BACKGROUND Thyroxine-binding globulin(TBG;the gene product of SERPINA7)is the main transporter of thyroid hormones in humans.Mutations in the TBG gene may lead to inherited TBG deficiency.There have been 28 reported m...BACKGROUND Thyroxine-binding globulin(TBG;the gene product of SERPINA7)is the main transporter of thyroid hormones in humans.Mutations in the TBG gene may lead to inherited TBG deficiency.There have been 28 reported mutations that associate with complete TBG deficiency(TBG-CD).Here we identified a novel frameshift mutation causing early termination of the TBG protein and TBG-CD in a Chinese family.CASE SUMMARY A 46-year-old Chinese man was referred to our hospital with normal free thyroxine,free triiodothyronine,thyrotropin,but lower total thyroxine and total triiodothyronine,and undetectable serum TBG,indicative of TBG-CD.Blood samples were obtained from the patient’s family members and thyroid function and serum TBG were evaluated.Genomic DNA from peripheral blood was sequenced to detect possible TBG mutation(s).Quantitative PCR high-resolution melting curve analysis was used to screen TBG-Poly(L283F)among 117 Chinese men.A novel mutation of TBG(p.Phe135Alafs*21),a 19-nucleotide insertion in exon 1,was identified,which resulted in a truncated TBG protein product and caused TBG-CD.The other mutation,identified in the proband’s father,is a known polymorphism,TBG-Poly(L283F).The frequency of the TBG-Poly allele among 117 unrelated Han Chinese men from northeast China was 21.37%.CONCLUSION A novel mutation in the TBG gene associated with the TBG-CD phenotype was identified in a Chinese family.Additionally,it was found that 21.37%of Chinese males had TBG-Poly(L283F).展开更多
There exist a lot of controversial issues around the subject of SW(Scalar Waves)and the purpose of this white paper is to take an innovative theoretical approach to prove and backup up existence of such phenomena.We b...There exist a lot of controversial issues around the subject of SW(Scalar Waves)and the purpose of this white paper is to take an innovative theoretical approach to prove and backup up existence of such phenomena.We basically define this wave as a SLW(Scalar Longitudinal Wave),whose existence derives from the MCE(More Complete Electrodynamic)theory aspect of Maxwell’s classical electrodynamic equations.MCE falls into the QED(Quantum Electrodynamic)aspect of the Maxwell’s equations,in particular out of his four famous classical equations,our interest focuses on the one that is known to us as Faraday’s Law of the Maxwell’s Equation set.展开更多
The pathogenesis of Alzheimer’s disease (AD) putatively involves a compromised blood-brain barrier (BBB). In particular, the importance of brain-to-blood transport of brain-derived metabolites across the BBB has gain...The pathogenesis of Alzheimer’s disease (AD) putatively involves a compromised blood-brain barrier (BBB). In particular, the importance of brain-to-blood transport of brain-derived metabolites across the BBB has gained increasing attention as a potential mechanism in the pathogenesis of neurodegenerative disorders such as AD, which is characterized by the aberrant polymerization and accumulation of specific misfolded proteins, particularly β-amyloid (Aβ), a neuropathological hallmark of AD. P-glycoprotein (P-gp), a major component of the BBB, plays a role in the etiology of AD through Aβ clearance from the brain. Our QSAR models on a series of purine-type and propafenone-type substrates of P-gp showed that the interaction between P-gp and its modulators depended on Molar Refractivity, LogP, and Shape Attribute of drugs it transports. Meanwhile, another model on BBB partitioning of some compounds revealed that BBB partitioning relied upon the polar surface area, LogP, Balaban Index, the strength of a molecule combined with the membrane-water complex, and the changeability of the structure of a solute-membrane-water complex. The predictive model on BBB partitioning contributes to the discovery of some molecules through BBB as potential AD therapeutic drugs. Moreover, the interaction model of P-gp and modulators for treatment of multidrug resistance (MDR) indicates the discovery of some molecules to increase Aβ clearance from the brain and reduce Aβ brain accumulation by regulating BBB P-gp in the early stages of AD. The mechanism provides a new insight into the therapeutic strategy for AD.展开更多
