Dental caries is characterized by a dysbiotic shift at the biofilm–tooth surface interface, yet comprehensive biochemical characterizations of the biofilm are scant. We used metabolomics to identify ...biochemical features of the supragingival biofilm associated with early childhood caries (ECC) prevalence and severity. The study’s analytical sample comprised 289 children ages 3 to 5 (51% with ECC) who attended public preschools in North Carolina and were enrolled in a community-based cross-sectional study of early childhood oral health. Clinical examinations were conducted by calibrated examiners in community locations using International Caries Detection and Classification System (ICDAS) criteria. Supragingival plaque collected from the facial/buccal surfaces of all primary teeth in the upper-left quadrant was analyzed using ultra-performance liquid chromatography–tandem mass spectrometry. Associations between individual metabolites and 18 clinical traits (based on different ECC definitions and sets of tooth surfaces) were quantified using Brownian distance correlations (dCor) and linear regression modeling of log2-transformed values, applying a false discovery rate multiple testing correction. A tree-based pipeline optimization tool (TPOT)–machine learning process was used to identify the best-fitting ECC classification metabolite model. There were 503 named metabolites identified, including microbial, host, and exogenous biochemicals. Most significant ECC-metabolite associations were positive (i.e., upregulations/enrichments). The localized ECC case definition (ICDAS ≥1 caries experience within the surfaces from which plaque was collected) had the strongest correlation with the metabolome (dCor P = 8 × 10−3). Sixteen metabolites were significantly associated with ECC after multiple testing correction, including fucose (P = 3.0 × 10−6) and N-acetylneuraminate (p = 6.8 × 10−6) with higher ECC prevalence, as well as catechin (P = 4.7 × 10−6) and epicatechin (P = 2.9 × 10−6) with lower. Catechin, epicatechin, imidazole propionate, fucose, 9,10-DiHOME, and N-acetylneuraminate were among the top 15 metabolites in terms of ECC classification importance in the automated TPOT model. These supragingival biofilm metabolite findings provide novel insights in ECC biology and can serve as the basis for the development of measures of disease activity or risk assessment.
Reproductive information since 1995 from the USDA national dairy database was used to calculate yearly Holstein and Jersey means for days to first breeding after calving (DFB), 70-d nonreturn rate, ...conception rate (CR), number of breedings per lactation (NB), interval between first and last breedings during the lactation, days to last breeding after calving (DLB), pregnancy rate (PR), calving interval (CI), and interval between consecutive breedings. Data were from nearly 20million breedings during >8million lactations of >5million cows in >23,000 herds. Means were also calculated for some traits by parity and breeding number for both breeds and by geographical region and synchronization status for Holsteins. The DFB declined for Holsteins from 92 d in 1996 to 85 d in 2007; the trend in yearly differences was not as consistent for Jerseys. First- and all-breeding 70-d nonreturn rate declined 5 to 9 percentage units over time. First- and all-breeding CR declined 2 to 4 percentage units. The DFB were longer for later parities of Holsteins than for early parities. Second- and third-breeding CR were sometimes 1 to 2 percentage units above first-breeding CR for Holsteins but lower (1 to 7 percentage units) for Jerseys. The CR within breeding number declined across parities for both breeds. The NB increased by 0.3 to 0.4 breedings over time but remained constant (2.5 or 2.6 breedings) across parities for Holsteins and increased (from 2.2 to 2.4 breedings) for Jerseys. Holstein DFB were fewest in the Northwest (78 d) and greatest in the Mountain region (92 d). Regional CR was highest for the Northeast and Southwest (33%) and lowest for the Southeast (26%); NB was fewest for the Northeast (2.3) and greatest for the Southeast (2.7). Mean DLB was fewest for the Southwest (127 d) and greatest for the Mountain region (157 d); CI was shortest for the Southwest (406 d) and longest for the Mideast (434 d). Mean PR was highest for the Southwest (28.3%) and lowest for the Mideast and Southeast (22.2%). Use of timed artificial insemination following synchronized estrus appears to have reduced DFB, lowered CR, and increased NB while reducing DLB and CI. However, synchronized breeding was not a primary cause of Holstein regional differences for reproductive traits. Since 2002, phenotypic performance for CR, DLB, and CI as well as genetic merit for daughter PR have stopped their historical declines and started to improve.
Trends since 1980 for calving age and calving interval, 2 factors that influence herd life, were examined by parity for 5 breeds of US dairy cattle. Calving data were from cows with records that ...passed edits for USDA genetic evaluations and were in herds that remained on Dairy Herd Improvement test. First-calf heifers calved at progressively younger ages over time, but the age decline was less for later parities because of longer calving intervals. Breed differences for calving age were evident for all parities; current mean age at first calving ranged from 24 mo for Jerseys to 28 mo for Ayrshires. Mean calving age across all parities declined over time for all breeds, primarily because of increased turnover rate, and ranged from 48 mo for Holsteins to 54 mo for Ayrshires. Across parity, annual increase in calving interval was reasonably consistent (0.90 to 1.07 d/yr) for all breeds except Jersey (0.49 d/yr). Within parity, regressions of calving interval on year were generally similar to overall breed trend. Breed means for first calving interval across time ranged from 390 d for Jerseys to 407 d for Brown Swiss.
Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with ...replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) ...results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.
Application of fluoroquinolone pharmacodynamics Wright, David H.; Brown, Gigi H.; Peterson, Marnie L. ...
Journal of antimicrobial chemotherapy,
11/2000, Volume:
46, Issue:
5
Journal Article
Peer reviewed
Open access
Pharmacodynamics provides a rational basis for optimizing dosing regimens by describing the relationship between drug, host and antimicrobial effect. The successful identification of meaningful ...pharmacodynamic outcome parameters can, therefore, greatly assist clinicians in making objective prescribing decisions rather than relying on static in vitro MIC data. While pharmacodynamic outcome parameters have been proposed for select antimicrobial agents, their clinical application remains to be defined fully. Quinolone antibiotics are generally considered to have concentration-dependent bactericidal activity and peak/MIC and AUC/MIC ratios have been identified as possible pharmacodynamic predictors of clinical and microbiological outcome as well as the development of bacterial resistance. Investigators have suggested that AUC/MIC ratios of 100–125 or peak/MIC ratios of >10 are required to predict clinical and microbiological success and to limit the development of bacterial resistance. These conclusions are derived primarily from studies of Gram-negative bacteria, and recent data suggest that these ratios may not be applicable for Streptococcus pneumoniae, where an AUC/MIC ratio of <40 appears to be a more accurate predictor. There is considerable variation in pharmacodynamic calculations and outcome parameters appear to be quinolone- and pathogen-specific. Additional prospective clinical research is needed to characterize quinolone pharmacodynamic parameters and answer unresolved questions regarding optimal pharmacodynamic outcome predictors for Gram-positive bacteria, anaerobes and atypical respiratory pathogens.
The Cryogenic Dark Matter Search low ionization threshold experiment (CDMSlite) achieved efficient detection of very small recoil energies in its germanium target, resulting in sensitivity to lightly ...ionizing particles (LIPs) in a previously unexplored region of charge, mass, and velocity parameter space. We report first direct-detection limits calculated using the optimum interval method on the vertical intensity of cosmogenically produced LIPs with an electric charge smaller than e / ( 3 × 105), as well as the strongest limits for charge ≤ e / 160 , with a minimum vertical intensity of 1.36 × 10−7 cm−2 s−1 sr−1 at charge e / 160 . These results apply over a wide range of LIP masses ( 5 MeV / c2 to 100 TeV / c2) and cover a wide range of β γ values ( 0.1 – 106), thus excluding nonrelativistic LIPs with β γ as small as 0.1 for the first time.
Full text
Available for:
CMK, CTK, FMFMET, NUK, UL
Successful treatment of multiple cancer types requires early detection and identification of reliable biomarkers present in specific cancer tissues. To test the feasibility of identifying proteins ...from archival cancer tissues, we have developed a methodology, termed direct tissue proteomics (DTP), which can be used to identify proteins directly from formalin-fixed paraffin-embedded prostate cancer tissue samples. Using minute prostate biopsy sections, we demonstrate the identification of 428 prostate-expressed proteins using the shotgun method. Because the DTP method is not quantitative, we employed the absolute quantification method and demonstrate picogram level quantification of prostate-specific antigen. In depth bioinformatics analysis of these expressed proteins affords the categorization of metabolic pathways that may be important for distinct stages of prostate carcinogenesis. Furthermore, we validate Wnt-3 as an upregulated protein in cancerous prostate cells by immunohistochemistry. We propose that this general strategy provides a roadmap for successful identification of critical molecular targets of multiple cancer types.
In order to extract the maximum possible power, it is important that the blades of small wind turbines start rotating at the lowest possible wind speed. The starting performance of a three-bladed, 2m ...diameter horizontal axis wind turbine was measured in field tests, and compared with calculations employing a quasi-steady blade element analysis. Accurate predictions of rotor acceleration were made for a large range of wind speeds, using a combination of interpolated aerofoil data and generic equations for lift and drag at high angles of incidence. Also, significantly different values for the wind speeds at which the turbine rotor starts and ceases to rotate were determined, indicating limitations in the traditional method of describing starting performance with a single ‘cut-in’ wind speed based on 10-min averages of wind speed and turbine power. The blade element calculations suggest that most of the starting torque is generated near the hub, whereas most power-producing torque comes from the tip region. The significance of these results for blade design is discussed.
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