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Abstract Background Even after years of exploration, the terrestrial origin of bio-molecules remains unsolved and controversial. Today, observation of amino acid composition in proteins has become an alternative way for a global understanding of the mystery encoded in whole genomes and seeking clues for the origin of amino acids. Results In this study, we statistically monitored the frequencies of 20 alpha-amino acids in 549 taxa from three kingdoms of life: archaebacteria, eubacteria, and eukaryotes. We found that the amino acids evolved independently in these three kingdoms; but, conserved linkages were observed in two groups of amino acids, (A, G, H, L, P, Q, R, and W) and (F, I, K, N, S, and Y). Moreover, the amino acids encoded by GC-poor codons (F, Y, N, K, I, and M) were found to "lose" their usage in the development from single cell eukaryotic organisms like S. cerevisiae to H. sapiens, while the amino acids encoded by GC-rich codons (P, A, G, and W) were found to gain usage. These findings further support the co-evolution hypothesis of amino acids and genetic codes. Conclusion We proposed a new chronological order of the appearance of amino acids (L, A, V/E/G, S, I, K, T, R/D, P, N, F, Q, Y, M, H, W, C). Two conserved evolutionary paths of amino acids were also suggested: A→G→R→P and K→Y.

Objective. Biomarkers for pancreatic cancer (PCa) prognosis provide evidence for improving the survival outcome of this disease. This study aimed to identify a prognostic risk model based on gene expression profiling of microarray bioinformatics analysis. Methods. Prognostic immune genes in the TCGA-PAAD cohort were identified using the univariate Cox regression and Kaplan–Meier survival analysis. Multivariate Cox regression (stepAIC) was used to identify prognostic genes from the top 20 hub genes in the protein-protein interaction (PPI) network. A prognostic risk model was established and its performance in predicting the overall survival in PCa was validated in GSE62452. Gene mutations and infiltration immune cells in PCa tumors were analyzed using online databases. Results. Univariate Cox regression and Kaplan–Meier survival analyses identified 128 prognostic genes. Multivariate Cox regression (stepAIC) identified five prognostic genes (PLCG1, MET, TNFSF10, CXCL9, and TLR3) out of the 20 hub genes in the PPI network. A prognostic risk model was established using the signature of five genes. This model had moderate to high accuracies (AUC > 0.700) in predicting 3-year and 5-year overall survival in TCGA and GSE62452 cohorts. The Kaplan–Meier survival analysis showed that high-risk scores were correlated with poor survival outcomes in PCa (p < 0.05). Also, mutations in the five genes were related to poor survival. The five genes were related to multiple immune cells. Conclusions. The prognostic risk model was significantly correlated with the survival in PCa patients. This model modulated PCa tumor progression and prognosis by regulating immune cell infiltration. [ABSTRACT FROM AUTHOR]

The in vitro effects of individual brominated flame retardants (BFRs), selected metals, and their binary mixtures on ethoxyresorufin-O-deethylase (EROD) activity were evaluated using a plate-reader method. The BFRs, 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), decabromodiphenyl oxide (BDE-209), hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA), were tested at doses ranging from 0.1 ng/L to 100 µg/L. Selected metals (Cu 2+ , Cd 2+ , Hg 2+ , and Zn 2+ ) were screened at doses of 0.1 mg/L to 50 mg/L. The activity of EROD was significantly induced by TBBPA, BDE-209, and Zn 2+ , while HBCD, Cu 2+ , Cd 2+ , and Hg 2+ decreased EROD activity. Moreover, following exposure to binary mixtures of metals and BFRs, the EROD activity dose-response curves were similar to those of the metals alone, indicating that EROD activity was governed by the metals. [ABSTRACT FROM AUTHOR]

