Systems biology

  • Article
    | Open Access

    The design of protein assemblies is a major thrust for biomolecular engineering and nanobiotechnology. Here the authors demonstrate a general mechanism for designing allosteric macromolecular assemblies and showcase a proof of concept for engineered allosteric protein assembly.

    • Luis A. Campos
    • , Rajendra Sharma
    • , Sara Alvira
    • , Federico M. Ruiz
    • , Beatriz Ibarra-Molero
    • , Mourad Sadqi
    • , Carlos Alfonso
    • , Germán Rivas
    • , Jose M. Sanchez-Ruiz
    • , Antonio Romero Garrido
    • , José M. Valpuesta
    •  & Victor Muñoz
  • Article
    | Open Access

    Multiple sequence alignments of proteins carry information about evolution, the protein’s fitness landscape and its stability in the face of mutations. Here, the authors demonstrate the utility of latent space models learned using variational autoencoders to infer these properties from sequences.

    • Xinqiang Ding
    • , Zhengting Zou
    •  & Charles L. Brooks III
  • Article
    | Open Access

    Here, Bhattacharya et al. chemically mutagenize Leishmania and identify genes associated with resistance to miltefosine and paromomycin by next generation sequencing. The study shows that a protein kinase (CDPK1) can mediate resistance to paromomycin by affecting translation.

    • Arijit Bhattacharya
    • , Philippe Leprohon
    • , Sophia Bigot
    • , Prasad Kottayil Padmanabhan
    • , Angana Mukherjee
    • , Gaétan Roy
    • , Hélène Gingras
    • , Anais Mestdagh
    • , Barbara Papadopoulou
    •  & Marc Ouellette
  • Article
    | Open Access

    There are many examples of cell populations exhibiting density-dependent collective oscillatory behaviour. Here, the authors show that sustained collective oscillations emerge when cells anticipate variation in signal and attempt to amplify it, a property that can be linked to adaptation.

    • Shou-Wen Wang
    •  & Lei-Han Tang
  • Article
    | Open Access

    Prior studies have examined fixed traits that correlate with plant invasiveness. Here the authors use a database of population matrices to compare demographic traits of invasive species in their native and invaded ranges, finding that demographic amplification is an important predictor of invasiveness.

    • Kim Jelbert
    • , Danielle Buss
    • , Jenni McDonald
    • , Stuart Townley
    • , Miguel Franco
    • , Iain Stott
    • , Owen Jones
    • , Roberto Salguero-Gómez
    • , Yvonne Buckley
    • , Tiffany Knight
    • , Matthew Silk
    • , Francesca Sargent
    • , Simon Rolph
    • , Phil Wilson
    •  & Dave Hodgson
  • Article
    | Open Access

    Intermediate transitions between epithelial and mesenchymal states are associated with tumor progression. Here using mass cytometry, Plevritis and colleagues develop a computational framework to resolve and map these trajectories in lung cancer cells and clinical specimens.

    • Loukia G. Karacosta
    • , Benedict Anchang
    • , Nikolaos Ignatiadis
    • , Samuel C. Kimmey
    • , Jalen A. Benson
    • , Joseph B. Shrager
    • , Robert Tibshirani
    • , Sean C. Bendall
    •  & Sylvia K. Plevritis
  • Article
    | Open Access

    Compared to single nucleotide variants and short indels, structural variants (SVs) are often more challenging to detect using high-throughput sequencing based methods. Here, the authors develop LinkedSV, a computational tool for SV detection using linked-read exome and genome sequencing data.

    • Li Fang
    • , Charlly Kao
    • , Michael V. Gonzalez
    • , Fernanda A. Mafra
    • , Renata Pellegrino da Silva
    • , Mingyao Li
    • , Sören-Sebastian Wenzel
    • , Katharina Wimmer
    • , Hakon Hakonarson
    •  & Kai Wang
  • Article
    | Open Access

    Tightly controlling cell output is challenging, which has limited development and applications of bacterial sensors. Here the authors develop tunable, fast-responding sensors to control production of metabolic pigments and use them to assess zinc deficiency in a low-cost, minimal equipment fashion.

