LipidFinder on LIPID MAPS: peak filtering, MS searching and statistical analysis for lipidomics

Summary We present LipidFinder online, hosted on the LIPID MAPS website, as a liquid chromatography/mass spectrometry (LC/MS) workflow comprising peak filtering, MS searching and statistical analysis components, highly customized for interrogating lipidomic data. The online interface of LipidFinder includes several innovations such as comprehensive parameter tuning, a MS search engine employing in-house customized, curated and computationally generated databases and multiple reporting/display options. A set of integrated statistical analysis tools which enable users to identify those features which are significantly-altered under the selected experimental conditions, thereby greatly reducing the complexity of the peaklist prior to MS searching is included. LipidFinder is presented as a highly flexible, extensible user-friendly online workflow which leverages the lipidomics knowledge base and resources of the LIPID MAPS website, long recognized as a leading global lipidomics portal

Mapping the human platelet lipidome reveals cytosolic phospholipase A2 as a regulator of mitochondrial bioenergetics during activation

Human platelets acutely increase mitochondrial energy generation following stimulation. Herein, a lipidomic circuit was uncovered whereby the substrates for this are exclusively provided by cPLA2, including multiple fatty acids and oxidized species that support energy generation via β-oxidation. This indicates that acute lipid membrane remodeling is required to support energetic demands during platelet activation. Phospholipase activity is linked to energy metabolism, revealing cPLA2 as a central regulator of both lipidomics and energy flux. Using a lipidomic approach (LipidArrays), we also estimated the total number of lipids in resting, thrombin-activated, and aspirinized platelets. Significant diversity between genetically unrelated individuals and a wealth of species was revealed. Resting platelets demonstrated ∼5,600 unique species, with only ∼50% being putatively identified. Thrombin elevated ∼900 lipids >2-fold with 86% newly appearing and 45% inhibited by aspirin supplementation, indicating COX-1 is required for major activation-dependent lipidomic fluxes. Many lipids were structurally identified. With ∼50% of the lipids being absent from databases, a major opportunity for mining lipids relevant to human health and disease is presente

Switches, Excitable Responses and Oscillations in the Ring1B/Bmi1 Ubiquitination System

In an active, self-ubiquitinated state, the Ring1B ligase monoubiquitinates histone H2A playing a critical role in Polycomb-mediated gene silencing. Following ubiquitination by external ligases, Ring1B is targeted for proteosomal degradation. Using biochemical data and computational modeling, we show that the Ring1B ligase can exhibit abrupt switches, overshoot transitions and self-perpetuating oscillations between its distinct ubiquitination and activity states. These different Ring1B states display canonical or multiply branched, atypical polyubiquitin chains and involve association with the Polycomb-group protein Bmi1. Bistable switches and oscillations may lead to all-or-none histone H2A monoubiquitination rates and result in discrete periods of gene (in)activity. Switches, overshoots and oscillations in Ring1B catalytic activity and proteosomal degradation are controlled by the abundances of Bmi1 and Ring1B, and the activities and abundances of external ligases and deubiquitinases, such as E6-AP and USP7

Transcriptome-wide gene-gene interaction associations elucidate pathways and functional enrichment of complex traits.

It remains unknown to what extent gene-gene interactions contribute to complex traits. Here, we introduce a new approach using predicted gene expression to perform exhaustive transcriptome-wide interaction studies (TWISs) for multiple traits across all pairs of genes expressed in several tissue types. Using imputed transcriptomes, we simultaneously reduce the computational challenge and improve interpretability and statistical power. We discover (in the UK Biobank) and replicate (in independent cohorts) several interaction associations, and find several hub genes with numerous interactions. We also demonstrate that TWIS can identify novel associated genes because genes with many or strong interactions have smaller single-locus model effect sizes. Finally, we develop a method to test gene set enrichment of TWIS associations (E-TWIS), finding numerous pathways and networks enriched in interaction associations. Epistasis is may be widespread, and our procedure represents a tractable framework for beginning to explore gene interactions and identify novel genomic targets

Do Campaign Contributions and Lobbying Expenditures by Firms Create “Political” Capital?

Political contributions, Lobbying expenditures, Tobin’s q , Political capital, D21, D72, G30, G31, G38,

Estimating habitat carrying capacity for migrating and wintering waterfowl: Considerations, pitfalls and improvements

Population-based habitat conservation planning for migrating and wintering waterfowl in North America is carried out by habitat Joint Venture (JV) initiatives and is based on the premise that food can limit demography (i.e. food limitation hypothesis). Consequently, planners use bioenergetic models to estimate food (energy) availability and population-level energy demands at appropriate spatial and temporal scales, and translate these values into regional habitat objectives. While simple in principle, there are both empirical and theoretical challenges associated with calculating energy supply and demand including: 1) estimating food availability, 2) estimating the energy content of specific foods, 3) extrapolating site-specific estimates of food availability to landscapes for focal species, 4) applicability of estimates from a single species to other species, 5) estimating resting metabolic rate, 6) estimating cost of daily behaviours, and 7) estimating costs of thermoregulation or tissue synthesis. Most models being used are daily ration models (DRMs) whose set of simplifying assumptions are well established and whose use is widely accepted and feasible given the empirical data available to populate such models. However, DRMs do not link habitat objectives to metrics of ultimate ecological importance such as individual body condition or survival, and largely only consider food-producing habitats. Agent-based models (ABMs) provide a possible alternative for creating more biologically realistic models under some conditions; however, ABMs require different types of empirical inputs, many of which have yet to be estimated for key North American waterfowl. Decisions about how JVs can best proceed with habitat conservation would benefit from the use of sensitivity analyses that could identify the empirical and theoretical uncertainties that have the greatest influence on efforts to estimate habitat carrying capacity. Development of ABMs at restricted, yet biologically relevant spatial scales, followed by comparisons of their outputs to those generated from more simplistic, deterministic models can provide a means of assessing degrees of dissimilarity in how alternative models describe desired landscape conditions for migrating and wintering waterfowl