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131.
Laron Z Silbergeld A Kauli R 《Anthropologischer Anzeiger; Bericht über die biologisch-anthropologische Literatur》2012,69(3):255-259
The differential growth effects of hGH and IGF-I on the upper/lower (U/L) body segment in relation to height (Ht) were analyzed in 15 patients with isolated Growth hormone deficiency (IGHD,:7M, 8F) mean age 5.0 +/- 3.2 (SD) years treated with hGH; 21 patients with multiple pituitary hormone deficiency including growth hormone (MPHD: 14M, 7F) aged 10.0 +/- 3.8, treated with hGH; 9 patients with Laron Syndrome (LS) (4M,5F) aged 6.9 +/- 5.6 years treated with IGF-I; 9 boys with intrauterine growth retardation (IUGR) aged 6.3 +/- 1.25 years treated by hGH; and 22 boys with idiopathic short stature (ISS) aged 8.0 +/- 1.55 years treated by hGH. The dose of hGH was 33 microg/kg/day, that of IGF-I 180-200 microg/kg/day. RESULTS: the U/L body segment ratio in IGHD patients decreased from 2.3 +/- 0.7 to 1.1 +/- 0.7 (p <0.001), and the Ht SDS increased from -4.9 +/- 1.3 to 2.3 +/- 1 (p < 0.001) following treatment. In MPHD patients the U/L body segment decreased from 1.1 +/- 1.1 to -0.6 +/- 1.0 (p < 0.001), and the Ht SDS increased from -3.3 +/- 1.4 to -2.5 +/- 1.0 (p < 0.009). In the LS group the U/L body segment ratio did not change with IGF-I treatment but Ht improved from -6.1 +/- 1.3 to -4.6 +/- 1.2 (p < 0.001), The differential growth response of the children with IUGR and with ISS resembled that of the children with LS. CONCLUSIONS: hGH and IGF-I act differentially on the spine and limbs. 相似文献
132.
Aminoglycoside–arginine conjugates (AAC and APAC) are multi-target inhibitors of human immunodeficiency virus type-1 (HIV-1).
Here, we predict new conjugates of neomycin with two arginine peptide chains binding at specific sites on neomycin [poly-arginine-neomycin-poly-arginine
(PA-Neo-PA)]. The rationale for the design of such compounds is to separate two short arginine peptides with neomycin, which
may extend the binding region of the CXC chemokine receptor type 4 (CXCR4). We used homology models of CXCR4 and unliganded
envelope glycoprotein 120 (HIV-1IIIB gp120) and docked PA-Neo-PAs and APACs to these using a multistep docking procedure. The results indicate that PA-Neo-PAs
spread over two negatively charged patches of CXCR4. PA-Neo-PA–CXCR4 complexes are energetically more favorable than AACs/APAC–CXCR4
complexes. Notably, our CXCR4 model and docking procedure can be applied to predict new compounds that are either inhibitors
of gp120–CXCR4 binding without affecting stromal cell-derived factor 1α (SDF-1α) chemotaxis activity, or inhibitors of SDF-1α–CXCR4
binding resulting in an anti-metastasis effect. We also predict that PA-Neo-PAs and APACs can interfere with CD4–gp120 binding
in unliganded conformation.
Figure The r5-Neo-r5-CXCR4 complex. CXCR4 is shown in CPK representation. The negatively charged residues are shown in red and positively charged residues in blue. The r5-Neo-r5 is shown in stick representation, neomycin core is colored yellow and arginine moieties are colored magenta. Two negatively charged patches separated by neutral and positively charged residues are visible. 相似文献
133.