    • Monica P. McNerney
    • , Cirstyn L. Michel
    • , Krishi Kishore
    • , Janet Standeven
    •  & Mark P. Styczynski
  • Article
    | Open Access

    Avian influenza A virus (IAV) strains replicate poorly in mammalian hosts, but mechanisms underlying species restriction are incompletely understood. Here, Bogdanow et al. show that avian and mammalian adapted IAV strains have evolved different RNA structure features for regulation of M segment RNA splicing.

    • Boris Bogdanow
    • , Xi Wang
    • , Katrin Eichelbaum
    • , Anne Sadewasser
    • , Immanuel Husic
    • , Katharina Paki
    • , Matthias Budt
    • , Martha Hergeselle
    • , Barbara Vetter
    • , Jingyi Hou
    • , Wei Chen
    • , Lüder Wiebusch
    • , Irmtraud M. Meyer
    • , Thorsten Wolff
    •  & Matthias Selbach
  • Article
    | Open Access

    Mechanistic insight into the regulation of transcriptional modules remains scarce. Here, the authors identify statistically independent gene sets by applying independent component analysis to a high-quality E. coli RNA-seq data compendium and find that most gene sets represent the effects of specific transcriptional regulators.

    • Anand V. Sastry
    • , Ye Gao
    • , Richard Szubin
    • , Ying Hefner
    • , Sibei Xu
    • , Donghyuk Kim
    • , Kumari Sonal Choudhary
    • , Laurence Yang
    • , Zachary A. King
    •  & Bernhard O. Palsson
  • Article
    | Open Access

    CRISPR-Cas systems have well characterized, modular structures. Here the authors use that architecture to design a Cas12a library of 560 synthetic chimeras, with altered PAM preferences and specificities.

    • R. M. Liu
    • , L. L. Liang
    • , E. Freed
    • , H. Chang
    • , E. Oh
    • , Z. Y. Liu
    • , A. Garst
    • , C. A. Eckert
    •  & R. T. Gill
  • Perspective
    | Open Access

    Recent research in motor neuroscience has focused on optimal feedback control of single, simple tasks while robotics and AI are making progress towards flexible movement control in complex environments employing hierarchical control strategies. Here, the authors argue for a return to hierarchical models of motor control in neuroscience.

    • Josh Merel
    • , Matthew Botvinick
    •  & Greg Wayne
  • Article
    | Open Access

    One of the underlying causes of aging is the accumulation of senescent cells, but their turnover rates and dynamics during ageing are unknown. Here the authors measure and model senescent cell production and removal and explore implications for mortality.

    • Omer Karin
    • , Amit Agrawal
    • , Ziv Porat
    • , Valery Krizhanovsky
    •  & Uri Alon
  • Article
    | Open Access

    The evolutionary trade-offs faced by tumors are poorly understood, yet could contribute to the molecular diversity of cancer. Here, the authors analyze the diversity of genetic alterations, genes expressed and drug sensitivities among solid tumors to explore what evolutionary trade-offs may explain the molecular diversity of tumors.

    • Jean Hausser
    • , Pablo Szekely
    • , Noam Bar
    • , Anat Zimmer
    • , Hila Sheftel
    • , Carlos Caldas
    •  & Uri Alon
  • Article
    | Open Access

    Haplotype information inferred by phasing is useful in genetic and genomic analysis. Here, the authors develop SHAPEIT4, a phasing method that exhibits sub-linear running time, provides accurate haplotypes and enables integration of external phasing information.

    • Olivier Delaneau
    • , Jean-François Zagury
    • , Matthew R. Robinson
    • , Jonathan L. Marchini
    •  & Emmanouil T. Dermitzakis
  • Article
    | Open Access

    Identification of clinically relevant gene expression signatures for cancer stratification remains challenging. Here, the authors introduce a flexible nonlinear signal superposition model that enables dissection of large gene expression data sets into signatures and extraction of gene interactions.