To study the structure-activity relationship of endomorphins (EMs), the action of opioid receptor binding (AORB), analgesic activity and vasodilator effects of EMs and their eight analogs were investigated, which were...To study the structure-activity relationship of endomorphins (EMs), the action of opioid receptor binding (AORB), analgesic activity and vasodilator effects of EMs and their eight analogs were investigated, which were prepared by rationally replacing the 2-/3-amino acid (Aa) of EMs. The results showed: (i) The 2-Aa was comparatively more related to the selectivity of EMs while the 3-Aa to their affinity; (ii) the analgesia and vasodilatation of EMs and their analogs were not completely dictated by their AORB (in vitro), the action of [D-Pro2]EM-2 was unusual; (iii) EMs lost their analgesia in the central nervous system and their vasodilatation in the circulatory system with different mechanisms; the former was due to the degradation of some peptidase, and the latter possibly due to the feedback inhibition.展开更多
The assessment of seismicity is strongly dependent on the recorded events as data base. A uniform catalog of earthquakes in Iran and neighbouring regions is provided to use for seismic hazard assessment of the countr...The assessment of seismicity is strongly dependent on the recorded events as data base. A uniform catalog of earthquakes in Iran and neighbouring regions is provided to use for seismic hazard assessment of the country. Since the recurrence time of maximum credible earthquake can not be estimated directly from m b, empirical relationships for different seismotectonic provinces are established to convert m b to M S , which is a suitable magnitude scale for our purpose. It emerges from completeness study of the catalog that many small and moderate earthquakes are missed out, specially in the historical and early instrumental time periods.展开更多
The mutation sites of the four mutants F35Y, P40V, V45E and V45Y of cytochrome b 5 are located at the edge of the heme binding pocket. The solvent accessible areas of the “pocket interior” of the four mutants ...The mutation sites of the four mutants F35Y, P40V, V45E and V45Y of cytochrome b 5 are located at the edge of the heme binding pocket. The solvent accessible areas of the “pocket interior” of the four mutants and the wild type cytochrome b 5 have been calculated based on their crystal structures at high resolution. The change in the hydrophobicity of the heme binding pocket resulting from the mutation can be quantitatively described using the difference of the solvent accessible area of the “pocket interior” of each mutant from that of the wild type cytochrome b 5. The influences of the hydrophobicity of the heme binding pocket on the protein stability and redox potential are discussed.展开更多
Structure Activity-Relationships (SARs) of the five possible isomers of RuCl<sub>2</sub>(Azpy)<sub>2</sub> were predicted thanks to DFT method. Azpy stands for 2-phenylazopyridine and the struc...Structure Activity-Relationships (SARs) of the five possible isomers of RuCl<sub>2</sub>(Azpy)<sub>2</sub> were predicted thanks to DFT method. Azpy stands for 2-phenylazopyridine and the structure of the isomers α-RuCl<sub>2</sub>(Azpy)<sub>2</sub>, β-RuCl<sub>2</sub>(Azpy)<sub>2</sub>, γ-RuCl2(Azpy)2, δ-RuCl<sub>2</sub>(Azpy)<sub>2</sub> and ε-RuCl<sub>2</sub>(Azpy)<sub>2</sub> call respectively α-Cl, β-Cl, γ-Cl, δ-Cl and ε-Cl are defined according to chlorine atoms orientations. Hence, they are divided into two groups. In the first group comprising α-Cl, β-Cl and ε-Cl, both chlorine atoms are in cis position and Azpy ligands are intervertical. Whereas the two others isomers (γ-Cl and δ-Cl), they form the second group. Here, both chlorine are in trans position and Azpy are planar. The