MOSBIE: A tool for comparison and analysis of rule-based biochemical models

Background: Mechanistic models that describe the dynamical behaviors of biochemical systems are common in computational systems biology, especially in the realm of cellular signaling. The development of families of such models, either by a single research group or by different groups working within the same area, presents significant challenges that range from identifying structural similarities and differences between models to understanding how these differences affect system dynamics.Results: We present the development and features of an interactive model exploration system, MOSBIE, which provides utilities for identifying similarities and differences between models within a family. Models are clustered using a custom similarity metric, and a visual interface is provided that allows a researcher to interactively compare the structures of pairs of models as well as view simulation results.Conclusions: We illustrate the usefulness of MOSBIE via two case studies in the cell signaling domain. We also present feedback provided by domain experts and discuss the benefits, as well as the limitations, of the approach

Unbiased Rare Event Sampling in Spatial Stochastic Systems Biology Models Using a Weighted Ensemble of Trajectories

The long-term goal of connecting scales in biological simulation can be facilitated by scale-agnostic methods. We demonstrate that the weighted ensemble (WE) strategy, initially developed for molecular simulations, applies effectively to spatially resolved cell-scale simulations. The WE approach runs an ensemble of parallel trajectories with assigned weights and uses a statistical resampling strategy of replicating and pruning trajectories to focus computational effort on difficult-to-sample regions. The method can also generate unbiased estimates of non-equilibrium and equilibrium observables, sometimes with significantly less aggregate computing time than would be possible using standard parallelization. Here, we use WE to orchestrate particle-based kinetic Monte Carlo simulations, which include spatial geometry (e.g., of organelles, plasma membrane) and biochemical interactions among mobile molecular species. We study a series of models exhibiting spatial, temporal and biochemical complexity and show that although WE has important limitations, it can achieve performance significantly exceeding standard parallel simulation—by orders of magnitude for some observables

Coagulopathy as initial manifestation of concomitant celiac disease and cystic fibrosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Celiac disease and cystic fibrosis have many common manifestations, such as malabsorption, steatorrhea and growth failure, and were for many years recognized as one clinical entity. Since their recognition as two separate diseases, their co-existence in a patient has been described sporadically; around 20 cases have been described in the literature. Taking into consideration the incidences of the two diseases, the chance of them occurring together is one in 2,000,000 in the general population.</p> <p>Case presentation</p> <p>We describe the case of a five-year-old boy of Turkish ethnicity with both celiac disease and cystic fibrosis, who presented initially with a skin hemorrhage. The diagnosis of celiac disease was made with a positive serum anti-tissue transglutaminase antibody test and the presence of HLA-DQ2 heterodimer, and confirmed on histology with small intestinal villous atrophy. A positive sweat test confirmed the diagnosis of associated cystic fibrosis.</p> <p>To the best of our knowledge there has been no previous report of this rare presentation of associated celiac disease and cystic fibrosis.</p> <p>Conclusion</p> <p>The clinical significance of this case is the consideration of malabsorption with both celiac disease and cystic fibrosis in patients who present with unexplained coagulopathy.</p

What Does It Drive the Relationship Between Suicides and Economic Conditions? New Evidence from Spain

In this paper we analyse suicides across the 17 Spanish regions over the period 2002?2013. In doing so, we estimate count panel data models considering gender differences taking into account before and during economic crisis periods. A range of aggregate socioeconomic regional-level factors have been considered. Our empirical results show that: (1) a socioeconomic urban?rural suicide differentials exist, (2) there exists a Mediterranean suicide pattern; and (3) unemployment levels have a marked importance during the crisis period. The results of this study may have usefulness for suicide prevention in Spain

Temperature Effects on Gametophyte Life-History Traits and Geographic Distribution of Two Cryptic Kelp Species

A major determinant of the geographic distribution of a species is expected to be its physiological response to changing abiotic variables over its range. The range of a species often corresponds to the geographic extent of temperature regimes the organism can physiologically tolerate. Many species have very distinct life history stages that may exhibit different responses to environmental factors. In this study we emphasized the critical role of the haploid microscopic stage (gametophyte) of the life cycle to explain the difference of edge distribution of two related kelp species. Lessonia nigrescens was recently identified as two cryptic species occurring in parapatry along the Chilean coast: one located north and the other south of a biogeographic boundary at latitude 29–30°S. Six life history traits from microscopic stages were identified and estimated under five treatments of temperature in eight locations distributed along the Chilean coast in order to (1) estimate the role of temperature in the present distribution of the two cryptic L. nigrescens species, (2) compare marginal populations to central populations of the two cryptic species. In addition, we created a periodic matrix model to estimate the population growth rate (λ) at the five temperature treatments. Differential tolerance to temperature was demonstrated between the two species, with the gametophytes of the Northern species being more tolerant to higher temperatures than gametophytes from the south. Second, the two species exhibited different life history strategies with a shorter haploid phase in the Northern species contrasted with considerable vegetative growth in the Southern species haploid stage. These results provide strong ecological evidence for the differentiation process of the two cryptic species and show local adaptation of the life cycle at the range limits of the distribution. Ecological and evolutionary implications of these findings are discussed

Poor concordance between interferon-γ release assays and tuberculin skin tests in diagnosis of latent tuberculosis infection among HIV-infected individuals

