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101.
Kansy JW Daubner SC Nishi A Sotogaku N Lloyd MD Nguyen C Lu L Haycock JW Hope BT Fitzpatrick PF Bibb JA 《Journal of neurochemistry》2004,91(2):374-384
Cyclin-dependent kinase 5 (Cdk5) is emerging as a neuronal protein kinase involved in multiple aspects of neurotransmission in both post- and presynaptic compartments. Within the reward/motor circuitry of the basal ganglia, Cdk5 regulates dopamine neurotransmission via phosphorylation of the postsynaptic signal transduction pathway integrator, DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, M(r) 32,000). Cdk5 has also been implicated in regulating various steps in the presynaptic vesicle cycle. Here we report that Cdk5 phosphorylates tyrosine hydroxylase (TH), the key enzyme for synthesis of dopamine. Using phosphopeptide mapping, site-directed mutagenesis, and phosphorylation state-specific antibodies, the site was identified as Ser31, a previously defined extracellular signal-regulated kinases 1/2 (ERK1/2) site. The phosphorylation of Ser31 by Cdk5 versus ERK1/2 was investigated in intact mouse striatal tissue using a pharmacological approach. The results indicated that Cdk5 phosphorylates TH directly and also regulates ERK1/2-dependent phosphorylation of TH through the phosphorylation of mitogen-activated protein kinase kinase 1 (MEK1). Finally, phospho-Ser31 TH levels were increased in dopaminergic neurons of rats trained to chronically self-administer cocaine. These results demonstrate direct and indirect regulation of the phosphorylation state of a Cdk5/ERK1/2 site on TH and suggest a role for these pathways in the neuroadaptive changes associated with chronic cocaine exposure. 相似文献
102.
Hope A. Cole Jenna M. Tabor-Godwin Jeffrey J. Hayes 《The Journal of biological chemistry》2010,285(4):2876-2885
The activity of uracil DNA glycosylases (UDGs), which recognize and excise uracil bases from DNA, has been well characterized on naked DNA substrates but less is known about activity in chromatin. We therefore prepared a set of model nucleosome substrates in which single thymidine residues were replaced with uracil at specific locations and a second set of nucleosomes in which uracils were randomly substituted for all thymidines. We found that UDG efficiently removes uracil from internal locations in the nucleosome where the DNA backbone is oriented away from the surface of the histone octamer, without significant disruption of histone-DNA interactions. However, uracils at sites oriented toward the histone octamer surface were excised at much slower rates, consistent with a mechanism requiring spontaneous DNA unwrapping from the nucleosome. In contrast to the nucleosome core, UDG activity on DNA outside the core DNA region was similar to that of naked DNA. Association of linker histone reduced activity of UDG at selected sites near where the globular domain of H1 is proposed to bind to the nucleosome as well as within the extra-core DNA. Our results indicate that some sites within the nucleosome core and the extra-core (linker) DNA regions represent hot spots for repair that could influence critical biological processes. 相似文献
103.
Potti A Dressman HK Bild A Riedel RF Chan G Sayer R Cragun J Cottrill H Kelley MJ Petersen R Harpole D Marks J Berchuck A Ginsburg GS Febbo P Lancaster J Nevins JR 《Nature medicine》2006,12(11):1294-1300
Using in vitro drug sensitivity data coupled with Affymetrix microarray data, we developed gene expression signatures that predict sensitivity to individual chemotherapeutic drugs. Each signature was validated with response data from an independent set of cell line studies. We further show that many of these signatures can accurately predict clinical response in individuals treated with these drugs. Notably, signatures developed to predict response to individual agents, when combined, could also predict response to multidrug regimens. Finally, we integrated the chemotherapy response signatures with signatures of oncogenic pathway deregulation to identify new therapeutic strategies that make use of all available drugs. The development of gene expression profiles that can predict response to commonly used cytotoxic agents provides opportunities to better use these drugs, including using them in combination with existing targeted therapies. 相似文献
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105.
Robert B. Jacobs Frank R. Thompson III Rolf R. Koford Frank A. La Sorte Hope D. Woodward Jane A. Fitzgerald 《The Journal of wildlife management》2012,76(2):372-381
Of 6 million ha of prairie that once covered northern and western Missouri, <36,500 ha remain, with planted, managed, and restored grasslands comprising most contemporary grasslands. Most grasslands are used as pasture or hayfields. Native grasses largely have been replaced by fescue (Festuca spp.) on most private lands (almost 7 million ha). Previously cropped fields set aside under the Conservation Reserve Program (CRP) varied from a mix of cool-season grasses and forbs, or mix of native warm-season grasses and forbs, to simple tall-grass monocultures. We used generalized linear mixed models and distance sampling to assess abundance of 8 species of breeding grassland birds on 6 grassland types commonly associated with farm practices in Missouri and located in landscapes managed for grassland-bird conservation. We selected Bird Conservation Areas (BCAs) for their high percentage of grasslands and grassland-bird species, and for <5% forest cover. We used an information-theoretic approach to assess the relationship between bird abundance and 6 grassland types, 3 measures of vegetative structure, and 2 landscape variables (% grassland and edge density within a 1-km radius). We found support for all 3 levels of model parameters, although there was less support for landscape than vegetation structure effects likely because we studied high-percentage-grassland landscapes (BCAs). Henslow's sparrow (Ammodramus henslowii) counts increased with greater percentage of grassland, vegetation height-density, litter depth, and shrub cover and lower edge density. Henslow's sparrow counts were greatest in hayed native prairie. Dickcissel (Spiza americana) counts increased with greater vegetation height-density and were greatest in planted CRP grasslands. Grasshopper sparrow (A. savannarum) counts increased with lower vegetation height, litter depth, and shrub cover. Based on distance modeling, breeding densities of Henslow's sparrow, dickcissel, and grasshopper sparrow in the 6 grassland types ranged 0.9–2.6, 1.4–3.2, and 0.1–1.5 birds/ha, respectively. We suggest different grassland types and structures (vegetation height, litter depth, shrub cover) are needed to support priority grassland-bird species in Missouri. © 2011 The Wildlife Society. 相似文献
106.
