In vivo activity of plant-based interleukin-12 in the lung of Balb/c mouse

<p>Abstract</p> <p>Background</p> <p>In the last years, plants are being used for the production of a wide variety of biopharmaceuticals, including cytokines, and have the potential to serve as vehicles for mucosal administration of these molecules. We had previously reported the expression of a cytokine, interleukin-12 (IL-12), in transgenic tomato plants and had demonstrated that it retained its biologic activity <it>in vitro</it>.</p> <p>Findings</p> <p>In this work, we administered crude extracts of IL-12-containing tomato fruits to mice through the intratracheal route, measuring endogenous IL-12 and determining biologic activity by quantification of interferon-gamma (IFN-γ) in lungs and by histological analysis. IFN-γ expression in lungs, as well as histological analysis, indicate that tomato-expressed IL-12 retains its biologic activity and, most importantly, its effects are restricted to the site of administration.</p> <p>Conclusion</p> <p>Our results indicate that the functional activity of tomato-expressed IL-12 is comparable to that of commercial recombinant IL-12 when given via the mucosal route. This opens the possibility of using crude extracts prepared from tomatoes expressing IL-12 for certain immunotherapies.</p

Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach. METHODS: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m2). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein–protein interaction (PPI) data. RESULTS: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3–5.6, P = 3.2 × 10−8) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling. CONCLUSIONS: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling

Foundations of Black Hole Accretion Disk Theory

This review covers the main aspects of black hole accretion disk theory. We begin with the view that one of the main goals of the theory is to better understand the nature of black holes themselves. In this light we discuss how accretion disks might reveal some of the unique signatures of strong gravity: the event horizon, the innermost stable circular orbit, and the ergosphere. We then review, from a first-principles perspective, the physical processes at play in accretion disks. This leads us to the four primary accretion disk models that we review: Polish doughnuts (thick disks), Shakura-Sunyaev (thin) disks, slim disks, and advection-dominated accretion flows (ADAFs). After presenting the models we discuss issues of stability, oscillations, and jets. Following our review of the analytic work, we take a parallel approach in reviewing numerical studies of black hole accretion disks. We finish with a few select applications that highlight particular astrophysical applications: measurements of black hole mass and spin, black hole vs. neutron star accretion disks, black hole accretion disk spectral states, and quasi-periodic oscillations (QPOs).Comment: 91 pages, 23 figures, final published version available at http://www.livingreviews.org/lrr-2013-

A Test of Highly Optimized Tolerance Reveals Fragile Cell-Cycle Mechanisms Are Molecular Targets in Clinical Cancer Trials

Robustness, a long-recognized property of living systems, allows function in the face of uncertainty while fragility, i.e., extreme sensitivity, can potentially lead to catastrophic failure following seemingly innocuous perturbations. Carlson and Doyle hypothesized that highly-evolved networks, e.g., those involved in cell-cycle regulation, can be resistant to some perturbations while highly sensitive to others. The “robust yet fragile” duality of networks has been termed Highly Optimized Tolerance (HOT) and has been the basis of new lines of inquiry in computational and experimental biology. In this study, we tested the working hypothesis that cell-cycle control architectures obey the HOT paradigm. Three cell-cycle models were analyzed using monte-carlo sensitivity analysis. Overall state sensitivity coefficients, which quantify the robustness or fragility of a given mechanism, were calculated using a monte-carlo strategy with three different numerical techniques along with multiple parameter perturbation strategies to control for possible numerical and sampling artifacts. Approximately 65% of the mechanisms in the G1/S restriction point were responsible for 95% of the sensitivity, conversely, the G2-DNA damage checkpoint showed a much stronger dependence on a few mechanisms; ∼32% or 13 of 40 mechanisms accounted for 95% of the sensitivity. Our analysis predicted that CDC25 and cyclin E mechanisms were strongly implicated in G1/S malfunctions, while fragility in the G2/M checkpoint was predicted to be associated with the regulation of the cyclin B-CDK1 complex. Analysis of a third model containing both G1/S and G2/M checkpoint logic, predicted in addition to mechanisms already mentioned, that translation and programmed proteolysis were also key fragile subsystems. Comparison of the predicted fragile mechanisms with literature and current preclinical and clinical trials suggested a strong correlation between efficacy and fragility. Thus, when taken together, these results support the working hypothesis that cell-cycle control architectures are HOT networks and establish the mathematical estimation and subsequent therapeutic exploitation of fragile mechanisms as a novel strategy for anti-cancer lead generation

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

A Systematic Review of Fitness Apps and Their Potential Clinical and Sports Utility for Objective and Remote Assessment of Cardiorespiratory Fitness

