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排序方式: 共有843条查询结果,搜索用时 15 毫秒
71.
Arnon Dias Jurberg Rita Aires Ana NóvoaJennifer Elizabeth Rowland Moisés Mallo 《Developmental biology》2014
Extension of the vertebrate body results from the concerted activity of many signals in the posterior embryonic end. Among them, Wnt3a has been shown to play relevant roles in the regulation of axial progenitor activity, mesoderm formation and somitogenesis. However, its impact on axial growth remains to be fully understood. Using a transgenic approach in the mouse, we found that the effect of Wnt3a signaling varies depending on the target tissue. High levels of Wnt3a in the epiblast prevented formation of neural tissues, but did not impair axial progenitors from producing different mesodermal lineages. These mesodermal tissues maintained a remarkable degree of organization, even within a severely malformed embryo. However, from the cells that failed to take a neural fate, only those that left the epithelial layer of the epiblast activated a mesodermal program. The remaining tissue accumulated as a folded epithelium that kept some epiblast-like characteristics. Together with previously published observations, our results suggest a dose-dependent role for Wnt3a in regulating the balance between renewal and selection of differentiation fates of axial progenitors in the epiblast. In the paraxial mesoderm, appropriate regulation of Wnt/β-catenin signaling was required not only for somitogenesis, but also for providing proper anterior–posterior polarity to the somites. Both processes seem to rely on mechanisms with different requirements for feedback modulation of Wnt/β-catenin signaling, once segmentation occurred in the presence of high levels of Wnt3a in the presomitic mesoderm, but not after permanent expression of a constitutively active form of β-catenin. Together, our findings suggest that Wnt3a/β-catenin signaling plays sequential roles during posterior extension, which are strongly dependent on the target tissue. This provides an additional example of how much the functional output of signaling systems depends on the competence of the responding cells. 相似文献
72.
The study of the parameters affecting Corpus Christi strain-induced protection in C3H(He) mice against Brazil strain T. cruzi infection is reported herein. A dose of 10(7) Corpus Christi epimastigotes was found to be the most effective dose for protection. Vaccination of mice 5 days to 11 wk prior to infection was determined to be the optimal time interval for protection. The subcutaneous route for vaccination and infection provides the most effective protection to experimental animals. Multiple inoculations with Corpus Christi, whether live or freeze thawed, increased the protective effect only slightly. The Corpus Christi strain of T. cruzi has proved to be quite suitable in providing protection to highly susceptible C3H(He) mice against an infection with the virulent Brazil strain of T. cruzi. 相似文献
73.
74.
Angell RM Atkinson FL Brown MJ Chuang TT Christopher JA Cichy-Knight M Dunn AK Hightower KE Malkakorpi S Musgrave JR Neu M Rowland P Shea RL Smith JL Somers DO Thomas SA Thompson G Wang R 《Bioorganic & medicinal chemistry letters》2007,17(5):1296-1301
The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site. 相似文献
75.
Alan Scarlett Martin N. Canty Emma L. Smith Steven J. Rowland Tamara S. Galloway 《人类与生态风险评估》2007,13(3):506-518
Amphipods are widely used in both acute and chronic (sub-lethal) sediment tests. Acute sediment tests provide relatively rapid results, but may fail to detect moderately toxic contaminants that are bound to the sediment, whereas chronic life-cycle tests are rarely performed as they are time consuming and expensive. Observations during chronic testing of oil-contaminated sediment suggested that there may be a link between the behavior of the marine amphipod Corophium volutator and reduction in growth rate. Behavior tests were performed with six individual amphipods per treatment using sediment spiked with weathered Forties oil with burrowing time, re-emergence from sediment, and activity prior to burrowing as endpoints. Further behavior tests were used to predict the chronic toxicity of sediments spiked with three crude oils each with a dominant unresolved complex mixture of hydrocarbons (UCM). The effect of sediment type on behavior was also investigated. The results suggested that although the behavior test could not be used alone as a viable alternative to sediment toxicity tests, it could prove useful as an adjunct to acute tests, and help select sediments that deserve further investigation. 相似文献
76.
