Polyamidoamine (PAMAM) Dendrimer Conjugates of “Clickable” Agonists of the A 3 Adenosine Receptor and Coactivation of the P2Y 14 Receptor by a Tethered Nucleotide

We previously synthesized a series of potent and selective A3 adenosine receptor (AR) agonists (North-methanocarba nucleoside 5′-uronamides) containing dialkyne groups on extended adenine C2 substituents. We coupled the distal alkyne of a 2-octadiynyl nucleoside by Cu(I)-catalyzed “click” chemistry to azide-derivatized G4 (fourth-generation) PAMAM dendrimers to form triazoles. A3AR activation was preserved in these multivalent conjugates, which bound with apparent Ki 0.1–0.3 nM. They were substituted with nucleoside moieties, solely or in combination with water-solubilizing carboxylic acid groups derived from hexynoic acid. A comparison with various amide-linked dendrimers showed that triazole-linked conjugates displayed selectivity and enhanced A3AR affinity. We prepared a PAMAM dendrimer containing equiproportioned peripheral azido and amino groups for conjugation of multiple ligands. A bifunctional conjugate activated both A3 and P2Y14 receptors (via amide-linked uridine-5′-diphosphoglucuronic acid), with selectivity in comparison to other ARs and P2Y receptors. This is the first example of targeting two different GPCRs with the same dendrimer conjugate, which is intended for activation of heteromeric GPCR aggregates. Synergistic effects of activating multiple GPCRs with a single dendrimer conjugate might be useful in disease treatment

Floral gene resources from basal angiosperms for comparative genomics research

BACKGROUND: The Floral Genome Project was initiated to bridge the genomic gap between the most broadly studied plant model systems. Arabidopsis and rice, although now completely sequenced and under intensive comparative genomic investigation, are separated by at least 125 million years of evolutionary time, and cannot in isolation provide a comprehensive perspective on structural and functional aspects of flowering plant genome dynamics. Here we discuss new genomic resources available to the scientific community, comprising cDNA libraries and Expressed Sequence Tag (EST) sequences for a suite of phylogenetically basal angiosperms specifically selected to bridge the evolutionary gaps between model plants and provide insights into gene content and genome structure in the earliest flowering plants. RESULTS: Random sequencing of cDNAs from representatives of phylogenetically important eudicot, non-grass monocot, and gymnosperm lineages has so far (as of 12/1/04) generated 70,514 ESTs and 48,170 assembled unigenes. Efficient sorting of EST sequences into putative gene families based on whole Arabidopsis/rice proteome comparison has permitted ready identification of cDNA clones for finished sequencing. Preliminarily, (i) proportions of functional categories among sequenced floral genes seem representative of the entire Arabidopsis transcriptome, (ii) many known floral gene homologues have been captured, and (iii) phylogenetic analyses of ESTs are providing new insights into the process of gene family evolution in relation to the origin and diversification of the angiosperms. CONCLUSION: Initial comparisons illustrate the utility of the EST data sets toward discovery of the basic floral transcriptome. These first findings also afford the opportunity to address a number of conspicuous evolutionary genomic questions, including reproductive organ transcriptome overlap between angiosperms and gymnosperms, genome-wide duplication history, lineage-specific gene duplication and functional divergence, and analyses of adaptive molecular evolution. Since not all genes in the floral transcriptome will be associated with flowering, these EST resources will also be of interest to plant scientists working on other functions, such as photosynthesis, signal transduction, and metabolic pathways