Interest in Ru anticancer drugs has been growing rapidly since NAMI-A ((ImH(+))[Ru(III)Cl(4)(Im)(S-dmso)], where Im = imidazole and S-dmso = S-bound dimethylsulfoxide) or KP1019 ((IndH(+))[Ru(III)Cl(4)(Ind)(2)], where Ind = indazole) have successfully completed phase I clinical trials and an array of other Ru complexes have shown promise for future development. Herein, the recent literature is reviewed critically to ascertain likely mechanisms of action of Ru-based anticancer drugs, with the emphasis on their reactions with biological media. The most likely interactions of Ru complexes are with: (i) albumin and transferrin in blood plasma, the former serving as a Ru depot, and the latter possibly providing active transport of Ru into cells; (ii) collagens of the extracellular matrix and actins on the cell surface, which are likely to be involved in the specific anti-metastatic action of Ru complexes; (iii) regulatory enzymes within the cell membrane and/or in the cytoplasm; and (iv) DNA in the cell nucleus. Some types of Ru complexes can also promote the intracellular formation of free radical species, either through irradiation (photodynamic therapy), or through reactions with cellular reductants. The metabolic pathways involve competition among reduction, aquation, and hydrolysis in the extracellular medium; binding to transport proteins, the extracellular matrix, and cell-surface biomolecules; and diffusion into cells; with the extent to which individual drugs participate in various steps along these pathways being crucial factors in determining whether they are mainly anti-metastatic or cytotoxic. This diversity of modes of action of Ru anticancer drugs is also likely to enhance their anticancer activities and to reduce the potential for them to develop tumour resistance. New approaches to metabolic studies, such as X-ray absorption spectroscopy and X-ray fluorescence microscopy, are required to provide further mechanistic insights, which could lead to the rational design of improved Ru anticancer drugs. 相似文献
134.
Yixuan Gong Evelyn Yao Ronglai Shen Aviva Goel Maria Arcila Julie Teruya-Feldstein Maureen F. Zakowski Stanley Frankel Martin Peifer Roman K. Thomas Marc Ladanyi William Pao 《PloS one》2009,4(10)
Background
The IGF receptor type 1 (IGF-1R) pathway is frequently deregulated in human tumors and has become a target of interest for anti-cancer therapy.Methodology/Principal Findings
We used a panel of 22 non-small cell lung cancer (NSCLC) cell lines to investigate predictive biomarkers of response to R1507, a fully-humanized anti-IGF-1R monoclonal antibody (Ab; Roche). 5 lines were moderately sensitive (25–50% growth inhibition) to R1507 alone. While levels of phospho-IGF-1R did not correlate with drug sensitivity, 4 out of 5 sensitive lines displayed high levels of total IGF-1R versus 1 out of 17 resistant lines (p = 0.003, Fisher''s Exact). Sensitive lines also harbored higher copy numbers of IGF-1R as assessed by independent SNP array analysis. Addition of erlotinib or paclitaxel to R1507 led to further growth inhibition in sensitive but not resistant lines. In one EGFR mutant lung adenocarcinoma cell line (11–18), R1507 and erlotinib co-treatment induced apoptosis, whereas treatment with either drug alone induced only cell cycle arrest. Apoptosis was mediated, in part, by the survival-related AKT pathway. Additionally, immunohistochemical (IHC) staining of total IGF-1R with an anti-total IGF-1R Ab (G11;Ventana) was performed on tissue microarrays (TMAs) containing 270 independent NSCLC tumor samples. Staining intensity was scored on a scale of 0 to 3+. 39.3% of tumors showed medium to high IGF-1R IHC staining (scores of 2+ or 3+, respectively), while 16.7% had scores of 3+.Conclusions/Significance
In NSCLC cell lines, high levels of total IGF-1R are associated with moderate sensitivity to R1507. These results suggest a possible enrichment strategy for clinical trials with anti-IGF-1R therapy. 相似文献135.
