A scalable machine-learning approach to recognize chemical names within large text databases

MOTIVATION: The use or study of chemical compounds permeates almost every scientific field and in each of them, the amount of textual information is growing rapidly. There is a need to accurately identify chemical names within text for a number of informatics efforts such as database curation, report summarization, tagging of named entities and keywords, or the development/curation of reference databases. RESULTS: A first-order Markov Model (MM) was evaluated for its ability to distinguish chemical names from words, yielding ~93% recall in recognizing chemical terms and ~99% precision in rejecting non-chemical terms on smaller test sets. However, because total false-positive events increase with the number of words analyzed, the scalability of name recognition was measured by processing 13.1 million MEDLINE records. The method yielded precision ranges from 54.7% to 100%, depending upon the cutoff score used, averaging 82.7% for approximately 1.05 million putative chemical terms extracted. Extracted chemical terms were analyzed to estimate the number of spelling variants per term, which correlated with the total number of times the chemical name appeared in MEDLINE. This variability in term construction was found to affect both information retrieval and term mapping when using PubMed and Ovid

Harnessing Naturally Occurring Tumor Immunity: A Clinical Vaccine Trial in Prostate Cancer

International audienceBACKGROUND:Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.METHODS AND FINDINGS:We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.CONCLUSIONS:An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine

An organ culture system to model early degenerative changes of the intervertebral disc

ABSTRACT: INTRODUCTION: Back pain, a significant source of morbidity in our society, is related to the degenerative changes of the intervertebral disc. At present, the treatment of disc disease consists of therapies that are aimed at symptomatic relief. This shortcoming stems in large part from our lack of understanding of the biochemical and molecular events that drive the disease process. The goal of this study is to develop a model of early disc degeneration using an organ culture. This approach is based on our previous studies that indicate that organ culture closely models molecular events that occur in vivo in an ex vivo setting. METHODS: To mimic a degenerative insult, discs were cultured under low oxygen tension in the presence of TNF-α, IL-1β and serum limiting conditions. RESULTS: Treatment resulted in compromised cell survival and changes in cellular morphology reminiscent of degeneration. There was strong suppression in the expression of matrix proteins including collagen types 1, 2, 6 and 9, proteoglycans, aggrecan and fibromodulin. Moreover, a strong induction in expression of catabolic matrix metalloproteinases (MMP) 3, 9 and 13 with a concomitant increase in aggrecan degradation was seen. An inductive effect on NGF expression was also noticed. Although similar, nucleus pulposus and annulus fibrosus tissues showed some differences in their response to the treatment. CONCLUSIONS: Results of this study show that perturbations in microenvironmental factors result in anatomical and gene expression change within the intervertebral disc that may ultimately compromise cell function and induce pathological deficits. This system would be a valuable screening tool to investigate interventional strategies aimed at restoring disc cell function

MultiMetEval: comparative and multi-objective analysis of genome-scale metabolic models

Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEv​al/downloads

Stringy Space-Time Foam and High-Energy Cosmic Photons

In this review, I discuss briefly stringent tests of Lorentz-violating quantum space-time foam models inspired from String/Brane theories, provided by studies of high energy Photons from intense celestial sources, such as Active Galactic Nuclei or Gamma Ray Bursts. The theoretical models predict modifications to the radiation dispersion relations, which are quadratically suppressed by the string mass scale, and time delays in the arrival times of photons (assumed to be emitted more or less simultaneously from the source), which are proportional to the photon energy, so that the more energetic photons arrive later. Although the astrophysics at the source of these energetic photons is still not understood, and such non simultaneous arrivals, that have been observed recently, might well be due to non simultaneous emission as a result of conventional physics effects, nevertheless, rather surprisingly, the observed time delays can also fit excellently the stringy space-time foam scenarios, provided the space-time defect foam is inhomogeneous. The key features of the model, that allow it to evade a plethora of astrophysical constraints on Lorentz violation, in sharp contrast to other field-theoretic Lorentz-violating models of quantum gravity, are: (i) transparency of the foam to electrons and in general charged matter, (ii) absence of birefringence effects and (iii) a breakdown of the local effective lagrangian formalism.Comment: 26 pages Latex, 4 figures, uses special macros. Keynote Lecture in the International Conference "Recent Developments in Gravity" (NEB14), Ioannina (Greece) June 8-11 201