How Global are Global Brands? An Empirical Brand Equity Analysis

The term 'global brand' has become widely used by the media and by consumers. Business week publishes annually its widely known ranking of the 'Best Global Brands' (with Coca-Cola as number 1 in the past years) and consumers on summer vacations purchase brands such as Heineken or Marlboro they are familiar with from their home country. Although media and consumers call these brands 'global' and centralized marketing departments manage these brands globally - are these 'global brands' really global? Are they really perceived everywhere in the same way by the customers? Can we talk about truly global brand equity? And if there were brand image differences between countries, which factors causes them? The authors conducted an empirical research during May and June 2009 with similarly aged University students (bachelor students at business school) in Germany (n=426) and Mexico (n=296). The goal was to identify if brand awareness rates differ between Germans and Mexicans, if the brand image of Apple iPod is perceived in the same way in Germany and in Mexico and what influencing factors might have an impact on any brand image discrepancy between the countries. Results prove that brand recall rates differ between the two countries (with higher rates in Mexico) as well as brand image attributes vary significantly (28 out of 34 brand image attributes are significantly different between Germany and Mexico), with Mexico showing higher levels of favorable brand image attributes. Key influencing factors on the different brand image perceptions are perceived quality, satisfaction and the influence of reference groups (such as friends and family). The results suggest that so-called 'global brands' are not perceived the same way in Germany and Mexico. As a consequence, brand management using standardized marketing instruments for its presumable 'global brands' might be better off with a more differentiated approach that takes account a specific local brand image

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Click Modification in the <i>N</i>⁶ Region of A₃ Adenosine Receptor-Selective Carbocyclic Nucleosides for Dendrimeric Tethering that Preserves Pharmacophore Recognition

Adenosine derivatives were modified with alkynyl groups on <i>N</i>⁶ substituents for linkage to carriers using Cu­(I)-catalyzed click chemistry. Two parallel series, both containing a rigid North-methanocarba (bicyclo[3.1.0]­hexane) ring system in place of ribose, behaved as A₃ adenosine receptor (AR) agonists: (5′-methyluronamides) or partial agonists (4′-truncated). Terminal alkynyl groups on a chain at the 3 position of a <i>N</i>⁶-benzyl group or simply through a <i>N</i>⁶-propargyl group were coupled to azido derivatives, which included both small molecules and G4 (fourth-generation) multivalent poly­(amidoamine) (PAMAM) dendrimers, to form 1,2,3-triazolyl linkers. The small molecular triazoles probed the tolerance in A₃AR binding of distal, sterically bulky groups such as 1-adamantyl. Terminal 4-fluoro-3-nitrophenyl groups anticipated nucleophilic substitution for chain extension and ¹⁸F radiolabeling. <i>N</i>⁶-(4-Fluoro-3-nitrophenyl)-triazolylmethyl derivative <b>32</b> displayed a <i>K</i>_i of 9.1 nM at A₃AR with ∼1000-fold subtype selectivity. Multivalent conjugates additionally containing click-linked water-solubilizing polyethylene glycol groups potently activated A₃AR in the 5′-methyluronamide, but not 4′ truncated series. <i>N</i>⁶-Benzyl nucleoside conjugate <b>43</b> (apparent <i>K</i>_i 24 nM) maintained binding affinity of the monomer better than a <i>N</i>⁶-triazolylmethyl derivative. Thus, the <i>N</i>⁶ region of 5′-methyluronamide derivatives, as modeled in receptor docking, is suitable for functionalization and tethering by click chemistry to achieve high A₃AR agonist affinity and enhanced selectivity

Electrochemical Study of the Energetics of the Oxygen Evolution Reaction at Nickel Iron (Oxy)Hydroxide Catalysts

Iron-doped nickel (oxy)­hydroxide catalysts (Fe_<i>x</i>Ni_1–<i>x</i>OOH) exhibit high electrocatalytic behavior for the oxygen evolution reaction in base. Recent findings suggest that the incorporation of Fe³⁺ into a NiOOH lattice leads to nearly optimal adsorption energies for OER intermediates on active Fe sites. Utilizing electrochemical impedance spectroscopy and activation energy measurements, we find that pure NiOOH and FeOOH catalysts exhibit exceedingly high Faradaic resistances and activation energies 40–50 kJ/mol⁻¹ higher than those of the most active Fe_<i>x</i>Ni_1–<i>x</i>OOH catalysts. Furthermore, the most active Fe_<i>x</i>Ni_1–<i>x</i>OOH catalysts in this study exhibit activation energies that approach those previously reported for IrO₂ OER catalysts