Featured
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Article
| Open AccessCD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells
Regulatory T (Treg) cells are important modulators of the tumor microenvironment. Here the authors perform transcriptome profiling of immune cells from patients with renal clear cell carcinoma to find a Treg signature that correlates with poorer prognosis, with CD177 being implicated as the main mediator for related alterations in Treg activity and tumor outcome.
- Myung-Chul Kim
- , Nicholas Borcherding
- & Weizhou Zhang
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Article
| Open AccessDesign principles of collateral sensitivity-based dosing strategies
Collateral sensitivity-based antibiotic treatments may have the potential to limit the emergence of antimicrobial resistance. Here, the authors use mathematical modelling to study the effects of pathogen- and drug-specific characteristics for different treatment designs on bacterial population dynamics and resistance evolution.
- Linda B. S. Aulin
- , Apostolos Liakopoulos
- & J. G. Coen van Hasselt
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Article
| Open AccessVEGA is an interpretable generative model for inferring biological network activity in single-cell transcriptomics
Developing interpretable models is a major challenge in single cell deep learning. Here we show that the VEGA variational autoencoder model, whose decoder wiring mirrors gene modules, can provide direct interpretability to the latent space further enabling the inference of biological module activity.
- Lucas Seninge
- , Ioannis Anastopoulos
- & Joshua Stuart
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Article
| Open AccessRapid prototyping and design of cybergenetic single-cell controllers
Practical implementation of genetic circuits is difficult due to low predictability and time-intensive troubleshooting. Here the authors present Cyberloop, which interfaces a computer with single cells to enable cell-in-the-loop testing and optimization of circuit designs before they are built.
- Sant Kumar
- , Marc Rullan
- & Mustafa Khammash
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Article
| Open AccessDissecting transition cells from single-cell transcriptome data through multiscale stochastic dynamics
How to infer transient cells and cell-fate transitions from snap-shot single cell transcriptome dataset remains a major challenge. Here the authors present a multiscale approach to construct single-cell dynamical manifold, quantify cell stability, and compute transition trajectory and probability between cell states.
- Peijie Zhou
- , Shuxiong Wang
- & Qing Nie
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Article
| Open AccessPromoter-proximal elongation regulates transcription in archaea
Transcription in archaea is known to be regulated through the recruitment of RNA polymerase to promoters. Here, the authors show that the archaeon Saccharolobus solfataricus regulates transcription globally through a rate-limiting promoter-proximal elongation step.
- Fabian Blombach
- , Thomas Fouqueau
- & Finn Werner
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Article
| Open AccessChromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma
Despite extensive genetic heterogeneity, nearly half of all multiple myeloma (MM) cases are driven by cyclin D2 (CCND2) over-expression. Here the authors dissect the chromatin landscape of MM to provide insights into the transcriptional regulatory landscape driving MM and divergent transcriptomes corresponding to different MM genetic subtypes.
- Jaime Alvarez-Benayas
- , Nikolaos Trasanidis
- & Anastasios Karadimitris
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Article
| Open AccessTime-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale
Combining improved sample preparation, data-independent acquisition mass spectrometry and deep learning, the authors develop a workflow for more robust and precise quantitative ubiquitinome profiling. They use this method to characterize targets of the deubiquitinase USP7 and effects of USP7 inhibitors.
- Martin Steger
- , Vadim Demichev
- & Henrik Daub
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Article
| Open AccessUnified AI framework to uncover deep interrelationships between gene expression and Alzheimer’s disease neuropathologies
The molecular basis of Alzheimer’s Disease has been obscured by heterogeneity and scarcity of brain gene expression data, which limit effectiveness in complex models. Here, the authors introduce a multi-task deep learning framework to learn generalizable and nuanced relationships between gene expression and neuropathology.
- Nicasia Beebe-Wang
- , Safiye Celik
- & Su-In Lee
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Article
| Open AccessSpatial localisation meets biomolecular networks
Complex biomolecular networks are fundamental to the functioning of living systems, both at the cellular level and beyond. In this paper, the authors develop a systems framework to elucidate the interplay of networks and the spatial localisation of network components.
