Model of host-pathogen Interaction dynamics links In vivo optical imaging and immune responses

Tracking disease progression in vivo is essential for the development of treatments against bacterial infection. Optical imaging has become a central tool for in vivo tracking of bacterial population development and therapeutic response. For a precise understanding of in vivo imaging results in terms of disease mechanisms derived from detailed postmortem observations, however, a link between the two is needed. Here, we develop a model that provides that link for the investigation of Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli (EPEC). We connect in vivo disease progression of C57BL/6 mice infected with bioluminescent bacteria, imaged using optical tomography and X-ray computed tomography, to postmortem measurements of colonic immune cell infiltration. We use the model to explore changes to both the host immune response and the bacteria and to evaluate the response to antibiotic treatment. The developed model serves as a novel tool for the identification and development of new therapeutic interventions

SynGAP isoforms exert opposing effects on synaptic strength

Peer reviewedPublisher PD

Southern Ocean albedo, inter-hemispheric energy transports and the double ITCZ: global impacts of biases in a coupled model

A causal link has been invoked between inter-hemispheric albedo, cross-equatorial energy transport and the double-IntertropicalConvergence Zone (ITCZ) bias in climate models. Southern Ocean cloud biases are a major determinant of inter-hemispheric albedo biases in many models, including HadGEM2-ES, a fully coupled model with a dynamical ocean. In this study, targeted albedo corrections are applied to explore the dynamical response to artificially reducing these biases. The Southern Hemisphere jet increases in strength in response to the increased tropical-extratropical temperature gradient, with increased energy transport into the mid-latitudes in the atmosphere, but no improvement is observed in the double-ITCZ bias or atmospheric cross-equatorial energy transport. The majority of the adjustment in energy transport in the tropics is achieved in the ocean, with the response further limited to the Pacific Ocean. As a result, the frequently argued teleconnection between the Southern Ocean and tropical precipitation biases is muted. Further experiments in which tropical longwave biases are also reduced do not yield improvement in the representation of the tropical atmosphere. These results suggest that the dramatic improvements in tropical precipitation that have been shown in previous studies may be a function of the lack of dynamical ocean and/or the simplified hemispheric albedo bias corrections applied in that work. It further suggests that efforts to correct the double ITCZ problem in coupled models that focus on large-scale energetic controls will prove fruitless without improvements in the representation of atmospheric processes.MKH, MC and JMH were supported by the Natural Environment Research Council/Department for International Development via the Future Climates for Africa (FCFA) funded project ’Improving Model Processes for African Climate’ (IMPALA, NE/M017265/1). JMH and AJ were supported by the Joint UK DECC/Defra Met Office Hadley Centre Climate Programme (GA01101)

Phylogenetic inferences of Atelinae (Platyrrhini) based on multi-directional chromosome painting in Brachyteles arachnoides, Ateles paniscus paniscus and Ateles b. marginatus

We performed multi-directional chromosome painting in a comparative cytogenetic study of the three Atelinae species Brachyteles arachnoides, Ateles paniscus paniscus and Ateles belzebuth marginatus, in order to reconstruct phylogenetic relationships within this Platyrrhini subfamily. Comparative chromosome maps between these species were established by multi-color fluorescence in situ hybridization ( FISH) employing human, Saguinus oedipus and Lagothrix lagothricha chromosome-specific probes. The three species included in this study and four previously analyzed species from all four Atelinae genera were subjected to a phylogenetic analysis on the basis of a data matrix comprised of 82 discrete chromosome characters. The results confirmed that Atelinae represent a monophyletic clade with a putative ancestral karyotype of 2n = 62 chromosomes. Phylogenetic analysis revealed an evolutionary branching sequence \{Alouatta \{Brachyteles \{Lagothrix and Ateles\}\}\} in Atelinae and \{Ateles belzebuth marginatus \{Ateles paniscus paniscus \{Ateles belzebuth hybridus and Ateles geoffroyi\}\}\} in genus Ateles. The chromosomal data support a re-evaluation of the taxonomic status of Ateles b. hybridus. Copyright (C) 2005 S. Karger AG, Basel

Exposure to benzene at work and the risk of leukemia: a systematic review and meta-analysis