Robustness of circadian clocks to daylight fluctuations: hints from the picoeucaryote Ostreococcus tauri

The development of systemic approaches in biology has put emphasis on identifying genetic modules whose behavior can be modeled accurately so as to gain insight into their structure and function. However most gene circuits in a cell are under control of external signals and thus quantitative agreement between experimental data and a mathematical model is difficult. Circadian biology has been one notable exception: quantitative models of the internal clock that orchestrates biological processes over the 24-hour diurnal cycle have been constructed for a few organisms, from cyanobacteria to plants and mammals. In most cases, a complex architecture with interlocked feedback loops has been evidenced. Here we present first modeling results for the circadian clock of the green unicellular alga Ostreococcus tauri. Two plant-like clock genes have been shown to play a central role in Ostreococcus clock. We find that their expression time profiles can be accurately reproduced by a minimal model of a two-gene transcriptional feedback loop. Remarkably, best adjustment of data recorded under light/dark alternation is obtained when assuming that the oscillator is not coupled to the diurnal cycle. This suggests that coupling to light is confined to specific time intervals and has no dynamical effect when the oscillator is entrained by the diurnal cycle. This intringuing property may reflect a strategy to minimize the impact of fluctuations in daylight intensity on the core circadian oscillator, a type of perturbation that has been rarely considered when assessing the robustness of circadian clocks

Environmental differences between sites control the diet and nutrition of the carnivorous plant Drosera rotundifolia

Background and aims: Carnivorous plants are sensitive to small changes in resource availability, but few previous studies have examined how differences in nutrient and prey availability affect investment in and the benefit of carnivory. We studied the impact of site-level differences in resource availability on ecophysiological traits of carnivory for Drosera rotundifolia L. Methods: We measured prey availability, investment in carnivory (leaf stickiness), prey capture and diet of plants growing in two bogs with differences in N deposition and plant available N: Cors Fochno (0.62 g m−2 yr.−1, 353 μg l−1), Whixall Moss (1.37 g m−2 yr.−1, 1505 μg l−1). The total N amount per plant and the contributions of prey/root N to the plants’ N budget were calculated using a single isotope natural abundance method. Results: Plants at Whixall Moss invested less in carnivory, were less likely to capture prey, and were less reliant on prey-derived N (25.5% compared with 49.4%). Actual prey capture did not differ between sites. Diet composition differed – Cors Fochno plants captured 62% greater proportions of Diptera. Conclusions: Our results show site-level differences in plant diet and nutrition consistent with differences in resource availability. Similarity in actual prey capture may be explained by differences in leaf stickiness and prey abundance

Assessing the validity of and factors that influence accurate self-reporting of HIV status after testing: a population-based study.

OBJECTIVES: To assess the validity of self-reported HIV status, and investigate factors that influence accurate reporting of HIV-positive status, in a population tested and informed of their HIV test result. DESIGN: Prospective cohort study. METHODS: We compared self-reported HIV status with biomarker-confirmed HIV test status among participants of Karonga Health and Demographic Surveillance Site in rural northern Malawi. We linked information on HIV test results to subsequent self-reported HIV status, and calculated sensitivity, specificity, positive predictive value and negative predictive value for self-reported HIV status (considered as a diagnostic test). We used Poisson regression with robust variance estimators to examine predictors of accurate self-reporting of HIV-positive status. RESULTS: Among 17?445 adults who tested for HIV, were recorded as having received their HIV test results, and had a subsequent self-reported HIV status between 2007 and 2018: positive predictive value of self-reported HIV status was 98.0% (95% confidence interval: 97.3-98.7); negative predictive value was 98.3 (98.1-98.5); sensitivity was 86.1% (84.5-87.7); and specificity was 99.8% (99.7-99.9). Among true HIV-positive people, those who were younger, interviewed in community settings, and had tested for HIV longer ago were more likely to misreport their HIV-positive status. CONCLUSION: In this setting, self-report provides good estimates of test-detected HIV prevalence, suggesting that it can be used when HIV test results are not available. Despite frequent HIV testing, younger people and those interviewed in community settings were less likely to accurately report their HIV-positive status. More research on barriers to self-reporting of HIV status is needed in these subgroups

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations