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571.
Gene expression as an intermediate molecular phenotype has been a focus of research interest. In particular, studies of expression quantitative trait loci (eQTL) have offered promise for understanding gene regulation through the discovery of genetic variants that explain variation in gene expression levels. Existing eQTL methods are designed for assessing the effects of common variants, but not rare variants. Here, we address the problem by establishing a novel analytical framework for evaluating the effects of rare or private variants on gene expression. Our method starts from the identification of outlier individuals that show markedly different gene expression from the majority of a population, and then reveals the contributions of private SNPs to the aberrant gene expression in these outliers. Using population-scale mRNA sequencing data, we identify outlier individuals using a multivariate approach. We find that outlier individuals are more readily detected with respect to gene sets that include genes involved in cellular regulation and signal transduction, and less likely to be detected with respect to the gene sets with genes involved in metabolic pathways and other fundamental molecular functions. Analysis of polymorphic data suggests that private SNPs of outlier individuals are enriched in the enhancer and promoter regions of corresponding aberrantly-expressed genes, suggesting a specific regulatory role of private SNPs, while the commonly-occurring regulatory genetic variants (i.e., eQTL SNPs) show little evidence of involvement. Additional data suggest that non-genetic factors may also underlie aberrant gene expression. Taken together, our findings advance a novel viewpoint relevant to situations wherein common eQTLs fail to predict gene expression when heritable, rare inter-individual variation exists. The analytical framework we describe, taking into consideration the reality of differential phenotypic robustness, may be valuable for investigating complex traits and conditions.  相似文献   
572.
The biology of modern Conidae (cone snails)—which includes the hyperdiverse genus Conus—has been intensively studied, but the fossil record of the clade remains poorly understood, particularly within an evolutionary framework. Here, ultraviolet light is used to reveal and characterize the original shell coloration patterns of 28 species of cone snails from three Neogene coral reef-associated deposits from the Cibao Valley, northern Dominican Republic. These fossils come from the upper Miocene Cercado Fm. and lower Pliocene Gurabo Fm., and range in age from about 6.6-4.8 Ma. Comparison of the revealed coloration patterns with those of extant species allow the taxa to be assigned to three genera of cone snails (Profundiconus, Conasprella, and Conus) and at least nine subgenera. Thirteen members of these phylogenetically diverse reef faunas are described as new species. These include: Profundiconus? hennigi, Conasprella (Ximeniconus) ageri, Conus anningae, Conus lyelli, Conus (Atlanticonus?) franklinae, Conus (Stephanoconus) gouldi, Conus (Stephanoconus) bellacoensis, Conus (Ductoconus) cashi, Conus (Dauciconus) garrisoni, Conus (Dauciconus?) zambaensis, Conus (Spuriconus?) kaesleri, Conus (Spuriconus?) lombardii, and Conus (Lautoconus?) carlottae. Each of the three reef deposits contain a minimum of 14–16 cone snail species, levels of diversity that are similar to modern Indo-Pacific reef systems. Finally, most of the 28 species can be assigned to modern clades and thus have important implications for understanding the biogeographic and temporal histories of these clades in tropical America.  相似文献   
573.
Urokinase plasminogen activator receptor (uPAR) has been proposed as a potential prognostic factor for colorectal cancer (CRC) patient survival. However, CRC uPAR expression remains controversial, especially regarding cell types where uPAR is overexpressed (e.g., epithelium (uPARE) or stroma-associated cells (uPARS)) and associated prognostic relevance. In this study, two epitope-specific anti-uPAR monoclonal antibodies (MAbs) could discriminate expression of uPARE from uPARS and were used to examine this association with survival of stages B and C rectal cancer (RC) patients. Using immunohistochemistry, MAbs #3937 and R4 were used to discriminate uPARE from uPARS respectively in the central and invasive frontal regions of 170 stage B and 179 stage C RC specimens. Kaplan-Meier and Cox regression analyses were used to determine association with survival. uPAR expression occurred in both epithelial and stromal compartments with differential expression observed in many cases, indicating uPARE and uPARS have different cellular roles. In the central and invasive frontal regions, uPARE was adversely associated with overall stage B survival (HR = 1.9; p = 0.014 and HR = 1.5; p = 0.031, respectively) reproducing results from previous studies. uPARS at the invasive front was associated with longer stage C survival (HR = 0.6; p = 0.007), reflecting studies demonstrating that macrophage peritumoural accumulation is associated with longer survival. This study demonstrates that different uPAR epitopes should be considered as being expressed on different cell types during tumour progression and at different stages in RC. Understanding how uPARE and uPARS expression affects survival is anticipated to be a useful clinical prognostic marker of stages B and C RC.  相似文献   
574.
575.
