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91.
W1282X is a common nonsense mutation among cystic fibrosis patients that results in the production of a truncated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Here we show that the channel activity of the W1282X-CFTR polypeptide is exceptionally low in excised membrane patches at normally saturating doses of ATP and PKA (single channel open probability (PO) < 0.01). However, W1282X-CFTR channels were stimulated by two CFTR modulators, the FDA-approved VX-770 and the dietary compound curcumin. Each of these compounds is an allosteric modulator of CFTR gating that promotes channel activity in the absence of the native ligand, ATP. Although W1282X-CFTR channels were stimulated by VX-770 in the absence of ATP their activities remained dependent on PKA phosphorylation. Thus, activated W1282X-CFTR channels should remain under physiologic control by cyclic nucleotide signaling pathways in vivo. VX-770 and curcumin exerted additive effects on W1282X-CFTR channel gating (opening/closing) in excised patches such that the Po of the truncated channel approached unity (> 0.9) when treated with both modulators. VX-770 and curcumin also additively stimulated W1282X-CFTR mediated currents in polarized FRT epithelial monolayers. In this setting, however, the stimulated W1282X-CFTR currents were smaller than those mediated by wild type CFTR (3–5%) due presumably to lower expression levels or cell surface targeting of the truncated protein. Combining allosteric modulators of different mechanistic classes is worth considering as a treatment option for W1282X CF patients perhaps when coupled with maneuvers to increase expression of the truncated protein. 相似文献
92.
Andras Falus Edward K. Wakeland Thomas J. McConnell Jonathan Gitlin Alexander S. Whitehead Harvey R. Colten M. D. 《Immunogenetics》1987,25(5):290-298
Genes encoding the second component (C2), factor B, and complement protein C4 and Slp (sex-limited protein) are members of the major histocompatibility complex class III gene cluster. In this report we describe isolation of a mouse C2 cDNA clone and its use together with factor B and C4 cDNA clones to examine the S region in a panel of 42 haplotypes in laboratory and wild mice representing 5 species and subspecies of Mus. Conservation of the C2 factor B gene duplex was evidenced by relatively limited polymorphism associated with speciation and nucleotide sequence homology between mouse and human C2 and factor B The C4-Slp gene duplex, on the other hand, showed extensive polymorphism by DNA blot analysis. This polymorphism correlated poorly with the C2/factor B restriction fragment length polymorphism, suggesting independent evolution of these two segments of the S region. Taken together, these data will be of particular importance in studies of mouse strains with abnormal regulation of immune effector systems since the class III gene products are essential for activation of the complement cascade. 相似文献
93.
Dunai A Novak M Chung SA Kayumov L Keszei A Levitan R Shapiro CM 《Obesity (Silver Spring, Md.)》2007,15(7):1749-1757
Objective: Increased physical activity is important given the concern over the growing rates of obesity. The aim of this study is to conduct a controlled investigation of the effects of bright light therapy and exercise on weight loss and body composition in overweight and obese individuals. Research Methods and Procedures: Twenty‐five overweight and obese subjects were assigned to 6 weeks of moderate exercise with or without bright light treatment. Outcome measure included changes in body mass and body composition and ratings of mood, seasonality, and sleep. Results: Body weight decreased significantly with exercise in subjects in the light and non‐light treatment groups, but the change was not significantly different between the groups. Similar results were found for BMI. With exercise, body fat decreased significantly only in the light treatment group. There was a significant effect of the interaction of group by time on body fat composition, but the group by time interaction failed to reach statistical significance for body weight and BMI. Mood scores improved significantly with exercise in the light group, but no significant changes were noted regarding sleep. Discussion: This preliminary study is the first to show that addition of bright light treatment to a 6‐week moderate exercise program can alter body composition by significantly reducing body fat. The reduction in body fat mass is of particular importance, because visceral fat has been particularly implicated as a major factor in the development of the metabolic syndrome. This study is an important step toward finding ways to maximize the effects of exercise. 相似文献
94.
Almo SC Bonanno JB Sauder JM Emtage S Dilorenzo TP Malashkevich V Wasserman SR Swaminathan S Eswaramoorthy S Agarwal R Kumaran D Madegowda M Ragumani S Patskovsky Y Alvarado J Ramagopal UA Faber-Barata J Chance MR Sali A Fiser A Zhang ZY Lawrence DS Burley SK 《Journal of structural and functional genomics》2007,8(2-3):121-140
95.
Predicting the three-dimensional structure of proteins from their amino acid sequences remains a challenging problem in molecular biology. While the current structural coverage of proteins is almost exclusively provided by template-based techniques, the modeling of the rest of the protein sequences increasingly require template-free methods. However, template-free modeling methods are much less reliable and are usually applicable for smaller proteins, leaving much space for improvement. We present here a novel computational method that uses a library of supersecondary structure fragments, known as Smotifs, to model protein structures. The library of Smotifs has saturated over time, providing a theoretical foundation for efficient modeling. The method relies on weak sequence signals from remotely related protein structures to create a library of Smotif fragments specific to the target protein sequence. This Smotif library is exploited in a fragment assembly protocol to sample decoys, which are assessed by a composite scoring function. Since the Smotif fragments are larger in size compared to the ones used in other fragment-based methods, the proposed modeling algorithm, SmotifTF, can employ an exhaustive sampling during decoy assembly. SmotifTF successfully predicts the overall fold of the target proteins in about 50% of the test cases and performs competitively when compared to other state of the art prediction methods, especially when sequence signal to remote homologs is diminishing. Smotif-based modeling is complementary to current prediction methods and provides a promising direction in addressing the structure prediction problem, especially when targeting larger proteins for modeling. 相似文献
96.
