Collagen-like triple helix formation of synthetic (Pro-Pro-Gly)10 analogues: (4(S)-hydroxyprolyl-4(R)-hydroxyprolyl-Gly)10, (4(R)-hydroxyprolyl-4(R)-hydroxyprolyl-Gly)10 and (4(S)-fluoroprolyl-4(R)-fluoroprolyl-Gly)10.

For the rational design of a stable collagen triple helix according to the conventional rule that the pyrrolidine puckerings of Pro, 4-hydroxyproline (Hyp) and 4-fluoroproline (fPro) should be down at the X-position and up at the Y-position in the X-Y-Gly repeated sequence for enhancing the triple helix propensities of collagen model peptides, a series of peptides were prepared in which X- and Y-positions were altogether occupied by Hyp(R), Hyp(S), fPro(R) or fPro(S). Contrary to our presumption that inducing the X-Y residues to adopt a down-up conformation would result in an increase in the thermal stability of peptides, the triple helices of (Hyp(S)-Hyp(R)-Gly)(10) and (fPro(S)-fPro(R)-Gly)(10) were less stable than those of (Pro-Hyp(R)-Gly)(10) and (Pro-fPro(R)-Gly)(10), respectively. As reported by B?chinger's and Zagari's groups, (Hyp(R)-Hyp(R)-Gly)(10) which could have an up-up conformation unfavorable for the triple helix, formed a triple helix that has a high thermal stability close to that of (Pro-Hyp(R)-Gly)(10). These results clearly show that the empirical rule based on the conformational preference of pyrrolidine ring at each of X and Y residues should not be regarded as still valid, at least for predicting the stability of collagen models in which both X and Y residues have electronegative groups at the 4-position.     

C(4) eudicots are not younger than C(4) monocots

C(4) photosynthesis is a plant adaptation to high levels of photorespiration. Physiological models predict that atmospheric CO(2) concentration selected for C(4) grasses only after it dropped below a critical threshold during the Oligocene (～30 Ma), a hypothesis supported by phylogenetic and molecular dating analyses. However the same models predict that CO(2) should have reached much lower levels before selecting for C(4) eudicots, making C(4) eudicots younger than C(4) grasses. In this study, different phylogenetic datasets were combined in order to conduct the first comparative analysis of the age of C(4) origins in eudicots. Our results suggested that all lineages of C(4) eudicots arose during the last 30 million years, with the earliest before 22 Ma in Chenopodiaceae and Aizoaceae, and the latest probably after 2 Ma in Flaveria. C(4) eudicots are thus not globally younger than C(4) monocots. All lineages of C(4) plants evolved in a similar low CO(2) atmosphere that predominated during the last 30 million years. Independent C(4) origins were probably driven by different combinations of specific factors, including local ecological characteristics such as habitat openness, aridity, and salinity, as well as the speciation and dispersal history of each clade. Neither the lower number of C(4) species nor the frequency of C(3)-C(4) intermediates in eudicots can be attributed to a more recent origin, but probably result from variation in diversification and evolutionary rates among the different groups that evolved the C(4) pathway.     

N(4)-amino-and N(4)-hydroxycytosines as base analogue mutagens

N(4)-Aminocytosine [N(4)NH₂C] and N(4)-amino-2′-deoxycytidine [N(4)NH₂dC] are highly mutagenic for Escherichia coli and phage φ 80 but not for T₄. There is some evidence that they are incorporated into the φ 80 DNA but $\text{[}{}^{14}\text{C}\text{]-N(4)}\text{NH}{}_2\text{C}$ could not be detected in the bacterial DNA.N(4)-Hydroxy-5,6-dihydro-6-hydroxylaminodeoxycytidine (di-NHOH-dC) is mutagenic for φ 80 and E. coli, but N(4)-hydroxydeoxycytidine [N(4)OH-dC] only has a strong inactivating effect.     

Carcinogenicity bioassay of 4-chloromethylbiphenyl (4CMB), 4-hydroxymethylbiphenyl (4HMB) and benzyl chloride (BC) on mouse skin: interim (7 month) report

4CMB, 4HMB, BC of benzo[a]pyrene (BP, positive control) dissolved in toluene have been applied twice weekly to the shaved dorsal region of groups of 20 Alderley Park Swiss albino mice. After 7 months of treatment, 6/20 of the BP test group were confirmed as having developed squamous cell carcinoma of the skin. However, none of the animals in the test groups appeared to have been affected by the test chemicals. This interim observation was supplemented by intercurrent sacrifice of 1 animal from each of the test groups, followed by histopathological examination of sections of the subcutaneous tissue. No neoplastic changes were discerned.     

Photosynthesis of F(1) Hybrids between C(4) and C(3)-C(4) Species of Flaveria

Photosynthetic characteristics were studied in several F₁ hybrids between C₄ and C₃-C₄ species of Flaveria. Stable carbon isotope ratios, O₂ inhibition of apparent photosynthesis, and phosphoenolpyruvate carboxylase activities in the hybrids were similar to the means for the parents. Values of CO₂ compensation concentrations were nearer to those of the C₄ parent and apparent photosynthesis was below that of both parents, being only 60 and 74% of that of the lowest (C₃-C₄) parent in two experiments. Reductions of CO₂ compensation concentration and O₂ inhibition of apparent photosynthesis as well as increases in carbon isotope ratios and phosphoenolpyruvate carboxylase activities compared to values in C₃-C₄ species suggest transfer of a limited degree of C₄ photosynthesis to the F₁ hybrids. However, the lower apparent photosynthesis of the hybrids suggests that transfer of C₄ characteristics to non-C₄ species is detrimental unless characteristics associated with C₄ photosynthesis are fully developed. There was a highly significant negative correlation (r = −0.90) between CO₂ compensation concentration and the logarithm of phosphoenolpyruvate carboxylase activity in the parents and hybrids, suggesting involvement of this enzyme in controlling the CO₂ compensation concentration. Although bundle-sheath cells were more developed in leaves of hybrids than in C₃-C₄ parents, they appeared to contain lower quantities of organelles than those of the C₄ parent. Reduced quantities of organelles in bundle-sheath cells could indicate incomplete compartmentation of partial pathways of the C₄ cycle in the hybrids. This may mean that the reduction of CO₂ compensation and O₂ inhibition of apparent photosynthesis relative to the C₃-C₄ parents is less dependent on fully developed Kranz anatomy than is increased apparent photosynthesis.     