The insulin receptor of rat brain is coupled to tyrosine kinase activity   总被引:13,自引:0,他引:13  
Insulin receptors from rat brain were studied for receptor-associated tyrosine kinase activity. In solubilized, lectin-purified receptor preparations, insulin stimulated the phosphorylation of the beta subunit of its receptor as well as of exogenous substrates. Phosphoamino acid analysis of casein phosphorylated by these preparations revealed that 32P incorporation occurred predominantly on tyrosine residues. Receptor and casein phosphorylations were specific for insulin and analogues that also bind to the insulin receptor. The insulin dose response for phosphorylation of brain receptor resembled that reported for the purified insulin receptor from human placenta (Kasuga, M., Fujita-Yamaguchi, Y., Blithe, D.L., and Kahn, C.R. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 2137-2141), suggesting similar insulin sensitivity and coupling of the brain receptor kinase. Four polyclonal antisera to the insulin receptor were able to bind and immunoprecipitate the brain receptor; however, only two antisera activated the receptor-associated kinase. Thus, the brain insulin receptor, like the well studied non-neural receptor, is coupled to tyrosine kinase activity, making regulation of cellular events by insulin in neural tissue possible.  相似文献   
576.
The susceptibility of four species of East African nonhuman primates to experimental infection with Leishmania major was investigated. Four Syke's monkeys (Cercopithecus mitis), two vervet monkeys (Cercopithecus aethiops), two baboons (Papio cynocephalus), and two brown bushbabies (Galago garnettii) were each inoculated intradermally on the left eyelid, left ear, and nose with 0.1 ml of medium containing 1 x 10(7) promastigotes of a characterized L. major strain. All the nonhuman primates except the bushbabies developed erythema and conspicuous nodules on the eyelids and ears by 3 weeks PI. The nodules increased rapidly in size and ulceration was evident on the eyelids and ears by 49 days PI in the vervets, Syke's, and baboons. The aspirates were positive in culture or smears at 35, 49, 63, and 77 days PI. No parasites were observed in cultures or smears at 92, 105, 128, 147, and 161 days PI. The lesions in these animals began resolving by 84 days PI and were completely healed by 112 days PI. The exception was one baboon in which lesion healing did not start until around 147 days and was completely healed by 182 days PI. Cultures from the liver failed to demonstrate visceralization of the parasite in any of the animals throughout the 68 weeks of the experiment. Challenge with the same strain of L. major 6 months PI, corresponding to about 3 months after self cure, failed to produce infection in any of these experimental hosts. All the nonhuman primates except the bushbaby when challenged with the same strain of L. major at 12 months PI developed lesions and were positive for parasites at 14 and 28 days PI. Positive cultures were obtained from the eyelid and ear of one vervet up to 42 days PI. However, the lesion sizes in all these animals were smaller than in the initial infection and did not ulcerate. The nodules disappeared within 6 to 8 weeks as compared to 16 weeks in the initial infection. The histopathological appearance of the lesions varied from diffuse infiltration of plasma cells and lymphocytes which increased progressively to granulomata with epitheloid cells. This study shows that the vervets, Syke's, and the baboons are equally susceptible to L. major infection, while bushbabies are refractory. The vervets, Syke's, and baboons demonstrate a self-healing phenomenon within about 3 months which is comparable to that observed in humans infected with L. major. These three species of nonhuman primates are therefore considered as suitable models for drug or vaccine trials against human zoonotic cutaneous leishmaniasis.  相似文献   
577.
The English bulldog: a natural model of sleep-disordered breathing   总被引:10,自引:0,他引:10  
To establish a natural model of sleep-disordered breathing, we investigated respiration during wakefulness and sleep in the English bulldog. This breed is characterized by an abnormal upper airway anatomy, with enlargement of the soft palate and narrowing of the oropharynx. During sleep, the animals had disordered respiration and episodes of O2 desaturation. These were worst in rapid-eye-movement (REM) sleep, with most bulldogs having O2 saturations of less than 90% for prolonged durations. In contrast, control dogs never desaturated. In REM sleep, the bulldogs had episodes of both central and obstructive apnea, the latter being associated with paradoxical movements of the rib cage and abdomen. During wakefulness, the bulldogs were hypersomnolent as evidenced by a shortened sleep latency (mean of 12 min compared with greater than 150 min for controls). This animal model should facilitate studies of the natural history of the sleep apnea syndrome and its complications.  相似文献   
578.