Inducible deletion of epidermal Dicer and Drosha reveals multiple functions for miRNAs in postnatal skin 总被引:1,自引:0,他引:1
Teta M Choi YS Okegbe T Wong G Tam OH Chong MM Seykora JT Nagy A Littman DR Andl T Millar SE 《Development (Cambridge, England)》2012,139(8):1405-1416
MicroRNAs (miRNAs) regulate the expression of many mammalian genes and play key roles in embryonic hair follicle development; however, little is known of their functions in postnatal hair growth. We compared the effects of deleting the essential miRNA biogenesis enzymes Drosha and Dicer in mouse skin epithelial cells at successive postnatal time points. Deletion of either Drosha or Dicer during an established growth phase (anagen) caused failure of hair follicles to enter a normal catagen regression phase, eventual follicular degradation and stem cell loss. Deletion of Drosha or Dicer in resting phase follicles did not affect follicular structure or epithelial stem cell maintenance, and stimulation of anagen by hair plucking caused follicular proliferation and formation of a primitive transient amplifying matrix population. However, mutant matrix cells exhibited apoptosis and DNA damage and hair follicles rapidly degraded. Hair follicle defects at early time points post-deletion occurred in the absence of inflammation, but a dermal inflammatory response and hyperproliferation of interfollicular epidermis accompanied subsequent hair follicle degradation. These data reveal multiple functions for Drosha and Dicer in suppressing DNA damage in rapidly proliferating follicular matrix cells, facilitating catagen and maintaining follicular structures and their associated stem cells. Although Drosha and Dicer each possess independent non-miRNA-related functions, the similarity in phenotypes of the inducible epidermal Drosha and Dicer mutants indicates that these defects result primarily from failure of miRNA processing. Consistent with this, Dicer deletion resulted in the upregulation of multiple direct targets of the highly expressed epithelial miRNA miR-205. 相似文献
97.
Czirok A Zach J Kozel BA Mecham RP Davis EC Rongish BJ 《Journal of cellular physiology》2006,207(1):97-106
Elastic fibers are responsible for the extensibility and resilience of many vertebrate tissues, and improperly assembled elastic fibers are implicated in a number of human diseases. It was recently demonstrated that in vitro, cells first secrete tropoelastin into a punctate pattern of globules. To study the dynamics of macroassembly, that is, the assembly of the secreted tropoelastin globules into elastic fibers, we utilized long-term time-lapse immunofluorescence imaging and a tropoelastin p Timer fusion protein, which shifts its fluorescence spectrum over time. Pulse-chase immunolabeling of the fibroblast-like RFL-6 cells demonstrates that tropoelastin globules aggregate in a hierarchical manner, creating progressively larger fibrillar structures. By analyzing the correlation between cell and extracellular matrix movements, we show that both the aggregation process and shaping the aggregates into fibrillar form is coupled to cell motion. We also show that the motion of non-adjacent cells becomes more coordinated as the physical size of elastin-containing aggregates increases. Our data imply that the formation of elastic fibers involves the concerted action and motility of multiple cells. 相似文献
98.
Szigeti A Bellyei S Gasz B Boronkai A Hocsak E Minik O Bognar Z Varbiro G Sumegi B Gallyas F 《FEBS letters》2006,580(27):6447-6454
We found that heme-binding protein 2/SOUL sensitised NIH3T3 cells to cell death induced by A23187 and etoposide, but it did not affect reactive oxygen species formation. In the presence of sub-threshold calcium, recombinant SOUL provoked mitochondrial permeability transition (mPT) in vitro that was inhibited by cyclosporine A (CsA). This effect was verified in vivo by monitoring the dissipation of mitochondrial membrane potential. Flow cytometry analysis showed that SOUL promoted necrotic death in A23187 and etoposide treated cells, which effect was prevented by CsA. These data suggest that besides its heme-binding properties SOUL promotes necrotic cell death by inducing mPT. 相似文献
99.
Cartridge-based high-throughput purification of oligonucleotides for reliable oligonucleotide arrays 总被引:1,自引:0,他引:1
Semenyuk A Ahnfelt M Estmer Nilsson C Yong Hao X Földesi A Kao YS Chen HH Kao WC Peck K Kwiatkowski M 《Analytical biochemistry》2006,356(1):132-141
A novel, cartridge-based procedure for the efficient and irreversible detritylation of oligonucleotides is reported. This method, combined with a process for the elimination of depurinated fragments produces, in a highly parallel fashion, oligonucleotides with better purity than those traditionally obtained using reversed-phase high-performance liquid chromotography purification. Our combined detritylation and purification methodology compares favorably with commercial cartridge-based purification systems. The benefits of working with pure oligonucleotides, with regard to higher signal and better signal linearity, are shown in array-based hybridization experiments. 相似文献
100.
Reshetnyak Y Tchedre KT Nair MP Pritchard PH Lacko AG 《Journal of biomolecular structure & dynamics》2006,24(1):75-82
Fluorescence spectroscopy has been used to investigate the conformational changes that occur upon binding of wild type (WT) and mutant (Thr123Ile) lecithin:cholesterol acyltransferase (LCAT) to the potential substrates (dioleoyl-phosphatidyl choline [DOPC] and high density lipoprotein [HDL]). For a detailed analysis of structural differences between WT and mutant LCAT, we performed decompositional analysis of a set of tryptophan fluorescence spectra, measured at increasing concentrations of external quenchers (acrylamide and KI). The data obtained show that Thr123Ile mutation in LCAT leads to a conformation that is likely to be more rigid (less mobile/flexible) than that of the WT protein with a redistribution of charged residues around exposed tryptophan fluorophores. We propose that the redistribution of charged residues in mutant LCAT may be a major factor responsible for the dramatically reduced activity of the enzyme with HDL and reconstituted high density lipoprotein (rHDL). 相似文献