    • Michael Grau
    • , Georg Lenz
    •  & Peter Lenz
  • Article
    | Open Access

    Structural variants may be omitted in sequence analysis despite their importance in genome variation and phenotypic impact. Here the authors present GraphTyper2, which uses pangenome graphs to genotype structural variants using short-reads and can be applied in large-scale sequencing studies.

    • Hannes P. Eggertsson
    • , Snaedis Kristmundsdottir
    • , Doruk Beyter
    • , Hakon Jonsson
    • , Astros Skuladottir
    • , Marteinn T. Hardarson
    • , Daniel F. Gudbjartsson
    • , Kari Stefansson
    • , Bjarni V. Halldorsson
    •  & Pall Melsted
  • Article
    | Open Access

    Established bacterial glycoengineering platforms limit access to protein and glycan substrates. Here the authors design a cytoplasmic protein glycosylation system, Glycoli, to generate a variety of multivalent glycostructures.

    • Hanne L. P. Tytgat
    • , Chia-wei Lin
    • , Mikail D. Levasseur
    • , Markus B. Tomek
    • , Christoph Rutschmann
    • , Jacqueline Mock
    • , Nora Liebscher
    • , Naohiro Terasaka
    • , Yusuke Azuma
    • , Michael Wetter
    • , Martin F. Bachmann
    • , Donald Hilvert
    • , Markus Aebi
    •  & Timothy G. Keys
  • Article
    | Open Access

    Constructing biosynthetic pathways to study and engineer glycoprotein structures is difficult. Here, the authors use GlycoPRIME, a cell-free workflow for mixing-and-matching glycosylation enzymes, to evaluate 37 putative glycosylation pathways and discover routes to 18 new glycoprotein structures

    • Weston Kightlinger
    • , Katherine E. Duncker
    • , Ashvita Ramesh
    • , Ariel H. Thames
    • , Aravind Natarajan
    • , Jessica C. Stark
    • , Allen Yang
    • , Liang Lin
    • , Milan Mrksich
    • , Matthew P. DeLisa
    •  & Michael C. Jewett
  • Article
    | Open Access

    Swimming bacteria perform collective motion at high cell density, yet it is unclear how this behaviour affects their ability to follow substance gradients in the environment. Here, Colin et al. address this question by studying motion of Escherichia coli in controlled chemical gradients.

    • Remy Colin
    • , Knut Drescher
    •  & Victor Sourjik
  • Perspective
    | Open Access

    Synthetic biology uses cells as its computing substrate, often based on the genetic circuit concept. In this Perspective, the authors argue that existing synthetic biology approaches based on classical models of computation limit the potential of biocomputing, and propose that living organisms have under-exploited capabilities.

    • Lewis Grozinger
    • , Martyn Amos
    • , Thomas E. Gorochowski
    • , Pablo Carbonell
    • , Diego A. Oyarzún
    • , Ruud Stoof
    • , Harold Fellermann
    • , Paolo Zuliani
    • , Huseyin Tas
    •  & Angel Goñi-Moreno
  • Article
    | Open Access

    Parkinson’s disease (PD) is characterized by neurodegeneration associated with loss of dopaminergic (DA) neurons and deposition of Lewy bodies. Here, Wang et al. use co-expression network analysis to pinpoint disease pathways and propose reduced expression of STMN2 as a cause of presynaptic function loss in PD.

    • Qian Wang
    • , Yuanxi Zhang
    • , Minghui Wang
    • , Won-Min Song
    • , Qi Shen
    • , Andrew McKenzie
    • , Insup Choi
    • , Xianxiao Zhou
    • , Ping-Yue Pan
    • , Zhenyu Yue
    •  & Bin Zhang
  • Article
    | Open Access

    The pathogenic bacterium Legionella pneumophila infects lung macrophages and environmental amoebae. Here, Personnic et al. show that the pathogen reversibly forms virulent, antibiotic-tolerant subpopulations during infection of macrophages and amoebae, in a process regulated by the Lqs quorum-sensing system.

