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| Open AccessPositive feedback induces switch between distributive and processive phosphorylation of Hog1
How cells shape signalling dynamics in MAPK cascades remains unclear. Here the authors combine mathematical modelling with in vivo validation to uncover a novel feedback mechanism that increases processivity and robustness of the yeast Hog1 module.
- Maximilian Mosbacher
- , Sung Sik Lee
- & Manfred Claassen
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Article
| Open AccessRobustness and innovation in synthetic genotype networks
Genotype networks are sets of genotypes connected by small mutational changes that share the same phenotype. Here the authors combine construction of over 20 synthetic gene regulatory networks with mathematical modeling to exemplify how gene regulatory networks provide robustness in face of mutations while enabling transitions to innovative phenotypes.
- Javier Santos-Moreno
- , Eve Tasiudi
- & Yolanda Schaerli
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Article
| Open AccessAutomated design of protein-binding riboswitches for sensing human biomarkers in a cell-free expression system
Cell-free genetically encoded biosensors have been developed to detect small molecules and nucleic acids, but they have yet to be reliably engineered to detect proteins. Here the authors develop an automated platform to convert protein-binding RNA aptamers into riboswitch sensors that operate within low-cost cell-free assays.
- Grace E. Vezeau
- , Lipika R. Gadila
- & Howard M. Salis
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Article
| Open AccessAddressable and adaptable intercellular communication via DNA messaging
Enabling high-bandwidth communication between cells is a prerequisite for engineering multicellular consortia that can perform sophisticated computations and functions. Here, the authors design a framework for addressable and adaptable DNA-based communication and implement it using plasmid conjugation in a E. coli population.
- John P. Marken
- & Richard M. Murray
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Article
| Open AccessTradeoff between lag time and growth rate drives the plasmid acquisition cost
Plasmid acquisition imposes a transient burden on bacterial hosts. Here, authors show this burden results in a tradeoff between growth and lag that dictates plasmid fate, favoring intermediate cost plasmids over both low and high cost counterparts.
- Mehrose Ahmad
- , Hannah Prensky
- & Allison J. Lopatkin
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Article
| Open AccessIn silico cancer immunotherapy trials uncover the consequences of therapy-specific response patterns for clinical trial design and outcome
Conventional clinical trial design methods are not necessarily tailored for the unique characteristics of immunotherapies. Here the authors use late-stage in silico cancer immunotherapy trials to investigate how design decisions affect the trial outcome.
- Jeroen H. A. Creemers
- , Ankur Ankan
- & Johannes Textor
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Article
| Open AccessUniversal structures for adaptation in biochemical reaction networks
At the molecular level, the evolution of life is driven by the generation and diversification of adaptation mechanisms. Here Araujo and Liotta identify definitive and universal structural requirements for adaptation via intermolecular interactions.
- Robyn P. Araujo
- & Lance A. Liotta
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Article
| Open AccessDamage dynamics and the role of chance in the timing of E. coli cell death
To understand why genetically identical cells die at different times the authors measured damage dynamics in individual cells. They report lifespan variation comes not from initial conditions but from stochastic accumulation of damage that saturates repair systems.
- Yifan Yang
- , Omer Karin
- & Uri Alon
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Article
| Open AccessDynamic fluctuations in a bacterial metabolic network
The interconnected network of cellular metabolism is potentially prone to generating oscillatory behaviour. Here, the authors use single-cell FRET measurements of pyruvate levels to reveal large periodic fluctuations in bacterial glycolysis.
- Shuangyu Bi
- , Manika Kargeti
- & Victor Sourjik
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Article
| Open AccessNucleocytoplasmic transport of active HER2 causes fractional escape from the DCIS-like state
HER2 receptor aberrations are more common in breast DCIS premalignancy than in breast cancer. Here the authors identify a feedback circuit involving HER2 nucleocytoplasmic transport that may explain why some DCIS lesions progress and others do not.