Key Points The validity and reliability of existing and/or underdevelopment fitness apps should be further investigated. Physiological signals should be incorporated into fitness apps, such as heart rate measures using a smartphone camera, during or after exercise testing. There is a need to develop interoperable fitness apps (e.g., different languages, apps integrated into both app markets, data that is device-independent). Fitness apps should incorporate evidence-based cutpoints of CRF, allowing interpretation of fitness testing resultsWe are grateful to Ms Carmen Sainz-Quinn for assistance with the English language.Background Cardiorespiratory fitness (CRF) assessment provides key information regarding general health status that has high clinical utility. In addition, in the sports setting, CRF testing is needed to establish a baseline level, prescribe an individualized training program and monitor improvement in athletic performance. As such, the assessment of CRF has both clinical and sports utility. Technological advancements have led to increased digitization within healthcare and athletics. Nevertheless, further investigation is needed to enhance the validity and reliability of existing fitness apps for CRF assessment in both contexts. Objectives The present review aimed to (1) systematically review the scientific literature, examining the validity and reliability of apps designed for CRF assessment; and (2) systematically review and qualitatively score available fitness apps in the two main app markets. Lastly, this systematic review outlines evidence-based practical recommendations for developing future apps that measure CRF. Data Sources The following sources were searched for relevant studies: PubMed, Web of Science®, ScopusTM, and SPORTDiscus, and data was also found within app markets (Google Play and the App Store). Study Eligibility Criteria Eligible scientific studies examined the validity and/or reliability of apps for assessing CRF through a field-based fitness test. Criteria for the app markets involved apps that estimated CRF. Study Appraisal and Synthesis Methods The scientific literature search included four major electronic databases and the timeframe was set between 01 January 2000 and 31 October 2018. A total of 2796 articles were identified using a set of fitness-related terms, of which five articles were finally selected and included in this review. The app market search was undertaken by introducing keywords into the search engine of each app market without specified search categories. A total of 691 apps were identified using a set of fitness-related terms, of which 88 apps were finally included in the quantitative and qualitative synthesis. Results Five studies focused on the scientific validity of fitness tests with apps, while only two of these focused on reliability. Four studies used a sub-maximal fitness test via apps. Out of the scientific apps reviewed, the SA-6MWTapp showed the best validity against a criterion measure (r = 0.88), whilst the InterWalk app showed the highest test–retest reliability (ICC range 0.85–0.86). Limitations Levels of evidence based on scientific validity/reliability of apps and on commercial apps could not be robustly determined due to the limited number of studies identified in the literature and the low-to-moderate quality of commercial apps. Conclusions The results from this scientific review showed that few apps have been empirically tested, and among those that have, not all were valid or reliable. In addition, commercial apps were of low-to-moderate quality, suggesting that their potential for assessing CRF has yet to be realized. Lastly, this manuscript has identified evidence-based practical recommendations that apps might potentially offer to objectively and remotely assess CRF as a complementary tool to traditional methods in the clinical and sports settings

Differential cell line susceptibility to the emerging Zika virus: implications for disease pathogenesis, non-vector-borne human transmission and animal reservoirs

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Functional polymorphisms in genes of the Angiotensin and Serotonin systems and risk of hypertrophic cardiomyopathy: AT1R as a potential modifier

<p>Abstract</p> <p>Background</p> <p>Angiotensin and serotonin have been identified as inducers of cardiac hypertrophy. DNA polymorphisms at the genes encoding components of the angiotensin and serotonin systems have been associated with the risk of developing cardiovascular diseases, including left ventricular hypertrophy (LVH).</p> <p>Methods</p> <p>We genotyped five polymorphisms of the <it>AGT</it>, <it>ACE</it>, <it>AT1R</it>, <it>5-HT2A</it>, and <it>5-HTT </it>genes in 245 patients with Hypertrophic Cardiomyopathy (HCM; 205 without an identified sarcomeric gene mutation), in 145 patients with LVH secondary to hypertension, and 300 healthy controls.</p> <p>Results</p> <p>We found a significantly higher frequency of <it>AT1R </it>1166 C carriers (CC+AC) among the HCM patients without sarcomeric mutations compared to controls (p = 0.015; OR = 1.56; 95%CI = 1.09-2.23). The <it>AT1R </it>1166 C was also more frequent among patients who had at least one affected relative, compared to sporadic cases. This allele was also associated with higher left ventricular wall thickness in both, HCM patients with and without sarcomeric mutations.</p> <p>Conclusions</p> <p>The 1166 C <it>AT1R </it>allele could be a risk factor for cardiac hypertrophy in patients without sarcomeric mutations. Other variants at the <it>AGT</it>, <it>ACE</it>, <it>5-HT2A </it>and <it>5-HTT </it>did not contribute to the risk of cardiac hypertrophy.</p

A Broad Assessment of Factors Determining Culicoides imicola Abundance: Modelling the Present and Forecasting Its Future in Climate Change Scenarios

Bluetongue (BT) is still present in Europe and the introduction of new serotypes from endemic areas in the African continent is a possible threat. Culicoides imicola remains one of the most relevant BT vectors in Spain and research on the environmental determinants driving its life cycle is key to preventing and controlling BT. Our aim was to improve our understanding of the biotic and abiotic determinants of C. imicola by modelling its present abundance, studying the spatial pattern of predicted abundance in relation to BT outbreaks, and investigating how the predicted current distribution and abundance patterns might change under future (2011–2040) scenarios of climate change according to the Intergovernmental Panel on Climate Change. C. imicola abundance data from the bluetongue national surveillance programme were modelled with spatial, topoclimatic, host and soil factors. The influence of these factors was further assessed by variation partitioning procedures. The predicted abundance of C. imicola was also projected to a future period. Variation partitioning demonstrated that the pure effect of host and topoclimate factors explained a high percentage (>80%) of the variation. The pure effect of soil followed in importance in explaining the abundance of C. imicola. A close link was confirmed between C. imicola abundance and BT outbreaks. To the best of our knowledge, this study is the first to consider wild and domestic hosts in predictive modelling for an arthropod vector. The main findings regarding the near future show that there is no evidence to suggest that there will be an important increase in the distribution range of C. imicola; this contrasts with an expected increase in abundance in the areas where it is already present in mainland Spain. What may be expected regarding the future scenario for orbiviruses in mainland Spain, is that higher predicted C. imicola abundance may significantly change the rate of transmission of orbiviruses