Closed-loop cycles of experiment design, execution, and learning accelerate systems biology model development in yeast

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1900548116/-/DCSupplemental.Copyright © 2019 The Author(s). One of the most challenging tasks in modern science is the development of systems biology models: Existing models are often very complex but generally have low predictive performance. The construction of high-fidelity models will require hundreds/thousands of cycles of model improvement, yet few current systems biology research studies complete even a single cycle. We combined multiple software tools with integrated laboratory robotics to execute three cycles of model improvement of the prototypical eukaryotic cellular transformation, the yeast (Saccharomyces cerevisiae) diauxic shift. In the first cycle, a model outperforming the best previous diauxic shift model was developed using bioinformatic and systems biology tools. In the second cycle, the model was further improved using automatically planned experiments. In the third cycle, hypothesis-led experiments improved the model to a greater extent than achieved using high-throughput experiments. All of the experiments were formalized and communicated to a cloud laboratory automation system (Eve) for automatic execution, and the results stored on the semantic web for reuse. The final model adds a substantial amount of knowledge about the yeast diauxic shift: 92 genes (+45%), and 1,048 interactions (+147%). This knowledge is also relevant to understanding cancer, the immune system, and aging. We conclude that systems biology software tools can be combined and integrated with laboratory robots in closed-loop cycles.HIST-ERA AdaLab project: The Engineering and Physical Sciences Research Council (EPSRC), UK(EP/M015661/1) ANR-14-CHR2-0001-01

Blood-based epigenome-wide analyses of cognitive abilities

BACKGROUND: Blood-based markers of cognitive functioning might provide an accessible way to track neurodegeneration years prior to clinical manifestation of cognitive impairment and dementia. RESULTS: Using blood-based epigenome-wide analyses of general cognitive function, we show that individual differences in DNA methylation (DNAm) explain 35.0% of the variance in general cognitive function (g). A DNAm predictor explains ~4% of the variance, independently of a polygenic score, in two external cohorts. It also associates with circulating levels of neurology- and inflammation-related proteins, global brain imaging metrics, and regional cortical volumes. CONCLUSIONS: As sample sizes increase, the ability to assess cognitive function from DNAm data may be informative in settings where cognitive testing is unreliable or unavailable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02596-5

Reconstruction of a scalar voltage-based neural field network from observed time series

We present a general method for reconstruction of a network of nonlinearly coupled neural fields from the observations. A prominent example of such a system is a dynamical random neural network model studied by Sompolinsky et. al [Phys. Rev. Lett., v. 61, 259 (1988)]. We develop a technique for inferring the properties of the system from the observations of the chaotic voltages. Only the structure of the model is assumed to be known, while the nonlinear gain functions of the interactions, the matrix of the coupling constants, and the time constants of the local dynamics are reconstructed from the time series.Comment: 5 page

Integrating transcriptional activity in genome-scale models of metabolism

International audienc

Overview and Evaluation of Recent Methods for Statistical Inference of Gene Regulatory Networks from Time Series Data

A challenging problem in systems biology is the reconstruction of gene regulatory networks from postgenomic data. A variety of reverse engineering methods from machine learning and computational statistics have been proposed in the literature. However, deciding on the best method to adopt for a particular application or data set might be a confusing task. The present chapter provides a broad overview of state-of-the-art methods with an emphasis on conceptual understanding rather than a deluge of mathematical details, and the pros and cons of the various approaches are discussed. Guidance on practical applications with pointers to publicly available software implementations are included. The chapter concludes with a comprehensive comparative benchmark study on simulated data and a real-work application taken from the current plant systems biology

Zygophyllum morgsana

Gene regulatory networks are powerful abstractions of biological systems. Since the advent of high-throughput measurement technologies in biology in the late 90s, reconstructing the structure of such networks has been a central computational problem in systems biology. While the problem is certainly not solved in its entirety, considerable progress has been made in the last two decades, with mature tools now available. This chapter aims to provide an introduction to the basic concepts underpinning network inference tools, attempting a categorisation which highlights commonalities and relative strengths. While the chapter is meant to be self-contained, the material presented should provide a useful background to the later, more specialised chapters of this book