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21.
MicroRNA-486-3p Regulates γ-Globin Expression in Human Erythroid Cells by Directly Modulating BCL11A
Valentina Lulli Paolo Romania Ornella Morsilli Paolo Cianciulli Marco Gabbianelli Ugo Testa Alessandro Giuliani Giovanna Marziali 《PloS one》2013,8(4)
MicroRNAs (miRNAs) play key roles in modulating a variety of cellular processes through repression of mRNAs target. The functional relevance of microRNAs has been proven in normal and malignant hematopoiesis. While analyzing miRNAs expression profile in unilineage serum-free liquid suspension unilineage cultures of peripheral blood CD34+ hematopoietic progenitor cells (HPCs) through the erythroid, megakaryocytic, granulocytic and monocytic pathways, we identified miR-486-3p as mainly expressed within the erythroid lineage. We showed that miR-486-3p regulates BCL11A expression by binding to the extra-long isoform of BCL11A 3′UTR. Overexpression of miR-486-3p in erythroid cells resulted in reduced BCL11A protein levels, associated to increased expression of γ-globin gene, whereas inhibition of physiological miR-486-3p levels increased BCL11A and, consequently, reduced γ-globin expression. Thus, miR-486-3p regulating BCL11A expression might contributes to fetal hemoglobin (HbF) modulation and arise the question as to what extent this miRNA might contribute to different HbF levels observed among β-thalassemia patients. Erythroid cells, differentiated from PB CD34+ cells of a small cohort of patients affected by major or intermedia β-thalassemia, showed miR-486-3p levels significantly higher than those observed in normal counterpart. Importantly, in these patients, miR-486-3p expression correlates with increased HbF synthesis. Thus, our data indicate that miR-486-3p might contribute to different HbF levels observed among thalassemic patients and, possibly, to the clinical severity of the disease. 相似文献
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Giovanna Poce Robert H. Bates Salvatore Alfonso Martina Cocozza Giulio Cesare Porretta Lluís Ballell Joaquin Rullas Fátima Ortega Alessandro De Logu Emanuela Agus Valentina La Rosa Maria Rosalia Pasca Edda De Rossi Baojie Wae Scott G. Franzblau Fabrizio Manetti Maurizio Botta Mariangela Biava 《PloS one》2013,8(2)
1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in
vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED99 of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery. 相似文献
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Silvia Rossi Valeria Studer Alessandro Moscatelli Caterina Motta Giancarlo Coghe Giuseppe Fenu Stacy Caillier Fabio Buttari Francesco Mori Francesca Barbieri Maura Castelli Valentina De Chiara Fabrizia Monteleone Raffaele Mancino Giorgio Bernardi Sergio E. Baranzini Maria G. Marrosu Jorge R. Oksenberg Diego Centonze 《PloS one》2013,8(6)
Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao’s brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms. 相似文献
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Barbara Cheney Paul M. Thompson Simon N. Ingram Philip S. Hammond Peter T. Stevick John W. Durban Ross M. Culloch Simon H. Elwen Laura Mandleberg Vincent M. Janik Nicola J. Quick Valentina ISLAS‐Villanueva Kevin P. Robinson Marina Costa Sonja M. Eisfeld Alice Walters Charlie Phillips Caroline R. Weir Peter G.H. Evans Pia Anderwald Robert J. Reid James B. Reid Ben Wilson 《Mammal Review》2013,43(1):71-88
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Nina Gabarayeva Valentina Grigorjeva Yana Kosenko 《Plant Systematics and Evolution》2013,299(6):1013-1035
Developmental stages during the tetrad period were examined in detail by transmission electron microscopy with an emphasis on substructure. Our purpose was to find out whether the sequence of sporoderm developmental events provides additional evidence for our recent hypothesis on the underlying cause of exine ontogeny as a sequence of self-assembling micellar mesophases initiated by genomically given physicochemical parameters. Osmiophilic globules encrusting the surface of postmeiotic microspores and tapetal cells are temporary prepattern units which come first. The second prepattern structures are highly ordered bundles of microfilaments and microtubules which determine the position of microspore surface invaginations and clusters of the glycocalyx inside them. The first glycocalyx units are microgranules which during the middle tetrad stage rearrange into radially oriented rod-like units. The latter form lens-like clusters of the glycocalyx-1, located inside the invaginations. These clusters predestine the position of the future luminae in the exine reticulum. The second glycocalyx layer is laid down as a continuous layer over the whole microspore surface and has similar substructure, that is radial rods. Glycocalyx-2 is a framework for procolumellae which appear at the late tetrad stage. Therefore, the sequence of substructural units in the primexine is: globules, microgranules, rod-like units, and layers of radially oriented rods tightly packed in the periplasmic space. This sequence corresponds to the first three mesophases of self-assembling micelles: spherical micelles, cylindrical micelles, and layers of hexagonally packed cylindrical micelles (middle mesophase). We observed the same sequence in other species during primexine development, and the findings of this study provide new evidence for our hypothesis. 相似文献