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991.
Wilna J. Moree Bin-Feng Li Said Zamani-Kord Jinghua Yu Timothy Coon Charles Huang Dragan Marinkovic Fabio C. Tucci Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Kayvon Jalali Chun Yang Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(19):5874-5878
Analogs of the known H1-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study. 相似文献
992.
T. Eric Ballard Xia Wang Igor Olekhnovich Taylor Koerner Craig Seymour Paul S. Hoffman Timothy L. Macdonald 《Bioorganic & medicinal chemistry letters》2010,20(12):3537-3539
Head group analogues of the antibacterial and antiparasitic drug nitazoxanide (NTZ) are presented. A library of 39 analogues was synthesized and assayed for their ability to suppress growth of Helicobacter pylori, Campylobacter jejuni, Clostridium difficile and inhibit NTZ target pyruvate:ferredoxin oxidoreductase (PFOR). Two head groups assayed recapitulated NTZ activity and possessed improved activity over their 2-amino-5-nitrothiazole counterparts, demonstrating that head group modification is a viable route for the synthesis of NTZ-related antibacterial analogues. 相似文献
993.
994.
Garret Suen Jarrod J. Scott Frank O. Aylward Sandra M. Adams Susannah G. Tringe Adrián A. Pinto-Tomás Clifton E. Foster Markus Pauly Paul J. Weimer Kerrie W. Barry Lynne A. Goodwin Pascal Bouffard Lewyn Li Jolene Osterberger Timothy T. Harkins Steven C. Slater Timothy J. Donohue Cameron R. Currie 《PLoS genetics》2010,6(9)
Herbivores can gain indirect access to recalcitrant carbon present in plant cell walls through symbiotic associations with lignocellulolytic microbes. A paradigmatic example is the leaf-cutter ant (Tribe: Attini), which uses fresh leaves to cultivate a fungus for food in specialized gardens. Using a combination of sugar composition analyses, metagenomics, and whole-genome sequencing, we reveal that the fungus garden microbiome of leaf-cutter ants is composed of a diverse community of bacteria with high plant biomass-degrading capacity. Comparison of this microbiome''s predicted carbohydrate-degrading enzyme profile with other metagenomes shows closest similarity to the bovine rumen, indicating evolutionary convergence of plant biomass degrading potential between two important herbivorous animals. Genomic and physiological characterization of two dominant bacteria in the fungus garden microbiome provides evidence of their capacity to degrade cellulose. Given the recent interest in cellulosic biofuels, understanding how large-scale and rapid plant biomass degradation occurs in a highly evolved insect herbivore is of particular relevance for bioenergy. 相似文献
995.
Duane L. Guernsey Haiyan Jiang Karen Bedard Susan C. Evans Meghan Ferguson Makoto Matsuoka Christine Macgillivray Mathew Nightingale Scott Perry Andrea L. Rideout Andrew Orr Mark Ludman David L. Skidmore Timothy Benstead Mark E. Samuels 《PLoS genetics》2010,6(8)
Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred. 相似文献
996.
Amoako AA Marczylo TH Lam PM Willets JM Derry A Elson J Konje JC 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(31):3231-3237
The endocannabinoids anandamide, palmitoylethanolamide and oleoylethanolamide have been detected in human seminal plasma and are bioactive lipids implicated in regulation of sperm motility, capacitation and acrosome reaction. Several methods exist for endocannabinoid quantification but none have been validated for measurement in human seminal plasma. We describe sensitive, robust, reproducible solid phase and isotope-dilution UHPLC-ESI-MS/MS methods for the extraction and quantification of anandamide, palmitoylethanolamide and oleoylethanolamide in human seminal plasma. Precision and accuracy were evaluated using pooled seminal plasma over a 4 day period. For all analytes, the inter- and intraday precision (CV%) was between 6.6-17.7% and 6.3-12.5%, respectively. Analyses were linear over the range 0.237-19nM for anandamide and oleoylethanolamide and 0.9-76nM for PEA. Limits of detection (signal-to-noise >3) were 50, 100 and 100fmol/mL and limits of quantification (signal-to-noise >10) were 100, 200 and 200fmol/mL, respectively for anandamide, palmitoylethanolamide and oleoylethanolamide. Anandamide and oleoylethanolamide were stable at -80°C for up to 4 weeks, but palmitoylethanolamide declined significantly. We assessed seminal plasma from 40 human donors with normozoospermia and found mean (inter-quartile range) concentrations of 0.21nM (0.09-0.27), 1.785nM (0.48-2.32) and 15.54nM (7.05-16.31) for anandamide, oleoylethanolamide and palmitoylethanolamide, respectively. Consequently, this UHPLC-ESI-MS/MS method represents a rapid, reliable and reproducible technique for the analysis of these endocannabinoids in fresh seminal plasma. 相似文献
997.
