Systems biology

  • Article
    | Open Access

    Stochastic fluctuations at the transcriptional level contribute to heterogeneity in isogenic cell populations. Here, the authors engineer TuNR which modulates the variability in gene expression of endogenous human genes independent of their mean expression.

    • Alain R. Bonny
    • , João Pedro Fonseca
    •  & Hana El-Samad
  • Article
    | Open Access

    Macrophages can be polarized by in vitro culture stimuli into M1 or M2 cells, but microenvironments in vivo are more complex. Here the authors analyze cultured macrophages stimulated with a combination of M1 and M2 stimuli by single-cell RNA sequencing, machine learning, and single-cell secretion profiling to show a surprising level of heterogeneity of response.

    • Andrés R. Muñoz-Rojas
    • , Ilana Kelsey
    •  & Kathryn Miller-Jensen
  • Article
    | Open Access

    Developing effective drugs for Alzheimer’s disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, the authors report an efficient network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of human cerebral organoids.

    • Jong-Chan Park
    • , So-Yeong Jang
    •  & Inhee Mook-Jung
  • Article
    | Open Access

    While temperature impacts the function of all cellular components, it’s hard to rule out how the temperature dependence of cell phenotypes emerged from the dependence of individual components. Here, the authors develop a Bayesian genome scale modelling approach to identify thermal determinants of yeast metabolism.

    • Gang Li
    • , Yating Hu
    •  & Jens Nielsen
  • Article
    | Open Access

    Integration of single cell data modalities increases the richness of information about the heterogeneity of cell states, but integration of imaging and transcriptomics is an open challenge. Here the authors use autoencoders to learn a probabilistic coupling and map these modalities to a shared latent space.

    • Karren Dai Yang
    • , Anastasiya Belyaeva
    •  & Caroline Uhler
  • Article
    | Open Access

    Anecdotal reports suggest potential severity and outcome differences between sexes following infection by SARS-CoV-2. Here, the authors perform meta-analyses of more than 3 million cases collected from global public data to demonstrate that male patients with COVID-19 are 3 times more likely to require intensive care, and have ~40% higher death rate.

    • Hannah Peckham
    • , Nina M. de Gruijter
    •  & Claire T. Deakin
  • Article
    | Open Access

    Innate-like T cells such as invariant natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cells both develop in the thymus. Here the authors use single-cell RNA sequencing to show that mouse iNKT and MAIT share components of developmental regulation, with a transcription factor, Hivep3, implicated for the maturation of both cell types.

    • S. Harsha Krovi
    • , Jingjing Zhang
    •  & Laurent Gapin
  • Article
    | Open Access

    Multiple co-occurring stressors may affect food webs in ways that are not predictable by studying individual stressors. Here the authors apply a network interaction model to a marine food web in the Arctic, finding that nonlinear interactions between stressors can more than double the risk of population collapse compared to simpler simulations.

    • K. R. Arrigo
    • , Gert L. van Dijken
    •  & R. M. Bailey
  • Perspective
    | Open Access

    The IMEx consortium provides one of the largest resources of curated, experimentally verified molecular interaction data. Here, the authors review how IMEx evolved into a fundamental resource for life scientists and describe how IMEx data can support biomedical research.

    • Pablo Porras
    • , Elisabet Barrera
    •  & Sandra Orchard
  • Article
    | Open Access

    Combinatorial treatments have become a standard of care for various complex diseases including cancers. Here, the authors show that combinatorial responses of two anticancer drugs can be accurately predicted using factorization machines trained on large-scale pharmacogenomic data for guiding precision oncology studies.

    • Heli Julkunen
    • , Anna Cichonska
    •  & Juho Rousu
  • Article
    | Open Access

    Bacterial vaginosis (BV) is typically caused by a shift in the vaginal microbiota from a Lactobacillus-dominant community to one colonised by strains of Gardenerella vaginalis and treatment with the antibiotic metronidazole (MNZ) often results in failure and recurrence. Here, the authors use modelling and in vitro assays to show that sequestration of MNZ by Lactobacillus is critical in reducing efficacy and women with a higher pre-treatment Lactobacillus/Gardnerella ratio are more likely to recur.

    • Christina Y. Lee
    • , Ryan K. Cheu
    •  & Kelly B. Arnold
  • Article
    | Open Access

    Robustness is a prominent feature of most biological systems, but most of the current efforts have been focused on studying homogeneous molecular networks. Here the authors propose a comprehensive framework for understanding how the interactions between genes, proteins, and metabolites contribute to the determinants of robustness.

    • Xueming Liu
    • , Enrico Maiorino
    •  & Amitabh Sharma
  • Article
    | Open Access

    Understanding evolutionary constraints in antibiotic resistance is crucial for prediction and control. Here, the authors use high-throughput laboratory evolution of Escherichia coli alongside machine learning to identify trade-off relationships associated with drug resistance.