- Lixin Wang
- , B. Bishal Paudel
- & Kevin A. Janes
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Perspective
| Open AccessA roadmap to establish a comprehensive platform for sustainable manufacturing of natural products in yeast
Yeasts, Saccharomyces cerevisiae and Pichia pastoris, are promising chassis for the production of nature products (NPs). Here, the author discusses establishing a comprehensive platform for sustainable production of NPs via system-associated optimization at genetics, temporal controllers, productivity screening, and scalability levels.
- Gita Naseri
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Article
| Open AccessTryptase β regulation of joint lubrication and inflammation via proteoglycan-4 in osteoarthritis
Altered expression and function of the extracellular matrix protein PRG4 have been associated with osteoarthritis. Here, the authors show that mast cell tryptase β cleaves PRG4, resulting in a reduction of lubrication and activation of inflammation in this context.
- Nabangshu Das
- , Luiz G. N. de Almeida
- & Antoine Dufour
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Article
| Open AccessAn integrase toolbox to record gene-expression during plant development
Synthetic circuits that can record in vivo signaling networks is critical in elucidating developmental process. Here, the authors describe the engineering and application of synthetic in vivo recorders with different promoters that can drive spatiotemporally-specific integrase switching during lateral root initiation.
- Sarah Guiziou
- , Cassandra J. Maranas
- & Jennifer L. Nemhauser
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Article
| Open AccessA comprehensive platform for analyzing longitudinal multi-omics data
The analysis of longitudinal bulk and single-cell multi-omics data is a highly complex task. Here, the authors introduce PALMO, a software platform with five modules to analyse longitudinal bulk and single-cell multi-omics data, which is extensively tested in external datasets that include multiple omics modalities.
- Suhas V. Vasaikar
- , Adam K. Savage
- & Xiao-jun Li
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Perspective
| Open AccessAn aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
In this perspective, the authors hypothesise that glial senescence, requiring senescent microglia burden, perpetuates further aging, Alzheimer’s pathologies, and senescence. Increasing glial senescence is proposed as necessary to drive individuals from healthy cognition into cognitive decline and dementia.
- Victor Lau
- , Leanne Ramer
- & Marie-Ève Tremblay
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Article
| Open AccessLacking mechanistic disease definitions and corresponding association data hamper progress in network medicine and beyond
Large-scale disease-association data are widely used for pathomechanism mining, even if disease definitions used for annotation are mostly phenotype-based. Here, the authors show that this bias can lead to a blurred view on disease mechanisms, highlighting the need for close-up studies based on molecular data for well-characterized patient cohorts.
- Sepideh Sadegh
- , James Skelton
- & David B. Blumenthal
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Article
| Open AccessAssessment of community efforts to advance network-based prediction of protein–protein interactions
Comprehensive understanding of the human protein-protein interaction network, aka the human interactome, can provide important insights into the molecular mechanisms of complex biological processes and diseases. Here the authors summarize the community efforts initiated by the International Network Medicine Consortium to benchmark the ability of 26 representative network-based methods to predict protein-protein interactions.
- Xu-Wen Wang
- , Lorenzo Madeddu
- & Yang-Yu Liu
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Article
| Open AccessPrecise programming of multigene expression stoichiometry in mammalian cells by a modular and programmable transcriptional system
Context-dependency of mammalian transcriptional elements has hindered the quantitative investigation of multigene expression stoichiometry and its biological functions. Here the authors present a host-orthogonal transcriptional system that drives tunable gene expression in mammalian cells, enabling predictive fine-tuning of multi-gene expression stoichiometry and the production optimization of virus-like particles from mammalian cells.
- Chenrui Qin
- , Yanhui Xiang
- & Chunbo Lou
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Article
| Open AccessA cybergenetic framework for engineering intein-mediated integral feedback control systems
Homeostasis and robust perfect adaptation are remarkable features of living cells. Here, to synthetically achieve this, the authors present a theoretical and experimental framework using inteins to implement compact biomolecular integral feedback controllers.
- Stanislav Anastassov
- , Maurice Filo
- & Mustafa Khammash
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Article
| Open AccessSize limits the sensitivity of kinetic schemes
Living things rely on extremely sensitive molecular circuits. Here, authors uncover a universal structural limit on kinetic scheme sensitivity, with implications for gene regulation & the functions of condensates.
