Identifying metabolites by integrating metabolome databases with mass spectrometry cheminformatics.

Novel metabolites distinct from canonical pathways can be identified through the integration of three cheminformatics tools: BinVestigate, which queries the BinBase gas chromatography-mass spectrometry (GC-MS) metabolome database to match unknowns with biological metadata across over 110,000 samples; MS-DIAL 2.0, a software tool for chromatographic deconvolution of high-resolution GC-MS or liquid chromatography-mass spectrometry (LC-MS); and MS-FINDER 2.0, a structure-elucidation program that uses a combination of 14 metabolome databases in addition to an enzyme promiscuity library. We showcase our workflow by annotating N-methyl-uridine monophosphate (UMP), lysomonogalactosyl-monopalmitin, N-methylalanine, and two propofol derivatives

Mycoplasma hyorhinis-contaminated cell lines activate primary innate immune cells via a protease-sensitive factor

Mycoplasma are a frequent and occult contaminant of cell cultures, whereby these prokaryotic organisms can modify many aspects of cell physiology, rendering experiments that are conducted with such contaminated cells problematic. Chronic Mycoplasma contamination in human monocytic cells lines has been associated with suppressed Toll-like receptor (TLR) function. In contrast, we show here that components derived from a Mycoplasma hyorhinis-infected cell line can activate innate immunity in non-infected primary immune cells. Release of pro-inflammatory cytokines such as IL-6 by dendritic cells in response to Mycoplasma hyorhinis-infected cell components was critically dependent on the adapter protein MyD88 but only partially on TLR2. Unlike canonical TLR2 signaling that is triggered in response to the detection of Mycoplasma infection, innate immune activation by components of Mycoplasma-infected cells was inhibited by chloroquine treatment and sensitive to protease treatment. We further show that in plasmacytoid dendritic cells, soluble factors from Mycoplasma hyorhinis-infected cells induce the production of large amounts of IFN-α. We conclude that Mycoplasma hyorhinis-infected cell lines release protein factors that can potently activate co-cultured innate immune cells via a previously unrecognized mechanism, thus limiting the validity of such co-culture experiments

The prevalence of obesity in children with autism: a secondary data analysis using nationally representative data from the National Survey of Children's Health

<p>Abstract</p> <p>Background</p> <p>The prevalence of childhood obesity has increased dramatically in the last two decades and numerous efforts to understand, intervene on, and prevent this significant threat to children's health are underway for many segments of the pediatric population. Understanding the prevalence of obesity in populations of children with developmental disorders is an important undertaking, as the factors that give rise to obesity may not be the same as for typically developing children, and because prevention and treatment efforts may need to be tailored to meet their needs and the needs of their families. The goal of the current study was to estimate the prevalence of obesity in children and adolescents with autism.</p> <p>Methods</p> <p>This study was a secondary data analysis of cross-sectional nationally representative data collected by telephone interview of parents/guardians on 85,272 children ages 3-17 from the 2003-2004 National Survey of Children's Health (NSCH). Autism was determined by response to the question, "Has a doctor or health professional ever told you that your child has autism?" Children and adolescents were classified as obese accordingto CDC guidelines for body mass index (BMI) for age and sex.</p> <p>Results</p> <p>The prevalence of obesity in children with autism was 30.4% compared to 23.6% of children without autism (p = .075). The unadjusted odds of obesity in children with autism was 1.42 (95% confidence interval (CI): 1.00, 2.02, p = .052) compared to children without autism.</p> <p>Conclusions</p> <p>Based on US nationally representative data, children with autism have a prevalence of obesity at least as high as children overall. These findings suggest that additional research is warranted to understand better the factors that influence the development of obesity in this population of children.</p

Achieving Pain Control in Rheumatoid Arthritis with Baricitinib or Adalimumab Plus Methotrexate: Results from the RA-BEAM Trial