    • Tomoya Maeda
    • , Junichiro Iwasawa
    •  & Chikara Furusawa
  • Article
    | Open Access

    Large volumes of true random numbers are needed for increasing requirements of secure data encryption. Here the authors use the stochastic nature of DNA synthesis to obtain millions of gigabytes of unbiased randomness.

    • Linda C. Meiser
    • , Julian Koch
    •  & Robert N. Grass
  • Article
    | Open Access

    Current efforts to establish synthetic carbon fixation in model heterotrophs rely on expression of heterologous enzymes. Here, the authors explore the presence and activity of a latent CO2-assimilation pathway in E. coli based only on endogenous enzymes and a reversible decarboxylase.

    • Ari Satanowski
    • , Beau Dronsella
    •  & Arren Bar-Even
  • Article
    | Open Access

    The design and optimisation of 3D DNA-origami can be a barrier to rapid application. Here the authors design barrel structure of stacked 2D double helical rings with complex surface patterns.

    • Shelley F. J. Wickham
    • , Alexander Auer
    •  & William M. Shih
  • Article
    | Open Access

    Translatome remodelling controls stress-adaptive protein output. Here the authors reveal that in response to stimuli, eIF5A functions as a pH-regulated translation factor that responds to fermentation-induced acidosis affecting cellular metabolism.

    • Nathan C. Balukoff
    • , J. J. David Ho
    •  & Stephen Lee
  • Article
    | Open Access

    Accurately predicting the behaviour of a genetic circuit remains difficult due to the lack of modularity. Here the authors quantify the effects of resource loading in mammalian systems and develop an endoribonuclease-based feedfoward controller to adapt gene expression to the effects of resource loading.

    • Ross D. Jones
    • , Yili Qian
    •  & Domitilla Del Vecchio
  • Article
    | Open Access

    Building regulatory networks often requires trade-offs between accuracy and speed. Here the authors show in a bistable network the transition from a slow decision making system to a rapid one dominated by small number fluctuations.

    • Ferdinand Greiss
    • , Shirley S. Daube
    •  & Roy Bar-Ziv
  • Article
    | Open Access

    Neuron-astrocyte communication plays a key role in pathophysiology, however systematic approaches to unveil it are limited. Here, the authors propose SEARCHIN, a multi-modal integrated workflow, as a tool to identify cross-compartment ligand-receptor interactions, applied to ALS models.

    • Vartika Mishra
    • , Diane B. Re
    •  & Serge Przedborski
  • Article
    | Open Access

    Conjugative plasmids mediate the spread and maintenance of diverse traits in microbial communities, but the conditions underlying plasmid persistence are poorly understood. Here, Wang and You present a modeling framework for analysis of gene flow and prediction of plasmid persistence and abundance in complex communities.

    • Teng Wang
    •  & Lingchong You
  • Article
    | Open Access

    Morphogen gradients can be dynamic and transient yet give rise to stable cellular patterns. Here the authors show that a synthetic morphogen-induced mutual inhibition circuit produces stable boundaries when the spatial average of morphogens falls within the region of bistability.

    • Paul K. Grant
    • , Gregory Szep
    •  & Andrew Phillips
  • Article
    | Open Access

    The trade-off between growth and production affects the application of engineered microbes. Here, the authors take the minimal cut set approach to predict metabolic reactions for elimination to couple metabolite production strongly with growth and achieve high production of indigoidine in Pseudomonas putida.

    • Deepanwita Banerjee
    • , Thomas Eng
    •  & Aindrila Mukhopadhyay
  • Article
    | Open Access

    Herold et al. present an integrated meta-omics framework to investigate how mixed microbial communities, such as oleaginous bacterial populations in biological wastewater treatment plants, respond with distinct adaptation strategies to disturbances. They show that community resistance and resilience are a function of phenotypic plasticity and niche complementarity.

    • Malte Herold
    • , Susana Martínez Arbas
    •  & Paul Wilmes
  • Article
    | Open Access

    The protein translation machinery is the most expensive cellular subsystem in fast growing bacteria. Providing a detailed mechanistic model for this complex system, the authors show that the translation machinery components are expressed such that their combined cost to the cell is minimal.

    • Xiao-Pan Hu
    • , Hugo Dourado
    •  & Martin J. Lercher
  • Article
    | Open Access

    Distributed multi-omic digitization of clinical specimen across multiple sites is a prerequisite for turning molecular precision medicine into reality. Here, the authors show that coordinated proteotype data acquisition is feasible using standardized MS data acquisition and analysis strategies.