    • Nicolas Personnic
    • , Bianca Striednig
    • , Emmanuelle Lezan
    • , Christian Manske
    • , Amanda Welin
    • , Alexander Schmidt
    •  & Hubert Hilbi
  • Article
    | Open Access

    Metabolic syndrome is characterized by complex phenotypes that increases the risk of cardiovascular disease and type 2 diabetes. Here the authors’ integrative network analysis suggests BTK inhibitor ibrutinib to be a promising treatment through its obesity-associated inflammation lowering effect.

    • Karla Misselbeck
    • , Silvia Parolo
    • , Francesca Lorenzini
    • , Valeria Savoca
    • , Lorena Leonardelli
    • , Pranami Bora
    • , Melissa J. Morine
    • , Maria Caterina Mione
    • , Enrico Domenici
    •  & Corrado Priami
  • Article
    | Open Access

    Imaging heart development is challenging due to constant tissue movement and changing physical landmarks. Here the authors present an algorithm capable of maintaining phase-locked imaging throughout a 24 hour timespan, enabling long term timelapse imaging studies of zebrafish heart development, repair and regeneration.

    • Jonathan M. Taylor
    • , Carl J. Nelson
    • , Finnius A. Bruton
    • , Aryan K. Baghbadrani
    • , Charlotte Buckley
    • , Carl S. Tucker
    • , Adriano G. Rossi
    • , John J. Mullins
    •  & Martin A. Denvir
  • Article
    | Open Access

    Our understanding of the mechanisms of drug interactions remains limited. Here the authors introduce a framework to study how complex cellular perturbations induced by different drugs affect each other in morphological feature space.

    • Michael Caldera
    • , Felix Müller
    • , Isabel Kaltenbrunner
    • , Marco P. Licciardello
    • , Charles-Hugues Lardeau
    • , Stefan Kubicek
    •  & Jörg Menche
  • Article
    | Open Access

    Cytochrome bd oxidases couple quinol oxidation and the release of protons to the periplasmic side with proton uptake from the cytoplasmic side to reduce dioxygen to water and they are the terminal reductases in bacterial and archaeal respiratory chains. Here the authors present the cryo-EM structure of Escherichia coli bd oxidase and discuss mechanistic implications.

    • Alexander Theßeling
    • , Tim Rasmussen
    • , Sabrina Burschel
    • , Daniel Wohlwend
    • , Jan Kägi
    • , Rolf Müller
    • , Bettina Böttcher
    •  & Thorsten Friedrich
  • Article
    | Open Access

    Individual bacteria within isogenic populations can differ in antibiotic tolerance. Here, Libby et al. show that antibiotic tolerance variability can be driven by ‘noisy’ expression of a gene encoding a (p)ppGpp synthetase, which is in turn regulated by multisite phosphorylation of a transcription factor.

    • Elizabeth A. Libby
    • , Shlomi Reuveni
    •  & Jonathan Dworkin
  • Article
    | Open Access

    Existing efforts have been focused on one of the elements in the automation of the design, build, test, and learn (DBTL) cycle for biosystems design. Here, the authors integrate a robotic system with machine learning algorithms to fully automate the DBTL cycle and apply it in optimizing the lycopene biosynthetic pathway.

    • Mohammad HamediRad
    • , Ran Chao
    • , Scott Weisberg
    • , Jiazhang Lian
    • , Saurabh Sinha
    •  & Huimin Zhao
  • Article
    | Open Access

    Here, the authors compare gene expression signatures in rectal tissues of African green monkeys (AGMs) and rhesus macaques (RMs) acutely infected with simian immunodeficiency virus and find that AGMs rapidly activate and maintain evolutionarily conserved regenerative wound healing mechanisms.

    • Fredrik Barrenas
    • , Kevin Raehtz
    • , Cuiling Xu
    • , Lynn Law
    • , Richard R. Green
    • , Guido Silvestri
    • , Steven E. Bosinger
    • , Andrew Nishida
    • , Qingsheng Li
    • , Wuxun Lu
    • , Jianshui Zhang
    • , Matthew J. Thomas
    • , Jean Chang
    • , Elise Smith
    • , Jeffrey M. Weiss
    • , Reem A. Dawoud
    • , George H. Richter
    • , Anita Trichel
    • , Dongzhu Ma
    • , Xinxia Peng
    • , Jan Komorowski
    • , Cristian Apetrei
    • , Ivona Pandrea
    •  & Michael Gale Jr
  • Article
    | Open Access

    C. elegans is a commonly used model organism in the study of ageing, and differences in genetic background can result in varying strain longevity. Here the authors demonstrate that a background mutation in fln-2 affects life-limiting pharyngeal infection and that in the mutant background the beneficial effect of sir-2.1 over-expression is suppressed.