The knowledge of accurate bond strengths is a fundamental basis for a proper analysis of chemical reaction mechanisms. Quantum chemical calculations at different levels of theory have been used to investigate heterolytic Feâ€'O and Feâ€'S bond energies of paraâ€substituted phenoxydicarbonyl( η5â€cyclopentadienyl) iron [ pâ€Gâ€C6H4O( η5â€C5H5)Fe(CO)2, abbreviated as pâ€Gâ€C6H4OFp ( 1), where G = NO2, CN, COMe, CO2Me, CF3, Br, Cl, F, H, Me, MeO, and NMe2] and paraâ€substituted benzenethiolatodicarbonyl( η5â€cyclopentadienyl) iron [ pâ€Gâ€C6H4S( η5â€C5H5)Fe(CO)2, abbreviated as pâ€Gâ€C6H4SFp ( 2)] complexes. The results show that BP86 and TPSSTPSS can provide the best price/performance ratio and more accurate predictions in the study of Î' Hhet(Feâ€'O)'s and Î' Hhet(Feâ€'S)'s. The excellent linear freeâ€energy relations [ r = 0.99 (g, 1a), 1.00 (g, 2b)] among the Î'Î' Hhet (Feâ€'O)'s and Î'p ka's of Oâ€'H bonds of pâ€Gâ€C6H4OH or Î'Î' Hhet(Feâ€S)'s and Î'p ka's of Sâ€'H bonds of pâ€Gâ€C6H4SH imply that the governing structural factors for these bond scissions are similar. And the linear correlations [ r = âˆ'0.99 (g, 1g), âˆ'0.98 (g, 2h)] among the Î'Î' Hhet (Feâ€O)'s or Î'Î' Hhet(Feâ€S)'s and the substituent σpâˆ' constants show that these correlations are in accordance with Hammett linear freeâ€energy relationships. The polar effects of these substituents and the basis set effects influence the accuracy of Î' Hhet(Feâ€'O)'s or Î' Hhet(Feâ€'S)'s. Î'Î' Hhet(Feâ€'O)'s(g) ( 1) and Î'Î' Hhet(Feâ€'S)'s(g)( 2) follow the Captoâ€dative principle. The substituent effects on the Feâ€'O bonds are much stronger than those on the less polar Feâ€'S bonds. Insight from this work may help the design of more effective catalytic processes. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Metal-ligand bond enthalpy data can afford invaluable insights into important reaction patterns in organometallic chemistry and . In this paper, the Fe-O and Fe-S homolytic bond dissociation energies [Δ Hhomo(Fe-O)'s and Δ Hhomo(Fe-S)'s] of two series of para-substituted phenoxydicarbonyl( η5-cyclopentadienyl) iron [ p-G-C6H4OFp ( 1)] and (para-substituted benzenethiolato)dicarbonyl( η5-cyclopentadienyl) iron [ p-G-C6H4SFp ( 2)] were studied using Hartree-Fock and density functional theory (DFT) methods with large basis sets. In this study, Fp is ( η5-C5H5)Fe(CO)2, and G are NO2, CN, COMe, CO2Me, CF3, Br, Cl, F, H, Me, MeO, and NMe2. The results show that DFT methods can provide the best price/performance ratio and accurate predictions of Δ Hhomo(Fe-O)'s and Δ Hhomo(Fe-S)'s. The remote substituent effects on Δ Hhomo(Fe-O)'s and Δ Hhomo(Fe-S)'s [ΔΔ Hhomo(Fe-O)'s and ΔΔ Hhomo(Fe-S)'s] can also be satisfactorily predicted. The good correlations [ r = 0.98 (g, 1), 0.98 (g, 2)] of ΔΔ Hhomo(Fe-O)'s and ΔΔ Hhomo(Fe-S)'s in series 1 and 2 with the substituent σp+ constants imply that the para-substituent effects on Δ Hhomo(Fe-O)'s and Δ Hhomo(Fe-S)'s originate mainly from polar effects, but those on radical stability originate from both spin delocalization and polar effects. ΔΔ Hhomo(Fe-O)'s ( 1) and ΔΔ Hhomo(Fe-S)'s ( 2) conform to the captodative principle. Insight from this work may help the design of more effective catalytic processes. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

By the B3P86/6-311G(3d,2p) method, remote substituent effects on trans-YCHCHCHF were investigated by examining their conformational stabilities, molecular geometries, and stereoelectronic interactions in this paper. The cis conformer is favored for YH, Cl, Me, Vinyl, CF, CN, CHO, and NO, whereas the gauche is favored for YOMe, OH. A correlation of Δ H with the substituent constants σ(Y) shows that the increasing electron-withdrawing ability of the substituent Y increases the relative stability of the cis conformer. It was found that the substituent effect on the molecule stabilization energies (relative to CHCHCHF) is more significant in the gauche conformers than in the cis conformers. In agreement, molecular structures of the gauche conformers were also observed to vary more significantly with the substitution than those of the cis conformers. By the second-order perturbation energy ( E(2)) in NBO analysis, it was found that the total C-C vicinal hyperconjugation is determinant in the enthalpy difference and consequently controls the conformational stability. Further analysis shows that the substituent effect on the C-C vicinal hyperconjugations is much higher in the gauche conformers than in the cis conformers. The highly sensitive π→σ* interaction to the substitution in the gauche conformers, is the leading factor in variation of molecular stability and geometry. Copyright © 2010 John Wiley & Sons, Ltd. In this paper, it was found that the conformational preference for the cis or gauche conformer in trans-YCH=CHCHF is highly related with the Y substitution. The substituent effect is transmitted through the double bond and influences the C−C vicinal hyperconjugations, which are the determinant factor for the conformational stability. [ABSTRACT FROM AUTHOR]