Richard A. J. O’Hair Craig M. Williams Timothy Clark 《Journal of molecular modeling》2010,16(3):559-565
We have used density-functional theory to investigate the neighboring-group stabilization of iodine, arsenic, and phosphorus-centered
oxyanion moieties in species such as deprotonated 2-iodoxybenzoic acid (IBX) and its analogs. The magnitudes of different
stabilizing effects and further candidates for analogous stabilization are analyzed.
相似文献
998.
Timothy M. A. Utteridge 《Kew Bulletin》2010,65(2):345-348
Platea malayana Utteridge is described and illustrated as a new species from the Cameron Highlands, Malaysia; notes on its conservation status
and taxonomic affinities are discussed. 相似文献
999.
Lisa M. Durso Gregory P. Harhay Timothy P. L. Smith James L. Bono Todd Z. DeSantis Dayna M. Harhay Gary L. Andersen James E. Keen William W. Laegreid Michael L. Clawson 《Applied and environmental microbiology》2010,76(14):4858-4862
The intestinal microbiota of beef cattle are important for animal health, food safety, and methane emissions. This full-length sequencing survey of 11,171 16S rRNA genes reveals animal-to-animal variation in communities that cannot be attributed to breed, gender, diet, age, or weather. Beef communities differ from those of dairy. Core bovine taxa are identified.The gastrointestinal tracts (GIT) of beef cattle are colonized by microorganisms that profoundly impact animal physiology, nutrition, health, and productivity (5). The GIT microbiota potentially impact food safety via pathogen shedding (13) by interacting with organisms such as Salmonella and competing for resources in the GIT. Cattle intestinal microbiota also play an important role in methane emissions, with U.S. beef cattle alone contributing an estimated 3.87 million metric tons of methane into the environment each year, both from rumen and large-intestine fermentations (7). Although the bovine fecal microbiota have been well characterized using culture-based methods, these techniques are necessarily limited to characterizing bacteria that can be grown in the laboratory. Culture-independent methods can reveal community members that are recalcitrant to culture. Only a handful of deep-sequencing studies have been done using culture-independent 16S rRNA-based methods (1, 11, 12, 14), all with dairy cattle, which have a fundamentally different diet and metabolism from beef cattle. Despite the potential contributions of the beef cattle GIT microbiota to animal health, food safety, and global warming, these communities remain poorly characterized. With the advent of pyrosequencing technology, researchers now have the tools to characterize these important communities. Pyrosequencing will allow rapid characterization of large-sample data sets (1). However, the taxonomic information generated by rapid sequencing is approximate by necessity (9), and full-length 16S-rRNA sequencing remains the “gold standard” method. Accordingly, we have characterized fecal bacteria from six feedlot cattle by full-length capillary sequence analysis of 11,171 16S rRNA gene clones (Fig. (Fig.11).Open in a separate windowFIG. 1.Bacterial diversity of six feedlot beef cattle. Gray bars represent the percentages of all 16S sequences that were assigned to each taxonomy. Colored dots represent the percentages of 16S sequences from each library that were assigned to each taxonomic group. Asterisks indicate unclassified members of the named taxon. Panel A shows the data for the first 99% of all the sequences. Panel B shows the data for the remaining 1% of sequences. Note differences in scales for panels A and B.Rectal grab fecal samples (n = 6) were collected according to institutional animal care guidelines. All animals were female cross-bred MARCIII beef heifers, 6 to 8 months of age, 214 to 241 kg, housed in the same feedlot pen for 2 months prior to fecal collection, and fed the same typical feedlot beef production growing rations consisting of 61.6% corn silage (41.3% dry matter), 15.2% alfalfa hay, 20.9% corn, and 2.3% liquid supplement.Total fecal DNA was isolated from homogenized samples using MoBio UltraClean fecal kit (Carlsbad, CA). PCR was performed using 27F and 1392R primers (11). Amplification consisted of 25 cycles, with an annealing temperature of 55°C. Amplicons from three reactions per sample were pooled (8), cloned using the Invitrogen TOPO TA cloning kit (Carlsbad, CA), and sequenced bidirectionally with M13 primers using an ABI 3700 sequencer (17). Low-quality and chimeric sequences (6) were excluded from further analysis. Distance matrices were compiled from ClustalW alignments (18) in PHYLIP (4). Pairwise estimates of shared richness were calculated using EstimateS, version 8.2 (R. K. Colwell; http://purl.oclc.org/estimates). DOTUR (16) was used to identify operational taxonomic units (OTUs) and to generate rarefaction curves (Fig. (Fig.2),2), richness and evenness estimates, and Shannon''s and Simpson''s diversity indices (Table (Table1).1). A 97% similarity cutoff and an 85% similarity cutoff for estimating OTUs were used to approximate species and class-level designations (15). Taxonomies were assigned to one member of each OTU using the RDP “classifier” tool (19), and the RDP taxonomic information was used for Fig. Fig.11 and and3.3. Common bovine taxa were identified based on inclusion in all three U.S. culture-independent studies (this study and references 1 and 11).Open in a separate windowFIG. 2.Rarefaction curves for six feedlot beef cattle. OTUs were assigned at the 85% DNA sequence similarity level. For comparison purposes, all six curves were truncated after 1,321 sequences.Open in a separate windowFIG. 3.Phylum-level distribution of bacterial sequences from six beef feedlot cattle. Asterisks indicate unclassified members of the named taxon.