five synthesized isomers were investigated as potential antitumor agents. Then, regarding the DNA, its bases are stacked by pair. Therefore, complexes are assumed to insert and to stack on them through intercalative mode. So the electronic and geometric structures become more important to describe their SARs. Consequently, group 2 regarding γ-Cl and δ-Cl presents the best structure to allow intercalation between DNA base-pairs. Besides, the energy order of the lower unoccupied molecular orbital (LUMO) of the isomers is ELUMO(β-Cl) > ELUMO(α-Cl) > ELUMO(ε-Cl) > ELUMO(γ-Cl) > ELUMO(δ-Cl). The energy gap between LUMO and HOMO was also sorted as Δ(L-H)(β-Cl) > Δ(L-H)(α-Cl) > Δ(L-H)(ε-Cl) > Δ(L-H)(γ-Cl) > Δ(L-H)(δ-Cl). In addition, the total dipole moment was classified as μ(ε-Cl) > μ(β-Cl) > μ(α-Cl) > μ(γ-Cl) > μ(δ-Cl). Finally, net charge of the ligand Azpy was also classified as QL(δ-Cl) > QL(γ-Cl) > QL(ε-Cl) > QL(α-Cl) > QL(β-Cl). All those parameters show that δ-Cl isomer displays the highest activity as antitumor drug when intercalating between the DNA basepairs Cytosine-Guanine/Cytosine-Guanine (CG/CG).展开更多
Pyrrosia petiolosa,Pyrrosia lingua and Pyrrosia sheareri are recorded as original plants of Pyrrosiae Folium(PF)and commonly used as Chinese herbal medicines.Due to the similar morphological features of PF and its adu...Pyrrosia petiolosa,Pyrrosia lingua and Pyrrosia sheareri are recorded as original plants of Pyrrosiae Folium(PF)and commonly used as Chinese herbal medicines.Due to the similar morphological features of PF and its adulterants,common DNA barcodes cannot accurately distinguish PF species.Knowledge of the chloroplast(cp)genome is widely used in species identification,molecular marker and phylogenetic analyses.Herein,we determined the complete cp genomes of three original species of PF via highthroughput sequencing technologies.The three cp genomes exhibited a typical quadripartite structure with sizes ranging from 158165 to 163026 bp.The cp genomes of P.petiolosa and P.lingua encoded 130 genes,whilst that of P.sheareri encoded 131 genes.The complete cp genomes were compared,and five highly divergent regions of pet A-psb J,mat K-rps16,ndh C-trn M,psb M-pet N and psa Cndh E were screened as potential DNA barcodes for identification of Pyrrosia genus species.The phylogenetic tree we obtained indicated that P.petiolosa and P.lingua are clustered in a single clade and,thus,share a close relationship.This study provides invaluable information for further studies on the species identification,taxonomy and phylogeny of Pyrrosia genus species.展开更多
Plant genomes harbor dozens to hundreds of nucleotide-binding site-leucine-rich repeat （NBS-LRR） genes; however, the long-term evolutionary history of these resistance genes has not been fully understood, This study...Plant genomes harbor dozens to hundreds of nucleotide-binding site-leucine-rich repeat （NBS-LRR） genes; however, the long-term evolutionary history of these resistance genes has not been fully understood, This study focuses on five Brassicaceae genomes and the Carica papaya genome to explore changes in NBS-LRR genes that have taken place in this Rosid II lineage during the past 72 million years. Various numbers of NBS-LRR genes were identified from Arabidopsis lyrata （198）, A. thaliana （165）, Brassica rapa （204）, Capsella rubella （127）, Thellungiella salsuginea （88）, and C. papaya （51）. In each genome, the identified NBS-LRR genes were found to be unevenly distributed among chromosomes and most of them were clustered together. Phylogenetic analysis revealed that, before and after Brassicaceae speciation events, both toll/interleukin-1 receptor-NBS-LRR （TNL） genes and non-toll/interleukin-1 receptor-NBS-LRR （nTNL） genes exhibited a pattern of first expansion and then contraction, suggesting that both subclasses of NBS-LRR genes were responding to pathogen pressures synchronically. Further, by examining the gain/loss of TNL and nTNL genes at different evolutionary nodes, this study revealed that both events often occurred more drastically in TNL genes. Finally, the phylogeny of nTNL genes suggested that this NBS-LRR subclass is composed of two separate ancient gene types： RPW8-NBS-LRR and Coiled-coiI-N BS-LRR.展开更多