Specific and dual antagonists of alpha(4)beta(1) and alpha(4)beta(7) integrins.

N-(3,5-Dichlorophenylsulfonyl)-(R)-thioprolyl biarylalanine 10a has been identified as a potent and specific antagonist of the alpha(4)beta(1) integrin. Altering the configuration of thioproline from R to S led to a series of dual antagonists of alpha(4)beta(1) and alpha(4)beta(7), and the N-acetyl analogue 8b was found to be the most potent dual antagonist. A binding site model for alpha(4)beta(1) and alpha(4)beta(7) is proposed to explain the structure-activity relationship.     

Imidazole Nucleosides IV Nucleosides of 5 (4)-Formamido-imidazole-4 (5)carboxamide

Abstract

Nucleosides of 5(4)-aminoimidazole-4(5)-carboxamide were formylated with sodium formate, formic acid and acetic anhydride to the β-D-ribo-, α-D-arabino-, α-L-arabino- and β-D-xylofuranosides of 5-formamidoimidazole-4-carboxamide, and to the β-D-ribo-, β-D-arabi-no-, α-D-arabino- and α-L-arabinopyranosides of 4-formamidoimidazole-5-carboxamide.     

Guanine quadruplex formation by RNA/DNA hybrid analogs of Oxytricha telomere G(4)T(4)G(4) fragment

Using circular dichroism spectroscopy, gel electrophoresis, and ultraviolet absorption spectroscopy, we have studied quadruplex folding of RNA/DNA analogs of the Oxytricha telomere fragment, G(4)T(4)G(4), which forms the well-known basket-type, antiparallel quadruplex. We have substituted riboguanines (g) for deoxyriboguanines (G) in the positions G1, G9, G4, and G12; these positions form the terminal tetrads of the G(4)T(4)G(4) quadruplex and adopt syn, syn, anti, and anti glycosidic geometries, respectively. We show that substitution of a single sugar was able to change the quadruplex topology. With the exception of G(4)T(4)G(3)g, which adopted an antiparallel structure, all the RNA/DNA hybrid analogs formed parallel, bimolecular quadruplexes in concentrated solution at low salt. In dilute solutions ( approximately 0.1 mM nucleoside), the RNA/DNA hybrids substituted at positions 4 or 12 adopted antiparallel quadruplexes, which were especially stable in Na(+) solutions. The hybrids substituted at positions 1 and 9 preferably formed parallel quadruplexes, which were more stable than the nonmodified G(4)T(4)G(4) quadruplex in K(+) solutions. Substitutions near the 3'end of the molecule affected folding more than substitutions near the 5'end. The ability to control quadruplex folding will allow further studies of biophysical and biological properties of the various folding topologies. (c) 2008 Wiley Periodicals, Inc. Biopolymers 89: 797-806, 2008.This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com.     

上调基因4与癌症

上调基因4（up-regulated gene-4,URG4）是受乙肝病毒X蛋白（hepatitis B virus X protein,HBx）激活的下游基因之一,最初在转染HBx的HepG2细胞中被克隆,因其上调细胞增殖效应而得名。与未转染的细胞相比,URG4在HBx转染后的HepG2细胞中表达明显增加,证实了URG4与乙肝病毒相关的肝细胞癌发生相关。近年来,人们发现URG4不仅在肝癌细胞中高表达,还与胃癌、骨肉瘤、非小细胞肺癌、神经母细胞瘤等多种癌症相关。本文结合近年来对URG4的研究成果,包括URG4基因及其蛋白质的结构与功能,URG4在癌症发生发展中的作用,以及在癌症早期诊断和预后中的意义进行综述,可望为后续深入地开展URG4与癌症的研究提供参考。     

Delta样配体4与血管生成

Notch信号转导途径参与了许多重要的发育过程,如神经发育、血管形成等,最近的一系列研究表明Notch受体与邻近细胞配体--Delta样配体4（Dll-4）共同参与了新生血管的生长和分支,通过抑制血管内皮顶端细胞的形成,细胞密度、位置以及行为方式的调节,而有效促进血管内皮细胞的正常分化和血管网的及时形成.Dll4在血管生成过程中的作用为相关疾病发生机制的理解、临床诊断及治疗提供了重要的帮助.     

Aza-bicyclic amino acid sulfonamides as alpha(4)beta(1)/alpha(4)beta(7) integrin antagonists

The design, synthesis, and biological activity of novel alpha(4)beta(1) and alpha(4)beta(7) integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent alpha(4)beta(1)-selective and dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma.     

Direct asymmetric aldol reactions catalyzed by (4R)-4-(beta-Naphthalenyl)methoxy-(S)-proline

A novel proline derivative, (4R)-4-(beta-Naphthalenyl)methoxy-(S)-proline, was conveniently prepared from the naturally occurring (4S)-hydroxy-(S)-proline; 5 mol % of this compound efficiently catalyzes the asymmetric aldol reactions of various benzaldehydes with acetone in excess of acetone as the solvent, giving the aldol adducts in good yields with ee up to 89.8%.