Open in a separate windowaCI, confidence interval.The GIT community of beef feedlot cattle characterized in this study was found to share many taxa with the bovine GIT community described for dairy cattle (1, 11, 14), although the relative abundances of the major bacterial groups differed considerably. The fecal microbiota of beef cattle were dominated by members of the Firmicutes, with 62.8% of the OTUs belonging to this taxonomic group (Fig. (Fig.3).3). Bacteroidetes (29.5% of the OTUs) and Proteobacteria (4.4% of the OTUs) were also represented in feces (Fig. (Fig.3).3). A total of seven phyla were found in our six animals.Total estimated species richness values (Chao) for each of the six animals were 372, 600, 1,393, 526, 612, and 320 (Table (Table1).1). These cattle richness numbers are higher than those observed for three human subjects (164, 332, and 297) (2). The mean of Chao pairwise estimates of shared richness between any two of the six cattle fecal libraries was 230.Our findings, in addition to those from pyrosequencing studies (1), identify a core set of bovine GIT bacterial taxa, including the Bacteroidetes Prevotella and Bacteroides; the Firmicutes Faecalibacterium, Ruminococcus, Roseburia, and Clostridium; and the proteobacterium Succinovibrio (Fig. (Fig.1).1). These genera are consistently identified in bovine feces and likely compose part of the bovine resident microbiota. Although the potential exists for culture-independent methods to reveal minority microbial community members, 16S rRNA gene sequencing in dairy (1, 11) and beef cattle supports the list of core taxa identified using culture-based methods.Comparisons between our data set and recent studies done with dairy cattle (1, 11, 12) suggest that although beef and dairy cattle share many of the same major bacterial groups, the relative abundances of these groups in beef and dairy cattle may differ, and there may be differences between the two groups in the compositions of minority community members. The most common genus in beef cattle from our study was Prevotella, representing 24% of the total number of sequences evaluated. In comparison, Dowd et al. (1) found that Prevotella spp. represented only 5.5% of the total 16S genes sequenced from 20 dairy cattle, and Prevotella was not listed in the top 10 most frequently occurring OTUs in either of the studies from McGarvey et al. (11, 12). Likewise, Clostridium represented only 1.5% of the total beef sequences but 19% of the dairy pyrosequences (1). There were a number of bacterial sequences present in the beef cattle sequences but not reported in the dairy sequences, including Arthrobacter, Asteroleplasma, Bifidobacterium, Collinsella, Delftia, Eggerthella, Lactobacillus, Mitsuokella, Olsenella, and Propionibacterium (1, 11), although a number of these genera have been cultured from dairy animals in the past. It must be noted that all of these sequencing studies examined only a small number of animals, and each method has limitations which affect interpretation of the results. The full-length sequencing performed as part of this beef cattle study and two dairy studies (11, 12) relies on a PCR step which can potentially affect the relative numbers of each taxon observed due to PCR bias, while the pyrosequeincg method used in the 20-animal dairy study suffers from artifacts that potentially affect taxonomic assignment and richness estimates due to short read lengths and potential biases in evenness (how many of each group) due to primer and template mismatches (3). Nonetheless, these studies indicate that there may be fundamental differences between the gastrointestinal communities of beef and dairy cattle, they provide a comprehensive examination of the communities present in the specific animals tested, and they serve to provide important baseline information for further studies examining various factors which can impact cattle gastrointestinal communities.The taxonomic information generated by deep sequencing of beef cattle feces revealed considerable animal-to-animal variation in the operational taxonomic unit (OTU) composition of the individual libraries (Fig. (Fig.1).1). The OTU designation facilitates an analysis of the community data without forcing the assignment of sequences into an incomplete and imperfect bacterial taxonomic system. It relies on DNA sequence similarity to assign sequences to a particular OTU defined by the level of DNA sequence similarity. In total, 1,906 OTUs (97% OTU designation) were identified in the six libraries. Of these, only 24 OTUs (1.2%) (comprising 1,253 [11.2%] of sequences) were present in all six libraries, while 1,348 OTUs (69%) were found only in individual libraries. Of these, 1,064 OTUs (77%) were unique, represented by a solitary clone (range of 3% to 29% of the total clones from each individual animal). These data hint at considerable animal-to-animal variation in bacterial community structure at the species level that cannot be readily attributed to breed, gender, age, macroecologic factors such as weather conditions, or diet, given that the animals in this study were controlled for these variables, and support the conclusions of Manter et al. (10) that pooling samples can obscure rare phylotypes.Our results from beef cattle suggest that there may be differences in the bacterial community members present in the GIT of each individual animal that cannot be attributed to diet, breed, gender, age, or macroecologic factors such as weather and suggest the need for the high-resolution community sequencing of much larger numbers of animals before “core” minority community members can be identified. Considering the limited nature of the community surveys to date and all of the genetic, management, geographic, and temporal factors that can contribute to the composition of GIT microbiota, much work remains before we are able to understand and predict the community composition of any individual animal. 相似文献
TABLE 1.
