On the Structural Regularity in Nucleobases and Amino Acids and Relationship to the Origin and Evolution of the Genetic Code

To explore how chemical structures of both nucleobases and amino acids may have played a role in shaping the genetic code, numbers of sp² hybrid nitrogen atoms in nucleobases were taken as a determinative measure for empirical stereo-electronic property to analyze the genetic code. Results revealed that amino acid hydropathy correlates strongly with the sp² nitrogen atom numbers in nucleobases rather than with the overall electronic property such as redox potentials of the bases, reflecting that stereo-electronic property of bases may play a role. In the rearranged code, five simple but stereo-structurally distinctive amino acids (Gly, Pro, Val, Thr and Ala) and their codon quartets form a crossed intersection “core”. Secondly, a re-categorization of the amino acids according to their β-carbon stereochemistry, verified by charge density (at β-carbon) calculation, results in five groups of stereo-structurally distinctive amino acids, the group leaders of which are Gly, Pro, Val, Thr and Ala, remarkably overlapping the above “core”. These two lines of independent observations provide empirical arguments for a contention that a seemingly “frozen” “core” could have formed at a certain evolutionary stage. The possible existence of this codon “core” is in conformity with a previous evolutionary model whereby stereochemical interactions may have shaped the code. Moreover, the genetic code listed in UCGA succession together with this codon “core” has recently facilitated an identification of the unprecedented icosikaioctagon symmetry and bi-pyramidal nature of the genetic code.     

Theoretical study on the aromaticity from d-AOs in cationic X 3 + (X = Sc,Y, La) clusters

The stable structures and aromatic characters for three cationic X₃⁺ (X = Sc, Y, and La) and three relevant neutral X₃Cl (X = Sc, Y, La) clusters are investigated at the DFT and post HF level of theory. The calculated results show that the X₃⁺ cations each has two stable structures: the regular trigon (D_3h) and the line (D_￥h {{\hbox{D}}_{\infty {\rm{h}}}} ) with the regular trigon (D_3h) being the ground state, while for three neutral X₃Cl clusters, Sc₃Cl has three stable isomers: the trigon-pyramidal (C_3v), bidentate (C_2v-1), and C_2v-2 structures, Y₃Cl and La₃Cl each has only two stable isomers: the trigon-pyramidal (C_3v) and bidentate (C_2v-1) structures. The ground states for three X₃Cl species are all the bidentate (C_2v-1) isomers. The calculations of the resonance energy (RE) and NICS show that trigonal X₃⁺ isomers exhibit higher degree of aromaticity. The detailed molecular orbital analyzes reveal that the isolated trigonal Sc₃⁺ and Y₃⁺ cations each has one delocalized π-type MO and shows single π-aromaticity, while the isolated trigonal La₃⁺ cation has one delocalized σ-type MO and shows single σ-aromaticity. The single π- or σ-aromaticity for X₃⁺ are attributed to the contributions mainly from the d AOs of the corresponding transition metal X atoms. However, when a singly negatively charged counterion Cl^- is added to Sc₃⁺, Y₃⁺, and La₃⁺ cations respectively, the aromatic type for the two Sc₃⁺, Y₃⁺ units in the corresponding neutral Sc₃Cl, Y₃Cl complexes are changed from π-aromaticity into σ-aromaticity, whereas the σ-aromaticity of the La₃⁺ units in the La₃Cl complex keeps unchanged in this process. Thus three Sc₃⁺, Y₃⁺, La₃⁺ units in the corresponding X₃Cl complexes all have only one σ-type MO and exhibit single σ-aromaticity.     

Studies on adenosine A2a receptor antagonists: comparison of three core heterocycles

Piperazine and (R)-2-(aminomethyl)pyrrolidine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been shown to be potent and selective adenosine A(2a) receptor antagonists. We have replaced the triazolotriazine core structure with two different heterocyclic cores. One of these, the one deriving from [1,2,4]triazolo[1,5-c]pyrimidine, appears to be particularly effective and selected analogs from this series have been shown to be orally active in a mouse catalepsy model of Parkinson's disease.     

Insulin-stimulated exocytosis of GLUT4 is enhanced by IRAP and its partner tankyrase

The glucose transporter GLUT4 and the aminopeptidase IRAP (insulin-responsive aminopeptidase) are the major cargo proteins of GSVs (GLUT4 storage vesicles) in adipocytes and myocytes. In the basal state, most GSVs are sequestered in perinuclear and other cytosolic compartments. Following insulin stimulation, GSVs undergo exocytic translocation to insert GLUT4 and IRAP into the plasma membrane. The mechanisms regulating GSV trafficking are not fully defined. In the present study, using 3T3-L1 adipocytes transfected with siRNAs (small interfering RNAs), we show that insulin-stimulated IRAP translocation remained intact despite substantial GLUT4 knockdown. By contrast, insulin-stimulated GLUT4 translocation was impaired upon IRAP knockdown, indicating that IRAP plays a role in GSV trafficking. We also show that knockdown of tankyrase, a Golgi-associated IRAP-binding protein that co-localizes with perinuclear GSVs, attenuated insulin-stimulated GSV translocation and glucose uptake without disrupting insulin-induced phosphorylation cascades. Moreover, iodixanol density gradient analyses revealed that tankyrase knockdown altered the basal-state partitioning of GLUT4 and IRAP within endosomal compartments, apparently by shifting both proteins toward less buoyant compartments. Importantly, the afore-mentioned effects of tankyrase knockdown were reproduced by treating adipocytes with PJ34, a general PARP (poly-ADP-ribose polymerase) inhibitor that abrogated tankyrase-mediated protein modification known as poly-ADP-ribosylation. Collectively, these findings suggest that physiological GSV trafficking depends in part on the presence of IRAP in these vesicles, and that this process is regulated by tankyrase and probably its PARP activity.     

Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand

IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Rα and gp130. Because of its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (S low Off-rate Modified Aptamers) that bind IL-6 and inhibit its biologic activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here, we report the co-crystal structure of a high affinity SOMAmer (K_d = 0.20 nm) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Rα and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (K_d = 270 nm). A single substitution from our diversely modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (K_d = 7.4 nm). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer·IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets.     

贵州五种菊头蝠的核型分析 *

采用常规骨髓细胞空气干燥法,研究了贵州5种菊头蝠的核型。贵州菊头蝠和中菊头蝠2n=62,两者染色体臂数(NF)均为60;托氏菊头蝠、小菊头蝠和栗黄菊头蝠的染色体数是2n=36,其中托氏菊头蝠和小菊头蝠染色体臂数(NF)是58,栗黄菊头蝠是60。5种菊头蝠的性别决定机制均是xY。     

Draft Genome Sequence of Salmonella enterica Serovar Typhimurium ST1660/06, a Multidrug-Resistant Clinical Strain Isolated from a Diarrheic Patient

Salmonella enterica serovar Typhimurium is one of the most prevalent serovars of Salmonella that causes human gastroenteritis. Here, we report the draft genome sequence of the S. Typhimurium multidrug-resistant strain ST1660/06. Comparative genomic analysis unveiled three strain-specific genomic islands that potentially confer the multidrug resistance and virulence of the strain.