Background A substantial number of epidemiologic studies have provided estimates of the relation between exposure to benzene at work and the risk of leukemia, but the results have been heterogeneous. To bridge this gap in knowledge, we synthesized the existing epidemiologic evidence on the relation between occupational exposure to benzene and the risk of leukemia, including all types combined and the four main subgroups acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). Methods A systematic literature review was carried out using two databases 'Medline' and 'Embase' from 1950 through to July 2009. We selected articles which provided information that can be used to estimate the relation between benzene exposure and cancer risk (effect size). Results In total 15 studies were identified in the search, providing 16 effect estimates for the main analysis. The summary effect size for any leukemia from the fixed-effects model was 1.40 (95% CI, 1.23-1.57), but the study-specific estimates were strongly heterogeneous (I2 = 56.5%, Q stat = 34.47, p = 0.003). The random-effects model yielded a summary- effect size estimate of 1.72 (95% CI, 1.37-2.17). Effect estimates from 9 studies were based on cumulative exposures. In these studies the risk of leukemia increased with a dose-response pattern with a summary-effect estimate of 1.64 (95% CI, 1.13-2.39) for low (< 40 ppm-years), 1.90 (95% CI, 1.26-2.89) for medium (40-99.9 ppm-years), and 2.62 (95% CI, 1.57-4.39) for high exposure category (> 100 ppm-years). In a meta-regression, the trend was statistically significant (P = 0.015). Use of cumulative exposure eliminated heterogeneity. The risk of AML also increased from low (1.94, 95% CI, 0.95-3.95), medium (2.32, 95% CI, 0.91-5.94) to high exposure category (3.20, 95% CI, 1.09-9.45), but the trend was not statistically significant. Conclusions Our study provides consistent evidence that exposure to benzene at work increases the risk of leukemia with a dose-response pattern. There was some evidence of an increased risk of AML and CLL. The meta-analysis indicated a lack of association between benzene exposure and the risk of CML

Squirrelpox virus: assessing prevalence, transmission and environmental degradation

Red squirrels (Sciurus vulgaris) declined in Great Britain and Ireland during the last century, due to habitat loss and the introduction of grey squirrels (Sciurus carolinensis), which competitively exclude the red squirrel and act as a reservoir for squirrelpox virus (SQPV). The disease is generally fatal to red squirrels and their ecological replacement by grey squirrels is up to 25 times faster where the virus is present. We aimed to determine: (1) the seropositivity and prevalence of SQPV DNA in the invasive and native species at a regional scale; (2) possible SQPV transmission routes; and, (3) virus degradation rates under differing environmental conditions. Grey (n = 208) and red (n = 40) squirrel blood and tissues were sampled. Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qPCR) techniques established seropositivity and viral DNA presence, respectively. Overall 8% of squirrels sampled (both species combined) had evidence of SQPV DNA in their tissues and 22% were in possession of antibodies. SQPV prevalence in sampled red squirrels was 2.5%. Viral loads were typically low in grey squirrels by comparison to red squirrels. There was a trend for a greater number of positive samples in spring and summer than in winter. Possible transmission routes were identified through the presence of viral DNA in faeces (red squirrels only), urine and ectoparasites (both species). Virus degradation analyses suggested that, after 30 days of exposure to six combinations of environments, there were more intact virus particles in scabs kept in warm (25°C) and dry conditions than in cooler (5 and 15°C) or wet conditions. We conclude that SQPV is present at low prevalence in invasive grey squirrel populations with a lower prevalence in native red squirrels. Virus transmission could occur through urine especially during warm dry summer conditions but, more notably, via ectoparasites, which are shared by both species

Trypanocidal and leishmanicidal activity of six limonoids

Six limonoids [kotschyienone A and B (1, 2), 7-deacetylgedunin (3), 7-deacetyl-7-oxogedunin (4), andirobin (5) and methyl angolensate (6)] were investigated for their trypanocidal and leishmanicidal activities using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. Whereas all compounds showed anti-trypanosomal activity, only compounds 1–4 displayed anti-leishmanial activity. The 50% growth inhibition (GI 50) values for the trypanocidal and leishmanicidal activity of the compounds ranged between 2.5 and 14.9 μM. Kotschyienone A (1) was found to be the most active compound with a minimal inhibition concentration (MIC) value of 10 μM and GI 50 values between 2.5 and 2.9 μM. Only compounds 1 and 3 showed moderate cytotoxicity against HL-60 cells with MIC and GI 50 values of 100 μM and 31.5–46.2 μM, respectively. Compound 1 was also found to show activity against intracellular amastigotes of L. major with a GI 50 value of 1.5 μM. The results suggest that limonoids have potential as drug candidates for the development of new treatments against trypanosomiasis and leishmaniasis

MCL-CAw: A refinement of MCL for detecting yeast complexes from weighted PPI networks by incorporating core-attachment structure