- Govind Menon
- & J. Krishnan
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Comment
| Open AccessGrowth-coupled selection of synthetic modules to accelerate cell factory development
Synthetic biology has brought about a conceptual shift in our ability to redesign microbial metabolic networks. Combining metabolic pathway-modularization with growth-coupled selection schemes is a powerful tool that enables deep rewiring of the cell factories’ biochemistry for rational bioproduction.
- Enrico Orsi
- , Nico J. Claassens
- & Steffen N. Lindner
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Article
| Open AccessQuantitative modelling of amino acid transport and homeostasis in mammalian cells
Cytosolic amino acid concentrations are carefully maintained, but how homeostasis occurs is unclear. Here, the authors show that amino acid transporters primarily determine intracellular amino acid levels and develop a model that predicts a perturbation response similar to experimental data.
- Gregory Gauthier-Coles
- , Jade Vennitti
- & Stefan Bröer
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Article
| Open AccessThe basis of easy controllability in Boolean networks
Boolean networks allow a simplified representation of interactions. Here, the authors systematically analyze regulation in dozens of biological Boolean networks, finding mathematical regularities that suggest biological systems could be controlled through a relatively small number of components.
- Enrico Borriello
- & Bryan C. Daniels
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Article
| Open AccessProgrammable receptors enable bacterial biosensors to detect pathological biomarkers in clinical samples
Bacterial biosensors have promising applications in medical and environmental diagnostics. Here the authors use EMeRALD synthetic receptors to design bile salt sensors for use in liver transplant patient serum.
- Hung-Ju Chang
- , Ana Zúñiga
- & Jerome Bonnet
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Article
| Open AccessBacterial cellulose spheroids as building blocks for 3D and patterned living materials and for regeneration
Bacterial cellulose is a promising cheap-to-produce programmable engineered living material. Here the authors present a method for production of spheroids for use as engineerable building blocks able to sense and respond to chemical inputs.
- Joaquin Caro-Astorga
- , Kenneth T. Walker
- & Tom Ellis
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Article
| Open AccessLive cell tagging tracking and isolation for spatial transcriptomics using photoactivatable cell dyes
Spatial transcriptomics aims to pair omic data with tissue structure. Here the authors report Spatially PhotoActivatable Colour Encoded Cell Address Tags (SPACECAT) to track and isolate live cells by location; this enables spatially informed downstream assays like scRNA-seq and flow cytometry.
- Alex S Genshaft
- , Carly G. K. Ziegler
- & Alex K. Shalek
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Article
| Open AccessGenome-scale target identification in Escherichia coli for high-titer production of free fatty acids
Identification of gene targets is one of the major challenges to construct superior microbial cell factory for chemical synthesis. Here, the authors employ CRISPRi and omics analyses for genome-scale target genes identification for high-titer production of free fatty acids in E. coli.
- Lixia Fang
- , Jie Fan
- & Hao Song
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Article
| Open AccessC. elegans colony formation as a condensation phenomenon
Phase separation phenomena have emerged as being of critical importance in biology. Here, using colony formation in C. elegans as model, the authors demonstrate that the basic concepts that underpin phase separation at a molecular level also apply to collective phenomena at the level of a population of organisms.
- Yuping Chen
- & James E. Ferrell Jr.
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Article
| Open AccessDownregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children
Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.
- Noam D. Beckmann
- , Phillip H. Comella
- & Alexander W. Charney
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Article
| Open AccessA genome-scale metabolic model of Saccharomyces cerevisiae that integrates expression constraints and reaction thermodynamics
Formulating metabolic networks mathematically can help researchers study metabolic diseases and optimize the production of industrially important molecules. Here, the authors propose a framework that allows to model eukaryotic metabolism considering gene expression and thermodynamic constraints.