Richness and diversity indices for 6 beef feedlot cattleLibrary and animal (n) | No. of OTUs observed | Species richness (CI)a by: | Diversity (CI) by: | ||
---|---|---|---|---|---|
Chao | ACE | Shannon''s index | Simpson''s index | ||
97% DNA sequence similarity | |||||
Animal 1 (2,485) | 198 | 372 (294-515) | 329 (280-408) | 3.89 (3.83-3.95) | 0.0422 |
Animal 2 (2,084) | 416 | 600 (538-694) | 604 (552-675) | 5.40 (5.35-5.45) | 0.0066 |
Animal 3 (1,710) | 696 | 1,393 (1,224-1,615) | 1,418 (1,327-1,523) | 6.13 (6.08-6.18) | 0.0027 |
Animal 4 (1,512) | 294 | 526 (439-665) | 483 (425-566) | 4.71 (4.63-4.78) | 0.0237 |
Animal 5 (2,059) | 314 | 612 (495-805) | 488 (434-566) | 4.93 (4.88-4.99) | 0.0126 |
Animal 6 (1,321) | 174 | 320 (252-447) | 289 (244-361) | 4.18 (4.11-4.25) | 0.0286 |
85% DNA sequence similarity | |||||
Animal 1 (2,485) | 48 | 61 (51-99) | 62 (52-90) | 2.64 (2.59-2.68) | 0.1056 |
Animal 2 (2,084) | 77 | 107 (87-165) | 102 (87-139) | 3.38 (3.34-3.43) | 0.0505 |
Animal 3 (1,710) | 130 | 153 (139-186) | 151 (140-174) | 4.07 (4.02-4.12) | 0.0254 |
Animal 4 (1,512) | 66 | 75 (68-98) | 77 (70-96) | 2.71 (2.64-2.78) | 0.0931 |
Animal 5 (2,059) | 69 | 80 (72-109) | 84 (75-110) | 3.31 (3.26-3.36) | 0.0545 |
Animal 6 (1,321) | 54 | 65 (57-102) | 61 (56-76) | 2.90 (2.83-2.97) | 0.0939 |
1000.
Karen L. Baab Sarah E. Freidline Steven L. Wang Timothy Hanson 《American journal of physical anthropology》2010,141(1):97-115
Variation in cranial robusticity among modern human populations is widely acknowledged but not well‐understood. While the use of “robust” cranial traits in hominin systematics and phylogeny suggests that these characters are strongly heritable, this hypothesis has not been tested. Alternatively, cranial robusticity may be a response to differences in diet/mastication or it may be an adaptation to cold, harsh environments. This study quantifies the distribution of cranial robusticity in 14 geographically widespread human populations, and correlates this variation with climatic variables, neutral genetic distances, cranial size, and cranial shape. With the exception of the occipital torus region, all traits were positively correlated with each other, suggesting that they should not be treated as individual characters. While males are more robust than females within each of the populations, among the independent variables (cranial shape, size, climate, and neutral genetic distances), only shape is significantly correlated with inter‐population differences in robusticity. Two‐block partial least‐squares analysis was used to explore the relationship between cranial shape (captured by three‐dimensional landmark data) and robusticity across individuals. Weak support was found for the hypothesis that robusticity was related to mastication as the shape associated with greater robusticity was similar to that described for groups that ate harder‐to‐process diets. Specifically, crania with more prognathic faces, expanded glabellar and occipital regions, and (slightly) longer skulls were more robust than those with rounder vaults and more orthognathic faces. However, groups with more mechanically demanding diets (hunter‐gatherers) were not always more robust than groups practicing some form of agriculture. Am J Phys Anthropol, 2010. © 2009 Wiley‐Liss, Inc. 相似文献