Holy Light in "Paradise Lost"

Paper by William B. Hunter, Jr. from the University of Idah

A Computational Framework for High-Throughput Isotopic Natural Abundance Correction of Omics-Level Ultra-High Resolution FT-MS Datasets

New metabolomics applications of ultra-high resolution and accuracy mass spectrometry can provide thousands of detectable isotopologues, with the number of potentially detectable isotopologues increasing exponentially with the number of stable isotopes used in newer isotope tracing methods like stable isotope-resolved metabolomics (SIRM) experiments. This huge increase in usable data requires software capable of correcting the large number of isotopologue peaks resulting from SIRM experiments in a timely manner. We describe the design of a new algorithm and software system capable of handling these high volumes of data, while including quality control methods for maintaining data quality. We validate this new algorithm against a previous single isotope correction algorithm in a two-step cross-validation. Next, we demonstrate the algorithm and correct for the effects of natural abundance for both 13C and 15N isotopes on a set of raw isotopologue intensities of UDP-N-acetyl-D-glucosamine derived from a 13C/15N-tracing experiment. Finally, we demonstrate the algorithm on a full omics-level dataset

Method and System for Identification of Metabolites Using Mass Spectra

A method and system is provided for mass spectrometry for identification of a specific elemental formula for an unknown compound which includes but is not limited to a metabolite. The method includes calculating a natural abundance probability (NAP) of a given isotopologue for isotopes of non-labelling elements of an unknown compound. Molecular fragments for a subset of isotopes identified using the NAP are created and sorted into a requisite cache data structure to be subsequently searched. Peaks from raw spectrum data from mass spectrometry for an unknown compound. Sample-specific peaks of the unknown com- pound from various spectral artifacts in ultra-high resolution Fourier transform mass spectra are separated. A set of possible isotope-resolved molecular formula (IMF) are created by iteratively searching the molecular fragment caches and combining with additional isotopes and then statistically filtering the results based on NAP and mass-to-charge (m/2) matching probabilities. An unknown compound is identified and its corresponding elemental molecular formula (EMF) from statistically-significant caches of isotopologues with compatible IMFs

Treatment with 2-AAF blocks the small hepatocyte-like progenitor cell response in retrorsine-exposed rats

Liver regeneration after partial hepatectomy (PH) in retrorsine-exposed rats is accomplished through proliferation and differentiation of small hepatocyte-like progenitor cells (SHPCs). The cells of origin of SHPCs are not known. We investigated the possibility that SHPCs are directly derived from oval cells, a known liver progenitor cell, by combining the retrorsine/PH (RP) model with 2-acetamidofluorene (2-AAF), an anti-mitotic agent that elicits an oval cell reaction in response to liver deficit

Distribution of independent components of binocular natural images

An influential theory of the function of early processing in the visual cortex is that it forms an efficient coding of ecologically valid stimuli. In particular, correlations and differences between visual signals from the two eyes are believed to be of great importance in solving both depth from disparity and binocular fusion. Techniques such as independent-component analysis have been developed to learn efficient codings from natural images; these codings have been found to resemble receptive fields of simple cells in V1. However, the extent to which this approach provides an explanation of the functionality of the visual cortex is still an open question. We compared binocular independent components with physiological measurements and found a broad range of similarities along with a number of key differences. In common with physiological measurements, we found components with a broad range of both phase- and position-disparity tuning. However, we also found a larger population of binocularly anticorrelated components than have been found physiologically. We found components focused narrowly on detecting disparities proportional to half-integer multiples of wavelength rather than the range of disparities found physiologically. We present the results as a detailed analysis of phase and position disparities in Gabor-like components generated by independent-component analysis trained on binocular natural images and compare these results to physiology. We find strong similarities between components learned from natural images, indicating that ecologically valid stimuli are important in understanding cortical function, but with significant differences that suggest that our current models are incomplete

Heterogeneity in ess transcriptional organization and variable contribution of the Ess/Type VII protein secretion system to virulence across closely related <em>Staphylocccus aureus </em>strains

The Type VII protein secretion system, found in Gram-positive bacteria, secretes small proteins, containing a conserved W-x-G amino acid sequence motif, to the growth medium. Staphylococcus aureus has a conserved Type VII secretion system, termed Ess, which is dispensable for laboratory growth but required for virulence. In this study we show that there are unexpected differences in the organization of the ess gene cluster between closely related strains of S. aureus. We further show that in laboratory growth medium different strains of S. aureus secrete the EsxA and EsxC substrate proteins at different growth points, and that the Ess system in strain Newman is inactive under these conditions. Systematic deletion analysis in S. aureus RN6390 is consistent with the EsaA, EsaB, EssA, EssB, EssC and EsxA proteins comprising core components of the secretion machinery in this strain. Finally we demonstrate that the Ess secretion machinery of two S. aureus strains, RN6390 and COL, is important for nasal colonization and virulence in the murine lung pneumonia model. Surprisingly, however, the secretion system plays no role in the virulence of strain SA113 under the same conditions