- Jeremy A. Owen
- & Jordan M. Horowitz
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Article
| Open AccessPeriodic temperature changes drive the proliferation of self-replicating RNAs in vesicle populations
How primordial cells could achieve inheritance of encapsulated components is still an open question. Here, the authors show that ribozymes can assemble in active forms and replicate in populations of membrane vesicles thanks to freeze-thaw cycles.
- Elia Salibi
- , Benedikt Peter
- & Hannes Mutschler
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Article
| Open AccessAn optogenetic toolkit for light-inducible antibiotic resistance
Antibiotics are a key control mechanism for synthetic biology and microbiology. Here, using an optogenetic recombinase, the authors develop genetic constructs where antibiotic resistance levels in bacteria can be controlled using light.
- Michael B. Sheets
- , Nathan Tague
- & Mary J. Dunlop
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Article
| Open AccessFour-dimensional trapped ion mobility spectrometry lipidomics for high throughput clinical profiling of human blood samples
The circulatory lipidome is a valuable source for disease markers, but reliable marker discovery requires continuous development of lipidomic methods for large-scale clinical profiling. Here, the authors present a 4-dimensional lipidomics solution for confident and reproducible blood lipidome profiling.
- Raissa Lerner
- , Dhanwin Baker
- & Laura Bindila
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Article
| Open AccessParallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT
Epithelial-to-mesenchymal transition (EMT) is a complex process regulated at multiple molecular levels. Here, the authors implement an analytic framework - PAMAF - to integrate data from twelve distinct omics modalities, which they use to understand the molecular changes and regulation during EMT in vitro.
- Indranil Paul
- , Dante Bolzan
- & Andrew Emili
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Article
| Open AccessDNA-Aeon provides flexible arithmetic coding for constraint adherence and error correction in DNA storage
The extensive information capacity of DNA makes it an attractive alternative to traditional data storage. DNA-Aeon is a DNA data storage solution that can correct all error types commonly observed in DNA storage, while encoding data into sequences that meet user-defined constraints such as GC content, homopolymer length, and no undesired motifs.
- Marius Welzel
- , Peter Michael Schwarz
- & Dominik Heider
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Article
| Open AccessA split ribozyme that links detection of a native RNA to orthogonal protein outputs
RNA provides a unique readout of a cell’s identity, physiologic status, and phenotype. Here the authors deliver an RNA sensing system that can use the information contained within cellular RNA to selectively control the activity of genetic programs.
- Lauren Gambill
- , August Staubus
- & James Chappell
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Article
| Open AccessMapping lesion-specific response and progression dynamics and inter-organ variability in metastatic colorectal cancer
Understanding the heterogeneity of growth, response to therapy and progression dynamics in metastatic colorectal cancer (mCRC) remains critical. Here, the authors analyse lesion-specific response heterogeneity in 4,308 mCRC patients and find that organ-level progression sequence is associated with long-term survival.
- Jiawei Zhou
- , Amber Cipriani
- & Yanguang Cao
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Article
| Open AccessJag1-Notch cis-interaction determines cell fate segregation in pancreatic development
Notch signaling is crucial for pancreatic cell fate choice. With mathematical modeling and experiments, Xu et al. provides new insights into how different Notch ligands and Hes1 oscillation guide the spatial-temporal dynamics of cell differentiation.
- Xiaochan Xu
- , Philip Allan Seymour
- & Palle Serup
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Article
| Open AccessFinding shortest and nearly shortest path nodes in large substantially incomplete networks by hyperbolic mapping
Shortest paths between the nodes of complex networks are challenging to obtain if the information on network structure is incomplete. Here the authors show that the shortest paths are geometrically localized in hyperbolic representations of networks, and can be detected even if the large amount of network links are missing. The authors demonstrate the utility of geometric pathfinding in Internet routing and the reconstruction of cellular pathways.
- Maksim Kitsak
- , Alexander Ganin
- & Igor Linkov
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Article
| Open AccessEvidence that endosperm turgor pressure both promotes and restricts seed growth and size
Using computational simulations and experiments, the authors propose a mechanical model of seed growth where endosperm pressure directly induces growth but indirectly inhibits it through force-dependent testa wall stiffening.