- Omid Oftadeh
- , Pierre Salvy
- & Vassily Hatzimanikatis
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Article
| Open AccessMolecular-level similarity search brings computing to DNA data storage
Storage technology based on DNA is emerging as an information dense and durable medium. Here the authors use machine learning-based encoding and hybridization probes to execute similarity searches in a DNA database.
- Callista Bee
- , Yuan-Jyue Chen
- & Luis Ceze
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Article
| Open AccessMuSyC is a consensus framework that unifies multi-drug synergy metrics for combinatorial drug discovery
The lack of a unifying metric characterizing combinatorial drug interactions has impeded the development of combinatorial therapies. Here, the authors present MuSyC, a consensus synergy metric that overcomes several caveats associated with other, popular metrics.
- David J. Wooten
- , Christian T. Meyer
- & Carlos F. Lopez
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Article
| Open AccessThe trans-omics landscape of COVID-19
COVID-19 is a critical public health threat, but molecular characterizations of patients’ immunity is still lacking. Here the authors collected blood from patients with various disease severity, and prefiltered to exclude selected comorbidity, to obtain genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles to report a trans-omics landscape.
- Peng Wu
- , Dongsheng Chen
- & Gang Chen
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Article
| Open AccessStochastic pausing at latent HIV-1 promoters generates transcriptional bursting
The ability of HIV to alternate between acute and latent forms is thought to rely on a transcriptional feedback loop where polymerase pausing is released by the viral protein Tat. Here, the authors show that viral genome transcription can occur in a burst-like stochastic manner in the absence of Tat.
- Katjana Tantale
- , Encar Garcia-Oliver
- & Edouard Bertrand
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Article
| Open AccessRational construction of genome-reduced Burkholderiales chassis facilitates efficient heterologous production of natural products from proteobacteria
An efficient chassis for heterologous expression of biosynthetic gene clusters (BGCs) from Gram-negative bacteria is still unavailable. Here, the authors report rational construction of genome-reduced Burkholderials chassis to facilitate production of a class of new compounds by expressing BGC from Chitinimonas koreensis.
- Jiaqi Liu
- , Haibo Zhou
- & Xiaoying Bian
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Article
| Open AccessEngineering self-organized criticality in living cells
Biological systems are known to behave in optimal ways when poised close to critical points, right on the edge between order and disorder. Here the authors show how this state can be engineered in living cells.
- Blai Vidiella
- , Antoni Guillamon
- & Ricard Solé
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Article
| Open AccessDevelopment of a fixed module repertoire for the analysis and interpretation of blood transcriptome data
The blood transcriptome of human subjects can be profiled on an almost routine basis in translational research settings. Here the authors show that a fixed and well-characterized repertoire of transcriptional modules can be employed as a reusable framework for the analysis, visualization and interpretation of such data
- Matthew C. Altman
- , Darawan Rinchai
- & Damien Chaussabel
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Article
| Open AccessA generative network model of neurodevelopmental diversity in structural brain organization
The formation of large-scale brain networks represents crucial developmental processes that can drive individual differences in cognition and which are associated with multiple neurodevelopmental conditions. Here, the authors use generative network modelling to provide a computational framework for understanding neurodevelopmental diversity.
- Danyal Akarca
- , Petra E. Vértes
- & Duncan E. Astle
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Article
| Open AccessHigh-throughput 5′ UTR engineering for enhanced protein production in non-viral gene therapies
The engineering of 5′ UTRs that modulate protein expression remains a great challenge. Here we leverage synthetic biology and computational design to develop a high-throughput strategy to design, screen, and optimize 5′ UTRs that enhance protein expression for non-viral gene therapies.
- Jicong Cao
- , Eva Maria Novoa
- & Timothy K. Lu
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Article
| Open AccessA synthetic circuit for buffering gene dosage variation between individual mammalian cells
Transient plasmid transfection produces a wide distribution of copy numbers and expression heterogeneity. Here the authors present synthetic circuits called Equalizers that buffer copy number variation at the single-cell level and minimize cell-to-cell expression variability.
