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61.
Deborah F. Tate Leslie Lytle Kristen Polzien Molly Diamond Kelsey R. Leonard John M. Jakicic Karen C. Johnson Christine M. Olson Kevin Patrick Laura P. Svetkey Rena R. Wing Pao‐Hwa Lin Mathilda Coday Melissa N. Laska Gina Merchant Sara J. Czaja Richard Schulz Steven H. Belle 《Obesity (Silver Spring, Md.)》2019,27(7):1085-1098
62.
Xu L Chong Y Hwang I D'Onofrio A Amore K Beardsley GP Li C Olson AJ Boger DL Wilson IA 《The Journal of biological chemistry》2007,282(17):13033-13046
The inosine monophosphate cyclohydrolase (IMPCH) component (residues 1-199) of the bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase, residues 200-593)/IMPCH (ATIC) catalyzes the final step in the de novo purine biosynthesis pathway that produces IMP. As a potential target for antineoplastic intervention, we designed IMPCH inhibitors, 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (heterocycle, 1), the corresponding nucleoside (2), and the nucleoside monophosphate (nucleotide) (3), as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH (K(i) values = 0.13-0.23 microm) with the simple heterocycle 1 exhibiting the most potent inhibition (K(i) = 0.13 microm). Crystal structures of bifunctional ATIC in complex with nucleoside 2 and nucleotide 3 revealed IMPCH binding modes similar to that of the IMPCH feedback inhibitor, xanthosine 5'-monophosphate. Surprisingly, the simpler heterocycle 1 had a completely different IMPCH binding mode and was relocated to the phosphate binding pocket that was identified from previous xanthosine 5'-monophosphate structures. The aromatic imidazole ring interacts with a helix dipole, similar to the interaction with the phosphate moiety of 3. The crystal structures not only revealed the mechanism of inhibition of these compounds, but they now serve as a platform for future inhibitor improvements. Importantly, the nucleoside-complexed structure supports the notion that inhibitors lacking a negatively charged phosphate can still inhibit IMPCH activity with comparable potency to phosphate-containing inhibitors. Provocatively, the nucleotide inhibitor 3 also binds to the AICAR Tfase domain of ATIC, which now provides a lead compound for the design of inhibitors that simultaneously target both active sites of this bifunctional enzyme. 相似文献
63.
Kobayashi T Antar AA Boehme KW Danthi P Eby EA Guglielmi KM Holm GH Johnson EM Maginnis MS Naik S Skelton WB Wetzel JD Wilson GJ Chappell JD Dermody TS 《Cell host & microbe》2007,1(2):147-157
Mammalian orthoreoviruses (reoviruses) are highly tractable experimental models for studies of double-stranded (ds) RNA virus replication and pathogenesis. Reoviruses infect respiratory and intestinal epithelium and disseminate systemically in newborn animals. Until now, a strategy to rescue infectious virus from cloned cDNA has not been available for any member of the Reoviridae family of dsRNA viruses. We report the generation of viable reovirus following plasmid transfection of murine L929 (L) cells using a strategy free of helper virus and independent of selection. We used the reovirus reverse genetics system to introduce mutations into viral capsid proteins sigma1 and sigma3 and to rescue a virus that expresses a green fluorescent protein (GFP) transgene, thus demonstrating the tractability of this technology. The plasmid-based reverse genetics approach described here can be exploited for studies of reovirus replication and pathogenesis and used to develop reovirus as a vaccine vector. 相似文献
64.
65.
66.
Anderson Kristen D. Cantin Neal E. Casey Jordan M. Pratchett Morgan S. 《Coral reefs (Online)》2019,38(6):1225-1240
Coral Reefs - Climate change is the greatest threat to coral reef ecosystems. Importantly, gradual changes in seawater chemistry compounds upon increasing temperatures leading to declines in... 相似文献
67.
Jorge D García-García Kristen Van Gelder Jaya Joshi Ulschan Bathe Bryan J Leong Steven D Bruner Chang C Liu Andrew D Hanson 《Plant physiology》2022,188(2):971
Continuous directed evolution of enzymes and other proteins in microbial hosts is capable of outperforming classical directed evolution by executing hypermutation and selection concurrently in vivo, at scale, with minimal manual input. Provided that a target enzyme’s activity can be coupled to growth of the host cells, the activity can be improved simply by selecting for growth. Like all directed evolution, the continuous version requires no prior mechanistic knowledge of the target. Continuous directed evolution is thus a powerful way to modify plant or non-plant enzymes for use in plant metabolic research and engineering. Here, we first describe the basic features of the yeast (Saccharomyces cerevisiae) OrthoRep system for continuous directed evolution and compare it briefly with other systems. We then give a step-by-step account of three ways in which OrthoRep can be deployed to evolve primary metabolic enzymes, using a THI4 thiazole synthase as an example and illustrating the mutational outcomes obtained. We close by outlining applications of OrthoRep that serve growing demands (i) to change the characteristics of plant enzymes destined for return to plants, and (ii) to adapt (“plantize”) enzymes from prokaryotes—especially exotic prokaryotes—to function well in mild, plant-like conditions.Continuous directed evolution using the yeast OrthoRep system is a powerful way to improve enzymes for use in plant engineering as illustrated by “plantizing” a bacterial thiamin synthesis enzyme. 相似文献
68.
