results reported earlier by many authors, notably by Jespersen, Metzler, and Fogedby (1999) for anomalous diffusion and del-Castillo-Negrete, Carreras, and Lynch (2003) for reaction-diffusion systems with L\'evy flights. The solution has been developed in terms of the H-function in a compact form with the help of Laplace and Fourier transforms. Most of the results obtained are in a form suitable for numerical computation.Comment: LaTeX, 17 pages, corrected typo

Solution of generalized fractional reaction-diffusion equations

This paper deals with the investigation of a closed form solution of a generalized fractional reaction-diffusion equation. The solution of the proposed problem is developed in a compact form in terms of the H-function by the application of direct and inverse Laplace and Fourier transforms. Fractional order moments and the asymptotic expansion of the solution are also obtained.Comment: LaTeX, 18 pages, corrected typo

Exceptional Laguerre and Jacobi polynomials and the corresponding potentials through Darboux-Crum Transformations

Simple derivation is presented of the four families of infinitely many shape invariant Hamiltonians corresponding to the exceptional Laguerre and Jacobi polynomials. Darboux-Crum transformations are applied to connect the well-known shape invariant Hamiltonians of the radial oscillator and the Darboux-P\"oschl-Teller potential to the shape invariant potentials of Odake-Sasaki. Dutta and Roy derived the two lowest members of the exceptional Laguerre polynomials by this method. The method is expanded to its full generality and many other ramifications, including the aspects of generalised Bochner problem and the bispectral property of the exceptional orthogonal polynomials, are discussed.Comment: LaTeX2e with amsmath, amssymb, amscd 26 pages, no figure

Estimation of the spontaneous mutation rate in Heliconius melpomene

This is the final published version. It first appeared at mbe.oxfordjournals.org/content/early/2014/11/03/molbev.msu302.abstract.We estimated the spontaneous mutation rate in Heliconius melpomene by genome sequencing of\ud a pair of parents and 30 of their offspring, based on the ratio of number of de novo heterozygotes\ud to the number of callable site-individuals. We detected nine new mutations, each one affecting a\ud single site in a single offspring. This yields an estimated mutation rate of 2.9 x 10-9 (95%\ud confidence interval, 1.3 x 10-9 - 5.5 x 10-9), which is similar to recent estimates in Drosophila\ud melanogaster, the only other insect species in which the mutation rate has been directly estimated.\ud We infer that recent effective population size of H. melpomene is about 2 million, a substantially\ud lower value than its census size, suggesting a role for natural selection reducing diversity. We\ud estimate that H. melpomene diverged from its M?llerian co-mimic H. erato about 6 MYA, a\ud somewhat later date than estimates based on a local molecular clock.CJ was funded by BBSRC [H01439X/1], JWD was funded by the Herchel Smith Fund and PDK and\ud RWN were funded by the BBSRC

Activation of TRPA1 by membrane permeable local anesthetics

<p>Abstract</p> <p>Background</p> <p>Low concentrations of local anesthetics (LAs) suppress cellular excitability by inhibiting voltage-gated Na⁺channels. In contrast, LAs at high concentrations can be excitatory and neurotoxic. We recently demonstrated that LA-evoked activation of sensory neurons is mediated by the capsaicin receptor TRPV1, and, to a lesser extent by the irritant receptor TRPA1. LA-induced activation and sensitization of TRPV1 involves a domain that is similar, but not identical to the vanilloid-binding domain. Additionally, activation of TRPV1 by LAs involves PLC and PI(4,5)P₂-signalling. In the present study we aimed to characterize essential structural determinants for LA-evoked activation of TRPA1.</p> <p>Results</p> <p>Recombinant rodent and human TRPA1 were expressed in HEK293t cells and investigated by means of whole-cell patch clamp recordings. The LA lidocaine activates TRPA1 in a concentration-dependent manner. The membrane impermeable lidocaine-derivative QX-314 is inactive when applied extracellularly. Lidocaine-activated TRPA1-currents are blocked by the TRPA1-antagonist HC-030031. Lidocaine is also an inhibitor of TRPA1, an effect that is more obvious in rodent than in human TRPA1. This species-specific difference is linked to the pore region (transmembrane domain 5 and 6) as described for activation of TRPA1 by menthol. Unlike menthol-sensitivity however, lidocaine-sensitivity is not similarly determined by serine- and threonine-residues within TM5. Instead, intracellular cysteine residues known to be covalently bound by reactive TRPA1-agonists seem to mediate activation of TRPA1 by LAs.</p> <p>Conclusions</p> <p>The structural determinants involved in activation of TRPA1 by LAs are disparate from those involved in activation by menthol or those involved in activation of TRPV1 by LAs.</p

