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101.
Sonali P. Jog Sharan Paul Warunee Dansithong Stephanie Tring Lucio Comai Sita Reddy 《PloS one》2012,7(11)
Myotonic dystrophy (DM1) is a highly variable, multi-system disorder resulting from the expansion of an untranslated CTG tract in DMPK. In DM1 expanded CUG repeat RNAs form hairpin secondary structures that bind and aberrantly sequester the RNA splice regulator, MBNL1. RNA splice defects resulting as a consequence of MBNL1 depletion have been shown to play a key role in the development of DM1 pathology. In patient populations, both the number and severity of DM1 symptoms increase broadly as a function of CTG tract length. However significant variability in the DM1 phenotype is observed in patients encoding similar CTG repeat numbers. Here we demonstrate that a gradual decrease in MBNL1 levels results both in the expansion of the repertoire of splice defects and an increase in the severity of the splice alterations. Thus, MBNL1 loss does not have an all or none outcome but rather shows a graded effect on the number and severity of the ensuing splice defects. Our results suggest that once a critical threshold is reached, relatively small dose variations of free MBNL1 levels, which may reflect modest changes in the size of the CUG tract or the extent of hairpin secondary structure formation, can significantly alter the number and severity of splice abnormalities and thus contribute to the phenotype variability observed in DM1 patients. 相似文献
102.
E. Arthur Bettis III Adrianne K. Milius Roy Larick Yan Rizal Stephanie A. Tassier-Surine Suminto 《Journal of human evolution》2009,56(1):11-19568
A sequence of paleosols in the Solo Basin, Central Java, Indonesia, documents the local and regional environments present when Homo erectus spread through Southeast Asia during the early Pleistocene. The earliest human immigrants encountered a low-relief lake-margin landscape dominated by moist grasslands with open woodlands in the driest landscape positions. By 1.5 Ma, large streams filled the lake and the landscape became more riverine in nature, with riparian forests, savanna, and open woodland. Paleosol morphology and carbon isotope values of soil organic matter and pedogenic carbonates indicate a long-term shift toward regional drying or increased duration of the annual dry season through the early Pleistocene. This suggests that an annual dry season associated with monsoon conditions was an important aspect of the paleoclimate in which early humans spread from Africa to Southeast Asia. 相似文献
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Farooqahmed S. Kittur Mamudou Bah Stephanie Archer-Hartmann Chiu-Yueh Hung Parastoo Azadi Mayumi Ishihara David C. Sane Jiahua Xie 《PloS one》2013,8(10)
Asialo-erythropoietin, a desialylated form of human erythropoietin (EPO) lacking hematopoietic activity, is receiving increased attention because of its broader protective effects in preclinical models of tissue injury. However, attempts to translate its protective effects into clinical practice is hampered by unavailability of suitable expression system and its costly and limit production from expensive mammalian cell-made EPO (rhuEPOM) by enzymatic desialylation. In the current study, we took advantage of a plant-based expression system lacking sialylating capacity but possessing an ability to synthesize complex N-glycans to produce cytoprotective recombinant human asialo-rhuEPO. Transgenic tobacco plants expressing asialo-rhuEPO were generated by stably co-expressing human EPO and β1,4-galactosyltransferase (GalT) genes under the control of double CaMV 35S and glyceraldehyde-3-phosphate gene (GapC) promoters, respectively. Plant-produced asialo-rhuEPO (asialo-rhuEPOP) was purified by immunoaffinity chromatography. Detailed N-glycan analysis using NSI-FTMS and MS/MS revealed that asialo-rhuEPOP bears paucimannosidic, high mannose-type and complex N-glycans. In vitro cytoprotection assays showed that the asialo-rhuEPOP (20 U/ml) provides 2-fold better cytoprotection (44%) to neuronal-like mouse neuroblastoma cells from staurosporine-induced cell death than rhuEPOM (21%). The cytoprotective effect of the asialo-rhuEPOP was found to be mediated by receptor-initiated phosphorylation of Janus kinase 2 (JAK2) and suppression of caspase 3 activation. Altogether, these findings demonstrate that plants are a suitable host for producing cytoprotective rhuEPO derivative. In addition, the general advantages of plant-based expression system can be exploited to address the cost and scalability issues related to its production. 相似文献
106.
We describe a novel 3D fibrin matrix model using recombinant hematopoietic stem cell cytokines under serum-free defined conditions which promotes the assembly of human endothelial cell (EC) tubes with co-associated pericytes. Individual ECs and pericytes are randomly mixed together and EC tubes form that is accompanied by pericyte recruitment to the EC tube abluminal surface over a 3-5 day period. These morphogenic processes are stimulated by a combination of the hematopoietic stem cell cytokines, stem cell factor, interleukin-3, stromal derived factor-1α, and Flt-3 ligand which are added in conjunction with fibroblast growth factor (FGF)-2 into the fibrin matrix. In contrast, this tube morphogenic response does not occur under serum-free defined conditions when VEGF and FGF-2 are added together in the fibrin matrices. We recently demonstrated that VEGF and FGF-2 are able to prime EC tube morphogenic responses (i.e. added overnight prior to the morphogenic assay) to hematopoietic stem cell cytokines in collagen matrices and, interestingly, they also prime EC tube morphogenesis in 3D fibrin matrices. EC-pericyte interactions in 3D fibrin matrices leads to marked vascular basement membrane assembly as demonstrated using immunofluorescence and transmission electron microscopy. Furthermore, we show that hematopoietic stem cell cytokines and pericytes stimulate EC sprouting in fibrin matrices in a manner dependent on the α5β1 integrin. This novel co-culture system, under serum-free defined conditions, allows for a molecular analysis of EC tube assembly, pericyte recruitment and maturation events in a critical ECM environment (i.e. fibrin matrices) that regulates angiogenic events in postnatal life. 相似文献
107.
This review explores the body of scientific information available on the antimicrobial properties of essential oils against pathogens responsible for respiratory infections and critically compares this to what is recommended in the Layman's aroma‐therapeutic literature. Essential oils are predominantly indicated for the treatment of respiratory infections caused by bacteria or viruses (total 79.0 %), the efficacy of which has not been confirmed through clinical trials. When used in combination, they are often blended for presumed holistic synergistic effects. Of the essential oils recommended, all show some degree of antioxidant activity, 50.0 % demonstrate anti‐inflammatory effects and 83.3 % of the essential oils showed antihistaminic activity. Of the essential oils reviewed, 43.8 % are considered non‐toxic while the remaining essential oils are considered slightly to moderately toxic (43.7 %) or the toxicity is unknown (12.5 %). Recommendations are made for further research into essential oil combinations. 相似文献
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Many Listeria species including L. monocytogenes contain the pathway for the biosynthesis of protocatechuate from shikimate and quinate. The qui1 and qui2 operons within these Listeria spp. encode enzymes for this pathway. The diversion of shikimate pathway intermediates in some Listeria species to produce protocatechuate suggests an important biological role for this compound to these organisms. A total of seven ORFs, including quiC2, were identified within qui1 and qui2, however only three proteins encoded by the operons have been functionally annotated. The final step in Listeria's protocatechuate biosynthesis involves the conversion of dehydroshikimate by a dehydroshikimate dehydratase (DSD). In this study, we demonstrate that QuiC2 functions as a DSD in Listeria spp. through biochemical and structural analyses. Moreover, we show that QuiC2 forms a phylogenetic cluster distinct from other functionally annotated DSDs. The individual phylogenetic clusters of DSD are represented by enzymes that produce protocatechuate for distinct biological processes. Similarly, QuiC2 is expected to produce protocatechuate for a novel biological process. We postulate that protocatechuate produced by DSDs found within the QuiC2 phylogenetic cluster provides an ecological niche for representative organisms. 相似文献
110.
Johanna Marin‐Carbonne Vincent Busigny Jennyfer Miot Claire Rollion‐Bard Elodie Muller Nadja Drabon Damien Jacob Sylvain Pont Martin Robyr Tomaso R. R. Bontognali Camille Franois Stephanie Reynaud Mark Van Zuilen Pascal Philippot 《Geobiology》2020,18(3):306-325
On the basis of phylogenetic studies and laboratory cultures, it has been proposed that the ability of microbes to metabolize iron has emerged prior to the Archaea/Bacteria split. However, no unambiguous geochemical data supporting this claim have been put forward in rocks older than 2.7–2.5 giga years (Gyr). In the present work, we report in situ Fe and S isotope composition of pyrite from 3.28‐ to 3.26‐Gyr‐old cherts from the upper Mendon Formation, South Africa. We identified three populations of microscopic pyrites showing a wide range of Fe isotope compositions, which cluster around two δ56Fe values of ?1.8‰ and +1‰. These three pyrite groups can also be distinguished based on the pyrite crystallinity and the S isotope mass‐independent signatures. One pyrite group displays poorly crystallized pyrite minerals with positive Δ33S values > +3‰, while the other groups display more variable and closer to 0‰ Δ33S values with recrystallized pyrite rims. It is worth to note that all the pyrite groups display positive Δ33S values in the pyrite core and similar trace element compositions. We therefore suggest that two of the pyrite groups have experienced late fluid circulations that have led to partial recrystallization and dilution of S isotope mass‐independent signature but not modification of the Fe isotope record. Considering the mineralogy and geochemistry of the pyrites and associated organic material, we conclude that this iron isotope systematic derives from microbial respiration of iron oxides during early diagenesis. Our data extend the geological record of dissimilatory iron reduction (DIR) back more than 560 million years (Myr) and confirm that micro‐organisms closely related to the last common ancestor had the ability to reduce Fe(III). 相似文献