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Article
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Fully-automated and ultra-fast cell-type identification using specific marker combinations from single-cell transcriptomic data
Cell types are typically identified in single cell transcriptomic data by manual annotation of cell clusters using established marker genes. Here the authors present a fully-automated computational platform that can quickly and accurately distinguish between cell types.
- Aleksandr Ianevski
- , Anil K. Giri
- & Tero Aittokallio
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Article
| Open Access
Fossil coleoid cephalopod from the Mississippian Bear Gulch Lagerstätte sheds light on early vampyropod evolution
The authors describe a new cephalopod from the Carboniferous (Mississippian) Bear Gulch Lagerstätte of Montana, USA. This specimen extends the fossil record of vampyropods back by ~82 million years and changes our understanding of their evolution.
- Christopher D. Whalen
- & Neil H. Landman
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Article
| Open Access
Hysteresis stabilizes dynamic control of self-assembled army ant constructions
Army ant bridges are a remarkable example of self-assembled living structures. Here, the authors investigate experimentally how army ant bridges respond to unstable ground, revealing how responses emerge from the decentralized actions of individuals.
- Helen F. McCreery
- , Georgina Gemayel
- & Radhika Nagpal
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| Open Access
Genome-wide functional screens enable the prediction of high activity CRISPR-Cas9 and -Cas12a guides in Yarrowia lipolytica
The successful use of CRISPR-based mutagenesis in non-conventional microorganisms requires high activity sgRNAs. Here, the authors present DeepGuide, a neural network-based architecture, that learns from genome-wide CRISPR activity profiles to accurately design Cas9 and Cas12a sgRNAs with high activity in the oleaginous yeast Yarrowia lipolytica.
- Dipankar Baisya
- , Adithya Ramesh
- & Ian Wheeldon
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Article
| Open Access
Protease-controlled secretion and display of intercellular signals
To program intercellular communication for biomedicine, it is crucial to regulate the secretion and surface display of signaling proteins. Here the authors develop RELEASE, a modular approach to control intercellular signals using protein-based circuits.
- Alexander E. Vlahos
- , Jeewoo Kang
- & Xiaojing J. Gao
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Article
| Open Access
Stratification of hospitalized COVID-19 patients into clinical severity progression groups by immuno-phenotyping and machine learning
Developing predictive methods to identify patients with high risk of severe COVID-19 disease is of crucial importance. Authors show here that by measuring anti-SARS-CoV-2 antibody and cytokine levels at the time of hospital admission and integrating the data by unsupervised hierarchical clustering/machine learning, it is possible to predict unfavourable outcome.
- Yvonne M. Mueller
- , Thijs J. Schrama
- & Peter D. Katsikis
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Article
| Open Access
Whole-cell modeling in yeast predicts compartment-specific proteome constraints that drive metabolic strategies
Metabolically active organelles compete for cytosolic space and resources during metabolism rewiring. Here, the authors develop a computational model of yeast metabolism and resource allocation to predict condition- and compartment-specific proteome constraints that govern metabolic strategies.
- Ibrahim E. Elsemman
- , Angelica Rodriguez Prado
- & Bas Teusink
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Article
| Open Access
Pluripotency factors determine gene expression repertoire at zygotic genome activation
Zygotic genome activation in zebrafish relies on pluripotency transcription factors Pou5f3 and Sox19b. Here the authors investigate how these factors interact in vivo by analyzing the changes in chromatin state and time-resolved transcription in Pou5f3 and Sox19b single and double mutant embryos.
- Meijiang Gao
- , Marina Veil
- & Daria Onichtchouk
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Article
| Open Access
In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells
T follicular helper (Tfh) and T help type 1 (Th1) cells both arise from naïve CD4 T cells, but detailed knowledge of their differentiation remains incomplete. Here the authors pursue an in vivo CRISPR screen to identify genes, focusing on druggable targets, regulating Tfh versus Th1 to provide a resource for related studies, while also implicating HIF-1α and VHL in this regulation.
- Bonnie Huang
- , James D. Phelan
- & Pamela L. Schwartzberg
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Article
| Open Access
Versioning biological cells for trustworthy cell engineering
Full traceability and transparency are important to establish trust in engineered cell lines. Here the authors argue that version control for cell engineering marks a significant step toward more open, reproducible, traceable and ultimately more trustworthy engineering biology.