Acidosis Activation of the Proton-Sensing GPR4 Receptor Stimulates Vascular Endothelial Cell Inflammatory Responses Revealed by Transcriptome Analysis

Acidic tissue microenvironment commonly exists in inflammatory diseases, tumors, ischemic organs, sickle cell disease, and many other pathological conditions due to hypoxia, glycolytic cell metabolism and deficient blood perfusion. However, the molecular mechanisms by which cells sense and respond to the acidic microenvironment are not well understood. GPR4 is a proton-sensing receptor expressed in endothelial cells and other cell types. The receptor is fully activated by acidic extracellular pH but exhibits lesser activity at the physiological pH 7.4 and minimal activity at more alkaline pH. To delineate the function and signaling pathways of GPR4 activation by acidosis in endothelial cells, we compared the global gene expression of the acidosis response in primary human umbilical vein endothelial cells (HUVEC) with varying level of GPR4. The results demonstrated that acidosis activation of GPR4 in HUVEC substantially increased the expression of a number of inflammatory genes such as chemokines, cytokines, adhesion molecules, NF-κB pathway genes, and prostaglandin-endoperoxidase synthase 2 (PTGS2 or COX-2) and stress response genes such as ATF3 and DDIT3 (CHOP). Similar GPR4-mediated acidosis induction of the inflammatory genes was also noted in other types of endothelial cells including human lung microvascular endothelial cells and pulmonary artery endothelial cells. Further analyses indicated that the NF-κB pathway was important for the acidosis/GPR4-induced inflammatory gene expression. Moreover, acidosis activation of GPR4 increased the adhesion of HUVEC to U937 monocytic cells under a flow condition. Importantly, treatment with a recently identified GPR4 antagonist significantly reduced the acidosis/GPR4-mediated endothelial cell inflammatory response. Taken together, these results show that activation of GPR4 by acidosis stimulates the expression of a wide range of inflammatory genes in endothelial cells. Such inflammatory response can be suppressed by GPR4 small molecule inhibitors and hold potential therapeutic value

Snowier Winters Extend Autumn Availability of High-quality Forage for Caribou in Arctic Alaska

Caribou (Rangifer tarandus) rely on the short Arctic growing season to restore body condition, support the demands of lactation, and prepare for the long arctic winter, making them susceptible to even small changes in forage availability or quality. Body condition in the summer and autumn is linked to winter survival rates and fecundity in cows, critical factors in the productivity of caribou populations. Climate change predictions of warmer and wetter northern winters suggest increased snowfall over Alaska’s North Slope, which has recently been verified between 1995 and 2017. However, a comprehensive analysis of how deeper snow will affect caribou forage quality is absent across Alaska. In this study, we quantify how snow depth alters the quality and seasonality of caribou forage using a long-term (24 yr) International Tundra Experiment snow depth manipulation to evaluate how winter climate change scenarios may affect tussock tundra systems in northern Alaska. Deeper snow in prior winters leads to increases in growing season leaf N and digestible protein (DP) in deciduous shrubs (and Betula spp.) and graminoids (Carex spp. and Eriophorum spp.), but not evergreen dwarf shrubs (Rhododendron spp. and Vaccinium spp.). Dry matter digestibility varied among species with small differences (\u3c5%) associated with snow depth. Most striking was the discovery that deeper snow in the prior winter increased the duration of DP levels above the minimum threshold for protein gain in caribou by as much as 25 d in Salix pulchra and 6–9 d in Betula nana and Carex bigelowii in late summer and early autumn. Consequently, deeper winter snow may provide an extended window of opportunity for foraging and the accumulation of lean body mass and fat reserves which promote winter survival and successful calving the following spring and potentially improve the productivity of caribou in northern Alaska