- Audrey Creff
- , Olivier Ali
- & Benoit Landrein
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Article
| Open AccessBenchmarking tools for detecting longitudinal differential expression in proteomics data allows establishing a robust reproducibility optimization regression approach
Longitudinal proteomics holds great promise for biomarker discovery, but the data interpretation has remained a challenge. Here, the authors evaluate several tools to detect longitudinal differential expression in proteomics data and introduce RolDE, a robust reproducibility optimization approach.
- Tommi Välikangas
- , Tomi Suomi
- & Laura L. Elo
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Article
| Open AccessAccuracy and data efficiency in deep learning models of protein expression
Synthetic biology often involves engineering microbial strains to express high-value proteins. Here the authors build deep learning predictors of protein expression from sequence that deliver accurate models with fewer data than previously assumed, helping to lower costs of model-driven strain design.
- Evangelos-Marios Nikolados
- , Arin Wongprommoon
- & Diego A. Oyarzún
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Article
| Open AccessBiosynthesis of mushroom-derived type II ganoderic acids by engineered yeast
The biosynthetic pathway of type II ganoderic acids (GAs) in Ganoderma lucidum, a traditional medicinal mushroom, is unknown. Here, the authors assemble the genome of type II GAs accumulating accession, identify CYPs involving in type II GAs biosynthesis, and achieve their production in engineered baker’s yeast.
- Wei Yuan
- , Chenjian Jiang
- & Han Xiao
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Article
| Open AccessMolecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms
Multiple sclerosis (MS) changes the composition of the CSF. Here the authors use patient samples and aggregate CSF biomarkers into models that predict disability across all MS phenotypes, and identify potentially causal mechanisms and molecular disease heterogeneity.
- Peter Kosa
- , Christopher Barbour
- & Bibiana Bielekova
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Article
| Open AccessInterpretable and tractable models of transcriptional noise for the rational design of single-molecule quantification experiments
Here the authors explore the distributional differences expected from distinct biophysical models of transcription and show how measurements from single-cell genomics experiments can shed light on the underlying biological processes.
- Gennady Gorin
- , John J. Vastola
- & Lior Pachter
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Article
| Open AccessSlowest possible replicative life at frigid temperatures for yeast
It is unclear what constraints exist on cellular life in frigid environments. Here, the authors demonstrate that reactive oxygen species and gene-expression speed impose a barrier to replication at low temperatures in yeast, with lower levels enabling quicker replication, and develop a model to describe this phenomenon.
- Diederik S. Laman Trip
- , Théo Maire
- & Hyun Youk
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Article
| Open AccessIncreases in reef size, habitat and metacommunity complexity associated with Cambrian radiation oxygenation pulses
During the Cambrian Radiation, oxygenation occurred in a series of short pulses. Here, the authors quantify episodic changes in reef size, extent of habitat and in metacommunity ecological complexity associated with these oxygenation pulses by examining archaeocyath sponges.
- Andrey Yu. Zhuravlev
- , Emily G. Mitchell
- & Amelia Penny
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Article
| Open AccessIntegrated proteomic and transcriptomic landscape of macrophages in mouse tissues
Macrophage is located in different tissue to serve diverse functions. Here the authors use mass spectrometry and bulk RNA-sequencing to profile 11 mouse macrophage populations from 8 tissues, and combine their de novo data with public datasets to report an integrated proteomic and transcriptomic landscape of mouse macrophage as a valuable resource.
- Jingbo Qie
- , Yang Liu
- & Chen Ding
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Article
| Open AccessGenetically personalised organ-specific metabolic models in health and disease
Here, the authors present a method to build genetically personalised metabolic models across tissues to estimate individualised reaction fluxes. A fluxome-wide association study in UK Biobank identifies fluxes associated with metabolites and coronary artery disease.
- Carles Foguet
- , Yu Xu
- & Michael Inouye
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Article
| Open AccessEngineering receptors in the secretory pathway for orthogonal signalling control
Artificial receptors targeted to the secretory pathway often fail to exhibit the expected activity due to post-translational modifications and/or improper folding. Here, the authors engineer diverse synthetic receptors that reside in the cytoplasm, inside the endoplasmic reticulum, or on the plasma membrane through orientation adjustment of the receptor parts and by elimination of dysfunctional PTMs sites.