Achdout H Arnon TI Markel G Gonen-Gross T Katz G Lieberman N Gazit R Joseph A Kedar E Mandelboim O 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(2):915-923
The NK cell cytotoxic activity is regulated by both inhibitory and activating NK receptors. Thus, changes in the expression levels and in the affinity or avidity of those receptors will have a major effect on the killing of target cells. In this study, we demonstrate that the binding of NK-inhibitory receptors is enhanced after influenza virus infection. Surprisingly, however, no change in the level of class I MHC protein expression was observed on the surface of the infected cells. The increased binding was general, because it was observed in both the killer cell Ig-like receptor 2 domain long tail 1 and leukocyte Ig-like receptor-1. The increased binding was functional, was not dependent on the interaction with viral hemagglutinin-neuraminidase, was not dependent on the glycosylation site, and was not abolished after mutating the transmembrane or cytosolic portions of the class I MHC proteins. Confocal microscopy experiments showed increased binding of NK receptor-coated beads to infected cells expressing the appropriate class I MHC proteins. In addition, specific cell-free bead aggregates covered with class I MHC proteins were observed only in infected cells. We therefore suggest that the influenza virus use a novel mechanism for the inhibition of NK cell activity. This mechanism probably involves the generation of class I MHC complexes in infected cells that cause increased recognition of NK receptors. 相似文献
136.
A comprehensive evolutionary classification of proteins encoded in complete eukaryotic genomes 总被引:5,自引:0,他引:5
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Koonin EV Fedorova ND Jackson JD Jacobs AR Krylov DM Makarova KS Mazumder R Mekhedov SL Nikolskaya AN Rao BS Rogozin IB Smirnov S Sorokin AV Sverdlov AV Vasudevan S Wolf YI Yin JJ Natale DA 《Genome biology》2004,5(2):R7-28
Background
Sequencing the genomes of multiple, taxonomically diverse eukaryotes enables in-depth comparative-genomic analysis which is expected to help in reconstructing ancestral eukaryotic genomes and major events in eukaryotic evolution and in making functional predictions for currently uncharacterized conserved genes.Results
We examined functional and evolutionary patterns in the recently constructed set of 5,873 clusters of predicted orthologs (eukaryotic orthologous groups or KOGs) from seven eukaryotic genomes: Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe and Encephalitozoon cuniculi. Conservation of KOGs through the phyletic range of eukaryotes strongly correlates with their functions and with the effect of gene knockout on the organism's viability. The approximately 40% of KOGs that are represented in six or seven species are enriched in proteins responsible for housekeeping functions, particularly translation and RNA processing. These conserved KOGs are often essential for survival and might approximate the minimal set of essential eukaryotic genes. The 131 single-member, pan-eukaryotic KOGs we identified were examined in detail. For around 20 that remained uncharacterized, functions were predicted by in-depth sequence analysis and examination of genomic context. Nearly all these proteins are subunits of known or predicted multiprotein complexes, in agreement with the balance hypothesis of evolution of gene copy number. Other KOGs show a variety of phyletic patterns, which points to major contributions of lineage-specific gene loss and the 'invention' of genes new to eukaryotic evolution. Examination of the sets of KOGs lost in individual lineages reveals co-elimination of functionally connected genes. Parsimonious scenarios of eukaryotic genome evolution and gene sets for ancestral eukaryotic forms were reconstructed. The gene set of the last common ancestor of the crown group consists of 3,413 KOGs and largely includes proteins involved in genome replication and expression, and central metabolism. Only 44% of the KOGs, mostly from the reconstructed gene set of the last common ancestor of the crown group, have detectable homologs in prokaryotes; the remainder apparently evolved via duplication with divergence and invention of new genes.Conclusions
The KOG analysis reveals a conserved core of largely essential eukaryotic genes as well as major diversification and innovation associated with evolution of eukaryotic genomes. The results provide quantitative support for major trends of eukaryotic evolution noticed previously at the qualitative level and a basis for detailed reconstruction of evolution of eukaryotic genomes and biology of ancestral forms. 相似文献137.