    • Yuan Zhao
    • , Hongyuan Wang
    • , Richard J. Poole
    •  & David Gems
  • Article
    | Open Access

    Existing heavy metal bioremediation systems are mainly based on plants, which require long growing time in specific conditions. Here, the authors mimic the characteristics of plant hyperaccumulators to engineer more tractable baker’s yeast and achieve 10–100-fold higher accumulation of chromium, arsenic, or cadmium.

    • George L. Sun
    • , Erin. E. Reynolds
    •  & Angela M. Belcher
  • Article
    | Open Access

    Flexizymes have been used to expand the scope of chemical substrates for ribosome-directed polymerization in vitro. Here the authors deduce design rules of Flexizyme-mediated tRNA acylation that more effectively predict the incorporation of new monomers into peptides.

    • Joongoo Lee
    • , Kenneth E. Schwieter
    • , Andrew M. Watkins
    • , Do Soon Kim
    • , Hao Yu
    • , Kevin J. Schwarz
    • , Jongdoo Lim
    • , Jaime Coronado
    • , Michelle Byrom
    • , Eric V. Anslyn
    • , Andrew D. Ellington
    • , Jeffrey S. Moore
    •  & Michael C. Jewett
  • Article
    | Open Access

    During high-intensity exercise, muscles convert glucose to lactate, in a process that is energetically less efficient than respiration. Here the authors develop a computational model based on muscle proteomic data showing that bypassing mitochondrial complex I increases ATP production rates, and validate these model predictions in an exercise test on 5 subjects.

    • Avlant Nilsson
    • , Elias Björnson
    • , Mikael Flockhart
    • , Filip J. Larsen
    •  & Jens Nielsen
  • Article
    | Open Access

    Lee et al. report an engineered IgG1 Fc domain that behaves like an hFcRn binding pH toggle switch. The authors show that this new half-life extension Fc domain confers improved pharmacokinetics in new humanized knock-in mouse strains that recapitulate the key processes for antibody persistence in circulation.

    • Chang-Han Lee
    • , Tae Hyun Kang
    • , Ophélie Godon
    • , Makiko Watanabe
    • , George Delidakis
    • , Caitlin M. Gillis
    • , Delphine Sterlin
    • , David Hardy
    • , Michel Cogné
    • , Lynn E. Macdonald
    • , Andrew J. Murphy
    • , Naxin Tu
    • , Jiwon Lee
    • , Jonathan R. McDaniel
    • , Emily Makowski
    • , Peter M. Tessier
    • , Aaron S. Meyer
    • , Pierre Bruhns
    •  & George Georgiou
  • Article
    | Open Access

    Is there an optimum difficulty level for training? In this paper, the authors show that for the widely-used class of stochastic gradient-descent based learning algorithms, learning is fastest when the accuracy during training is 85%.

    • Robert C. Wilson
    • , Amitai Shenhav
    • , Mark Straccia
    •  & Jonathan D. Cohen
  • Article
    | Open Access

    Transcript assembly is an important step in analysis of RNA-seq data whose accuracy influences downstream quantification, detection and characterization of alternative splice variants. Here, the authors develop PsiCLASS, a transcript assembler leveraging simultaneous analysis of multiple RNA-seq samples.

    • Li Song
    • , Sarven Sabunciyan
    • , Guangyu Yang
    •  & Liliana Florea
  • Article
    | Open Access

    Microbial production of aromatic amino acid (AAA)-derived chemicals remains an outstanding metabolic engineering challenge. Here, the authors engineer baker’s yeast for high levels p-coumaric acid production by rewiring the central carbon metabolism and channeling more flux to the AAA biosynthetic pathway.

