On Data Integration Problems With Manifolds

<p>This article focuses on data integration problems where the predictor variables for some response variable partition into known subsets. This type of data is often referred to as multi-view data, and each subset of the predictors is called a data view. Accounting for data views can add practical value in terms of both interpretation and predictive performance. Many existing approaches for multi-view data rely on view-agreement principles, strong smoothness assumptions, or regularization penalties. The former approaches can be sensitive to modest noise in the response or predictor variables, while the latter approach is linear and can usually be out-performed. We develop semiparametric data integration methods to span key tradeoffs including the bias-variance tradeoff on prediction error, the possibility that the data may be fully viewed with no appreciable view relationships, and the use of sparse anchor point methods to detect and use manifolds (i.e., possibly nonelliptical structures) within views if they enhance performance. Theoretical results help justify the new technique, and its effectiveness and computational feasibility are demonstrated empirically. This new semiparametric methodology is available for public use through the supplemental R package mvltools. Additional supplementary material for this article is also available online.</p

Analysis of Repeatability and Reproducibility Studies With Ordinal Measurements

<p>A Bayesian inferential approach with a noninformative prior is introduced to analyze ordinal repeatability and reproducibility (R&R) data using the De Mast–Van Wieringen model. This approach is extended with a weakly informative prior and random effects to allow for the consideration of a population of raters and prediction of a new rater. This random-effects approach is also shown to result in partial pooling of estimates across raters. In addition, match-probability-based measures to decompose ordinal R&R study data into contributions due to repeatability and due to reproducibility are defined. All extensions involving Bayesian inference (for fixed or random effects) and measures are illustrated on real and simulated ordinal R&R study data and are applicable in business and industry settings. This methodology can be implemented using the supplemental R package ordinalRR available from CRAN. Additional supplementary material for this article is available online.</p

Image_1_IL-27 alters inflammatory cytokine expression and limits protective immunity against Mycobacterium tuberculosis in a neonatal BCG vaccination model.tif

BackgroundEfforts to control tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), have been hampered by the immense variability in protection from BCG vaccination. While BCG protects young children from some forms of TB disease, long-term protection against pulmonary disease is more limited, suggesting a poor memory response. New vaccines or vaccination strategies are required to have a realistic chance of eliminating TB disease. In TB endemic areas, routine immunization occurs during the neonatal period and as such, we hypothesized that inadequate protective immunity elicited by BCG vaccination could be the result of the unique early-life immune landscape. Interleukin (IL)-27 is a heterodimeric cytokine with immune suppressive activity that is elevated in the neonatal period.ObjectiveWe investigated the impact of IL-27 on regulation of immune responses during neonatal BCG vaccination and protection against Mtb.MethodsHere, we used a novel model of neonatal vaccination and adult aerosol challenge that models the human timeline of vaccine delivery and disease transmission.ResultsOverall, we observed improved control of Mtb in mice unresponsive to IL-27 (IL-27Rα-/-) that was consistent with altered expression patterns of IFN-γ and IL-17 in the lungs. The balance of these cytokines with TNF-α expression may be key to effective bacterial clearance.ConclusionsOur findings suggest the importance of evaluating new vaccines and approaches to combat TB in the neonatal population most likely to receive them as part of global vaccination campaigns. They further indicate that temporal strategies to antagonize IL-27 during early life vaccination may improve protection.</p

Image_2_IL-27 alters inflammatory cytokine expression and limits protective immunity against Mycobacterium tuberculosis in a neonatal BCG vaccination model.tif

BackgroundEfforts to control tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), have been hampered by the immense variability in protection from BCG vaccination. While BCG protects young children from some forms of TB disease, long-term protection against pulmonary disease is more limited, suggesting a poor memory response. New vaccines or vaccination strategies are required to have a realistic chance of eliminating TB disease. In TB endemic areas, routine immunization occurs during the neonatal period and as such, we hypothesized that inadequate protective immunity elicited by BCG vaccination could be the result of the unique early-life immune landscape. Interleukin (IL)-27 is a heterodimeric cytokine with immune suppressive activity that is elevated in the neonatal period.ObjectiveWe investigated the impact of IL-27 on regulation of immune responses during neonatal BCG vaccination and protection against Mtb.MethodsHere, we used a novel model of neonatal vaccination and adult aerosol challenge that models the human timeline of vaccine delivery and disease transmission.ResultsOverall, we observed improved control of Mtb in mice unresponsive to IL-27 (IL-27Rα-/-) that was consistent with altered expression patterns of IFN-γ and IL-17 in the lungs. The balance of these cytokines with TNF-α expression may be key to effective bacterial clearance.ConclusionsOur findings suggest the importance of evaluating new vaccines and approaches to combat TB in the neonatal population most likely to receive them as part of global vaccination campaigns. They further indicate that temporal strategies to antagonize IL-27 during early life vaccination may improve protection.</p

Image_3_IL-27 alters inflammatory cytokine expression and limits protective immunity against Mycobacterium tuberculosis in a neonatal BCG vaccination model.tif

BackgroundEfforts to control tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), have been hampered by the immense variability in protection from BCG vaccination. While BCG protects young children from some forms of TB disease, long-term protection against pulmonary disease is more limited, suggesting a poor memory response. New vaccines or vaccination strategies are required to have a realistic chance of eliminating TB disease. In TB endemic areas, routine immunization occurs during the neonatal period and as such, we hypothesized that inadequate protective immunity elicited by BCG vaccination could be the result of the unique early-life immune landscape. Interleukin (IL)-27 is a heterodimeric cytokine with immune suppressive activity that is elevated in the neonatal period.ObjectiveWe investigated the impact of IL-27 on regulation of immune responses during neonatal BCG vaccination and protection against Mtb.MethodsHere, we used a novel model of neonatal vaccination and adult aerosol challenge that models the human timeline of vaccine delivery and disease transmission.ResultsOverall, we observed improved control of Mtb in mice unresponsive to IL-27 (IL-27Rα-/-) that was consistent with altered expression patterns of IFN-γ and IL-17 in the lungs. The balance of these cytokines with TNF-α expression may be key to effective bacterial clearance.ConclusionsOur findings suggest the importance of evaluating new vaccines and approaches to combat TB in the neonatal population most likely to receive them as part of global vaccination campaigns. They further indicate that temporal strategies to antagonize IL-27 during early life vaccination may improve protection.</p

Discovery and Optimization of Benzotriazine Di-<i>N</i>-Oxides Targeting Replicating and Nonreplicating Mycobacterium tuberculosis

Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-<i>N</i>-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (<b>20q</b>) from this series with an MIC of 0.31 μg/mL against H37Rv and a cytotoxicity (CC₅₀) against Vero cells of 25 μg/mL. <b>20q</b> also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. <b>20q</b> was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs