229 research outputs found
Analysis of X-inactivation status in a Rett syndrome natural history study cohort
BACKGROUND: Rett syndrome (RTT) is a rare neurodevelopmental disorder associated with pathogenic MECP2 variants. Because the MECP2 gene is subject to X-chromosome inactivation (XCI), factors including MECP2 genotypic variation, tissue differences in XCI, and skewing of XCI all likely contribute to the clinical severity of individuals with RTT.
METHODS: We analyzed the XCI patterns from blood samples of 320 individuals and their mothers. It includes individuals with RTT (n = 287) and other syndromes sharing overlapping phenotypes with RTT (such as CDKL5 Deficiency Disorder [CDD, n = 16]). XCI status in each proband/mother duo and the parental origin of the preferentially inactivated X chromosome were analyzed.
RESULTS: The average XCI ratio in probands was slightly increased compared to their unaffected mothers (73% vs. 69%, p = .0006). Among the duos with informative XCI data, the majority of individuals with classic RTT had their paternal allele preferentially inactivated (n = 180/220, 82%). In sharp contrast, individuals with CDD had their maternal allele preferentially inactivated (n = 10/12, 83%). Our data indicate a weak positive correlation between XCI skewing ratio and clinical severity scale (CSS) scores in classic RTT patients with maternal allele preferentially inactivated XCI (r
CONCLUSION: These results extend our understanding of the pathogenesis of RTT and other syndromes with overlapping clinical features by providing insight into the both XCI and the preferential XCI of parental alleles
The Drosophila Fry protein interacts with Trc and is highly mobile in vivo
<p>Abstract</p> <p>Background</p> <p>Cell polarity is a common feature of eukaryotic cells. The NDR kinases have been found to regulate polarized growth in both animal cells and fungi. Drosophila Tricornered is an NDR kinase that is essential for the normal polarized growth of extensions of epidermal cells and for the tiling and branching of dendrites of da sensory neurons. Tricornered function requires interacting with the large Furry protein (3479 amino acid).</p> <p>Results</p> <p>We constructed a <it>furry </it>(<it>fry</it>) transgene and established that it rescued the lethality of <it>fry </it>null mutations. The encoded protein was tagged at both its amino and carboxy termini and this allowed us to demonstrate that the protein existed as an uncleaved protein in vivo. We used the C terminal GFP tag to follow the protein in vivo and found it to be highly mobile. Interestingly Fry accumulated at the distal tip of growing bristles. We established that Fry and Trc could be co-immunoprecipitated from wing discs.</p> <p>Conclusions</p> <p>The mobility of Fry in both bristles and dendrites suggests that it could function in directing/mediating the intracellular transport needed for polarized growth. Our observations that full length Fry and Trc show only partial co-localization in growing bristles while an amino terminal fragment of Fry shows close to complete co-localization with Trc suggests that the interaction between these proteins is transient and regulated.</p
Stereoselective Regulations of P-Glycoprotein by Ginsenoside Rh2 Epimers and the Potential Mechanisms From the View of Pharmacokinetics
Chirality is an interesting topic and it is meaningful to explore the interactions between chiral small molecules and stereoselective biomacromolecules, with pre-clinical and clinical significances. We have previously demonstrated that 20(S)-ginsenoside Rh2 is an effective P-glycoprotein (P-gp) inhibitor in vitro and in vivo. Considering the stereochemistry of ginsenoside Rh2, in our present study, the regulatory effects of 20(R)-Rh2 on P-gp were assayed in vivo, and the differential regulations of P-gp by ginsenoside Rh2 epimers in vivo were compared and studied. Results showed that 20(S)-Rh2 enhanced the oral absorption of digoxin in rats in a dose-dependent manner; 20(R)-Rh2 at low dosage increased the oral absorption of digoxin, but this effect diminished with elevated dosage of 20(R)-Rh2. Further studies indicated stereoselective pharmacokinetic profiles and intestinal biotransformations of Rh2 epimers. In vitro studies showed that Rh2 epimers and their corresponding deglycosylation metabolites protopanaxadiol (Ppd) epimers all exhibited stereoselective regulations of P-gp. In conclusion, in view of the in vitro and in vivo dispositions of Rh2 and the regulations of P-gp by Rh2 and Ppd, it is suggested that the P-gp regulatory effect of Rh2 in vivo actually is a double actions of both Rh2 and Ppd, and the net effect is determined by the relative balance between Rh2 and Ppd with the same configuration. Our study provides new evidence of the chiral characteristics of P-gp, and is helpful to elucidate the stereoselective P-gp regulation mechanisms of ginsenoside Rh2 epimers in vivo from a pharmacokinetic view
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Diacenaphthylene-fused benzo[1,2-b:4,5-b‘]dithiophenes: polycyclic heteroacenes containing full-carbon five-membered aromatic rings
We herein report on an efficient synthesis of diacenaphthylenefused benzo[1,2-b:4,5-b’]dithiphenes and demonstrate that their packing structure in the solid state depends on the substituent groups. These compounds form dimers with their radical cations in high solution concentration and display good field-effect mobility
The Dynamics of an Impulsive Predator-Prey System with Stage Structure and Holling Type III Functional Response
Based on the biological resource management of natural resources, a stage-structured predator-prey model with Holling type III functional response, birth pulse, and impulsive harvesting at different moments is proposed in this paper. By applying comparison theorem and some analysis techniques, the global attractivity of predator-extinction periodic solution and the permanence of this system are studied. At last, examples and numerical simulations are given to verify the validity of the main results
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Auxin response factor 6A regulates photosynthesis, sugar accumulation, and fruit development in tomato.