Interactions between the minor groove of the DNA and DNA polymerases appear to play a major role in the catalysis and fidelity of DNA replication. In particular, Arg668 of Escherichia coli DNA polymerase I (Klenow fragment) makes a critical contact with the N-3-position of guanine at the primer terminus. We investigated the interaction between Arg668 and the ring oxygen of the incoming deoxynucleotide triphosphate (dNTP) using a combination of site-specific mutagenesis of the protein and atomic substitution of the DNA and dNTP. Hydrogen bonds from Arg668 were probed with the site-specific mutant R668A. Hydrogen bonds from the DNA were probed with oligodeoxynucleotides containing either guanine or 3-deazaguanine (3DG) at the primer terminus. Hydrogen bonds from the incoming dNTP were probed with (1 'R,3 'R,4 'R)-1-[3-hydroxy-4-(triphosphorylmethyl)cyclopent-1-yl]uracil (dcUTP), an analog of dUTP in which the ring oxygen of the deoxyribose moiety was replaced by a methylene group. We found that the pre-steady-state parameter kpol was decreased 1,600 to 2,000-fold with each of the single substitutions. When the substitutions were combined, there was no additional decrease (R668A and 3DG), a 5-fold decrease (3DG and dcUTP), and a 50-fold decrease (R668A and dcUTP) in kpol. These results are consistent with a hydrogen-bonding fork from Arg668 to the primer terminus and incoming dNTP. These interactions may play an important role in fidelity as well as catalysis of DNA replication. 相似文献
138.
Aronov O Horowitz AT Gabizon A Fuertes MA Pérez JM Gibson D 《Bioconjugate chemistry》2004,15(4):814-823
Carboplatin is a low-molecular-weight anticancer drug that acts by binding to the nuclear DNA of cells. Thus, efficient delivery of the platinum drugs to the nucleus of the cancer cells may enhance the cytotoxicity of the drug. Efficient drug delivery to the nucleus of cancer cells requires three levels of localization: targeting to the cancerous tissue, accumulation in the cancer cells, and intracellular localization in the nucleus. Nuclear localization signals (NLS) are short positively charged basic peptides that actively transport large proteins across the nuclear membrane. We have prepared conjugates in which the NLS is tethered to poly(ethyleneglycol)carboplatin conjugate (NLS-PEG-Pt) and compared their pharmacological properties to those of their untargeted analogues that do not possess the NLS (PEG-Pt). NLS-PEG-Pt conjugates are rapidly internalized into cancer cells and accumulate in the nucleus. Despite their rapid nuclear localization, they form less Pt-DNA adducts than the untargeted analogues, PEG-Pt, and are also less cytotoxic. These results support the hypothesis that carboplatin (unlike cisplatin) may require cytosolic activation prior to its binding to nuclear DNA. 相似文献
139.
Tiran J Ben-Oved N Elan E Slovik Y Leiberman A Weisel-Eichler A Kaplan DM 《Journal of biomechanical engineering》2005,127(6):994-997
Rhinomanometry is a method for measuring nasal resistance for the purpose of providing an objective evaluation of nasal patency. Posterior rhinomanometry is accomplished without the use of a mask, thus allowing the patient to breathe naturally. Here, we report on the improvements we have made to the existing posterior rhinomanometry system. In this system, nasal airflow is measured indirectly by measuring the pressure differential across a small mesh window in the body plethysmograph. We have calibrated this measurement and developed software that automatically provides the correct values for all airflow rates. Also, we have developed software that automatically corrects for the phase shift caused by the plethysmograph structure. These refinements should provide more accurate values for nasal resistance. 相似文献
140.
Ambient temperature perception in plants 总被引:3,自引:0,他引:3
Since plants are sessile they must be able to sense and rapidly respond to changes in ambient temperature. Key aspects of plant development, including the transition to flowering and the circadian clock, have important inputs from ambient temperature. In the model system Arabidopsis thaliana, molecular candidates for mediating these roles have recently been uncovered, which will be critical for obtaining an understanding of the mechanisms involved. 相似文献