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41.
Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease. 相似文献
42.
Ohren JF Chen H Pavlovsky A Whitehead C Zhang E Kuffa P Yan C McConnell P Spessard C Banotai C Mueller WT Delaney A Omer C Sebolt-Leopold J Dudley DT Leung IK Flamme C Warmus J Kaufman M Barrett S Tecle H Hasemann CA 《Nature structural & molecular biology》2004,11(12):1192-1197
MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition. 相似文献
43.
Matsunaga I Naka T Talekar RS McConnell MJ Katoh K Nakao H Otsuka A Behar SM Yano I Moody DB Sugita M 《The Journal of biological chemistry》2008,283(43):28835-28841
Trehalose dimycolate (TDM), also known as cord factor, is a major surface glycolipid of the cell wall of mycobacteria. Because of its potent biological functions in models of infection, adjuvancy, and immunotherapy, it is important to determine how its biosynthesis is regulated. Here we show that glucose, a host-derived product that is not readily available in the environment, causes Mycobacterium avium to down-regulate TDM expression while up-regulating production of another major glycolipid with immunological roles in T cell activation, glucose monomycolate (GMM). In vitro, the mechanism of reciprocal regulation of TDM and GMM involves competitive substrate selection by antigen 85A. The switch from TDM to GMM biosynthesis occurs near the physiological concentration of glucose present in mammalian hosts. We further demonstrate that GMM is produced in vivo by mycobacteria growing in mouse lung. These results establish an enzymatic pathway for GMM production. More generally, these observations provide a specific enzymatic mechanism for dynamic alterations of cell wall glycolipid remodeling in response to the transition from noncellular to cellular growth environments, including factors that are monitored by the host immune system. 相似文献
44.
A spin-labeled β-galactoside has been synthesized. It is a substrate for β-galactosidase and is accumulated by E. coli ML 308-225 and K12-N2244. The accumulation appears to be active transport via the lactose permease since it is inhibited with lactose and the energy poison, amytal. Induction of the K12 strain with isopropylthiogalactoside results in a 100-fold stimulation of uptake of the spin-labeled β-galactoside. Binding of the spin-labeled sugar to membranes derived from the ML strain is inhibited by lactose. 相似文献
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Peter M. Bowers Tamlyn Y. Neben Geoffery L. Tomlinson Jennifer L. Dalton Larry Altobell Xue Zhang John L. Macomber Betty F. Wu Rachelle M. Toobian Audrey D. McConnell Petra Verdino Betty Chau Robert A. Horlick David J. King 《The Journal of biological chemistry》2013,288(11):7688-7696
A method for simultaneous humanization and affinity maturation of monoclonal antibodies has been developed using heavy chain complementarity-determining region (CDR) 3 grafting combined with somatic hypermutation in vitro. To minimize the amount of murine antibody-derived antibody sequence used during humanization, only the CDR3 region from a murine antibody that recognizes the cytokine hβNGF was grafted into a nonhomologous human germ line V region. The resulting CDR3-grafted HC was paired with a CDR-grafted light chain, displayed on the surface of HEK293 cells, and matured using in vitro somatic hypermutation. A high affinity humanized antibody was derived that was considerably more potent than the parental antibody, possessed a low pm dissociation constant, and demonstrated potent inhibition of hβNGF activity in vitro. The resulting antibody contained half the heavy chain murine donor sequence compared with the same antibody humanized using traditional methods. 相似文献
49.
Xinyue?LuEmail author Dilber?Nurmemet David?L?Bolduc Thomas?B?Elliott Juliann?G?Kiang 《Cell & Bioscience》2013,3(1):36
Background
Our previous research demonstrated that one subcutaneous injection of 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) 24 hours (h) before irradiation (8.75 Gy) increased mouse survival by 75%. However, the protective mechanism of 17-DMAG is currently unknown. The present study aimed to investigate whether oral administration of 17-DMAG was also radioprotective and the potential role it may play in radioprotection.Results
A single dose of orally pre-administered (24, 48, or 72 h) 17-DMAG (10 mg/kg) increased irradiated mouse survival, reduced body weight loss, improved water consumption, and decreased facial dropsy, whereas orally post-administered 17-DMAG failed. Additional oral doses of pre-treatment did not improve 30-day survival. The protective effect of multiple pre-administrations (2?3 times) of 17-DMAG at 10 mg/kg was equal to the outcome of a single pre-treatment. In 17-DMAG-pretreated mice, attenuation of bone marrow aplasia in femurs 30 days after irradiation with recovered expressions of cluster of differentiation 34, 44 (CD34, CD44), and survivin in bone marrow cells were observed. 17-DMAG also elevated serum granulocyte-colony stimulating factor (G-CSF), decreased serum fms-related tyrosine kinase 3 ligand, and reduced white blood cell depletion. 17-DMAG ameliorated small intestinal histological damage, promoted recovery of villus heights and intestinal crypts including stem cells, where increased leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) was found 30 days after irradiation.Conclusions
17-DMAG is a potential radioprotectant for bone marrow and small intestine that results in survival improvement.50.
Thiyagaragan?M.?Achariyar Baoman?Li Weiguo?Peng Philip?B.?Verghese Yang?Shi Evan?McConnell Abdellatif?Benraiss Tristan?Kasper Wei?Song Takahiro?Takano David?M.?Holtzman Maiken?Nedergaard Rashid?DeaneEmail author 《Molecular neurodegeneration》2016,11(1):74