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81.
Genome and exome sequencing yield extensive catalogues of human genetic variation. However, pinpointing the few phenotypically causal variants among the many variants present in human genomes remains a major challenge, particularly for rare and complex traits wherein genetic information alone is often insufficient. Here, we review approaches to estimate the deleteriousness of single nucleotide variants (SNVs), which can be used to prioritize disease-causal variants. We describe recent advances in comparative and functional genomics that enable systematic annotation of both coding and non-coding variants. Application and optimization of these methods will be essential to find the genetic answers that sequencing promises to hide in plain sight. 相似文献
82.
Liao YC Huang TW Chen FC Charusanti P Hong JS Chang HY Tsai SF Palsson BO Hsiung CA 《Journal of bacteriology》2011,193(7):1710-1717
Klebsiella pneumoniae is a Gram-negative bacterium of the family Enterobacteriaceae that possesses diverse metabolic capabilities: many strains are leading causes of hospital-acquired infections that are often refractory to multiple antibiotics, yet other strains are metabolically engineered and used for production of commercially valuable chemicals. To study its metabolism, we constructed a genome-scale metabolic model (iYL1228) for strain MGH 78578, experimentally determined its biomass composition, experimentally determined its ability to grow on a broad range of carbon, nitrogen, phosphorus and sulfur sources, and assessed the ability of the model to accurately simulate growth versus no growth on these substrates. The model contains 1,228 genes encoding 1,188 enzymes that catalyze 1,970 reactions and accurately simulates growth on 84% of the substrates tested. Furthermore, quantitative comparison of growth rates between the model and experimental data for nine of the substrates also showed good agreement. The genome-scale metabolic reconstruction for K. pneumoniae presented here thus provides an experimentally validated in silico platform for further studies of this important industrial and biomedical organism. 相似文献
83.
Fairfield H Gilbert GJ Barter M Corrigan RR Curtain M Ding Y D'Ascenzo M Gerhardt DJ He C Huang W Richmond T Rowe L Probst FJ Bergstrom DE Murray SA Bult C Richardson J Kile BT Gut I Hager J Sigurdsson S Mauceli E Di Palma F Lindblad-Toh K Cunningham ML Cox TC Justice MJ Spector MS Lowe SW Albert T Donahue LR Jeddeloh J Shendure J Reinholdt LG 《Genome biology》2011,12(9):R86-12
We report the development and optimization of reagents for in-solution, hybridization-based capture of the mouse exome. By validating this approach in a multiple inbred strains and in novel mutant strains, we show that whole exome sequencing is a robust approach for discovery of putative mutations, irrespective of strain background. We found strong candidate mutations for the majority of mutant exomes sequenced, including new models of orofacial clefting, urogenital dysmorphology, kyphosis and autoimmune hepatitis. 相似文献
84.
Nakashima H Terabe M Berzofsky JA Husain SR Puri RK 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(10):4935-4946
Optimum efficacy of therapeutic cancer vaccines may require combinations that generate effective antitumor immune responses, as well as overcome immune evasion and tolerance mechanisms mediated by progressing tumor. Previous studies showed that IL-13Rα2, a unique tumor-associated Ag, is a promising target for cancer immunotherapy. A targeted cytotoxin composed of IL-13 and mutated Pseudomonas exotoxin induced specific killing of IL-13Rα2(+) tumor cells. When combined with IL-13Rα2 DNA cancer vaccine, surprisingly, it mediated synergistic antitumor effects on tumor growth and metastasis in established murine breast carcinoma and sarcoma tumor models. The mechanism of synergistic activity involved direct killing of tumor cells and cell-mediated immune responses, as well as elimination of myeloid-derived suppressor cells and, consequently, regulatory T cells. These novel results provide a strong rationale for combining immunotoxins with cancer vaccines for the treatment of patients with advanced cancer. 相似文献
85.