- Jin Yang
- , Jihwan Lee
- & François St-Pierre
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Article
| Open AccessSynchronization of gene expression across eukaryotic communities through chemical rhythms
Synchronizing gene expression across eukaryotic communities presents complex challenges. Here the authors construct a compact synthetic system inspired by bacteria response to antibiotics that robustly converts chemical rhythms into synchronized gene expression across populations.
- Sara Pérez-García
- , Mario García-Navarrete
- & Krzysztof Wabnik
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Article
| Open AccessResolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1
The response to neoadjuvant immune checkpoint blockade (ICB) in patients with recurrent gliolastoma multiforme (GBM) has been challenging to interpret. Here the authors develop a tumor analysis framework that reveals molecular similarities between GBM and melanoma and unique patterns of immunosuppression in GBM indicating potential co-targets for neoadjuvant ICB.
- Yue Lu
- , Alphonsus H. C. Ng
- & James R. Heath
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Article
| Open AccessProton gradients from light-harvesting E. coli control DNA assemblies for synthetic cells
Controlled actuation is an important aspect of synthetic cellular systems. Here, the authors combine pH responsive DNA origami structures with light triggered proton pump engineered E. coli to trigger a change in pH and control the deformation of giant unilamellar vesicles by simple illumination.
- Kevin Jahnke
- , Noah Ritzmann
- & Kerstin Göpfrich
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Article
| Open AccessIon identity molecular networking for mass spectrometry-based metabolomics in the GNPS environment
Molecular networking connects molecules based on their fragment ion mass spectra (MS2), but may leave adduct species from the same molecular family separate. To address this issue, the authors develop a networking approach that fuses MS1- and MS2-based networks and integrate it into the GNPS environment.
- Robin Schmid
- , Daniel Petras
- & Pieter C. Dorrestein
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Article
| Open AccessA distinct growth physiology enhances bacterial growth under rapid nutrient fluctuations
Here the authors use microfluidics and single-cell microscopy to quantify the growth dynamics of individual E. coli cells exposed to nutrient fluctuations with periods as short as 30 seconds, finding that nutrient fluctuations reduce growth rates up to 50% compared to a steady nutrient delivery of equal average concentration, implying that temporal variability is an important parameter in bacterial growth.
- Jen Nguyen
- , Vicente Fernandez
- & Roman Stocker
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Article
| Open AccessThe geometry of clinical labs and wellness states from deeply phenotyped humans
Longitudinal multi-omics measurements are highly valuable in studying heterogeneity in health and disease phenotypes. Here, the authors apply Pareto Task Inference to analyze the clinical lab tests of 3094 individuals and find three wellness states, and one aberrant health state defining this cohort.
- Anat Zimmer
- , Yael Korem
- & Nathan D. Price
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Article
| Open AccessPromiscuous molecules for smarter file operations in DNA-based data storage
The molecular architecture of DNA data storage opens up interesting possibilities and functionalities. Here the authors leverage thermodynamics to control the access of different subsets of data in a file.
- Kyle J. Tomek
- , Kevin Volkel
- & Albert J. Keung
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Article
| Open AccessTime trajectories in the transcriptomic response to exercise - a meta-analysis
Regular exercise promotes overall health and prevents non-communicable diseases, but the adaptation mechanisms are unclear. Here, the authors perform a meta-analysis to reveal time-specific patterns of the acute and long-term exercise response in human skeletal muscle, and identify sex- and age-specific changes.
- David Amar
- , Malene E. Lindholm
- & Euan A. Ashley
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Article
| Open AccessClinical and molecular characteristics of COVID-19 patients with persistent SARS-CoV-2 infection
Some patients with COVID-19 fail to clear the viral infection quickly, yet our understanding for the underlying immune characteristics is still lacking. Here the authors use single-cell RNA sequencing and other data form such patients to show that persistent infection is associated with immune suppression and reduced expression of ribosomal protein genes.