From July 1965 until November 1971, New Zealand Defence Force Personnel fought in the Vietnam War. During this time more than 76,500,000 litres of phenoxylic herbicides were sprayed over parts of Southern Vietnam and Laos, the most common being known as 'Agent Orange'. The current study aimed to ascertain whether or not New Zealand Vietnam War veterans show evidence of genetic disturbance arising as a consequence of their now confirmed exposure to these defoliants. A sample group of 24 New Zealand Vietnam War veterans and 23 control volunteers were compared using an SCE (sister chromatid exchange) analysis. The results from the SCE study show a highly significant difference (P < 0.001) between the mean of the experimental group (11.05) and the mean of a matched control group (8.18). The experimental group also has an exceptionally high proportion of HFCs (cells with high SCE frequencies) above the 95th percentile compared to the controls (11.0 and 0.07%, respectively). We conclude that the New Zealand Vietnam War veterans studied here were exposed to a clastogenic substance(s) which continues to exert an observable genetic effect today, and suggest that this is attributable to their service in Vietnam. 相似文献
77.
Shannen L. Cravens Joseph D. Schonhoft Meng M. Rowland Alyssa A. Rodriguez Breeana G. Anderson James T. Stivers 《Nucleic acids research》2015,43(8):4087-4097
Intracellular space is at a premium due to the high concentrations of biomolecules and is expected to have a fundamental effect on how large macromolecules move in the cell. Here, we report that crowded solutions promote intramolecular DNA translocation by two human DNA repair glycosylases. The crowding effect increases both the efficiency and average distance of DNA chain translocation by hindering escape of the enzymes to bulk solution. The increased contact time with the DNA chain provides for redundant damage patrolling within individual DNA chains at the expense of slowing the overall rate of damaged base removal from a population of molecules. The significant biological implication is that a crowded cellular environment could influence the mechanism of damage recognition as much as any property of the enzyme or DNA.A significant triumph in biochemistry over the last 20 years was the ability to isolate human DNA repair enzymes and study their in vitro properties using defined DNA substrates containing damaged sites. Typically, these studies have been performed using dilute conditions, where the concentration of the enzyme, DNA and buffer components were low compared to the concentration of water. Although a wealth of insights into the thermodynamic, kinetic and structural properties of enzymes have resulted from such approaches (1–7), DNA repair enzymes act in a crowded cellular environment with quite different physical properties (8,9). Thus, an open question is how the complex intracellular milieu affects the ability of enzymes to locate and repair damage sites embedded in a large polymeric DNA substrate.The human intracellular environment has numerous physical properties that could dramatically affect enzyme activity. These include high inorganic ion and metabolite concentrations (10,11), lower dielectric properties (12–14), higher bulk viscosity (15,16), and the presence of high concentrations of macromolecules which consume available volume (‘molecular crowding’) (17,18). Indeed, the concentration of macromolecules in human cells is an astounding ∼100–300 mg/ml (9,19), which means that 10–40% of the total cellular volume is consumed by large molecules (often called the excluded volume). Taken together, these parameters could affect association of an enzyme with its target in complex ways. For instance, high ion concentrations are expected to shield electrostatic interactions between an enzyme and its highly charged DNA substrate (10,20,21), while a lower dielectric constant could have an opposite effect. Increases in macroscopic viscosity will slow the translational movement of macromolecules and due to entropic effects, crowded environments will push macromolecular association when the complex consumes a smaller volume than the free component species (9,22,23).Although volume exclusion largely explains the effects of crowded environments on binding equilibria, crowding has been reported to have a surprisingly small effect on the diffusion-controlled association kinetics of macromolecules (24). Indeed, it has been observed that some diffusion-controlled association reactions occur at nearly the same rates in crowded solutions and in cells as they do in dilute solution (24,25). These kinetic