Responses in stomatal conductance to elevated CO2 in 12 grassland species that differ in growth form
Responses in stomatal conductance (g
st
) and leaf xylem pressure potential (
leaf
) to elevated CO2 (2x ambient) were compared among 12 tallgrass prairie species that differed in growth form and growth rate. Open-top chambers (OTCs, 4.5 m diameter, 4.0 m in height) were used to expose plants to ambient and elevated CO2 concentrations from April through November in undisturbed tallgrass prairie in NE Kansas (USA). In June and August,
leaf
was usually higher in all species at elevated CO2 and was lowest in adjacent field plots (without OTCs). During June, when water availability was high, elevated CO2 resulted in decreased g
st
in 10 of the 12 species measured. Greatest decreases in g
st
(ca. 50%) occurred in growth forms with the highest potential growth rates (C3 and C4 grasses, and C3 ruderals). In contrast, no significant decrease in g
st
was measured in the two C3 shrubs. During a dry period in September, reductions in g
st
at elevated CO2 were measured in only two species (a C3 ruderal and a C4 grass) whereas increased g
st
at elevated CO2 was measured in the shrubs and a C3 forb. These increases in g
st
were attributed to enhanced
leaf
in the elevated CO2 plants resulting from increased soil water availability and/or greater root biomass. During a wet period in September, only reductions in g
st
were measured in response to elevated CO2. Thus, there was significant interspecific variability in stomatal responses to CO2 that may be related to growth form or growth rate and plant water relations. The effect of growth in the OTCs, relative to field plants, was usually positive for g
st
and was greatest (>30%) when water availability was low, but only 6–12% when
leaf
was high.The results of this study confirm the importance of considering interactions between indirect effects of high CO2 of plant water relations and direct effects of elevated CO2 on g
st
, particularly in ecosystems such as grasslands where water availability often limits productivity. A product of this interaction is that the potential exists for either positive or negative responses in g
st
to be measured at elevated levels of CO2. 相似文献
86.
Molecular mechanisms underlying the emergence of bacterial pathogens: an ecological perspective 下载免费PDF全文
The rapid emergence of new bacterial diseases negatively affects both human health and agricultural productivity. Although the molecular mechanisms underlying these disease emergences are shared between human‐ and plant‐pathogenic bacteria, not much effort has been made to date to understand disease emergences caused by plant‐pathogenic bacteria. In particular, there is a paucity of information in the literature on the role of environmental habitats in which plant‐pathogenic bacteria evolve and on the stress factors to which these microbes are unceasingly exposed. In this microreview, we focus on three molecular mechanisms underlying pathogenicity in bacteria, namely mutations, genomic rearrangements and the acquisition of new DNA sequences through horizontal gene transfer (HGT). We briefly discuss the role of these mechanisms in bacterial disease emergence and elucidate how the environment can influence the occurrence and regulation of these molecular mechanisms by directly impacting disease emergence. The understanding of such molecular evolutionary mechanisms and their environmental drivers will represent an important step towards predicting bacterial disease emergence and developing sustainable management strategies for crops. 相似文献
87.
DISTRIBUTION AND ABUNDANCE OF THE AMAZON RIVER DOLPHIN (INIA GEOFFRENSIS) AND THE TUCUXI (SOTALIA FLUVIATILIS) IN THE UPPER AMAZON RIVER 总被引:1,自引:0,他引:1
Omar Vidal Jay Barlow Luis A. Hurtado Jorge Torre Patricia Cendón Zully Ojeda 《Marine Mammal Science》1997,13(3):427-445
A boat survey was conducted from 5 to 26 June 1993 to estimate the abundance of the Amazon river dolphin ( Inia geoffrensis ) and the tucuxi ( Sotalia fluviatilis ) along ca . 120 km of the Amazon River bordering Colombia, Peru, and Brazil. Two survey methods were used: line transects during 5 d and strip transects during 15 d. The line transects were used to estimate the abundance of both species in the main channels of the Amazon at distances greater than 200 m from river banks and islands, and strip transects were used to estimate abundance in the remainder of the habitat. A total of 29 sightings was obtained using line transects, including 8 of Inia , 15 of Sotalia , and 6 with both species present. The total number of sightings made while using strip transects was 143, including 78 of Inia , 51 of Sotalia , and 14 with both species present. The distributions of sightings with respect to distance from the nearest bank were not significantly different between the two species. Based on the results from the two methods, we estimate that there are 346 (CV = 0.12) Inia and 409 (CV = 0.13) Sotalia in the study area. Overall, the mean group size for Inia was 2.9 individuals and for Sotalia was 3.9 individuals. Inia density (dolphin/km2 ) was highest in tributaries (4.8), followed by areas around islands (2.7) and along main banks (2.0); while Sotalia density was highest in lakes (8.6), followed by areas along main banks (2.8) and around islands (2.0). These are among the highest densities measured to date for any cetacean. 相似文献
88.
