A random set scoring model for prioritization of disease candidate genes using protein complexes and data-mining of GeneRIF, OMIM and PubMed records.

BACKGROUND: Prioritizing genetic variants is a challenge because disease susceptibility loci are often located in genes of unknown function or the relationship with the corresponding phenotype is unclear. A global data-mining exercise on the biomedical literature can establish the phenotypic profile of genes with respect to their connection to disease phenotypes. The importance of protein-protein interaction networks in the genetic heterogeneity of common diseases or complex traits is becoming increasingly recognized. Thus, the development of a network-based approach combined with phenotypic profiling would be useful for disease gene prioritization. RESULTS: We developed a random-set scoring model and implemented it to quantify phenotype relevance in a network-based disease gene-prioritization approach. We validated our approach based on different gene phenotypic profiles, which were generated from PubMed abstracts, OMIM, and GeneRIF records. We also investigated the validity of several vocabulary filters and different likelihood thresholds for predicted protein-protein interactions in terms of their effect on the network-based gene-prioritization approach, which relies on text-mining of the phenotype data. Our method demonstrated good precision and sensitivity compared with those of two alternative complex-based prioritization approaches. We then conducted a global ranking of all human genes according to their relevance to a range of human diseases. The resulting accurate ranking of known causal genes supported the reliability of our approach. Moreover, these data suggest many promising novel candidate genes for human disorders that have a complex mode of inheritance. CONCLUSION: We have implemented and validated a network-based approach to prioritize genes for human diseases based on their phenotypic profile. We have devised a powerful and transparent tool to identify and rank candidate genes. Our global gene prioritization provides a unique resource for the biological interpretation of data from genome-wide association studies, and will help in the understanding of how the associated genetic variants influence disease or quantitative phenotypes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2105-15-315) contains supplementary material, which is available to authorized users

Numerical Results for Ground States of Mean-Field Spin Glasses at low Connectivities

An extensive list of results for the ground state properties of spin glasses on random graphs is presented. These results provide a timely benchmark for currently developing theoretical techniques based on replica symmetry breaking that are being tested on mean-field models at low connectivity. Comparison with existing replica results for such models verifies the strength of those techniques. Yet, we find that spin glasses on fixed-connectivity graphs (Bethe lattices) exhibit a richer phenomenology than has been anticipated by theory. Our data prove to be sufficiently accurate to speculate about some exact results.Comment: 4 pages, RevTex4, 5 ps-figures included, related papers available at http://www.physics.emory.edu/faculty/boettcher

XY models with disorder and symmetry-breaking fields in two dimensions

The combined effect of disorder and symmetry-breaking fields on the two-dimensional XY model is examined. The study includes disorder in the interaction among spins in the form of random phase shifts as well as disorder in the local orientation of the field. The phase diagrams are determined and the properties of the various phases and phase transitions are calculated. We use a renormalization group approach in the Coulomb gas representation of the model. Our results differ from those obtained for special cases in previous works. In particular, we find a changed topology of the phase diagram that is composed of phases with long-range order, quasi-long-range order, and short-range order. The discrepancies can be ascribed to a breakdown of the fugacity expansion in the Coulomb gas representation. Implications for physical systems such as planar Josephson junctions and the faceting of crystal surfaces are discussed.Comment: 17 pages Latex with 5 eps figures, change: acknowledgment extende

Glassy Vortex State in a Two-Dimensional Disordered XY-Model

The two-dimensional XY-model with random phase-shifts on bonds is studied. The analysis is based on a renormalization group for the replicated system. The model is shown to have an ordered phase with quasi long-range order. This ordered phase consists of a glass-like region at lower temperatures and of a non-glassy region at higher temperatures. The transition from the disordered phase into the ordered phase is not reentrant and is of a new universality class at zero temperature. In contrast to previous approaches the disorder strength is found to be renormalized to larger values. Several correlation functions are calculated for the ordered phase. They allow to identify not only the transition into the glassy phase but also an additional crossover line, where the disconnected vortex correlation changes its behavior on large scales non-analytically. The renormalization group approach yields the glassy features without a breaking of replica symmetry.Comment: latex 12 pages with 3 figures, using epsf.sty and multicol.st

Local field distributions in spin glasses

Numerical results for the local field distributions of a family of Ising spin-glass models are presented. In particular, the Edwards-Anderson model in dimensions two, three, and four is considered, as well as spin glasses with long-range power-law-modulated interactions that interpolate between a nearest-neighbour Edwards-Anderson system in one dimension and the infinite-range Sherrington-Kirkpatrick model. Remarkably, the local field distributions only depend weakly on the range of the interactions and the dimensionality, and show strong similarities except for near zero local field.Comment: 17 pages, 34 eps-figs included, extensive updates and new results, as to appear in JPA, find related articles at http://www.physics.emory.edu/faculty/boettche

Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology

Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia-touching plaques, neighboring plaques, and far from plaques in an aged Alzheimer’s mouse model with late plaque development. In 18-month-old APPNL-F/NL-F knockin mice, with and without the Alzheimer’s disease risk mutation Trem2R47H/R47H, we report that expression of 38/55 PIGs have plaque-induced microglial upregulation, with a subset only upregulating in microglia directly contacting plaques. For seven PIGs, including Trem2, this upregulation is prevented in APPNL-F/NL-FTrem2R47H/R47H mice. These TREM2-dependent genes are all involved in phagocytic and degradative processes that we show correspond to a decrease in phagocytic markers and an increase in the density of small plaques in Trem2-mutated mice. Furthermore, despite the R47H mutation preventing increased Trem2 gene expression, TREM2 protein levels and microglial density are still marginally increased on plaques. Hence, both microglial contact with plaques and functioning TREM2 are necessary for microglia to respond appropriately to amyloid patholog

Trends in serotypes and sequence types among cases of invasive pneumococcal disease in Scotland, 1999-2010.

INTRODUCTION: The 7-valent pneumococcal conjugate vaccine (Prevenar(®), Wyeth; PCV7) was introduced to the UK paediatric immunisation schedule in 2006. This study investigates trends in serotypes and multi locus sequence types (STs) among cases of invasive pneumococcal disease (IPD) in Scotland prior to, and following, the introduction of PCV7. METHODS: Scottish Invasive Pneumococcal Disease Enhanced Surveillance has records of all cases of IPD in Scotland since 1999. Cases diagnosed from blood or cerebrospinal fluid isolates until 2010 were analysed. Logistic and poisson regression modelling was used to assess trends prior to and following the introduction of PCV7. RESULTS: Prior to PCV7 use, on average 650 cases of IPD were reported each year; 12% occurred in those aged <5 years and 35% affected those aged over 65 years. Serotypes in PCV7 represented 47% of cases (68% in <5 year olds). The serotype and ST distribution was relatively stable with only serotype 1 and associated ST 306 showing an increasing trend. PCV7 introduction was associated with a 69% (95% CI: 50%, 80%) reduction in the incidence of IPD among those aged <5 years, a 57% (95% CI: 47%, 66%) reduction among those aged 5-64 years but no significant change among those aged 65 years and over where increases in non-PCV7 serotypes were observed. Serotypes which became more prevalent post-PCV7 are those which were associated with STs related to the PCV7 serotypes. CONCLUSIONS: Routine serotyping and sequence typing in Scotland allowed the assessment of the relationship between the capsule and the clones in the post vaccination era. Changes in the distribution of serotypes post PCV7 introduction appear to be driven by associations between serotypes and STs prior to PCV7 introduction. This has implications for the possible effects of the introduction of higher valency vaccines and could aid in predicting replacement serotypes in IPD

Upregulation of Trem2 expression occurs exclusively on microglial contact with plaques

Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia touching plaques, neighboring plaques, and far from plaques in 18-month-old APPNLF/NLF knock-in mice with and without the Alzheimer’s disease risk mutation Trem2R47H/R47H. We report that, in AppNLF/NLF mice, expression of 35/55 PIGs, is exclusively upregulated in microglia that are touching plaques. In 7 PIGs including Trem2 this upregulation is prevented by the Trem2R47H/R47H mutation. Unlike in young mice, knockin of the Trem2R47H/R47H mutation does not significantly decrease the Trem2 expression but decreases protein levels by 20% in the absence of plaques. On plaques, despite the mutation preventing increased gene expression, TREM2 protein levels increased by 1.6-fold (compared to 3-fold with Trem2WT/WT) and microglial density increased 20-fold compared to 30-fold. Hence microglia must touch plaques before Trem2 gene expression is increased but small changes in protein expression can increase microglia density without a change in gene expression

Questioning the rise of gelatinous zooplankton in the World's oceans

During the past several decades, high numbers of gelatinous zooplankton species have been reported in many estuarine and coastal ecosystems. Coupled with media-driven public perception, a paradigm has evolved in which the global ocean ecosystems are thought to be heading toward being dominated by “nuisance” jellyfish. We question this current paradigm by presenting a broad overview of gelatinous zooplankton in a historicalcontext to develop the hypothesis that population changes reflect the human-mediated alteration of global ocean ecosystems. To this end, we synthesize information related to the evolutionary context of contemporary gelatinous zooplankton blooms, the human frame of reference forchanges in gelatinous zooplankton populations, and whether sufficient data are available to have established the paradigm. We conclude that the current paradigm in which it is believed that there has been a global increase in gelatinous zooplankton is unsubstantiated, and we develop a strategy for addressing the critical questions about long-term, human-related changes in the sea as they relate to gelatinous zooplankton blooms