MHC class II molecules influence antigen-specific CD4+ T lymphocyte responses primed by immunization and infection. CD4+ T cell responses are important for controlling infection by many bacterial pathogens including Anaplasma marginale and are observed in cattle immunized with the protective A. marginale outer membrane (OM) vaccine. Immunogenic proteins that comprise the protective OM vaccine include type IV secretion system (T4SS) proteins VirB9-1, VirB9-2 and VirB10, candidates for inclusion in a multiepitope vaccine. Our goal was to determine the breadth of the VirB9-1, VirB9-2 and VirB10 T cell response and MHC class II restriction elements in six cattle with different MHC class II haplotypes defined by DRB3, DQA and DQB allele combinations for each animal. Overlapping peptides spanning each T4SS protein were tested in T cell proliferation assays with autologous antigen-presenting cells (APC) and artificial APC expressing combinations of bovine DR and DQ molecules. Twenty immunostimulatory peptides were identified; three representing two or more epitopes in VirB9-1, ten representing eight or more epitopes in VirB9-2 and seven representing seven or more epitopes in VirB10. Of the eight DRA/DRB3 molecules, four presented 15 peptides, which was biased as DRA/DRB3*1201 presented ten and DRA/DRB3*1101 presented four peptides. Four DQA/DQB molecules composed of two intrahaplotype and two interhaplotype pairs presented seven peptides, of which five were uniquely presented by DQ molecules. In addition, three functional mixed isotype (DQA/DRB3) restriction elements were identified. The immunogenicity and broad MHC class II presentation of multiple VirB9-1, VirB9-2 and VirB10 peptide epitopes justify their testing as a multiepitope vaccine against A. marginale. 相似文献
107.
Biswas HH Ortega O Gordon A Standish K Balmaseda A Kuan G Harris E 《PLoS neglected tropical diseases》2012,6(3):e1562
Background
Tens of millions of dengue cases and approximately 500,000 life-threatening complications occur annually. New tools are needed to distinguish dengue from other febrile illnesses. In addition, the natural history of pediatric dengue early in illness in a community-based setting has not been well-defined.Methods
Data from the multi-year, ongoing Pediatric Dengue Cohort Study of approximately 3,800 children aged 2–14 years in Managua, Nicaragua, were used to examine the frequency of clinical signs and symptoms by day of illness and to generate models for the association of signs and symptoms during the early phase of illness and over the entire course of illness with testing dengue-positive. Odds ratios (ORs) and 95% confidence intervals were calculated using generalized estimating equations (GEE) for repeated measures, adjusting for age and gender.Results
One-fourth of children who tested dengue-positive did not meet the WHO case definition for suspected dengue. The frequency of signs and symptoms varied by day of illness, dengue status, and disease severity. Multivariable GEE models showed increased odds of testing dengue-positive associated with fever, headache, retro-orbital pain, myalgia, arthralgia, rash, petechiae, positive tourniquet test, vomiting, leukopenia, platelets ≤150,000 cells/mL, poor capillary refill, cold extremities and hypotension. Estimated ORs tended to be higher for signs and symptoms over the course of illness compared to the early phase of illness.Conclusions
Day-by-day analysis of clinical signs and symptoms together with longitudinal statistical analysis showed significant associations with testing dengue-positive and important differences during the early phase of illness compared to the entire course of illness. These findings stress the importance of considering day of illness when developing prediction algorithms for real-time clinical management. 相似文献108.
I Anderson E Saunders A Lapidus M Nolan S Lucas H Tice TG Del Rio JF Cheng C Han R Tapia LA Goodwin S Pitluck K Liolios K Mavromatis I Pagani N Ivanova N Mikhailova A Pati A Chen K Palaniappan M Land L Hauser CD Jeffries YJ Chang EM Brambilla M Rohde S Spring M Göker JC Detter T Woyke J Bristow JA Eisen V Markowitz P Hugenholtz NC Kyrpides HP Klenk 《Standards in genomic sciences》2012,6(2):155-164
Thermodesulfatator indicus Moussard et al. 2004 is a member of the Thermodesulfobacteriaceae, a family in the phylum Thermodesulfobacteria that is currently poorly characterized at the genome level. Members of this phylum are of interest because they represent a distinct, deep-branching, Gram-negative lineage. T. indicus is an anaerobic, thermophilic, chemolithoautotrophic sulfate reducer isolated from a deep-sea hydrothermal vent. Here we describe the features of this organism, together with the complete genome sequence, and annotation. The 2,322,224 bp long chromosome with its 2,233 protein-coding and 58 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. 相似文献
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