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101.
We are examining various plant-based systems to produce enzymes for the treatment of human lysosomal storage disorders. Constitutive expression of the gene encoding the human lysosomal enzyme, alpha-L-iduronidase (IDUA; EC 3.2.1.76) in leaves of transgenic tobacco plants resulted in low-enzyme activity, and the protein appeared to be subject to proteolysis. Toward enhancing production of this recombinant enzyme in vegetative tissues, transgenic tobacco plants were generated to co-express a CaMV35S:Chamaecyparis nootkatensis Abscisic Acid Insensitive3 (CnABI3) gene construct, along with the human gene construct. The latter contained regulatory sequences of the Phaseolus vulgaris arcelin 5-I gene (5'-flanking, signal-peptide-encoding, and 3'-flanking regions). Ectopic synthesis of the CnABI3 protein led to the transactivation of the arcelin promoter and accordingly high activity (e.g., 25,000 pmol/min/mg total soluble protein) and levels of recombinant IDUA mRNA and protein were induced in leaves of transgenic tobacco, particularly in the presence of 150-200 microM S-(+)-ABA. Synthesis of human IDUA containing a carboxy-terminal ER retention (SEKDEL) sequence was also inducible by ABA in leaves co-transformed with the CnABI3 gene. As compared to the natural S-(+)-ABA, two persistent ABA analogues, (+)-8' acetylene ABA and (+)-8'methylene ABA, led to greater levels of beta-glucuronidase (GUS) reporter activities in leaves co-expressing the CnABI3 gene and a vicilin:GUS chimeric gene. In contrast, (+)-8' acetylene ABA and natural ABA appeared to be equally effective in stimulating the CnABI3-induced expression of an arcelin:GUS gene, and of the human IDUA gene, the latter also driven by arcelin-gene-regulatory sequences. Various stress-related treatments, particularly high concentrations of NaCl, had an even greater effect than ABA in promoting accumulation of human IDUA in co-transformed tobacco leaves. This strategy provides the means of enhancing the yields of recombinant proteins in transgenic plant vegetative tissues and potentially in cultured plant cells. The human recombinant protein can be readily induced in the presence of chemicals such as NaCl that can be added to cell cultures or even whole plants without a significant increase in production costs. 相似文献
102.
Broughton SK Chen H Riddle A Kuhn SE Nagalla S Roberts CT Back SA 《Journal of neurochemistry》2007,100(3):628-638
Multipotent neural stem cells (NSCs) are competent for commitment to the oligodendrocyte (OL) lineage both in vitro and in vivo. We exploited this property to develop a rat neurospheres (NS)/oligospheres (OS)-based culture system to generate large numbers of highly enriched late OL progenitors (preOLs) and mature OLs (MatOLs). CNS neuroblastoma cell line B104-derived conditioned medium promoted the generation of nearly pure populations of preOLs from dissociated OS. The subsequent culture of preOLs with ciliary neurotrophic factor (CNTF) and 3,3',5'-triiodo-L-thyronine (T(3)) generated nearly pure populations of MatOLs. OL lineage specificity was confirmed by immunocytochemistry, quantitative RT-PCR and gene expression profiling, which demonstrated large differences between preOLs and MatOLs. The insulin-like growth factors (IGFs) are potent neuro-protective agents required for OL survival. We used this system to systematically define maturation-dependent changes in IGF signaling during the course of OL differentiation. The IGF-I and insulin receptors, insulin receptor substrate-1 (IRS-1) and IRS-2, protein kinase B (PKB)/Akt and Janus kinase (JNK) were expressed at higher levels in NS and preOLs compared with OS and MatOLs. Erk expression increased markedly from NS to OS, decreased only partially upon commitment to preOLs, and, in MatOLs, returned to a low level similar to NS. IGF activation of the generally proliferative Erk pathway was gradually acquired during NSC differentiation, whereas IGF activation of the generally pro-survival, anti-apoptotic PI3K/PKB pathway was consistently robust at each developmental stage. 相似文献
103.
Muscle geometry affects accuracy of forearm volume determination by magnetic resonance imaging (MRI) 总被引:1,自引:0,他引:1
Upper extremity musculoskeletal modeling is becoming increasingly sophisticated, creating a growing need for subject-specific muscle size parameters. One method for determining subject-specific muscle volume is magnetic resonance imaging (MRI). The purpose of this study was to determine the validity of MRI-derived muscle volumes in the human forearm across a variety of muscle sizes and shapes. Seventeen cadaveric forearms were scanned using a fast-spoiled gradient echo pulse sequence with high isotropic spatial resolution (1mm(3) voxels) on a 3T MR system. Pronator teres (PT), extensor carpi radialis brevis (ECRB), extensor pollicis longus (EPL), flexor carpi ulnaris (FCU), and brachioradialis (BR) muscles were manually segmented allowing volume to be calculated. Forearms were then dissected, muscles isolated, and muscle masses obtained, which allowed computation of muscle volume. Intraclass correlation coefficients (ICC(2,1)) and absolute volume differences were used to compare measurement methods. There was excellent agreement between the anatomical and MRI-derived muscle volumes (ICC = 0.97, relative error = 12.8%) when all 43 muscles were considered together. When individual muscles were considered, there was excellent agreement between measurement methods for PT (ICC = 0.97, relative error = 8.4%), ECRB (ICC = 0.93, relative error = 7.7%), and FCU (ICC = 0.91, relative error = 9.8%), and fair agreement for EPL (ICC = 0.68, relative error = 21.6%) and BR (ICC = 0.93, relative error = 17.2%). Thus, while MRI-based measurements of muscle volume produce relatively small errors in some muscles, muscles with high surface area-to-volume ratios may predispose them to segmentation error, and, therefore, the accuracy of these measurements may be unacceptable. 相似文献
104.
Abrams PA 《The American naturalist》2007,169(5):581-594
The role of habitat choice behavior in the dynamics of predator-prey systems is explored using simple mathematical models. The models assume a three-species food chain in which each population is distributed across two or more habitats. The predator and prey adjust their locations dynamically to maximize individual per capita growth, while the prey's resource has a low rate of random movement. The two consumer species have Type II functional responses. For many parameter sets, the populations cycle, with predator and prey "chasing" each other back and forth between habitats. The cycles are driven by the aggregation of prey, which is advantageous because the predator's saturating functional response induces a short-term positive density dependence in prey fitness. The advantage of aggregation in a patch is only temporary because resources are depleted and predators move to or reproduce faster in the habitat with the largest number of prey, perpetuating the cycle. Such spatial cycling can stabilize population densities and qualitatively change the responses of population densities to environmental perturbations. These models show that the coupled processes of moving to habitats with higher fitness in predator and prey may often fail to produce ideal free distributions across habitats. 相似文献
105.
Hay BA Abrams B Zumbrunn AY Valentine JJ Warren LC Petras SF Shelly LD Xia A Varghese AH Hawkins JL Van Camp JA Robbins MD Landschulz K Harwood HJ 《Bioorganic & medicinal chemistry letters》2007,17(16):4411-4414
The discovery and efficacy of a series of potent aminopyrrolidineamide-based inhibitors of sterol regulatory element binding protein site-1 protease is described. 相似文献
106.
107.
Trivedi CM Luo Y Yin Z Zhang M Zhu W Wang T Floss T Goettlicher M Noppinger PR Wurst W Ferrari VA Abrams CS Gruber PJ Epstein JA 《Nature medicine》2007,13(3):324-331
In the adult heart, a variety of stresses induce re-expression of a fetal gene program in association with myocyte hypertrophy and heart failure. Here we show that histone deacetylase-2 (Hdac2) regulates expression of many fetal cardiac isoforms. Hdac2 deficiency or chemical histone deacetylase (HDAC) inhibition prevented the re-expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp5f) resulting in constitutive activation of glycogen synthase kinase 3beta (Gsk3beta) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1). In contrast, Hdac2 transgenic mice had augmented hypertrophy associated with inactivated Gsk3beta. Chemical inhibition of activated Gsk3beta allowed Hdac2-deficient adults to become sensitive to hypertrophic stimulation. These results suggest that Hdac2 is an important molecular target of HDAC inhibitors in the heart and that Hdac2 and Gsk3beta are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure. 相似文献
108.
Behavioral economists stress that experiments on judgment and decision-making using economic games should be played with real money if the results are to have generality. Behavior analysts have sometimes disputed this contention and have reported results in which hypothetical rewards and real money have produced comparable outcomes. We review studies that have compared hypothetical and real money and discuss the results of two relevant experiments. In the first, using the Sharing Game developed in our laboratory, subjects' choices differed markedly depending on whether the rewards were real or hypothetical. In the second, using the Ultimatum and Dictator Games, we again found sharp differences between real and hypothetical rewards. However, this study also showed that time off from a tedious task could serve as a reinforcer every bit as potent as money. In addition to their empirical and theoretical contributions, these studies make the methodological point that meaningful studies may be conducted with economic games without spending money: time off from a tedious task can serve as a powerful reward. 相似文献
109.
Lisheng Kong Patrick von Aderkas Stacey J. Owen Tia Wagner Suzanne R. Abrams 《Trees - Structure and Function》2011,25(6):1103-1110
In lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia Engelm.), cone bud initiation within long-shoot buds varies according to genotype. We chose to study hormone profiles of
two genotypes that differed significantly in cone yield. Phytohormone profiles were established by high performance liquid
chromatography–electrospray ionization tandem mass spectrometry in multiple reaction monitoring mode with samples collected
from genotypes 299 and 233, the typically high and low cone producers. Generally, concentrations of trans-zeatin-O-glucoside were higher in genotype 299, whereas dihydrozeatin concentrations were higher in genotype 233. Both isopentenyl
adenine and isopentenyl adenosine were present at higher concentrations in genotype 233. The ratio of total quantifiable zeatin
(Z)-type cytokinins to isopentenyl (iP)-type cytokinins was approximately threefold higher in genotype 299 during female cone
bud differentiation. In genotype 299, ABA concentration was significantly lower than in genotype 233 on the first sampling
date, while the phaseic acid concentration was lower consistently throughout the period investigated. Dihydrophaseic acid
was present in low concentrations in most samples of genotype 233, but was not quantifiable in genotype 299. Our study reveals
that long-shoot buds of the high cone-producing genotype had higher ratios of Z-type cytokinins to iP-type cytokinins than
were found in the low cone-producing genotype. High cone-producing buds also contained less ABA, phaseic acid and dihydrophaseic
acid during female cone bud differentiation. 相似文献
110.
Koltun E Richards S Chan V Nachtigall J Du H Noson K Galan A Aay N Hanel A Harrison A Zhang J Won KA Tam D Qian F Wang T Finn P Ogilvie K Rosen J Mohan R Larson C Lamb P Nuss J Kearney P 《Bioorganic & medicinal chemistry letters》2011,21(22):6773-6777
A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo. 相似文献