Thymidylate synthase (TS) is a critical enzyme for DNA biosynthesis and many nonclassical lipophilic antifolates targeting this enzyme are quite eflicient and encouraging as antitumor drugs. In this paper, the binding model of 14 antifolates of substituted benzylamino- and heterocyclylmethylamino-carbodithioate derivatives of 4-(3H)-quinazolinone with TS is examined using molecular simulation methods—FlexiDock and SCORE2.0. The resulting conformation and orientation of these antifolates are directly applied to CoMFA study. The robust QSAR model, its three-dimensional contour map, and binding score of these antifolates derived from SCORE2.0 provide guidelines for structural optimization of current antifolates. The experiment indicates that deletion of cancer chemopreventive structure of dithiocarbamate is unfavorable for interaction between TS and antifolates. [ABSTRACT FROM AUTHOR]

Abstract In this work, a new approach for TMPyP [5,10,15,20-tetrakis (1-methylpyridinium-4-yl) porphyrin] and TMAPP [5,10,15,20-tetrakis (N,N,N-trimethyl-anilinium-4-yl) porphyrin] intercalation into a-phase of zirconium hydrogen phosphate (a-ZrP) was described: porphyrins were inserted through exchanging pre-intercalated alkylamine. Pre-intercalated n-butylamine (BA) could form either a mobile monolayer or a stable bilayer in a-ZrP. The exchange speed between porphyrins and BA in mobile monolayer is obviously faster than that in stable bilayer. Therefore mobility of spacers is one important intercalation factor. In addition, we investigated the interlayer state of TMPyP by XRD, visible spectrum, fluorescence spectrum and molecular modeling. The results collectively revealed that the porphyrin was orderly arranged with their planes inclined to the host lamella and was presented as monomer instead of aggregation in the gallery of a-ZrP. [ABSTRACT FROM AUTHOR]

Abstract: In this work, molecular modeling methods have been applied to study the structural characterization of the interaction of transitional metal complexes containing the ligands such as bpy, phen, dpq, dppz, tpphz and phi with the oligonucleotide d(CGCAATTGCG)2. The optimum binding position of each complex in relation to the B-DNA fragment was found by analyzing the potential curve of docking process; and the qualitative correlation between structure and intercalative behavior for the ruthenium complexes was found by exploring the complex shapes that fit best with the intercalation sites. The modeling results should extend the knowledge of the nature of the binding of these complexes to B-DNA. Moreover, the studies suggest that Amber96 force field used in this study should become a very useful tool for the further development of the field of ruthenium polypyridyl chemistry. [Copyright &y& Elsevier]

The binding of Tacrine derivatives to Acetylcholinesterase is examined to evaluate the viability of a practical method calculating absolute binding free energy based on the finite difference thermodynamic integration. The method assumes that ΔGbind is given by the difference between the absolute free energy of an inhibitor in protein environment, (ΔGinh)protein, and that in water environment, (ΔGinh)water. The results obtained from the method were found to correlate well with the experimental active data, Spearman''s correlation coefficient, rs=0.90. Moreover, using the CVFF force field found in the commercial package Discover without any special parameters against a set of experimental binding data, the method can expediently and qualitatively rank affinity order of the compounds. [Copyright &y& Elsevier]