effects are counterintuitive, but can be understood by considering that macromolecular crowders alter the macroscopic viscosity and available volume in crowded solutions, but do not change the microscopic viscosity (26,27). Thus, over short nanometer distances, the rotational and translational diffusion of proteins is not greatly affected by crowding because the protein only feels the microscopic viscosity of the solvent that is present in the spaces between the larger crowding molecules (28). Over larger distances, hard sphere repulsion between the protein and crowding molecules increases the effective viscosity and slows translational diffusion (8,28,29). When two binding partners approach one another, they are captured within a low viscosity (high mobility) cage created by the larger crowding molecules, which increases the probability for a productive encounter event. Surprisingly, the capture of two binding partners within a high mobility cage can in some cases offset all of the negative effects of high viscosity on the overall association rate (29).The above considerations raise the interesting question of what effect molecular crowding has on enzyme association with DNA, and in particular, the property of facilitated diffusion along a DNA chain? Facilitated diffusion on the DNA chain (‘translocation’) is a distinct process that involves transient states of an enzyme and DNA that are not directly observable in equilibrium binding, steady-state or rapid kinetic measurements (1–4,30). Here, we measure the effect of inert crowding agents on the probability that the DNA repair enzymes uracil and 8-oxguanine DNA repair glycosylase will successfully translocate between two damaged sites in a DNA chain. We find that crowding increases the likelihood that each enzyme will successfully translocate between their respective target sites without dissociation to bulk solution and also increases the average translocation distance. For both enzymes, crowding biases the damage search process toward a chain tracking search mode rather than a 3D search mode. Such a crowder-induced transition in the search mode could significantly impact the effectiveness of the damage search in a crowded nuclear environment. These enzymes represent two of the largest superfamilies of glycosylases and their similar behavior in these studies suggests that the findings will be general for other related glycosylases. 相似文献
78.
Surface hydrolysis of sphingomyelin by the outer membrane protein Rv0888 supports replication of Mycobacterium tuberculosis in macrophages 下载免费PDF全文
Alexander Speer Jim Sun Olga Danilchanka Virginia Meikle Jennifer L. Rowland Kerstin Walter Bradford R. Buck Mikhail Pavlenok Christoph Hölscher Sabine Ehrt Michael Niederweis 《Molecular microbiology》2015,97(5):881-897
Sphingomyelinases secreted by pathogenic bacteria play important roles in host–pathogen interactions ranging from interfering with phagocytosis and oxidative burst to iron acquisition. This study shows that the Mtb protein Rv0888 possesses potent sphingomyelinase activity cleaving sphingomyelin, a major lipid in eukaryotic cells, into ceramide and phosphocholine, which are then utilized by Mtb as carbon, nitrogen and phosphorus sources, respectively. An Mtb rv0888 deletion mutant did not grow on sphingomyelin as a sole carbon source anymore and replicated poorly in macrophages indicating that Mtb utilizes sphingomyelin during infection. Rv0888 is an unusual membrane protein with a surface‐exposed C‐terminal sphingomyelinase domain and a putative N‐terminal channel domain that mediated glucose and phosphocholine uptake across the outer membrane in an M. smegmatis porin mutant. Hence, we propose to name Rv0888 as SpmT (sp hingomyelinase of M ycobacterium t uberculosis). Erythrocyte membranes contain up to 27% sphingomyelin. The finding that Rv0888 accounts for half of Mtb's hemolytic activity is consistent with its sphingomyelinase activity and the observation that Rv0888 levels are increased in the presence of erythrocytes and sphingomyelin by 5‐ and 100‐fold, respectively. Thus, Rv0888 is a novel outer membrane protein that enables Mtb to utilize sphingomyelin as a source of several essential nutrients during intracellular growth. 相似文献
79.
Burch JD Farand J Colucci J Sturino C Ducharme Y Friesen RW Lévesque JF Gagné S Wrona M Therien AG Mathieu MC Denis D Vigneault E Xu D Clark P Rowland S Han Y 《Bioorganic & medicinal chemistry letters》2011,21(3):1041-1046
Two new series of EP4 antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP4 receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development. 相似文献
80.