Neutrophil Dynamics Affect Mycobacterium tuberculosis Granuloma Outcomes and Dissemination

Neutrophil infiltration into tuberculous granulomas is often associated with higher bacteria loads and severe disease but the basis for this relationship is not well understood. To better elucidate the connection between neutrophils and pathology in primate systems, we paired data from experimental studies with our next generation computational model GranSim to identify neutrophil-related factors, including neutrophil recruitment, lifespan, and intracellular bacteria numbers, that drive granuloma-level outcomes. We predict mechanisms underlying spatial organization of neutrophils within granulomas and identify how neutrophils contribute to granuloma dissemination. We also performed virtual deletion and depletion of neutrophils within granulomas and found that neutrophils play a nuanced role in determining granuloma outcome, promoting uncontrolled bacterial growth in some and working to contain bacterial growth in others. Here, we present three key results: We show that neutrophils can facilitate local dissemination of granulomas and thereby enable the spread of infection. We suggest that neutrophils influence CFU burden during both innate and adaptive immune responses, implying that they may be targets for therapeutic interventions during later stages of infection. Further, through the use of uncertainty and sensitivity analyses, we predict which neutrophil processes drive granuloma severity and structure

Spectral Analysis for Matrix Hamiltonian Operators

In this work, we study the spectral properties of matrix Hamiltonians generated by linearizing the nonlinear Schr\"odinger equation about soliton solutions. By a numerically assisted proof, we show that there are no embedded eigenvalues for the three dimensional cubic equation. Though we focus on a proof of the 3d cubic problem, this work presents a new algorithm for verifying certain spectral properties needed to study soliton stability. Source code for verification of our comptuations, and for further experimentation, are available at http://www.math.toronto.edu/simpson/files/spec_prop_code.tgz.Comment: 57 pages, 22 figures, typos fixe

Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization

Lung granulomas are the pathologic hallmark of tuberculosis (TB). T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb) infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few “multi-functional” T cells were observed. However, granulomas were found to be “multi-functional” with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF) and/or T-17 (IL-17) cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17) were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not accurately reflect local T cell responses within granulomas

Nonpolitical Images Evoke Neural Predictors of Political Ideology

Political ideologies summarize dimensions of life that define how a person organizes their public and private behavior, including their attitudes associated with sex, family, education, and personal autonomy [1, 2]. Despite the abstract nature of such sensibilities, fundamental features of political ideology have been found to be deeply connected to basic biological mechanisms [3–7] that may serve to defend against environmental challenges like contamination and physical threat [8–12]. These results invite the provocative claim that neural responses to nonpolitical stimuli (like contaminated food or physical threats) should be highly predictive of abstract political opinions (like attitudes toward gun control and abortion) [13]. We applied a machinelearning method to fMRI data to test the hypotheses that brain responses to emotionally evocative images predict individual scores on a standard political ideology assay. Disgusting images, especially those related to animalreminder disgust (e.g., mutilated body), generate neural responses that are highly predictive of political orientation even though these neural predictors do not agree with participants’ conscious rating of the stimuli. Images from other affective categories do not support such predictions. Remarkably, brain responses to a single disgusting stimulus were sufficient to make accurate predictions about an individual subject’s political ideology. These results provide strong support for the idea that fundamental neural processing differences that emerge under the challenge of emotionally evocative stimuli may serve to structure political beliefs in ways formerly unappreciated

Behavioral Economic Measurement of Cigarette Demand: A Descriptive Review of Published Approaches to the Cigarette Purchase Task

The cigarette purchase task (CPT) is a behavioral economic method for assessing demand for cigarettes. Growing interest in behavioral correlates of tobacco use in clinical and general populations as well as empirical efforts to inform policy has seen an increase in published articles employing the CPT. Accordingly, an examination of the published methods and procedures for obtaining these behavioral economic metrics is timely. The purpose of this investigation was to provide a review of published approaches to using the CPT. We searched specific Boolean operators ([“behavioral economic” AND “purchase task”] OR [“demand” AND “cigarette”]) and identified 49 empirical articles published through the year 2018 that reported administering a CPT. Articles were coded for participant characteristics (e.g., sample size, population type, age), CPT task structure (e.g., price framing, number and sequence of prices; vignettes, contextual factors), and data analytic approach (e.g., method of generating indices of cigarette demand). Results of this review indicate no standard approach to administering the CPT and underscore the need for replicability of these behavioral economic measures for the purpose of guiding clinical and policy decisions

Decreased Muscle Strength in Children With Repaired Tetralogy of Fallot:Relation With Exercise Capacity

Background: The aim of this study is to describe muscle strength in pediatric patients with repaired tetralogy of Fallot compared with healthy peers and to analyze the correlation between muscle strength and peak oxygen uptake, exercise capacity (mL/min).Methods and Results: A prospective, cross-sectional study was carried out in the University Medical Center Groningen between March 2016 and December 2019, which included 8 -to-19-year-old patients with repaired tetralogy of Fallot. Exclusion criteria comprised the following: Down syndrome, unstable pulmonary disease and severe scoliosis affecting pulmonary function, neuromuscular disease, and mental or physical limitations that prohibit the execution of the functional tests. Muscle strength was compared with 2 healthy pediatric cohorts from the Northern Netherlands. Handgrip strength, maximal voluntary isometric contraction, and dynamic muscle strength in correlation with peak oxygen uptake, exercise capacity (mL/min) were the main outcomes of the study. The 67 patients with repaired tetralogy of Fallot (42% female; aged 12.9 [interquartile range, 10.0-16.3] years old) were compared with healthy children. The patients showed reduced grip strength ( z-score [mean±SD] -1.5±1.2, P&lt;0.001), and total muscle strength ( z-score -0.9±1.3, P&lt;0.001). Dynamic strength (Bruininks-Oseretsky test) was significantly reduced ( z-score -0.3±0.8, P=0.001), but running, speed, and agility were normal ( z-score 0.1±0.7, P=0.4). Univariate correlation analyses showed strong correlations between absolute peak oxygen uptake, exercise capacity (mL/min), and muscle strength (grip strength r=0.83, total muscle strength r=0.88; P&lt;0.001). In multivariate analyses, including correction for age and sex, total muscle strength (B 0.3; P=0.009), and forced vital capacity (B 0.5; P=0.02) correlated with peak oxygen uptake, exercise capacity (mL/min), independent of conventional cardiovascular parameters.Conclusions: Children with repaired tetralogy of Fallot show reduced muscle strength, which strongly correlated with their exercise performance. </p