Molecular modeling methods have been applied to the structural characterization of the interaction between chiral metal complexes [Co(phen)2dppz]3+ (where phen = 1, 10-phenanthroline, dppz = dipyrido[3,2-a: 2′, 3′ -c]phenazine) and the oligonucleotide (B-DNA fragment). The natures of two kinds of the binding modes, which are currently intense controversy, have been explored. Barton proposed that there is enantio-selective DNA binding by the octahedral complexes and intercalative access by these complexes from the major groove; but Norden suggested that both enantiomers bind extremely strongly to DNA from the minor groove without any noticeable enantio-selectivity. Our results support and extend structural models based upon Norden’s studies, and conflict with Barton’ model. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the sensitivities of diverse cell lines on DNA damage effects and genotoxic effects of three brominated flame retardants (BFRs) and three metal ions (Cu2+, Cd2+, Hg2+) by comet assay. First, THP-1 was identified as the most sensitive cell line in terms of DNA damage among 11 kinds of cells screened. Accordingly, the THP-1 cell line was used as a model in subsequent single/combined genotoxicity tests. Single exposure tests to BFRs or metal ions revealed that the DNA damage effects increased with increasing exposure concentration. In combined exposure tests, BFRs (at concentrations of 1/2 EC 50) were deployed in combination with different concentrations of Cu2+, Cd2+, or Hg2+. The results showed that the % tail DNA values were significantly increased by most mixtures. Our findings on combined toxic effects by comet assay provide valuable information for setting valid environmental safety evaluation standards. Image 1 • The sensitivity of diverse cell lines for DNA damage effects was different. • THP-1 was screened to be the most sensitive cell line by comet assay. • The mixture effects of BFRs and metals on DNA damage were significantly increased. • The combined toxicity should not be overlooked in environmental safety standards. [ABSTRACT FROM AUTHOR]

Glucagon receptor plays an important role in the regulation of glucose metabolism. Studies have revealed that glucagon receptor antagonism is a potential effective treatment for diabetes. However, the functions of GCGR have not been fully illustrated. Although two Gcgr truncation knockout mice models have been widely used for GCGR function studies, truncated gene may remain neomorphic and/or dominant-negative function. In this study, we took the advantages of Crispr-Cas9 technique and generated a novel allele of GCGR in the mouse that yields complete loss of GCGR protein. Our studies reveal that complete deletion of Gcgr results in hyperglucagonemia, α-cell hyperplasia, improvement of glucose tolerance. These results are similar to the Gcgr-truncated mutation in mice. Hence, we provide a novel strain of GCGR knockout mice for the GCGR function studies. • Mice knockout model with complete deletion of Gcgr was generate by Crispr-Cas9 technique in this study. • Complete deletion of Gcgr results in hyperglucagonemia, α-cell hyperplasia, improvement of glucose tolerance. • Complete deletion of Gcgr resulted in changing identity in a small portion α cells. [ABSTRACT FROM AUTHOR]

The knowledge of accurate bond strengths is a fundamental basis for a proper analysis of chemical reaction mechanisms. Quantum chemical calculations at different levels of theory have been used to investigate heterolytic Feâ€'O and Feâ€'S bond energies of paraâ€substituted phenoxydicarbonyl( η5â€cyclopentadienyl) iron [ pâ€Gâ€C6H4O( η5â€C5H5)Fe(CO)2, abbreviated as pâ€Gâ€C6H4OFp ( 1), where G = NO2, CN, COMe, CO2Me, CF3, Br, Cl, F, H, Me, MeO, and NMe2] and paraâ€substituted benzenethiolatodicarbonyl( η5â€cyclopentadienyl) iron [ pâ€Gâ€C6H4S( η5â€C5H5)Fe(CO)2, abbreviated as pâ€Gâ€C6H4SFp ( 2)] complexes. The results show that BP86 and TPSSTPSS can provide the best price/performance ratio and more accurate predictions in the study of Î' Hhet(Feâ€'O)'s and Î' Hhet(Feâ€'S)'s. The excellent linear freeâ€energy relations [ r = 0.99 (g, 1a), 1.00 (g, 2b)] among the Î'Î' Hhet (Feâ€'O)'s and Î'p ka's of Oâ€'H bonds of pâ€Gâ€C6H4OH or Î'Î' Hhet(Feâ€S)'s and Î'p ka's of Sâ€'H bonds of pâ€Gâ€C6H4SH imply that the governing structural factors for these bond scissions are similar. And the linear correlations [ r = âˆ'0.99 (g, 1g), âˆ'0.98 (g, 2h)] among the Î'Î' Hhet (Feâ€O)'s or Î'Î' Hhet(Feâ€S)'s and the substituent σpâˆ' constants show that these correlations are in accordance with Hammett linear freeâ€energy relationships. The polar effects of these substituents and the basis set effects influence the accuracy of Î' Hhet(Feâ€'O)'s or Î' Hhet(Feâ€'S)'s. Î'Î' Hhet(Feâ€'O)'s(g) ( 1) and Î'Î' Hhet(Feâ€'S)'s(g)( 2) follow the Captoâ€dative principle. The substituent effects on the Feâ€'O bonds are much stronger than those on the less polar Feâ€'S bonds. Insight from this work may help the design of more effective catalytic processes. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this paper, we demonstrated the potential of an in vitro method of liver homogenate-based ethoxyresorufin-O-deethylase (EROD) to determine the toxicological effects of multiple kinds of contaminants. We evaluated the in vitro impact of nine pharmaceutically active compounds (PhACs), 13 polycyclic aromatic hydrocarbons (PAHs), and three polychlorinated biphenyls (PCBs). There were different responses of EROD to these contaminants. The response of EROD to PhACs was quite complex, exhibiting both induction and inhibition effects. PAHs and PCBs elicited a strong inhibitory response on EROD activity at high concentrations in a dose-dependent manner. PAHs showed more inhibitory effects as the number of benzene rings increased. Our in vitro bioassay seems to be a potential method for toxicological screening of multiple types of contaminants. Unlabelled Image • Feasibility of in vitro method of liver homogenate-based EROD was demonstrated. • PAHs and PCBs inhibited EROD in a dose-dependent manner. • PAHs showed more inhibition effects as the number of benzene rings increased. • PhACs exhibited both induction and inhibition effects on EROD activity. • EROD in vitro could be an effective supplement way of toxicant evaluation [ABSTRACT FROM AUTHOR]

Abstract: Paired-like homeobox ( PHOX ) 2B is considered to be the causative gene of congenital central hypoventilation syndrome (CCHS), a dominant genetic disorder that results in abnormal central respiratory control with resulting hypoventilation during sleep. In this study, we report a novel c.676&#95;677insG (p.Ala226fs) mutation in a patient with severe CCHS, and we evaluated the function of this mutation. The mutation reduced the translation of the mutant PHOX2B protein and impaired its ability to activate the PHOX2A promoter, due to a haploinsufficiency effect. The mutant PHOX2B was able to interact with wildtype PHOX2B, resulting in retention of PHOX2B on the nuclear membrane, which may impair the normal function of the nuclear membrane, and leading to cellular morbidity. Our study provides useful information for the functional studies of PHOX2B and understanding the pathogenesis of CCHS, and thus is beneficial for the prognosis of, genetic counseling for, and development of pharmaceuticals for PHOX2B-associated diseases., (© 2019 American Academy of Sleep Medicine.)

The in vitro effects of individual brominated flame retardants (BFRs), selected metals, and their binary mixtures on ethoxyresorufin-O-deethylase (EROD) activity were evaluated using a plate-reader method. The BFRs, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), decabromodiphenyl oxide (BDE-209), hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA), were tested at doses ranging from 0.1 ng/L to 100 µg/L. Selected metals (Cu 2+ , Cd 2+ , Hg 2+ , and Zn 2+ ) were screened at doses of 0.1 mg/L to 50 mg/L. The activity of EROD was significantly induced by TBBPA, BDE-209, and Zn 2+ , while HBCD, Cu 2+ , Cd 2+ , and Hg 2+ decreased EROD activity. Moreover, following exposure to binary mixtures of metals and BFRs, the EROD activity dose-response curves were similar to those of the metals alone, indicating that EROD activity was governed by the metals., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Even after years of exploration, the terrestrial origin of bio-molecules remains unsolved and controversial. Today, observation of amino acid composition in proteins has become an alternative way for a global understanding of the mystery encoded in whole genomes and seeking clues for the origin of amino acids., Results: In this study, we statistically monitored the frequencies of 20 alpha-amino acids in 549 taxa from three kingdoms of life: archaebacteria, eubacteria, and eukaryotes. We found that the amino acids evolved independently in these three kingdoms; but, conserved linkages were observed in two groups of amino acids, (A, G, H, L, P, Q, R, and W) and (F, I, K, N, S, and Y). Moreover, the amino acids encoded by GC-poor codons (F, Y, N, K, I, and M) were found to "lose" their usage in the development from single cell eukaryotic organisms like S. cerevisiae to H. sapiens, while the amino acids encoded by GC-rich codons (P, A, G, and W) were found to gain usage. These findings further support the co-evolution hypothesis of amino acids and genetic codes., Conclusion: We proposed a new chronological order of the appearance of amino acids (L, A, V/E/G, S, I, K, T, R/D, P, N, F, Q, Y, M, H, W, C). Two conserved evolutionary paths of amino acids were also suggested: A-->G-->R-->P and K-->Y.