Assessing classical swine fever disease control measures using an individual-based model

Lange, M., Kramer-Schadt, S., Thulke, H.-H

Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders

A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer’s Disease (AD), and the psychiatric disorder schizophrenia (SZ), we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to c

Orientational transition in a nematic liquid crystal at a patterned surface

T. J. Atherton and J. Roy Sambles, Physical Review E, Vol. 74, article 022701 (2006) "Copyright © 2006 by the American Physical Society."We consider a semi-infinite nematic in contact with a periodic patterned surface with alternate planar and homeotropic stripes. Extending the work of Barbero et al., we find the free energy (assuming K1=K3) for the situations where the easy direction on the planar stripe is either perpendicular or parallel to the length of the stripes. We find the bulk free energy difference between the structures to be proportional to √ K2/K1 and so we consider the possibility of a spontaneous transition between the two states if the azimuthal anchoring energy is sufficiently weak and K1≠K2. We compute the critical azimuthal anchoring energy for such a transition in terms of the relative width of the stripes and the period of the pattern and find it to be ~10−6 J m−2, comparable to experimental values

Habitat selection models for European wildcat conservation

Populations of the European wildcat (Felis silvestris) are only slowly recovering in Central Europe after a severe decline in the last centuries and require specific conservation plans in many areas. However, detailed information on wildcat occurrence and habitat require- ments is still scarce and controversial. We present a fine-scale habitat selection model for wildcats based on detailed species and land use information and evaluate its accu- racy to predict habitat distribution in new areas. We analysed habitat use within home ranges using single locations of 12 radio-tracked individuals from south western Germany. Several competing models were fitted and compared using generalised linear mixed models (GLMM) and information-theoretic approaches. Radio-tracking data of 9 and 10 wildcats from two distant areas were used to evaluate the models. The selected model predicted habitat associated to close distance to forest, watercourses and mead- ows and a critical distance to villages, single houses and roads. To predict area suitable for home ranges we superimposed rules derived from home range attributes at a higher level of selection. Predictions from the combination of the fine-scale habitat model and home range rules matched well with more than 2000 wildcat observations of south- western Germany. We discuss the application of the model in wildcat conservation for finding potential reintroduction sites, identifying small isolated populations and aiding in the evaluation of the needs of mitigation and compensation within the scope of the European Habitats Directive.Peer Reviewe

Comprehensive User Engagement Sites (CUES) in Philadelphia: A Constructive Proposal

This paper is a study about Philadelphia’s comprehensive user engagement sites (CUESs) as the authors address and examine issues related to the upcoming implementation of a CUES while seeking solutions for its disputed questions and plans. Beginning with the federal drug schedules, the authors visit some of the medical and public health issues vis-à-vis safe injection facilities (SIFs). Insite, a successful Canadian SIF, has been thoroughly researched as it represents a paradigm for which a Philadelphia CUES can expand upon. Also, the existing criticisms against SIFs are revisited while critically unpackaged and responded to in favor of the establishment. In the main section, the authors propose the layout and services of the upcoming CUES, much of which would be in congruent to Vancouver’s Insite. On the other hand, the CUES would be distinct from Insite, as the authors emphasize, in that it will offer an information center run by individuals in recovery and place additional emphasis on early education for young healthcare professionals by providing them a platform to work at the site. The paper will also briefly investigate the implementation of a CUES site under an ethical scope of the Harm Reduction Theory. Lastly, the authors recommend some strategic plans that the Philadelphia City government may consider employing at this crucial stage

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

Psychological and behavioural impact of returning personal results from whole-genome sequencing: the HealthSeq project

Providing ostensibly healthy individuals with personal results from whole-genome sequencing could lead to improved health and well-being via enhanced disease risk prediction, prevention, and diagnosis, but also poses practical and ethical challenges. Understanding how individuals react psychologically and behaviourally will be key in assessing the potential utility of personal whole-genome sequencing. We conducted an exploratory longitudinal cohort study in which quantitative surveys and in-depth qualitative interviews were conducted before and after personal results were returned to individuals who underwent whole-genome sequencing. The participants were offered a range of interpreted results, including Alzheimer’s disease, type 2 diabetes, pharmacogenomics, rare disease-associated variants, and ancestry. They were also offered their raw data. Of the 35 participants at baseline, 29 (82.9%) completed the 6-month follow-up. In the quantitative surveys, test-related distress was low, although it was higher at 1-week than 6-month follow-up (Z=2.68, P=0.007). In the 6-month qualitative interviews, most participants felt happy or relieved about their results. A few were concerned, particularly about rare disease-associated variants and Alzheimer’s disease results. Two of the 29 participants had sought clinical follow-up as a direct or indirect consequence of rare disease-associated variants results. Several had mentioned their results to their doctors. Some participants felt having their raw data might be medically useful to them in the future. The majority reported positive reactions to having their genomes sequenced, but there were notable exceptions to this. The impact and value of returning personal results from whole-genome sequencing when implemented on a larger scale remains to be seen

Genetical genomics: spotlight on QTL hotspots

No abstract available

Autotransporters but not pAA are critical for rabbit colonization by Shiga toxin-producing Escherichia coli O104:H4

The outbreak of diarrhea and hemolytic uremic syndrome that occurred in Germany in 2011 was caused by a Shiga toxin-producing enteroaggregative Escherichia coli (EAEC) strain. The strain was classified as EAEC due to the presence of a plasmid (pAA) that mediates a characteristic pattern of aggregative adherence on cultured cells, the defining feature of EAEC that has classically been associated with virulence. Here, we describe an infant rabbit-based model of intestinal colonization and diarrhea caused by the outbreak strain, which we use to decipher the factors that mediate the pathogen’s virulence. Shiga toxin is the key factor required for diarrhea. Unexpectedly, we observe that pAA is dispensable for intestinal colonization and development of intestinal pathology. Instead, chromosome-encoded autotransporters are critical for robust colonization and diarrheal disease in this model. Our findings suggest that conventional wisdom linking aggregative adherence to EAEC intestinal colonization is false for at least a subset of strains

Expression quantitative trait loci are highly sensitive to cellular differentiation state

Blood cell development from multipotent hematopoietic stem cells to specialized blood cells is accompanied by drastic changes in gene expression for which the triggers remain mostly unknown. Genetical genomics is an approach linking natural genetic variation to gene expression variation, thereby allowing the identification of genomic loci containing gene expression modulators (eQTLs). In this paper, we used a genetical genomics approach to analyze gene expression across four developmentally close blood cell types collected from a large number of genetically different but related mouse strains. We found that, while a significant number of eQTLs (365) had a consistent “static” regulatory effect on gene expression, an even larger number were found to be very sensitive to cell stage. As many as 1,283 eQTLs exhibited a “dynamic” behavior across cell types. By looking more closely at these dynamic eQTLs, we show that the sensitivity of eQTLs to cell stage is largely associated with gene expression changes in target genes. These results stress the importance of studying gene expression variation in well-defined cell populations. Only such studies will be able to reveal the important differences in gene regulation between different ce