    • Yue Xuan
    • , Nicholas W. Bateman
    •  & Thomas P. Conrads
  • Article
    | Open Access

    Global interaction of chromatin-associated RNAs and DNA can be identified in situ. Here the authors report the genome-wide increase of interchromosomal RNA-DNA interactions and demonstrate the importance of such RNA-DNA contacts exemplified by LINC00607 RNA and SERPINE1 gene’s super enhancer in dysfunctional endothelial cell models.

    • Riccardo Calandrelli
    • , Lixia Xu
    •  & Sheng Zhong
  • Article
    | Open Access

    Tocotrienols are valuable supplementations to α-tocopherol-dominated Vitamin E products. Here, the authors engineer baker’s yeast by combining the heterologous genes from photosynthetic organisms with the endogenous pathway for the production of tocotrienols under cold-shock-triggered temperature control.

    • Bin Shen
    • , Pingping Zhou
    •  & Hongwei Yu
  • Article
    | Open Access

    The periodic organization of cells is typically associated with mechanisms based on intercellular signaling such as lateral inhibition and Turing patterning. Here the authors show that hair cells in the inner ear rearrange gradually into a checkerboard-like pattern through a tissue-wide shear motion that coordinates intercalation and delamination events.

    • Roie Cohen
    • , Liat Amir-Zilberstein
    •  & David Sprinzak
  • Article
    | Open Access

    Addition of fluorine to organic structures is a unique strategy for tuning molecular properties, but approaches to integrate fluorometabolites into the biochemistry of living cells are scarce. Here, the authors develop a fluoride-responsive genetic circuit to enable in vivo biofluorination in engineered Pseudomonas putida.

    • Patricia Calero
    • , Daniel C. Volke
    •  & Pablo I. Nikel
  • Article
    | Open Access

    The design of synthetic biology circuits remains challenging due to poorly understood design rules. Here the authors introduce STORM and NuSpeak, two deep-learning architectures to characterize and optimize toehold switches.

    • Jacqueline A. Valeri
    • , Katherine M. Collins
    •  & Diogo M. Camacho
  • Article
    | Open Access

    Single cell expression data allows for inferring cell-cell communication between cells expressing ligands and those expressing their cognate receptors. Here the authors present an updated and curated database of ligand-receptor pairs and a Python-based toolkit to construct and analyse communication networks from single cell and bulk expression data.

    • Rui Hou
    • , Elena Denisenko
    •  & Alistair R. R. Forrest
  • Article
    | Open Access

    The chemical stability of DNA makes complete erasure of DNA-encoded data difficult. Here the authors mix true and false messages, differentiated by whether a truth marker oligo is bound to it, and show that brief exposure to elevated temperatures randomizes the binding of truth markers preventing data recovery.

    • Jangwon Kim
    • , Jin H. Bae
    •  & David Yu Zhang
  • Article
    | Open Access

    Tropical rainforests partly create their own climatic conditions by promoting precipitation, therefore rainforest losses may trigger dramatic shifts. Here the authors combine remote sensing, hydrological modelling, and atmospheric moisture tracking simulations to assess forest-rainfall feedbacks in three major tropical rainforest regions on Earth and simulate potential changes under a severe climate change scenario.

    • Arie Staal
    • , Ingo Fetzer
    •  & Obbe A. Tuinenburg
  • Article
    | Open Access

    ATP drives most cellular processes, although ATP production and consumption levels during mitosis remain unreported. Here, the authors combine metabolic measurements and modeling to quantify ATP levels and synthesis dynamics, revealing that ATP synthesis and consumption are lowered during mitosis.

    • Joon Ho Kang
    • , Georgios Katsikis
    •  & Teemu P. Miettinen
  • Article
    | Open Access

    In quantitative genetics, it is widely assumed that mutations combine additively or epistasis can be predicted with statistical or mechanistic models. Here, the authors use the phage lambda repressor model to show how biophysical ambiguity and non-monotonic functions confound phenotypic prediction.

    • Xianghua Li
    •  & Ben Lehner
  • Article
    | Open Access

    In metabolic engineering, mechanistic models require prior metabolism knowledge of the chassis strain, whereas machine learning models need ample training data. Here, the authors combine the mechanistic and machine learning models to improve prediction performance of tryptophan metabolism in baker’s yeast.

    • Jie Zhang
    • , Søren D. Petersen
    •  & Michael K. Jensen
  • Article
    | Open Access

    Synthetic Biology often lacks the predictive power needed for efficient bioengineering. Here the authors present ART, a machine learning and probabilistic predictive tool to guide synthetic biology design in a systematic fashion.

    • Tijana Radivojević
    • , Zak Costello
    •  & Hector Garcia Martin
  • Article
    | Open Access

    Protein tyrosine O-sulfation is crucial for biomolecular interactions. Here the authors report in vitro engineering and in vivo validation of a tyrosyl-tRNA synthetase mutant for the genetic encoding of sulfotyrosine in mammalian cells.

    • Xinyuan He
    • , Yan Chen
    •  & Wei Niu