- Mohamed Mahameed
- , Pengli Wang
- & Martin Fussenegger
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Article
| Open AccessEnhanced access to the human phosphoproteome with genetically encoded phosphothreonine
Protein phosphorylation is a ubiquitous post-translational modification used to regulate cellular processes and proteome architecture by modulating protein-protein interactions. Here the authors optimize genetically encoded phosphothreonine to study the regulation of CHK2 kinase using large-scale DNA arrays that enable phosphoproteome expression techniques to identify sitespecific overlap between CHK2 substrates and 14-3-3 interactions.
- Jack M. Moen
- , Kyle Mohler
- & Jesse Rinehart
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Article
| Open AccessKinetics of mRNA nuclear export regulate innate immune response gene expression
The UCLA Ribonomics group reports that the nuclear export efficiency of innate immune mRNAs varies over a hundred-fold range such that for many genes only a small fraction of the newly synthesized premRNA reaches the cytoplasm. They show that nuclear export and cytoplasmic decay rates are correlated thereby ensuring similar expression levels of short-lived and long-lived mRNAs.
- Diane Lefaudeux
- , Supriya Sen
- & Sri Kosuri
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Article
| Open AccessMulti-omics signatures of the human early life exposome
Environmental exposures in early life can have lasting health effects, but the molecular mechanisms are not well understood. Here, the authors discover >1000 associations between exposure factors and child multi-omics profiles, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions.
- Léa Maitre
- , Mariona Bustamante
- & Martine Vrijheid
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Article
| Open AccessAn atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation
By comprehensively mapping the impact that different classes of mutations (substitutions, insertions, deletions) have on the ability of the amyloid beta peptide to nucleate amyloids, the authors identify a large set of likely pathogenic variants of amyloid beta that are specifically enriched at its polar N-terminal region.
- Mireia Seuma
- , Ben Lehner
- & Benedetta Bolognesi
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Article
| Open AccessFeedforward growth rate control mitigates gene activation burden
Heterologous gene activation causes non-physiological burden on cellular resources that cells are unable to adjust to. Here the authors present a tunable, modular, and portable feedforward controller that allows dynamic modulation of a genes expression to possibly high-levels without substantially affecting growth rate.
- Carlos Barajas
- , Hsin-Ho Huang
- & Domitilla Del Vecchio
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Article
| Open AccessA Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice
Monitoring the aging process in vivo is challenging. Here the authors generate a Glb1+/m‒Glb1-2A-mCherry (GAC) reporter mouse model, where the GAC signal is consistently correlated with established biomarkers of cellular senescence, cardiac hypertrophy and shortened lifespan, which may prove helpful for studies developing anti-aging interventions.
- Jie Sun
- , Ming Wang
- & Baohua Liu
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Article
| Open AccessTwo simple movement mechanisms for spatial division of labour in social insects
Ant and honeybee workers specialize on certain tasks and also on zones within the nest; but how do they avoid straying into the wrong zone? The authors conduct automated tracking experiments following thousands of individuals, revealing that workers use context-dependent rules to navigate inside the nest.
- Thomas O. Richardson
- , Nathalie Stroeymeyt
- & Laurent Keller
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Article
| Open AccessTransposable elements orchestrate subgenome-convergent and -divergent transcription in common wheat
How subgenome-divergent and -convergent transcription is mediated and harmonized in hexaploid common wheat genome remains unclear. Here, via characterizing the cistrome maps, the authors reveal that transposon elements with transcription factor binding ability have the potential to make the contribution.
- Yuyun Zhang
- , Zijuan Li
- & Yijing Zhang
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Article
| Open AccessIntrinsic brain dynamics in the Default Mode Network predict involuntary fluctuations of visual awareness
The default mode network (DMN) is known to be involved in consciousness. Here the authors show intrinsic EEG oscillations in default mode network can predict upcoming involuntarily perceptual transitions.
- Dian Lyu
- , Shruti Naik
- & Emmanuel A. Stamatakis
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