A tandem evolutionary algorithm for identifying causal rules from complex data

We propose a new evolutionary approach for discovering causal rules in complex classification problems from batch data. Key aspects include (a) the use of a hypergeometric probability mass function as a principled statistic for assessing fitness that quantifies the probability that the observed association between a given clause and target class is due to chance, taking into account the size of the dataset, the amount of missing data, and the distribution of outcome categories, (b) tandem age-layered evolutionary algorithms for evolving parsimonious archives of conjunctive clauses, and disjunctions of these conjunctions, each of which have probabilistically significant associations with outcome classes, and (c) separate archive bins for clauses of different orders, with dynamically adjusted order-specific thresholds. The method is validated on majority-on and multiplexer benchmark problems exhibiting various combinations of heterogeneity, epistasis, overlap, noise in class associations, missing data, extraneous features, and imbalanced classes. We also validate on a more realistic synthetic genome dataset with heterogeneity, epistasis, extraneous features, and noise. In all synthetic epistatic benchmarks, we consistently recover the true causal rule sets used to generate the data. Finally, we discuss an application to a complex real-world survey dataset designed to inform possible ecohealth interventions for Chagas disease

A quantitative metric for the comparative evaluation of optical clearing protocols for 3D multicellular spheroids

3D multicellular spheroids quickly emerged as in vitro models because they represent the in vivo tumor environment better than standard 2D cell cultures. However, with current microscopy technologies, it is difficult to visualize individual cells in the deeper layers of 3D samples mainly because of limited light penetration and scattering. To overcome this problem several optical clearing methods have been proposed but defining the most appropriate clearing approach is an open issue due to the lack of a gold standard metric. Here, we propose a guideline for 3D light microscopy imaging to achieve single-cell resolution. The guideline includes a validation experiment focusing on five optical clearing protocols. We review and compare seven quality metrics which quantitatively characterize the imaging quality of spheroids. As a test environment, we have created and shared a large 3D dataset including approximately hundred fluorescently stained and optically cleared spheroids. Based on the results we introduce the use of a novel quality metric as a promising method to serve as a gold standard, applicable to compare optical clearing protocols, and decide on the most suitable one for a particular experiment

Seasonal and spatial variations of saltmarsh benthic foraminiferal communities from North Norfolk, England

Time series foraminiferal data were obtained from samples collected from three sites at Brancaster Overy Staithe, Burnham Overy Staithe and Thornham on the North Norfolk coast over a 1-year period. At each collection point, six environmental variables—temperature, chlorophyll, sand, mud, pH and salinity—were also measured. The principle aim of this study was to examine the benthic foraminiferal fauna in regard to the temporal variability of foraminiferal abundance, seasonal trend, dominant species, species diversity and the impact of environmental variables on the foraminiferal communities in the top 1 cm of sediment over a 1-year time series. The foraminiferal assemblages at the three sites were dominated by three species: Haynesina germanica, Ammonia sp. and Elphidium williamsoni. Foraminiferal species showed considerable seasonal and temporal fluctuation throughout the year at the three investigated sites. The foraminiferal assemblage at the three low marsh zones showed a maximum abundance in autumn between September and November and a minimum abundance observed between July and August. There were two separate peaks in the abundance of Ammonia sp. and E. williamsoni, one in spring and another in autumn. In contrast, H. germanica showed a single peak in its abundance in autumn. A generalized additive modelling approach was used to explain the variation in the observed foraminiferal abundance and to estimate the significant impact of each of the environmental variables on living foraminiferal assemblages, with taxa abundance as the dependent variable. When included in the model as predictors, most of the environmental variables contributed little in explaining the observed variation in foraminiferal species abundance. However, the hypotheses for differences amongst sites, salinity and pH were significant and explained most of the variability in species relative abundance

Vernalization-Repression of Arabidopsis FLC Requires Promoter Sequences but Not Antisense Transcripts

The repression of Arabidopsis FLC expression by vernalization (extended cold) has become a model for understanding polycomb-associated epigenetic regulation in plants. Antisense and sense non-coding RNAs have been respectively implicated in initiation and maintenance of FLC repression by vernalization. We show that the promoter and first exon of the FLC gene are sufficient to initiate repression during vernalization; this initial repression of FLC does not require antisense transcription. Long-term maintenance of FLC repression requires additional regions of the gene body, including those encoding sense non-coding transcripts

Coverage, Continuity and Visual Cortical Architecture

The primary visual cortex of many mammals contains a continuous representation of visual space, with a roughly repetitive aperiodic map of orientation preferences superimposed. It was recently found that orientation preference maps (OPMs) obey statistical laws which are apparently invariant among species widely separated in eutherian evolution. Here, we examine whether one of the most prominent models for the optimization of cortical maps, the elastic net (EN) model, can reproduce this common design. The EN model generates representations which optimally trade of stimulus space coverage and map continuity. While this model has been used in numerous studies, no analytical results about the precise layout of the predicted OPMs have been obtained so far. We present a mathematical approach to analytically calculate the cortical representations predicted by the EN model for the joint mapping of stimulus position and orientation. We find that in all previously studied regimes, predicted OPM layouts are perfectly periodic. An unbiased search through the EN parameter space identifies a novel regime of aperiodic OPMs with pinwheel densities lower than found in experiments. In an extreme limit, aperiodic OPMs quantitatively resembling experimental observations emerge. Stabilization of these layouts results from strong nonlocal interactions rather than from a coverage-continuity-compromise. Our results demonstrate that optimization models for stimulus representations dominated by nonlocal suppressive interactions are in principle capable of correctly predicting the common OPM design. They question that visual cortical feature representations can be explained by a coverage-continuity-compromise.Comment: 100 pages, including an Appendix, 21 + 7 figure

Biological properties of extracellular vesicles and their physiological functions

In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system

Special considerations for studies of extracellular vesicles from parasitic helminths: a community-led roadmap to increase rigour and reproducibility

Over the last decade, research interest in defining how extracellular vesicles (EVs) shape cross-species communication has grown rapidly. Parasitic helminths, worm species found in the phyla Nematoda and Platyhelminthes, are well-recognised manipulators of host immune function and physiology. Emerging evidence supports a role for helminth-derived EVs in these processes and highlights EVs as an important participant in cross-phylum communication. While the mammalian EV field is guided by a community-agreed framework for studying EVs derived from model organisms or cell systems [e.g., Minimal Information for Studies of Extracellular Vesicles (MISEV)], the helminth community requires a supplementary set of principles due to the additional challenges that accompany working with such divergent organisms. These challenges include, but are not limited to, generating sufficient quantities of EVs for descriptive or functional studies, defining pan-helminth EV markers, genetically modifying these organisms, and identifying rigorous methodologies for in vitro and in vivo studies. Here, we outline best practices for those investigating the biology of helminth-derived EVs to complement the MISEV guidelines. We summarise community-agreed standards for studying EVs derived from this broad set of non-model organisms, raise awareness of issues associated with helminth EVs and provide future perspectives for how progress in the field will be achieved