The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate in RA-BEAM (NCT0170358). A randomized, double-blind trial was conducted, comparing baricitinib (N = 487), adalimumab (N = 330), and placebo (N = 488) plus methotrexate. Pain was evaluated by patient’s assessment on a 0–100 mm visual analog scale (VAS). The following were assessed through a 24-week placebo-controlled period: the proportion of patients who achieved ≥30%, ≥50%, and ≥70% pain relief, the time to achieve these pain relief thresholds, remaining pain (VAS ≤ 10 mm, ≤20 mm, or ≤40 mm), and the relationship between inflammation markers and pain relief. Baricitinib-treated patients were more likely (p < 0.05) to achieve ≥30%, ≥50%, and ≥70% pain relief than placebo- and adalimumab-treated patients, as early as Week 1 vs. placebo and at Week 4 vs. adalimumab. A greater proportion of baricitinib-treated patients achieved ≤20 mm or ≤40 mm remaining pain vs. placebo- and adalimumab-treated patients. Baricitinib-treated patients tended to demonstrate consistent pain relief independent of levels of inflammation control. In RA patients with an inadequate response to methotrexate, baricitinib provided greater and more rapid pain relief than adalimumab and placebo. Analyses suggest the relationship between inflammation and pain may be different for baricitinib and adalimumab treatments

Interactions between Surround Suppression and Interocular Suppression in Human Vision

Several types of suppression phenomena have been observed in the visual system. For example, the ability to detect a target stimulus is often impaired when the target is embedded in a high-contrast surround. This contextual modulation, known as surround suppression, was formerly thought to occur only in the periphery. Another type of suppression phenomena is interocular suppression, in which the sensitivity to a monocular target is reduced by a superimposed mask in the opposite eye. Here, we explored how the two types of suppression operating across different spatial regions interact with one another when they simultaneously exert suppressive influences on a common target presented at the fovea. In our experiments, a circular target grating presented to the fovea of one eye was suppressed interocularly by a noise pattern of the same size in the other eye. The foveal stimuli were either shown alone or surrounded by a monocular annular grating. The orientation and eye-of-origin of the surround grating were varied. We found that the detection of the foveal target subjected to interocular suppression was severely impaired by the addition of the surround grating, indicating strong surround suppression in the fovea. In contrast, when the interocular suppression was released by superimposing a binocular fusion ring onto both the target and the dichoptic mask, the surround suppression effect was found to be dramatically decreased. In addition, the surround suppression was found to depend on the contrast of the dichoptic noise with the greatest surround suppression effect being obtained only when the noise contrast was at an intermediate level. These findings indicate that surround suppression and interocular suppression are not independent of each other, but there are strong interactions between them. Moreover, our results suggest that strong surround suppression may also occur at the fovea and not just the periphery

The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease

Geomorphological evolution of a debris‐covered glacier surface

There exists a need to advance our understanding of debris‐covered glacier surfaces over relatively short timescales due to rapid, climatically induced areal expansion of debris cover at the global scale, and the impact debris has on mass balance. We applied unpiloted aerial vehicle structure‐from‐motion (UAV‐SfM) and digital elevation model (DEM) differencing with debris thickness and debris stability modelling to unravel the evolution of a 0.15 km2 region of the debris‐covered Miage Glacier, Italy, between June 2015 and July 2018. DEM differencing revealed widespread surface lowering (mean 4.1 ± 1.0 m a‐1; maximum 13.3 m a‐1). We combined elevation change data with local meteorological data and a sub‐debris melt model, and used these relationships to produce high resolution, spatially distributed maps of debris thickness. These maps were differenced to explore patterns and mechanisms of debris redistribution. Median debris thicknesses ranged from 0.12 to 0.17 m and were spatially variable. We observed localized debris thinning across ice cliff faces, except those which were decaying, where debris thickened. We observed pervasive debris thinning across larger, backwasting slopes, including those bordered by supraglacial streams, as well as ingestion of debris by a newly exposed englacial conduit. Debris stability mapping showed that 18.2–26.4% of the survey area was theoretically subject to debris remobilization. By linking changes in stability to changes in debris thickness, we observed that slopes that remain stable, stabilize, or remain unstable between periods almost exclusively show net debris thickening (mean 0.07 m a‐1) whilst those which become newly unstable exhibit both debris thinning and thickening. We observe a systematic downslope increase in the rate at which debris cover thickens which can be described as a function of the topographic position index and slope gradient. Our data provide quantifiable insights into mechanisms of debris remobilization on glacier surfaces over sub‐decadal timescales, and open avenues for future research to explore glacier‐scale spatiotemporal patterns of debris remobilization