- Bin Yang
- , Junpeng Fan
- & Chaoyang Sun
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Article
| Open AccessDesigning an irreversible metabolic switch for scalable induction of microbial chemical production
A promising strategy to increase product synthesis from bacteria uses inducible systems to switch metabolism to production. Here, the authors use models to show how engineering positive feedback loops into the genetic circuitry creates a switch that requires only temporary induction with a cheap nutrient to switch metabolism irreversibly, and so drastically reduce inducer use and cost.
- Ahmad A. Mannan
- & Declan G. Bates
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Article
| Open AccessLiving fabrication of functional semi-interpenetrating polymeric materials
Cell based materials production has potential for generating diverse materials with a range of functions. Here, the authors report development of living fabrication of biohybrid semi interpenetrating polymer networks by encapsulating protein producing bacteria within polymer microcapsules.
- Zhuojun Dai
- , Xiaoyu Yang
- & Lingchong You
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Article
| Open AccessMOGONET integrates multi-omics data using graph convolutional networks allowing patient classification and biomarker identification
Our understanding of human disease can be improved by integrating the abundance of high throughput biomedical data. Here, the authors use deep learning methods successfully used on images to integrate various types of omics data to improve patient classification and identify disease biomarkers.
- Tongxin Wang
- , Wei Shao
- & Kun Huang
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Perspective
| Open AccessTowards an engineering theory of evolution
Effective biological engineering requires the acknowledgement of evolution and its consideration during the design process. In this perspective, the authors present the concept of the evotype to reason about and shape the evolutionary potential of natural and engineered biosystems.
- Simeon D. Castle
- , Claire S. Grierson
- & Thomas E. Gorochowski
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Article
| Open AccessSmart-watch-programmed green-light-operated percutaneous control of therapeutic transgenes
Wearable smart devices often have green light diodes to monitor health. Here the authors use this to control a light-activated genetic switch for GLP1 production in diabetic mice.
- Maysam Mansouri
- , Marie-Didiée Hussherr
- & Martin Fussenegger
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Article
| Open AccessDesign of synthetic human gut microbiome assembly and butyrate production
Microbiomes designed with predictable functions could enable broad applications in health, agriculture and bioprocessing. Here the authors use a model-guided approach to design diverse synthetic human gut communities for production of the health-relevant metabolite butyrate.
- Ryan L. Clark
- , Bryce M. Connors
- & Ophelia S. Venturelli
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Article
| Open AccessEnhancing CRISPR-Cas9 gRNA efficiency prediction by data integration and deep learning
High-quality gRNA activity data is needed for accurate on-target efficiency predictions. Here the authors generate activity data for over 10,000 gRNA and build a deep learning model CRISPRon for improved performance predictions.
- Xi Xiang
- , Giulia I. Corsi
- & Yonglun Luo
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Article
| Open AccessPareto optimality between growth-rate and lag-time couples metabolic noise to phenotypic heterogeneity in Escherichia coli
It is unclear how noise in gene expression propagates to phenotypic heterogeneity in clonal bacterial populations. Here, the authors explore how variability in central sugar metabolism in E. coli can mediate and promote population diversification.
- Diego Antonio Fernandez Fuentes
- , Pablo Manfredi
- & Mattia Zampieri
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Article
| Open AccessThe quantitative metabolome is shaped by abiotic constraints
Evolution selects for the fittest but must operate within the realm of the physically possible. Here, the authors present a theoretical framework that allows them to explore how ten abiotic constraints can shape the operation, regulation, and adaptation of metabolism in E. coli.
- Amir Akbari
- , James T. Yurkovich
- & Bernhard O. Palsson
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Article
| Open AccessLongitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit
Aging is associated with an increased risk of chronic diseases and functional decline. Here, the authors investigate the fluctuations of physiological indices along aging trajectories and observed a characteristic decrease in the organism state recovery rate.
- Timothy V. Pyrkov
- , Konstantin Avchaciov
- & Peter O. Fedichev
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