Auxin response factors (ARFs) are involved in auxin-mediated transcriptional regulation in plants. In this study, we performed functional characterization of SlARF6A in tomato. SlARF6A is located in the nucleus and exhibits transcriptional activator activity. Overexpression of SlARF6A increased chlorophyll contents in the fruits and leaves of tomato plants, whereas downregulation of SlARF6A decreased chlorophyll contents compared with those of wild-type (WT) plants. Analysis of chloroplasts using transmission electron microscopy indicated increased sizes of chloroplasts in SlARF6A-overexpressing plants and decreased numbers of chloroplasts in SlARF6A-downregulated plants. Overexpression of SlARF6A increased the photosynthesis rate and accumulation of starch and soluble sugars, whereas knockdown of SlARF6A resulted in opposite phenotypes in tomato leaves and fruits. RNA-sequence analysis showed that regulation of SlARF6A expression altered the expression of genes involved in chlorophyll metabolism, photosynthesis and sugar metabolism. SlARF6A directly bound to the promoters of SlGLK1, CAB, and RbcS genes and positively regulated the expression of these genes. Overexpression of SlARF6A also inhibited fruit ripening and ethylene production, whereas downregulation of SlARF6A increased fruit ripening and ethylene production. SlARF6A directly bound to the SAMS1 promoter and negatively regulated SAMS1 expression. Taken together, these results expand our understanding of ARFs with regard to photosynthesis, sugar accumulation and fruit development and provide a potential target for genetic engineering to improve fruit nutrition in horticulture crops
Extracorporeal Delivery of a Therapeutic Enzyme
To remove circulating harmful small biochemical(s)/substrates causing/deteriorating certain chronic disease, therapeutic enzyme(s) delivered via vein injection/infusion suffer(s) from immunoresponse after repeated administration at proper intervals for a long time and short half-lives since delivery. Accordingly, a novel, generally-applicable extracorporeal delivery of a therapeutic enzyme is proposed, by refitting a conventional hemodialysis device bearing a dialyzer, two pumps and connecting tubes, to build a routine extracorporeal blood circuit but a minimal dialysate circuit closed to circulate the therapeutic enzyme in dialysate. A special quantitative index was derived to reflect pharmacological action and thus pharmacodynamics of the delivered enzyme. With hyperuricemic blood in vitro and hyperuricemic geese, a native uricase via extracorporeal delivery was active in the dialysate for periods much longer than that in vivo through vein injection, and exhibited the expected pharmacodynamics to remove uric acid in hyperuricemic blood in vitro and multiple forms of uric acid in hyperuricemic geese. Therefore, the extracorporeal delivery approach of therapeutic enzymes was effective to remove unwanted circulating small biochemical(s)/substrates, and was expected to avoid immunogenicity problems of therapeutic enzymes after repeated administration at proper intervals for a long time due to no contacts with macromolecules and cells in the body
Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis
Introduction: Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases. The aim of the study was to investigate the expression pattern and function of miRNAs in CD4 + T cells from patients with rheumatoid arthritis (RA).Methods: The expression profile of miRNAs in CD4 + T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis. The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis. The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry. A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.Results: miRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4 + T cells of RA patients. The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-α), and in vitro studies showed TNF-α upregulated miR-146a expression in T cells. Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis. Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.Conclusions: We have detected increased miR-146a in CD4 + T cells of RA patients and its close correlation with TNF-α levels. Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets. © 2010 Li et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.published_or_final_versio
Superparamagnetic core-shell polymer particles for efficient purification of his-tagged proteins
地址:
1. Xiamen Univ, Coll Chem & Chem Engn, State Key Lab Phys Chem Solid Surfaces, Xiamen 361005, Peoples R China
2. Xiamen Univ, Coll Chem & Chem Engn, Dept Chem, Xiamen 361005, Peoples R China
电子邮件地址: [email protected] core-shell Fe3O4@SiO2@poly(styrene-alt-maleic anhydride) spheres enriched with Ni-NTA on their surface have been prepared by precipitation polymerization. The spheres have a core composed of superparamagnetic polycrystalline magnetite having a uniform size of similar to 220 nm, endowing the spheres with excellent magnetic responsivity and dispersity. The shell composition of poly(styrene-alt-maleic anhydride) allows the incorporation of more Ni-NTA affinity sites onto the surface of the magnetic spheres. Owing to the multivalency effect, the separation capacity of His-tagged proteins by the as-prepared Fe3O4@SiO2@polymer/Ni-NTA composites was four times as that by Fe3O4@SiO2/Ni-NTA, making them particularly promising for the magnetic separation of low-concentration His-tagged proteins. The magnentic polymer hybrid particles also exhibited excellent performance in the direct separation of His-tagged proteins from cells lysates.NSFC 20925103,20871100,20721001
Fok Ying Tung Education Foundation, 121011
MSTC,2009CB930703;NSF of Fujian Province 2009J06005; Key Scientific Project of Fujian Province 2009HZ0002-
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