Keller Larkin M Deng WM Holder K Tworoger M Clegg N Ruohola-Baker H 《Development genes and evolution》1999,209(5):301-311
During Drosophila oogenesis the body axes are determined by signaling between the oocyte and the somatic follicle cells that surround the egg
chamber. A key event in the establishment of oocyte anterior-posterior polarity is the differential patterning of the follicle
cell epithelium along the anterior-posterior axis. Both the Notch and epithelial growth factor (EGF) receptor pathways are
required for this patterning. To understand how these pathways act in the process we have analyzed markers for anterior and
posterior follicle cells accompanying constitutive activation of the EGF receptor, loss of Notch function, and ectopic expression
of Delta. We find that a constitutively active EGF receptor can induce posterior fate in anterior but not in lateral follicle
cells, showing that the EGF receptor pathway can act only on predetermined terminal cells. Furthermore, Notch function is
required at both termini for appropriate expression of anterior and posterior markers, while loss of both the EGF receptor
and Notch pathways mimic the Notch loss-of-function phenotype. Ectopic expression of the Notch ligand, Delta, disturbs EGF
receptor dependent posterior follicle cell differentiation and anterior-posterior polarity of the oocyte. Our data are consistent
with a model in which the Notch pathway is required for early follicle cell differentiation at both termini, but is then repressed
at the posterior for proper determination of the posterior follicle cells by the EGF receptor pathway.
Received: 5 November 1998 / Accepted: 14 December 1998 相似文献
69.
Differential regulation of platelet-derived growth factor stimulated migration and proliferation in osteoblastic cells 总被引:3,自引:0,他引:3
Osteoblastic migration and proliferation in response to growth factors are essential for skeletal development, bone remodeling, and fracture repair, as well as pathologic processes, such as metastasis. We studied migration in response to platelet-derived growth factor (PDGF, 10 ng/ml) in a wounding model. PDGF stimulated a twofold increase in migration of osteoblastic MC3T3-E1 cells and murine calvarial osteoblasts over 24-48 h. PDGF also stimulated a tenfold increase in 3H-thymidine (3H-TdR) incorporation in MC3T3-E1 cells. Migration and DNA replication, as measured by BrdU incorporation, could be stimulated in the same cell. Blocking DNA replication with aphidicolin did not reduce the distance migrated. To examine the role of mitogen-activated protein (MAP) kinases in migration and proliferation, we used specific inhibitors of p38 MAP kinase, extracellular signal regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). For these signaling studies, proliferation was measured by carboxyfluorescein diacetate succinimidyl ester (CFSE) using flow cytometry. Inhibition of the p38 MAP kinase pathway by SB203580 and SB202190 blocked PDGF-stimulated migration but had no effect on proliferation. Inhibition of the ERK pathway by PD98059 and U0126 inhibited proliferation but did not inhibit migration. Inhibition of JNK activity by SP600125 inhibited both migration and proliferation. Hence, the stimulation of migration and proliferation by PDGF occurred by both overlapping and independent pathways. The JNK pathway was involved in both migration and proliferation, whereas the p38 pathway was predominantly involved in migration and the ERK pathway predominantly involved in proliferation. 相似文献
70.
Recently, it has been shown that PKA-mediated phosphorylation of the β2-adrenergic receptor (β2-AR) by the cyclic AMP-dependent protein kinase (PKA) reduces its affinity for Gs and increases its affinity for Gi. Here we demonstrate that, like the β2-AR, the β1-AR is also capable of “switching” its coupling from Gs to Gi in a PKA-dependent manner. The β1-AR is capable of activating adenylate cyclase via Gs, and can also activate the extracellular-regulated kinases, p44 and p42 (ERK1/2). In transfected CHO cells, the observed β1-AR-mediated activation of ERK is both sensitive to pertussis toxin (PTX), indicating involvement of Gi/Go, and to the PKA inhibitor, H-89. β1-ARs with PKA phosphorylation sites mutated to alanines are unable to activate ERK. Mutating these same residues to aspartic acid, mimicking PKA phosphorylation, leads to a decrease in Gs-stimulated cAMP accumulation and an increase in PTX-sensitive ERK activation. These results strongly support the hypothesis that the β1-AR, like the β2-AR, can undergo PKA-dependent “Gs/Gi switching”. 相似文献