- Jonathan Tellechea-Luzardo
- , Leanne Hobbs
- & Natalio Krasnogor
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Article
| Open Access
Human transcription factor protein interaction networks
Transcription factors (TFs) interact with several other proteins in the process of transcriptional regulation. Here the authors identify 6703 and 1536 protein–protein interactions for 109 different human TFs through BioID and AP-MS analyses, respectively.
- Helka Göös
- , Matias Kinnunen
- & Markku Varjosalo
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Perspective
| Open Access
Sculpting tissues by phase transitions
Many biological processes require changes in the physical properties of cells and their surroundings. Here, Lenne and Trivedi discuss recent findings in biological systems in terms of phase transitions in inert physical systems from both theoretical and experimental perspectives.
- Pierre-François Lenne
- & Vikas Trivedi
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Article
| Open Access
Genetically stable CRISPR-based kill switches for engineered microbes
Biocontainment is a key to developing safe genetically-engineered microbes (GEMs). Here the authors demonstrate genetically stable CRISPR-based kill switches that control GEMs’ viability in animal hosts, enabling their safe biomedical applications.
- Austin G. Rottinghaus
- , Aura Ferreiro
- & Tae Seok Moon
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| Open Access
Inferring protein expression changes from mRNA in Alzheimer’s dementia using deep neural networks
Protein changes in a brain with Alzheimer’s are not often accompanied by transcriptional differences. Here, using a deep neural network that predicts protein abundance from mRNA expression, the authors track the early protein changes in Alzheimer’s dementia.
- Shinya Tasaki
- , Jishu Xu
- & Chris Gaiteri
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Article
| Open Access
A pan-CRISPR analysis of mammalian cell specificity identifies ultra-compact sgRNA subsets for genome-scale experiments
Context specificity confounds genetic analysis and prevents reproducible genome engineering. Here, the authors report a pan-CRISPR analysis of specificity in mammalian cells and identify ultra-compact sgRNA subsets for genome-scale screens.
- Boyang Zhao
- , Yiyun Rao
- & Justin R. Pritchard
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Article
| Open Access
The mouse metallomic landscape of aging and metabolism
The metallome is crucial for normal cell functioning but remains largely overlooked in mammals. Here the authors analyze the metallome and copper and zinc isotope compositions in aging mice and show networks of interactions that are organ-specific, age-dependent, isotopically-typified and associated with a wealth of clinical and molecular traits.
- Jean-David Morel
- , Lucie Sauzéat
- & Vincent Balter
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Article
| Open Access
A non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host
The herpesvirus protein ORF45 can bind the two host kinases ERK and RSK but how this affects cell signalling is unclear. Here, the authors show that ORF45 hijacks the ERK-RSK complex by binding to the two kinases with optimized linear motifs and interfering with the host kinase docking systems.
- Anita Alexa
- , Péter Sok
- & Attila Reményi
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Article
| Open Access
Massively parallel characterization of engineered transcript isoforms using direct RNA sequencing
Transcriptional terminators are generally viewed as hard endpoints for transcribing RNA polymerases. Here, the authors reimagine terminators as transcriptional valves with predictable read through. They engineer and characterize 1780 valves and use them for multiplexed gene regulation.
- Matthew J. Tarnowski
- & Thomas E. Gorochowski
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Article
| Open Access
Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19
SARS-CoV-2 infection can lead to progressive pathology in patients with COVID-19, but information for this disease progression is sparse. Here the authors use multi-omics approach to profile the immune responses of patients, assessing immune repertoire and effects of tocilizumab treatments, to find a dyssynchrony between innate and adaptive immunity in progressive COVID-19.
- Avraham Unterman
- , Tomokazu S. Sumida
- & Charles S. Dela Cruz
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Article
| Open Access
Biosensor for branched-chain amino acid metabolism in yeast and applications in isobutanol and isopentanol production
There are a lack of eukaryotic biosensors specific for branched-chain amino acid (BCAA)-derived products. Here the authors report a genetically encoded biosensor for BCAA metabolism based on the Leu3p transcriptional regulator; they use this to monitor yeast production of isobutanol and isopentanol.