Vincent E. Sollars Ed Pequignot Jay L. Rothstein Arthur M. Buchberg 《Mammalian genome》2006,17(8):808-821
The myeloid progenitor cell compartment (MPC) exhibits pronounced expansion in human myeloid leukemias. It is becoming more
apparent that progression of myelodysplastic syndromes and myeloproliferative diseases to acute myelogenous leukemia is the
result of defects in progenitor cell maturation. The MPC of bone marrow was analyzed in mice using a cell culture assay for
measuring the relative frequency of proliferative myeloid progenitors. Response to the cytokines SCF, IL-3, and GM-CSF was
determined by this assay for the leukemic mouse strain BXH-2 and ten other inbred mouse strains. Significant differences were
found to exist among ten inbred mouse strains in the nature of their MPC in bone marrow, indicating the presence of genetic
polymorphisms responsible for the divergence. The SWR/J and FVB/J strains show consistently low frequencies of myeloid progenitors,
while the DBA/2J and SJL/J inbred strains show consistently high frequencies of myeloid progenitors within the bone marrow
compartment. In addition, in silico linkage disequilibrium analysis was conducted to identify possible chromosomal regions responsible for the phenotypic variation.
Given the importance of this cell compartment in leukemia progression and the soon to be released genomic sequence of 15 mouse
strains, these differences may provide a valuable tool for research into leukemia. 相似文献
89.
Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway 总被引:11,自引:0,他引:11
Wang Y Singh R Lefkowitch JH Rigoli RM Czaja MJ 《The Journal of biological chemistry》2006,281(22):15258-15267
In vitro studies of hepatocytes have implicated over-activation of c-Jun N-terminal kinase (JNK) signaling as a mechanism of tumor necrosis factor-alpha (TNF)-induced apoptosis. However, the functional significance of JNK activation and the role of specific JNK isoforms in TNF-induced hepatic apoptosis in vivo remain unclear. JNK1 and JNK2 function was, therefore, investigated in the TNF-dependent, galactosamine/lipopolysaccharide (GalN/LPS) model of liver injury. The toxin GalN converted LPS-induced JNK signaling from a transient to prolonged activation. Liver injury and mortality from GalN/LPS was equivalent in wild-type and jnk1-/- mice but markedly decreased in jnk2-/- mice. This effect was not secondary to down-regulation of TNF receptor 1 expression or TNF production. In the absence of jnk2, the caspase-dependent, TNF death pathway was blocked, as reflected by the failure of caspase-3 and -7 and poly(ADP-ribose) polymerase cleavage to occur. JNK2 was critical for activation of the mitochondrial death pathway, as in jnk2-/- mice Bid cleavage and mitochondrial translocation and cytochrome c release were markedly decreased. This effect was secondary to the failure of jnk2-/- mice to activate caspase-8. Liver injury and caspase activation were similarly decreased in jnk2 null mice after GalN/TNF treatment. Ablation of jnk2 did not inhibit GalN/LPS-induced c-Jun kinase activity, although activity was completely blocked in jnk1-/- mice. Toxic liver injury is, therefore, associated with JNK over-activation and mediated by JNK2 promotion of caspase-8 activation and the TNF mitochondrial death pathway through a mechanism independent of c-Jun kinase activity. 相似文献
90.
Enoch S. Huang Patrice Koehl Michael Levitt Rohit V. Pappu Jay W. Ponder 《Proteins》1998,33(2):204-217
The ab initio folding problem can be divided into two sequential tasks of approximately equal computational complexity: the generation of native-like backbone folds and the positioning of side chains upon these backbones. The prediction of side-chain conformation in this context is challenging, because at best only the near-native global fold of the protein is known. To test the effect of displacements in the protein backbones on side-chain prediction for folds generated ab initio, sets of near-native backbones (≤ 4 Å Cα RMS error) for four small proteins were generated by two methods. The steric environment surrounding each residue was probed by placing the side chains in the native conformation on each of these decoys, followed by torsion-space optimization to remove steric clashes on a rigid backbone. We observe that on average 40% of the χ1 angles were displaced by 40° or more, effectively setting the limits in accuracy for side-chain modeling under these conditions. Three different algorithms were subsequently used for prediction of side-chain conformation. The average prediction accuracy for the three methods was remarkably similar: 49% to 51% of the χ1 angles were predicted correctly overall (33% to 36% of the χ1+2 angles). Interestingly, when the inter-side-chain interactions were disregarded, the mean accuracy increased. A consensus approach is described, in which side-chain conformations are defined based on the most frequently predicted χ angles for a given method upon each set of near-native backbones. We find that consensus modeling, which de facto includes backbone flexibility, improves side-chain prediction: χ1 accuracy improved to 51–54% (36–42% of χ1+2). Implications of a consensus method for ab initio protein structure prediction are discussed. Proteins 33:204–217, 1998. © 1998 Wiley-Liss, Inc. 相似文献