<p>Abstract</p> <p>Background</p> <p>A new generation of diagnostic tests, the interferon-γ release assays (IGRAs), have been developed for the detection of latent tuberculosis infection (LTBI). Limited data are available on their use in HIV-infected persons.</p> <p>Methods</p> <p>A cross-sectional study was carried out at 2 HIV clinics in Atlanta to assess the utility of two IGRA tests (T-SPOT.TB [TSPOT] and QuantiFERON-TB Gold in Tube [QFT-3G]) compared to the tuberculin skin test (TST).</p> <p>Results</p> <p>336 HIV-infected persons were enrolled. Median CD4 count was 335 cells/μl and median HIV viral load was 400 copies/ml. Overall, 27 patients (8.0%) had at least 1 positive diagnostic test for LTBI: 7 (2.1%) had a positive TST; 9 (2.7%) a positive QFT-3G; and 14 (4.2%) a positive TSPOT. Agreement between the 3 diagnostic tests was poor: TST and TSPOT, [κ = 0.16, 95% CI (-0.06, 0.39)], TST and QFT-3G [κ = 0.23, 95% CI (-0.05, 0.51)], QFT-3G and TSPOT [κ = 0.06, 95% CI (-0.1, 0.2)]. An indeterminate test result occurred among 6 (1.8%) of QFT-3G and 47 (14%) of TSPOT tests. In multivariate analysis, patients with a CD4 ≤ 200 cells/μl were significantly more likely to have an indeterminate result [OR = 3.6, 95% CI (1.9, 6.8)].</p> <p>Conclusion</p> <p>We found a low prevalence of LTBI and poor concordance between all 3 diagnostic tests. Indeterminate test results were more likely at CD4 counts ≤ 200 cells/μl. Additional studies among HIV-infected populations with a high prevalence of TB are needed to further assess the utility of IGRAs in this patient population.</p

Identification of hematein as a novel inhibitor of protein kinase CK2 from a natural product library

<p>Abstract</p> <p>Background</p> <p>Casein kinase 2 (CK2) is dysregulated in various human cancers and is a promising target for cancer therapy. To date, there is no small molecular CK2 inhibitor in clinical trial yet. With the aim to identify novel CK2 inhibitors, we screened a natural product library.</p> <p>Methods</p> <p>We adopted cell-based proliferation and CK2 kinase assays to screen CK2 inhibitors from a natural compound library. Dose-dependent response of CK2 inhibitors <it>in vitro </it>was determined by a radioisotope kinase assay. Western blot analysis was used to evaluate down stream Akt phosphorylation and apoptosis. Apoptosis was also evaluated by annexin-V/propidium iodide (PI) labeling method using flow cytometry. Inhibition effects of CK2 inhibitors on the growth of cancer and normal cells were evaluated by cell proliferation and viability assays.</p> <p>Results</p> <p>Hematein was identified as a novel CK2 inhibitor that is highly selective among a panel of kinases. It appears to be an ATP non-competitive and partially reversible CK2 inhibitor with an IC₅₀value of 0.55 μM. In addition, hematein inhibited cancer cell growth partially through down-regulation of Akt phosphorylation and induced apoptosis in these cells. Furthermore, hematein exerted stronger inhibition effects on the growth of cancer cells than in normal cells.</p> <p>Conclusion</p> <p>In this study, we showed that hematein is a novel selective and cell permeable small molecule CK2 inhibitor. Hematein showed stronger growth inhibition effects to cancer cells when compared to normal cells. This compound may represent a promising class of CK2 inhibitors.</p

Analyzing musculoskeletal neck pain, measured as present pain and periods of pain, with three different regression models: a cohort study

<p>Abstract</p> <p>Background</p> <p>In the literature there are discussions on the choice of outcome and the need for more longitudinal studies of musculoskeletal disorders. The general aim of this longitudinal study was to analyze musculoskeletal neck pain, in a group of young adults. Specific aims were to determine whether psychosocial factors, computer use, high work/study demands, and lifestyle are long-term or short-term factors for musculoskeletal neck pain, and whether these factors are important for developing or ongoing musculoskeletal neck pain.</p> <p>Methods</p> <p>Three regression models were used to analyze the different outcomes. Pain at present was analyzed with a marginal logistic model, for number of years with pain a Poisson regression model was used and for developing and ongoing pain a logistic model was used. Presented results are odds ratios and proportion ratios (logistic models) and rate ratios (Poisson model). The material consisted of web-based questionnaires answered by 1204 Swedish university students from a prospective cohort recruited in 2002.</p> <p>Results</p> <p>Perceived stress was a risk factor for pain at present (PR = 1.6), for developing pain (PR = 1.7) and for number of years with pain (RR = 1.3). High work/study demands was associated with pain at present (PR = 1.6); and with number of years with pain when the demands negatively affect home life (RR = 1.3). Computer use pattern (number of times/week with a computer session ≥ 4 h, without break) was a risk factor for developing pain (PR = 1.7), but also associated with pain at present (PR = 1.4) and number of years with pain (RR = 1.2). Among life style factors smoking (PR = 1.8) was found to be associated to pain at present. The difference between men and women in prevalence of musculoskeletal pain was confirmed in this study. It was smallest for the outcome ongoing pain (PR = 1.4) compared to pain at present (PR = 2.4) and developing pain (PR = 2.5).</p> <p>Conclusion</p> <p>By using different regression models different aspects of neck pain pattern could be addressed and the risk factors impact on pain pattern was identified. Short-term risk factors were perceived stress, high work/study demands and computer use pattern (break pattern). Those were also long-term risk factors. For developing pain perceived stress and computer use pattern were risk factors.</p