- Yanfei Zhang
- , Jeremy D. Cortez
- & José L. Avalos
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Article
| Open Access
Postmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation
Postmortem analyses provide useful information for COVID-19 etiology. Here the authors profile 22 deceased severe COVID-19 patients with transcriptomic and histological approaches to find correlations between the presence of viral antigens with lymphocyte suppression yet myeloid activation, hinting distinct functions of these cells during pathogenesis.
- Haibo Wu
- , Peiqi He
- & Cheng Sun
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Article
| Open Access
Mini-batch optimization enables training of ODE models on large-scale datasets
Ordinary differential equation (ODE) models are widely used to understand multiple processes. Here the authors show how the concept of mini-batch optimization can be transferred from the field of Deep Learning to ODE modelling.
- Paul Stapor
- , Leonard Schmiester
- & Jan Hasenauer
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Article
| Open Access
Metabolic drug survey highlights cancer cell dependencies and vulnerabilities
Metabolic reprogramming contributes to cancer development and progression. Here, the authors show the utility of a metabolic drug library to uncover metabolic vulnerabilities and obtain functional insights into myeloid leukemia biology.
- Tea Pemovska
- , Johannes W. Bigenzahn
- & Giulio Superti-Furga
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Article
| Open Access
Optogenetic relaxation of actomyosin contractility uncovers mechanistic roles of cortical tension during cytokinesis
The subcellular dynamics of actomyosin contractility is currently hard to study. Here the authors report OptoMYPT, an optogenetic method to induce relaxation of actomyosin contractility by allowing light-dependent recruitment of endogenous protein phosphatase 1c (PP1c) to the plasma membrane.
- Kei Yamamoto
- , Haruko Miura
- & Kazuhiro Aoki
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Article
| Open Access
Fish predators control outbreaks of Crown-of-Thorns Starfish
Outbreaks of Crown-of-Thorn Starfish (CoTS) have caused coral cover declines across the Indo-Pacific. Here the authors analyse long-term CoTS, coral reef fish monitoring, and fisheries catch data from the Great Barrier Reef to demonstrate removal of predatory fish as a contributor to CoTS outbreaks.
- Frederieke J. Kroon
- , Diego R. Barneche
- & Michael J. Emslie
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Article
| Open Access
Single-cell analysis identifies a key role for Hhip in murine coronal suture development
Craniofacial development depends on formation and maintenance of sutures between bones of the skull. Here the authors identify enriched expression of the hedgehog inhibitor Hhip, specifically in the mesenchyme of the murine coronal suture, and show sutural dysgenesis in Hhip−/− mutants.
- Greg Holmes
- , Ana S. Gonzalez-Reiche
- & Ethylin Wang Jabs
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Article
| Open Access
High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content
Exercise training can be therapeutic but how mitochondria respond remains unclear. Here, the authors use multiple omics techniques to reveal a complex network of non-stoichiometric mitochondrial adaptations that are prioritized or deprioritised during different phases of exercise training.
- Cesare Granata
- , Nikeisha J. Caruana
- & David J. Bishop
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Article
| Open Access
Independent control of mean and noise by convolution of gene expression distributions
Gene expression noise can reduce fitness but analysis is hampered by a scaling relationship between noise and expression level. Here the authors show that gene expression mean and noise can be independently controlled by expressing two copies of a gene from separate inducible promoters in the same cell.
- Karl P. Gerhardt
- , Satyajit D. Rao
- & Jeffrey J. Tabor
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Article
| Open Access
Versatile selective evolutionary pressure using synthetic defect in universal metabolism
Rational design of enzymes with new or improved properties is rarely straightforward, and artificial selection pressure approaches that link an improvement in the target to cell growth are an alternative. Here, the authors show that diverse enzymes sharing the ubiquitous cofactor NAD(P)+ can substitute for defective NAD+ regeneration, representing a very broadly-applicable artificial selection.
- Lara Sellés Vidal
- , James W. Murray
- & John T. Heap
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Article
| Open Access
Programmable microbial ink for 3D printing of living materials produced from genetically engineered protein nanofibers
Living cells can precisely assemble to build 3D functional architectures. Here the authors produce an extrudable microbial ink entirely from the engineered cells, which can be further programmed to 3D print functional living materials.
- Anna M. Duraj-Thatte
- , Avinash Manjula-Basavanna
- & Neel S. Joshi
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Article
| Open Access
Design of modular autoproteolytic gene switches responsive to anti-coronavirus drug candidates
SARS-CoV-2 proteases are key targets for anti-viral drug development. Here the authors present modular tunable autoproteolytic gene switches for virus free cell culture screening of inhibitors.
- Nik Franko
- , Ana Palma Teixeira
- & Martin Fussenegger
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Article
| Open Access
Complementary resource preferences spontaneously emerge in diauxic microbial communities
Many microbes grow diauxically, utilizing resources one at a time rather than simultaneously. This study developed a minimal model of diauxic microbial communities assembling in a serially diluted culture, providing testable predictions for the assembly of natural as well as synthetic communities of diauxically shifting microorganisms.
- Zihan Wang
- , Akshit Goyal
- & Sergei Maslov
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Article
| Open Access
Optogenetic control of receptors reveals distinct roles for actin- and Cdc42-dependent negative signals in chemotactic signal processing
Here the authors use optogenetic tools to directly measure spatial signal processing in leukocyte chemotaxis. Their results reveal the importance of multiple negative feedback loops for maintaining spatial information in chemotaxis.
- George R. R. Bell
- , Esther Rincón
- & Sean R. Collins
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Article
| Open Access
Introns control stochastic allele expression bias
Stochastic autosomal allele expression bias has been widely documented, yet the mechanisms behind this consequential phenomenon remain poorly understood. Here the authors show that the presence of introns greatly restricts monoallelic expression in a C. elegans model.
- Bryan Sands
- , Soo Yun
- & Alexander R. Mendenhall
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Article
| Open Access
Discovery of putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in acute myeloid leukemia cells
CRISPR-based knockout screens in cancer cells have suggested the existence of proliferation suppressor genes (PSG). Here, the authors develop an approach to systematically identify them, and reveal a PSG module involved in fatty acid synthesis and tumour suppression in acute myeloid leukemia cell lines.
- W. Frank Lenoir
- , Micaela Morgado
- & Traver Hart
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Article
| Open Access
Network analysis reveals rare disease signatures across multiple levels of biological organization
Despite the clear causal relationship between genotype and phenotype in rare diseases, identifying the pathobiological mechanisms at various levels of biological organization remains a practical and conceptual challenge. Here, the authors introduce a network approach for evaluating the impact of rare gene defects across biological scales.
- Pisanu Buphamalai
- , Tomislav Kokotovic
- & Jörg Menche
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Article
| Open Access
Physics-informed deep learning characterizes morphodynamics of Asian soybean rust disease
Deep learning (DL) can be used to automatically extract complex features from dynamic systems. Here, the authors combine high-content imaging, DL and mechanistic models to extract and explain drug-induced morphological changes in the growth of the fungus responsible for Asian soybean rust.
- Henry Cavanagh
- , Andreas Mosbach
- & Robert G. Endres
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Article
| Open Access
Single-cell normalization and association testing unifying CRISPR screen and gene co-expression analyses with Normalisr
Normalisr removes technical bias in single-cell RNA-seq and detects gene differential and coexpression accurately and efficiently. It also infers gene regulatory and co-expression networks from conventional and CRISPR screen single-cell RNA-seq datasets.
- Lingfei Wang
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Article
| Open Access
CLAVATA3 mediated simultaneous control of transcriptional and post-translational processes provides robustness to the WUSCHEL gradient
WUSCHEL is a critical regulator of stem cell homeostasis at shoot apical meristems. Here the authors show that CLV3 regulates WUSCHEL by not only repressing WUSCHEL transcription but also by controlling nuclear export of WUSCHEL and therefore its diffusion between adjacent cells.
- Alexander Plong
- , Kevin Rodriguez
- & G. Venugopala Reddy
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Article
| Open Access
The composition of human vaginal microbiota transferred at birth affects offspring health in a mouse model
Exposure at birth to maternal microbiota has significant effects on offspring health and development. Here, the authors validate a model where inoculation of mice at birth with human vaginal microbiota produces significant effects on offspring health that are further amplified by an unhealthy prenatal environment.
- Eldin Jašarević
- , Elizabeth M. Hill
- & Tracy L. Bale
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Article
| Open Access
Selection on adaptive and maladaptive gene expression plasticity during thermal adaptation to urban heat islands
Anthropogenic change, such as urban heat islands, present challenges to biodiversity that can be overcome through phenotypic plasticity. Unlike their ancestral counterparts, urban lizards have fewer maladaptive gene expression responses to higher temperatures in a common garden experiment, suggesting the evolution of adaptive plasticity.
- Shane C. Campbell-Staton
- , Jonathan P. Velotta
- & Kristin M. Winchell
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Article
| Open Access
Engineering digitizer circuits for chemical and genetic screens in human cells
Cell-based transcriptional reporters are an invaluable part of highthroughput screening, but many such reporters have weak or transient responses. Here, the authors describe a digitizer circuit for amplifying reporter activity, increasing sensitivity, and retaining memory of pathway activation.
- Nicole M. Wong
- , Elizabeth Frias
- & Wilson W. Wong
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Article
| Open Access
High-coverage metabolomics uncovers microbiota-driven biochemical landscape of interorgan transport and gut-brain communication in mice
The gut microbiota harbours neuroactive potential with links to neurological disorders. Here, the authors apply global metabolomics with an integrated annotation strategy to comparatively profile fecal, blood serum and cerebral cortical brain tissues of eight-week-old germ-free mice vs. age-matched specific-pathogen-free mice, providing a snapshot of the metabolome status linked to the gut-brain axis.
- Yunjia Lai
- , Chih-Wei Liu
- & Kun Lu
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Article
| Open Access
Rapid incidence estimation from SARS-CoV-2 genomes reveals decreased case detection in Europe during summer 2020
The true number of infections from SARS-Cov-2 is unknown and believed to exceed the reported numbers by several fold. National testing policies, in particular, can strongly affect the proportion of undetected cases. Here, the authors propose a method that reconstructs incidence profiles within minutes, solely from publicly available, time-stamped viral genomes.
- Maureen Rebecca Smith
- , Maria Trofimova
- & Max von Kleist
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Article
| Open Access
OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity
OTULIN is a deubiquitinase for linear ubiquitin chains. Here the authors show, using genetic mouse models and single-cell RNA-sequencing, that deficiency of OTULIN in keratinocytes causes skin inflammation and verrucous carcinoma via the induction of keratinocyte death, thereby implicating a function of OTULIN in keratinocyte homeostasis.
- Esther Hoste
- , Kim Lecomte
- & Geert van Loo
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Article
| Open Access
ClusterMap for multi-scale clustering analysis of spatial gene expression
In situ transcriptomics maps RNA expression patterns across intact tissues taking our understanding of gene expression to a new level. Here, the authors present a computational method that uncovers gene expression, cell niche, and tissue region patterns from 2D and 3D spatial transcriptomics.
- Yichun He
- , Xin Tang
- & Xiao Wang
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Perspective
| Open Access
A proteomics sample metadata representation for multiomics integration and big data analysis
The number of publicly available proteomics datasets is growing rapidly, but a standardized approach for describing the associated metadata is lacking. Here, the authors propose a format and a software pipeline to present and validate metadata, and integrate them into ProteomeXchange repositories.
- Chengxin Dai
- , Anja Füllgrabe
- & Yasset Perez-Riverol
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Article
| Open Access
Integrated omics networks reveal the temporal signaling events of brassinosteroid response in Arabidopsis
Brassinosteroids (BR) regulate plant development and stress responses. Here, by integrating multiple omics datasets and inferring networks, the authors profile BR signaling in Arabidopsis and characterize BRONTOSAURUS, a BR-regulated transcription factor that impacts cell division in roots.
- Natalie M. Clark
- , Trevor M. Nolan
- & Justin W. Walley
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Article
| Open Access
A light tunable differentiation system for the creation and control of consortia in yeast
Artificial microbial consortia use division-of-labour to optimize production. Here the authors develop an optogenetic differentiation system in yeast to generate consortia from a single strain with tunable composition.
- Chetan Aditya
- , François Bertaux
- & Jakob Ruess
Machine learning discovery of missing links that mediate alternative branches to plant alkaloidsBrowse broader subjects
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