基金Supported by the National Natural Science Foundation of China,No.81570711National Clinical Key College Fund and the Key Platform Foundation of Science and Technology for the Universities in Liaoning Province,No.16010
文摘BACKGROUND Thyroxine-binding globulin(TBG;the gene product of SERPINA7)is the main transporter of thyroid hormones in humans.Mutations in the TBG gene may lead to inherited TBG deficiency.There have been 28 reported mutations that associate with complete TBG deficiency(TBG-CD).Here we identified a novel frameshift mutation causing early termination of the TBG protein and TBG-CD in a Chinese family.CASE SUMMARY A 46-year-old Chinese man was referred to our hospital with normal free thyroxine,free triiodothyronine,thyrotropin,but lower total thyroxine and total triiodothyronine,and undetectable serum TBG,indicative of TBG-CD.Blood samples were obtained from the patient’s family members and thyroid function and serum TBG were evaluated.Genomic DNA from peripheral blood was sequenced to detect possible TBG mutation(s).Quantitative PCR high-resolution melting curve analysis was used to screen TBG-Poly(L283F)among 117 Chinese men.A novel mutation of TBG(p.Phe135Alafs*21),a 19-nucleotide insertion in exon 1,was identified,which resulted in a truncated TBG protein product and caused TBG-CD.The other mutation,identified in the proband’s father,is a known polymorphism,TBG-Poly(L283F).The frequency of the TBG-Poly allele among 117 unrelated Han Chinese men from northeast China was 21.37%.CONCLUSION A novel mutation in the TBG gene associated with the TBG-CD phenotype was identified in a Chinese family.Additionally,it was found that 21.37%of Chinese males had TBG-Poly(L283F).
文摘There exist a lot of controversial issues around the subject of SW(Scalar Waves)and the purpose of this white paper is to take an innovative theoretical approach to prove and backup up existence of such phenomena.We basically define this wave as a SLW(Scalar Longitudinal Wave),whose existence derives from the MCE(More Complete Electrodynamic)theory aspect of Maxwell’s classical electrodynamic equations.MCE falls into the QED(Quantum Electrodynamic)aspect of the Maxwell’s equations,in particular out of his four famous classical equations,our interest focuses on the one that is known to us as Faraday’s Law of the Maxwell’s Equation set.
文摘The pathogenesis of Alzheimer’s disease (AD) putatively involves a compromised blood-brain barrier (BBB). In particular, the importance of brain-to-blood transport of brain-derived metabolites across the BBB has gained increasing attention as a potential mechanism in the pathogenesis of neurodegenerative disorders such as AD, which is characterized by the aberrant polymerization and accumulation of specific misfolded proteins, particularly β-amyloid (Aβ), a neuropathological hallmark of AD. P-glycoprotein (P-gp), a major component of the BBB, plays a role in the etiology of AD through Aβ clearance from the brain. Our QSAR models on a series of purine-type and propafenone-type substrates of P-gp showed that the interaction between P-gp and its modulators depended on Molar Refractivity, LogP, and Shape Attribute of drugs it transports. Meanwhile, another model on BBB partitioning of some compounds revealed that BBB partitioning relied upon the polar surface area, LogP, Balaban Index, the strength of a molecule combined with the membrane-water complex, and the changeability of the structure of a solute-membrane-water complex. The predictive model on BBB partitioning contributes to the discovery of some molecules through BBB as potential AD therapeutic drugs. Moreover, the interaction model of P-gp and modulators for treatment of multidrug resistance (MDR) indicates the discovery of some molecules to increase Aβ clearance from the brain and reduce Aβ brain accumulation by regulating BBB P-gp in the early stages of AD. The mechanism provides a new insight into the therapeutic strategy for AD.
基金This work was supported by the National Natural Science Foundation of China (Grant No. 20072014) the Teaching and Research Award Program for Outstanding Young Teachers in Higher Education Institutions of MOE of China Gansu Provincial Key Science and
文摘To study the structure-activity relationship of endomorphins (EMs), the action of opioid receptor binding (AORB), analgesic activity and vasodilator effects of EMs and their eight analogs were investigated, which were prepared by rationally replacing the 2-/3-amino acid (Aa) of EMs. The results showed: (i) The 2-Aa was comparatively more related to the selectivity of EMs while the 3-Aa to their affinity; (ii) the analgesia and vasodilatation of EMs and their analogs were not completely dictated by their AORB (in vitro), the action of [D-Pro2]EM-2 was unusual; (iii) EMs lost their analgesia in the central nervous system and their vasodilatation in the circulatory system with different mechanisms; the former was due to the degradation of some peptidase, and the latter possibly due to the feedback inhibition.
文摘The assessment of seismicity is strongly dependent on the recorded events as data base. A uniform catalog of earthquakes in Iran and neighbouring regions is provided to use for seismic hazard assessment of the country. Since the recurrence time of maximum credible earthquake can not be estimated directly from m b, empirical relationships for different seismotectonic provinces are established to convert m b to M S , which is a suitable magnitude scale for our purpose. It emerges from completeness study of the catalog that many small and moderate earthquakes are missed out, specially in the historical and early instrumental time periods.
文摘The mutation sites of the four mutants F35Y, P40V, V45E and V45Y of cytochrome b 5 are located at the edge of the heme binding pocket. The solvent accessible areas of the “pocket interior” of the four mutants and the wild type cytochrome b 5 have been calculated based on their crystal structures at high resolution. The change in the hydrophobicity of the heme binding pocket resulting from the mutation can be quantitatively described using the difference of the solvent accessible area of the “pocket interior” of each mutant from that of the wild type cytochrome b 5. The influences of the hydrophobicity of the heme binding pocket on the protein stability and redox potential are discussed.
文摘Structure Activity-Relationships (SARs) of the five possible isomers of RuCl<sub>2</sub>(Azpy)<sub>2</sub> were predicted thanks to DFT method. Azpy stands for 2-phenylazopyridine and the structure of the isomers α-RuCl<sub>2</sub>(Azpy)<sub>2</sub>, β-RuCl<sub>2</sub>(Azpy)<sub>2</sub>, γ-RuCl2(Azpy)2, δ-RuCl<sub>2</sub>(Azpy)<sub>2</sub> and ε-RuCl<sub>2</sub>(Azpy)<sub>2</sub> call respectively α-Cl, β-Cl, γ-Cl, δ-Cl and ε-Cl are defined according to chlorine atoms orientations. Hence, they are divided into two groups. In the first group comprising α-Cl, β-Cl and ε-Cl, both chlorine atoms are in cis position and Azpy ligands are intervertical. Whereas the two others isomers (γ-Cl and δ-Cl), they form the second group. Here, both chlorine are in trans position and Azpy are planar. The five synthesized isomers were investigated as potential antitumor agents. Then, regarding the DNA, its bases are stacked by pair. Therefore, complexes are assumed to insert and to stack on them through intercalative mode. So the electronic and geometric structures become more important to describe their SARs. Consequently, group 2 regarding γ-Cl and δ-Cl presents the best structure to allow intercalation between DNA base-pairs. Besides, the energy order of the lower unoccupied molecular orbital (LUMO) of the isomers is ELUMO(β-Cl) > ELUMO(α-Cl) > ELUMO(ε-Cl) > ELUMO(γ-Cl) > ELUMO(δ-Cl). The energy gap between LUMO and HOMO was also sorted as Δ(L-H)(β-Cl) > Δ(L-H)(α-Cl) > Δ(L-H)(ε-Cl) > Δ(L-H)(γ-Cl) > Δ(L-H)(δ-Cl). In addition, the total dipole moment was classified as μ(ε-Cl) > μ(β-Cl) > μ(α-Cl) > μ(γ-Cl) > μ(δ-Cl). Finally, net charge of the ligand Azpy was also classified as QL(δ-Cl) > QL(γ-Cl) > QL(ε-Cl) > QL(α-Cl) > QL(β-Cl). All those parameters show that δ-Cl isomer displays the highest activity as antitumor drug when intercalating between the DNA basepairs Cytosine-Guanine/Cytosine-Guanine (CG/CG).