Essential role for proteinase-activated receptor-2 in arthritis

Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis

A Randomized Trial of Patellofemoral Bracing for Treatment of Patellofemoral Osteoarthritis

Purpose The number of effective knee osteoarthritis (OA) interventions, especially those tailored to specific compartmental involvement, are small. The objective of this study was to determine the efficacy of a realigning patellofemoral (PF) brace in improving pain and function among persons with symptomatic lateral PF OA. Method We conducted a double blind, randomized crossover trial of a realigning PF brace for persons with lateral PF OA. Participants had lateral PF OA with anterior knee symptoms on most days of the month, lateral PF joint space narrowing, and radiographic evidence of a definite osteophyte in the PF joint. We compared two treatments: (1) Control treatment consisting of a BioSkin Q Brace with patellar realigning strap removed; and (2) Active treatment consisting of a realigning BioSkin Q Brace with the strap applied. For each participant, the trial lasted 18 weeks, including 6 weeks each of active and control treatment period separated by a 6-week washout period. The order of treatments was randomized. The primary outcome was change in knee pain on the visual analog scale (VAS). Secondary outcomes included WOMAC pain, function, and stiffness. An unstructured correlation matrix for observations within participants was used in generalized estimating equation fitting to derive a linear regression model that expressed the relation between the intervention and change in VAS pain. Results 80 participants (63 F) with a mean age and body mass index of 61 years and 28 kg/m2, respectively, were randomized by order of treatment. A model examining the main effects for change in VAS knee pain (0–100) demonstrated no significant treatment effect (−0.68 VAS units, 95% CI: −6.2, 4.8 units, P = 0.81) and no differential carryover effect. There was also no significant difference between active and control treatments for WOMAC pain, function, or stiffness outcomes. Conclusion The effects of a specific realigning PF brace are not of clinical or statistical significance

Validation of Kepler's Multiple Planet Candidates. III: Light Curve Analysis & Announcement of Hundreds of New Multi-planet Systems

The Kepler mission has discovered over 2500 exoplanet candidates in the first two years of spacecraft data, with approximately 40% of them in candidate multi-planet systems. The high rate of multiplicity combined with the low rate of identified false-positives indicates that the multiplanet systems contain very few false-positive signals due to other systems not gravitationally bound to the target star (Lissauer, J. J., et al., 2012, ApJ 750, 131). False positives in the multi- planet systems are identified and removed, leaving behind a residual population of candidate multi-planet transiting systems expected to have a false-positive rate less than 1%. We present a sample of 340 planetary systems that contain 851 planets that are validated to substantially better than the 99% confidence level; the vast majority of these have not been previously verified as planets. We expect ~2 unidentified false-positives making our sample of planet very reliable. We present fundamental planetary properties of our sample based on a comprehensive analysis of Kepler light curves and ground-based spectroscopy and high-resolution imaging. Since we do not require spectroscopy or high-resolution imaging for validation, some of our derived parameters for a planetary system may be systematically incorrect due to dilution from light due to additional stars in the photometric aperture. None the less, our result nearly doubles the number of verified exoplanets.Comment: 138 pages, 8 Figures, 5 Tables. Accepted for publications in the Astrophysical Journa

Evaluating the influence of a constraint manipulation on technical, tactical and physical athlete behaviour

Evaluating practice design is an important component of supporting skill acquisition and improving team-sport performance. Constraint manipulations, including creating a numerical advantage or disadvantage during training, may be implemented by coaches to influence aspects of player or team behaviour. This study presents methods to evaluate the interaction between technical, tactical and physical behaviours of professional Australian Football players during numerical advantage and disadvantage conditions within a small-sided game. During each repetition of the game, team behaviour was manually annotated to determine: repetition duration, disposal speed, total disposals, efficiency, and disposal type. Global Positioning System devices were used to quantify tactical (surface area) and physical (velocity and high intensity running) variables. A rule association and classification tree analysis were undertaken. The top five rules for each constraint manipulation had confidence levels between 73.3% and 100%, which identified the most frequent behaviour interactions. Specifically, four advantage rules involved high surface area and medium high intensity running indicating the attacking team's frequent movement solution within this constraint. The classification tree included three behaviour metrics: surface area, velocity 1SD and repetition duration, and identified two unique movement solutions for each constraint manipulation. These results may inform if player behaviour is achieving the desired outcomes of a constraint manipulation, which could help practitioners determine the efficacy of a training task. Further, critical constraint values provided by the models may guide practitioners in their ongoing constraint manipulations to facilitate skill acquisition. Sport practitioners can adapt these methods to evaluate constraint manipulations and inform practice design