The purposes of this study were 1) to characterize the immediate inspiratory muscle and ventilation responses to inspiratory resistive loading during sleep in humans and 2) to determine whether upper airway caliber was compromised in the presence of a resistive load. Ventilation variables, chest wall, and upper airway inspiratory muscle electromyograms (EMG), and upper airway resistance were measured for two breaths immediately preceding and immediately following six applications of an inspiratory resistive load of 15 cmH2O.l-1 X s during wakefulness and stage 2 sleep. During wakefulness, chest wall inspiratory peak EMG activity increased 40 +/- 15% (SE), and inspiratory time increased 20 +/- 5%. Therefore, the rate of rise of chest wall EMG increased 14 +/- 10.9% (NS). Upper airway inspiratory muscle activity changed in an inconsistent fashion with application of the load. Tidal volume decreased 16 +/- 6%, and upper airway resistance increased 141 +/- 23% above pre-load levels. During sleep, there was no significant chest wall or upper airway inspiratory muscle or timing responses to loading. Tidal volume decreased 40 +/- 7% and upper airway resistance increased 188 +/- 52%, changes greater than those observed during wakefulness. We conclude that 1) the immediate inspiratory muscle and timing responses observed during inspiratory resistive loading in wakefulness were absent during sleep, 2) there was inadequate activation of upper airway inspiratory muscle activity to compensate for the increased upper airway inspiratory subatmospheric pressure present during loading, and 3) the alteration in upper airway mechanics during resistive loading was greater during sleep than wakefulness.  相似文献   
579.
Brefeldin A (BFA) blocks protein export from the endoplasmic reticulum (ER) and causes dismantling of the Golgi cisternae with relocation of resident Golgi proteins to the ER in many cultured cell lines. We examined the effects of BFA on Golgi organization and the distribution of Golgi markers in the rat exocrine pancreas. Immediately after BFA addition, Golgi stacks began to disorganize and Golgi cisternae to vesiculate, and by 15 min no intact Golgi cisternae remained. However, even after prolonged BFA incubation, clusters of small vesicles surrounded by transitional elements of the ER persisted both in the Golgi region and dispersed throughout the apical cytoplasm. These vesicles were morphologically heterogeneous in the density of their content and in the presence of cytoplasmic coats. Immunogold labeling demonstrated that some vesicles within the clusters contained gp58, a cis Golgi marker, and some contained alpha-mannosidase II, a middle/trans Golgi marker in this cell type. Neither marker was detected in the rough ER by immunogold or immunofluorescence labeling. When AlF4- was added during BFA treatment some of the vesicles in the clusters appeared coated. When microsomes were subfractionated into Golgi (light) and rough ER (heavy) fractions on sucrose density gradients, greater than 65% of alpha-mannosidase II and galactosyltransferase activities were found in light fractions (1.14-1.16 g/ml) in both control and BFA-treated lobules. In both cases equally low enzyme activity was recovered in heavier fractions (1.2-1.23 g/ml) containing RNA and alpha-glucosidase activity. However, 5 to 8% of the total recovered RNA consistently codistributed with the Golgi enzyme peak. These results indicate that BFA rapidly inhibits secretion and causes dismantling of the Golgi stacks in pancreatic acinar cells, but clusters of vesicles consisting of bona fide Golgi remnants persist even with prolonged exposure to BFA. Many of the vesicles contain Golgi markers by immunolabeling. By cell fractionation Golgi membrane enzyme activities are recovered in equal amounts in light (Golgi) fractions in both controls and BFA-treated specimens. These findings indicate that in the exocrine pancreas there is a dissociation of BFA's effects on the exocytic pathway: there is a block in transport and Golgi organization is disrupted, but remnant Golgi vesicles and tubules persist and retain Golgi membrane antigens and enzyme activities.  相似文献   
580.
Rainbow trout respond to a range of natural and synthetic dietary tumor modulators. Observed modulations of final tumor incidence include inhibition, promotion and cocarcinogenesis, depending on modulator, carcinogen, target organ, and relative order of carcinogen and modulator exposure. Despite several obvious limitations (e.g. lung, colon, mammary gland, bladder are not available as target organs), the trout model possesses several important features that have made it valuable for tumor modulation studies. (1) The comparative advantage. Since rodents are not perfect human surrogates, studies with alternative vertebrates such as trout have provided important comparative mechanism information for confident extrapolation of animal studies to humans. For example, beta-naphthoflavone appears to inhibit aflatoxin B1 hepatocarcinogenicity by species-independent mechanisms that readily extrapolate to humans. By contrast other modulators, including butylated hydroxyanisole, inhibit aflatoxin B1 hepatocarcinogenesis in rats by an enabling mechanism shown to be absent in trout, namely the induction of an aflatoxin B1-specific glutathione S-transferase isozyme. Interestingly, evidence is presently lacking that this determinant mechanism would be operative in humans. (2) The sensitivity advantage. Trout sensitivity and small body size at exposure have permitted tumor studies with carcinogens and HPLC-purified anticarcinogen intermediates too scarce to study in rodents. (3) The low cost advantage. The very low cost of trout tumor studies has enabled statistically challenging issues in molecular dosimetry, dose-response, and risk-benefit analysis to be addressed using as many as 9600 animals per tumor study at modest budget. In particular, these designs provide modulator-mediated alterations in precisely determined carcinogen TD50 values, rather than changes in simple tumor incidence, to quantify more rigorously modulator potencies for tumor inhibition or promotion as a function of dietary concentrations.  相似文献   
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