基金supported by the Major Scientific and Technological Special Project for“Significant New Drugs Creation”(No.2018ZX09711001-008-007)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS,No.2016-I2M-3-016)。
文摘Pyrrosia petiolosa,Pyrrosia lingua and Pyrrosia sheareri are recorded as original plants of Pyrrosiae Folium(PF)and commonly used as Chinese herbal medicines.Due to the similar morphological features of PF and its adulterants,common DNA barcodes cannot accurately distinguish PF species.Knowledge of the chloroplast(cp)genome is widely used in species identification,molecular marker and phylogenetic analyses.Herein,we determined the complete cp genomes of three original species of PF via highthroughput sequencing technologies.The three cp genomes exhibited a typical quadripartite structure with sizes ranging from 158165 to 163026 bp.The cp genomes of P.petiolosa and P.lingua encoded 130 genes,whilst that of P.sheareri encoded 131 genes.The complete cp genomes were compared,and five highly divergent regions of pet A-psb J,mat K-rps16,ndh C-trn M,psb M-pet N and psa Cndh E were screened as potential DNA barcodes for identification of Pyrrosia genus species.The phylogenetic tree we obtained indicated that P.petiolosa and P.lingua are clustered in a single clade and,thus,share a close relationship.This study provides invaluable information for further studies on the species identification,taxonomy and phylogeny of Pyrrosia genus species.
基金supported by the National Natural Science Foundation of China(30930008,31170210,31200177,91231102,31300190,31400201 and 31470327)China Postdoctoral Science Foundation(2013M540435 and 2014T70503)+3 种基金Postdoctoral Science Foundation of Jiangsu Province(1302131C)Fundamental Research Funds for the Central Universities(20620140546 and 20620140558)Natural Science Founding of Jiangsu Province(BK20130565)Qing Lan Project of Jiangsu Province
文摘Plant genomes harbor dozens to hundreds of nucleotide-binding site-leucine-rich repeat （NBS-LRR） genes; however, the long-term evolutionary history of these resistance genes has not been fully understood, This study focuses on five Brassicaceae genomes and the Carica papaya genome to explore changes in NBS-LRR genes that have taken place in this Rosid II lineage during the past 72 million years. Various numbers of NBS-LRR genes were identified from Arabidopsis lyrata （198）, A. thaliana （165）, Brassica rapa （204）, Capsella rubella （127）, Thellungiella salsuginea （88）, and C. papaya （51）. In each genome, the identified NBS-LRR genes were found to be unevenly distributed among chromosomes and most of them were clustered together. Phylogenetic analysis revealed that, before and after Brassicaceae speciation events, both toll/interleukin-1 receptor-NBS-LRR （TNL） genes and non-toll/interleukin-1 receptor-NBS-LRR （nTNL） genes exhibited a pattern of first expansion and then contraction, suggesting that both subclasses of NBS-LRR genes were responding to pathogen pressures synchronically. Further, by examining the gain/loss of TNL and nTNL genes at different evolutionary nodes, this study revealed that both events often occurred more drastically in TNL genes. Finally, the phylogeny of nTNL genes suggested that this NBS-LRR subclass is composed of two separate ancient gene types： RPW8-NBS-LRR and Coiled-coiI-N BS-LRR.