    • Quanli Liu
    • , Tao Yu
    • , Xiaowei Li
    • , Yu Chen
    • , Kate Campbell
    • , Jens Nielsen
    •  & Yun Chen
  • Article
    | Open Access

    The Min biochemical network regulates bacterial cell division and is a prototypical example of self-organizing molecular systems. Here authors synthesize Min proteins from their genes inside liposomes and observe dynamic protein patterns and liposome shape deformation.

    • Elisa Godino
    • , Jonás Noguera López
    • , David Foschepoth
    • , Céline Cleij
    • , Anne Doerr
    • , Clara Ferrer Castellà
    •  & Christophe Danelon
  • Article
    | Open Access

    Engineering cell lines often requires multiple plasmids with different selection markers. Here the authors present SiMPl, a method based on rationally engineered split enzymes which get reconstituted via intein-mediated protein splicing to maintain two plasmids using a single antibiotic.

    • Navaneethan Palanisamy
    • , Anna Degen
    • , Anna Morath
    • , Jara Ballestin Ballestin
    • , Claudia Juraske
    • , Mehmet Ali Öztürk
    • , Georg A. Sprenger
    • , Jung-Won Youn
    • , Wolfgang W. Schamel
    •  & Barbara Di Ventura
  • Article
    | Open Access

    It is difficult to fit mechanistic, biophysically constrained circuit models to spike train data from in vivo extracellular recordings. Here the authors present analytical methods that enable efficient parameter estimation for integrate-and-fire circuit models and inference of the underlying connectivity structure in subsampled networks.

    • Josef Ladenbauer
    • , Sam McKenzie
    • , Daniel Fine English
    • , Olivier Hagens
    •  & Srdjan Ostojic
  • Article
    | Open Access

    Single cell RNA-Seq data can report on cellular types and states, but low signal-to noise and sparse data can make interpretation of cellular state difficult. Here the authors propose a transformation strategy to map RNA-Seq data to biological process activities that are species-agnostic and allow for comparison across species.

    • Hongxu Ding
    • , Andrew Blair
    • , Ying Yang
    •  & Joshua M. Stuart
  • Article
    | Open Access

    Osteoarthritis results from the progressive destruction of cartilage matrix. Here, Kim et al. identify tankyrase as a regulator of cartilage matrix anabolism, and find that tankyrase inhibition, by preventing SOX9 PARylation, protects from cartilage destruction in a mouse model of osteoarthritis.

    • Sukyeong Kim
    • , Sangbin Han
    • , Yeongjae Kim
    • , Hyeon-Seop Kim
    • , Young-Ran Gu
    • , Donghyun Kang
    • , Yongsik Cho
    • , Hyeonkyeong Kim
    • , Jeeyeon Lee
    • , Yeyoung Seo
    • , Moon Jong Chang
    • , Chong Bum Chang
    • , Seung-Baik Kang
    •  & Jin-Hong Kim
  • Article
    | Open Access

    The availability of high performance recombinases with low basal activity and high dynamic range is limited. Here the authors present a library of over 20 orthogonal split recombinases that can be induced by small molecules, light and temperature in vivo.

    • Benjamin H. Weinberg
    • , Jang Hwan Cho
    • , Yash Agarwal
    • , N. T. Hang Pham
    • , Leidy D. Caraballo
    • , Maciej Walkosz
    • , Charina Ortega
    • , Micaela Trexler
    • , Nathan Tague
    • , Billy Law
    • , William K. J. Benman
    • , Justin Letendre
    • , Jacob Beal
    •  & Wilson W. Wong
  • Article
    | Open Access

    Engineering Taxol pathway in microbes needs to overcome the difficulty of expressing plant P450 enzymes. Here, the authors use a compartmentalized metabolic engineering strategy to construct the taxanes production pathway in chloroplasts of Nicotiana benthamiana and realize the production of taxadience-5α-ol.

    • Jianhua Li
    • , Ishmael Mutanda
    • , Kaibo Wang
    • , Lei Yang
    • , Jiawei Wang
    •  & Yong Wang