Abstract Background The reconstruction of protein complexes from the physical interactome of organisms serves as a building block towards understanding the higher level organization of the cell. Over the past few years, several independent high-throughput experiments have helped to catalogue enormous amount of physical protein interaction data from organisms such as yeast. However, these individual datasets show lack of correlation with each other and also contain substantial number of false positives (noise). Over these years, several affinity scoring schemes have also been devised to improve the qualities of these datasets. Therefore, the challenge now is to detect meaningful as well as novel complexes from protein interaction (PPI) networks derived by combining datasets from multiple sources and by making use of these affinity scoring schemes. In the attempt towards tackling this challenge, the Markov Clustering algorithm (MCL) has proved to be a popular and reasonably successful method, mainly due to its scalability, robustness, and ability to work on scored (weighted) networks. However, MCL produces many noisy clusters, which either do not match known complexes or have additional proteins that reduce the accuracies of correctly predicted complexes. Results Inspired by recent experimental observations by Gavin and colleagues on the modularity structure in yeast complexes and the distinctive properties of "core" and "attachment" proteins, we develop a core-attachment based refinement method coupled to MCL for reconstruction of yeast complexes from scored (weighted) PPI networks. We combine physical interactions from two recent "pull-down" experiments to generate an unscored PPI network. We then score this network using available affinity scoring schemes to generate multiple scored PPI networks. The evaluation of our method (called MCL-CAw) on these networks shows that: (i) MCL-CAw derives larger number of yeast complexes and with better accuracies than MCL, particularly in the presence of natural noise; (ii) Affinity scoring can effectively reduce the impact of noise on MCL-CAw and thereby improve the quality (precision and recall) of its predicted complexes; (iii) MCL-CAw responds well to most available scoring schemes. We discuss several instances where MCL-CAw was successful in deriving meaningful complexes, and where it missed a few proteins or whole complexes due to affinity scoring of the networks. We compare MCL-CAw with several recent complex detection algorithms on unscored and scored networks, and assess the relative performance of the algorithms on these networks. Further, we study the impact of augmenting physical datasets with computationally inferred interactions for complex detection. Finally, we analyse the essentiality of proteins within predicted complexes to understand a possible correlation between protein essentiality and their ability to form complexes. Conclusions We demonstrate that core-attachment based refinement in MCL-CAw improves the predictions of MCL on yeast PPI networks. We show that affinity scoring improves the performance of MCL-CAw.http://deepblue.lib.umich.edu/bitstream/2027.42/78256/1/1471-2105-11-504.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78256/2/1471-2105-11-504-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78256/3/1471-2105-11-504-S2.ZIPhttp://deepblue.lib.umich.edu/bitstream/2027.42/78256/4/1471-2105-11-504.pdfPeer Reviewe

ReadNet: A Hierarchical Transformer Framework for Web Article Readability Analysis

Analyzing the readability of articles has been an important sociolinguistic task. Addressing this task is necessary to the automatic recommendation of appropriate articles to readers with different comprehension abilities, and it further benefits education systems, web information systems, and digital libraries. Current methods for assessing readability employ empirical measures or statistical learning techniques that are limited by their ability to characterize complex patterns such as article structures and semantic meanings of sentences. In this paper, we propose a new and comprehensive framework which uses a hierarchical self-attention model to analyze document readability. In this model, measurements of sentence-level difficulty are captured along with the semantic meanings of each sentence. Additionally, the sentence-level features are incorporated to characterize the overall readability of an article with consideration of article structures. We evaluate our proposed approach on three widely-used benchmark datasets against several strong baseline approaches. Experimental results show that our proposed method achieves the state-of-the-art performance on estimating the readability for various web articles and literature.Comment: ECIR 202

Investigating Conceptual Models for the Relationship Between Depression and Condomless Sex Among Gay, Bisexual, and Other Men Who have Sex with Men: Using Structural Equation Modelling to Assess Mediation

The aim of this study is to investigate five hypothesized mechanisms of causation between depression and condomless sex with ≥ 2 partners (CLS2+) among gay, bisexual, and other men who have sex with men (GBMSM), involving alternative roles of self-efficacy for sexual safety and recreational drug use. Data were from the AURAH cross-sectional study of 1340 GBMSM attending genitourinary medicine clinics in England (2013–2014). Structural equation modelling (SEM) was used to investigate which conceptual model was more consistent with the data. Twelve percent of men reported depression (PHQ-9 ≥ 10) and 32% reported CLS2+ in the past 3 months. AURAH data were more consistent with the model in which depression was considered to lead to CLS2+ indirectly via low self-efficacy for sexual safety (indirect Beta = 0.158; p < 0.001) as well as indirectly via higher levels of recreational drug use (indirect Beta = 0.158; p < 0.001). SEM assists in understanding the relationship between depression and CLS among GBMSM