Featured
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Article
| Open AccessModelling genetic mosaicism of neurodevelopmental disorders in vivo by a Cre-amplifying fluorescent reporter
Genetic mosaicism is frequently present in monogenic diseases of the central nervous system. Here the authors design a dual-colour reporter system that can be used to tune the degree of mosaicism in mouse models.
- Francesco Trovato
- , Riccardo Parra
- & Gian Michele Ratto
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Article
| Open AccessPathway engineering in yeast for synthesizing the complex polyketide bikaverin
Bikaverin is a fungal-derived tetracyclic polyketide with antibiotic, antifungal and anticancer properties. Here, the authors employ various pathway engineering strategies to achieve high level production of bikaverin in baker’s yeast.
- Meng Zhao
- , Yu Zhao
- & Jef D. Boeke
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Article
| Open AccessIn vivo biomolecular imaging of zebrafish embryos using confocal Raman spectroscopy
Raman spectroscopic imaging (RSI) can provide information on the chemical composition of a sample, but application to living organisms has lacked sufficient spatial resolution and signal strength. Here the authors apply confocal RSI to whole-mount zebrafish embryos to distinguish different infectious bacteria and to living zebrafish embryos to monitor the wound healing process.
- Håkon Høgset
- , Conor C. Horgan
- & Molly M. Stevens
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Article
| Open AccessIdentification and characterization of constrained non-exonic bases lacking predictive epigenomic and transcription factor binding annotations
Genome-wide maps of evolutionary constraint and large-scale compendia of epigenomic and transcription factor data provide complementary information for genome annotation. Here, the authors develop the Constrained Non-Exonic Predictor (CNEP) that enables better understanding of their relationship.
- Olivera Grujic
- , Tanya N. Phung
- & Jason Ernst
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Article
| Open AccessRadiation-induced DNA damage and repair effects on 3D genome organization
Genomic aberrations disrupting chromosome spatial domains can lead to disease. Here, the authors investigate the impact of DNA damage response and repair on 3D genome folding, comparing wild type cells and ataxia telangiectasia mutated patient cells, and characterise both cell type-specific and shared changes to genome organization during the response to damage.
- Jacob T. Sanders
- , Trevor F. Freeman
- & Rachel Patton McCord
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Article
| Open AccessDisposable silicon-based all-in-one micro-qPCR for rapid on-site detection of pathogens
Designing efficient, rapid and low-cost diagnostic technologies targeting nucleic acids remains a challenge. Here the authors present a disposable silicon-based integrated Point-of-Need transducer produced in a standard wet lab and able to chemically-amplify and detect pathogen-specific sequences of nucleic acids quantitatively in real-time.
- Estefania Nunez-Bajo
- , Alexander Silva Pinto Collins
- & Firat Güder
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Article
| Open AccessUltrasensitive antibody-aptamer plasmonic biosensor for malaria biomarker detection in whole blood
Reliable plasmonic biosensors with high throughput and ease of use are highly sought after. Here, the authors report a plasmon-enhanced fluorescence antibody-aptamer biosensor based on a gold nanoparticle array, and demonstrate its use for effective specific detection of a malaria marker, at femtomolar level, in whole blood.
- Antonio Minopoli
- , Bartolomeo Della Ventura
- & Raffaele Velotta
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Article
| Open AccessNon-invasive single-cell morphometry in living bacterial biofilms
Accurate cell detection in dense bacterial biofilms is challenging. Here, the authors report an image analysis pipeline that is able to accurately segment and classify single bacterial cells in 3D fluorescence images: Bacterial Cell Morphometry 3D (BCM3D).
- Mingxing Zhang
- , Ji Zhang
- & Andreas Gahlmann
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Article
| Open AccessNon-invasive focusing and imaging in scattering media with a fluorescence-based transmission matrix
Light scattering represents the main limitation to image at depth in biological microscopy. The authors present a strategy to characterize light propagation in and out of a scattering medium based on linear fluorescence feedback and from the same measurements exploit memory effect correlations to image and reconstruct extended objects.
- Antoine Boniface
- , Jonathan Dong
- & Sylvain Gigan
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Article
| Open AccessGlycoproteomics-based signatures for tumor subtyping and clinical outcome prediction of high-grade serous ovarian cancer
Altered protein glycosylation is increasingly recognized as a hallmark of cancer. Here, the authors profile the glycoproteome of 119 high-grade serous ovarian carcinoma tissues, showing that glycosylation patterns correlate with tumor molecular subtypes and clinical outcomes.
- Jianbo Pan
- , Yingwei Hu
- & Hui Zhang
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Article
| Open AccessConformational maps of human 20S proteasomes reveal PA28- and immuno-dependent inter-ring crosstalks
Immune cells express immunoproteasomes (i20S), which bind to specialized regulators, contain different catalytic subunits and generate immunogenic peptides. HDX-MS—based assessment of the differences between the conformational dynamics of standard and i20s reveals specific, allosteric changes in i20S and upon regulator binding.
- Jean Lesne
- , Marie Locard-Paulet
- & Julien Marcoux
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Article
| Open AccessCohesin depleted cells rebuild functional nuclear compartments after endomitosis
The role of cohesin in organizing a functional nuclear architecture remains poorly understood. Here the authors show that cohesin depleted cells pass through endomitosis forming a multilobulated nucleus able to proceed through S-phase with typical features of active and inactive nuclear compartments and spatio-temporal patterns of replication domains.
- Marion Cremer
- , Katharina Brandstetter
- & Thomas Cremer
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Article
| Open AccessSpatially expandable fiber-based probes as a multifunctional deep brain interface
Existing neural interfaces are limited in accessing one, small brain region. Here, the authors introduce a scaffold with helix hollow channels, which direct multisite multifunctional fibre probes into the brain at different angles, allowing for simultaneous recording and stimulation across distant regions.
- Shan Jiang
- , Dipan C. Patel
- & Xiaoting Jia
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Article
| Open AccessSound generation in zebrafish with Bio-Opto-Acoustics
Existing tools to study hearing are limited. Here the authors report Bio-OptoAcoustic (BOA) stimulation wherein they use optical forces to generate localised sound and activate the auditory system of zebrafish larvae.
- Itia A. Favre-Bulle
- , Michael A. Taylor
- & Ethan K. Scott
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Article
| Open AccessAn expanded palette of improved SPLICS reporters detects multiple organelle contacts in vitro and in vivo
The authors have previously reported split-GFP-based contact site sensors (SPLICS) to document endoplasmic reticulum/mitochondria contact sites. Here they extend this work and develop a range of improved SPLICS sensors to detect single and multiple organelle contact sites at different distances.
- Francesca Vallese
- , Cristina Catoni
- & Tito Calì
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Article
| Open AccessA Cas-embedding strategy for minimizing off-target effects of DNA base editors
DNA base editors can display off-target effects on DNA and RNA. Here the authors embed the base editing enzymes in the middle of nCas9 to reduce these without impacting on-target editing.
- Yajing Liu
- , Changyang Zhou
- & Tian Chi
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Article
| Open AccessIn vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo
Ex vivo engineering of antigen-specific T cells has shown therapeutic efficacy but can be costly and scarce. Here the authors show that in vitro-transcribed antigen receptor mRNA packaged in nanocarriers can directly induce, in vivo, transient their expression in circulating T cells to provide therapeutic effects in mouse models of cancer or viral infection.
- N. N. Parayath
- , S. B. Stephan
- & M. T. Stephan
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Article
| Open AccessQuantification of purified endogenous miRNAs with high sensitivity and specificity
MicroRNAs are potentially powerful biomarkers, though clinical use requires rapid and reliable profiling. Here the authors report amplification-free multicolour single-molecule imaging with single base mismatch sensitivity.
- Soochul Shin
- , Yoonseok Jung
- & Sungchul Hohng
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Article
| Open AccessA grass-specific cellulose–xylan interaction dominates in sorghum secondary cell walls
Sorghum is a source of lignocellulosic biomass for the production of renewable fuels. Here the authors characterise the sorghum secondary cell wall using multi-dimensional magic angle spinning solid-state NMR and present a model dominated by interactions between three-fold screw xylan and amorphous cellulose.
- Yu Gao
- , Andrew S. Lipton
- & Jenny C. Mortimer
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Article
| Open AccessThe structural basis of promiscuity in small multidrug resistance transporters
Gdx-Clo is a bacterial transporter from the small multidrug resistance (SMR) family. Here, the authors use solid supported membrane electrophysiology to characterize Gdx-Clo functionally and report crystal structures of Gdx-Clo which confirm the dual topology architecture and offer insight into substrate binding and transport mechanism.
- Ali A. Kermani
- , Christian B. Macdonald
- & Randy B. Stockbridge
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Article
| Open AccessMiCas9 increases large size gene knock-in rates and reduces undesirable on-target and off-target indel edits
Cas9 fused to DNA damage repair proteins can improve rates of gene knock-in but the chimeric protein is often large. Here the authors fuse Cas9 to a minimal Brex27 motif from BRCA2 consisting of thirty-six amino acids to enhance the efficacy and safety of gene editing.
- Linyuan Ma
- , Jinxue Ruan
- & Jie Xu
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Article
| Open AccessTranscription-dependent cohesin repositioning rewires chromatin loops in cellular senescence
Senescence is a state of stable proliferative arrest. Here, the authors perform Hi-C analysis on oncogenic RAS-induced senescence in human fibroblasts and characterize the changes in the 3D genome folding associated with the senescence-specific gene expression profile, which are mediated in part through cohesin redistribution on chromatin.
- Ioana Olan
- , Aled J. Parry
- & Masashi Narita
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Article
| Open AccessAnalysis of inositol phosphate metabolism by capillary electrophoresis electrospray ionization mass spectrometry
Myo-Inositol phosphates (InsPs) and pyrophosphates (PP-InsPs) are important second messengers but their analysis remains challenging. Here, the authors develop a capillary electrophoresis-mass spectrometry method for the identification and quantitation of InsP and PP-InsP isomers in cells and tissues.
- Danye Qiu
- , Miranda S. Wilson
- & Henning J. Jessen
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Article
| Open AccessUMI-linked consensus sequencing enables phylogenetic analysis of directed evolution
The success of protein evolution is dependent on the sequence context mutations are introduced into. Here the authors present UMIC-seq that allows consensus generation for closely related genes by using unique molecular identifiers linked to gene variants.
- Paul Jannis Zurek
- , Philipp Knyphausen
- & Florian Hollfelder
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Article
| Open AccessDirect RNA sequencing reveals m6A modifications on adenovirus RNA are necessary for efficient splicing
Adenovirus transcripts contain N6-methyladenosine (m6A) modification. Here the authors profile m6A modification sites on adenovirus mRNAs using Illumina meRIP-Seq and nanopore direct RNA sequencing, and showcase a role for m6A in splicing of viral late mRNAs.
- Alexander M. Price
- , Katharina E. Hayer
- & Matthew D. Weitzman
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Article
| Open AccessHigh-speed volumetric two-photon fluorescence imaging of neurovascular dynamics
Monitoring hemodynamics in the brain is important in understanding medical imaging data and mechanisms of disease. Here the authors use high-throughput two-photon microscopy with an axially-extended Bessel focus to measure vessel size and blood flow down to capillary scale in the awake mouse brain.
- Jiang Lan Fan
- , Jose A. Rivera
- & Na Ji
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Article
| Open AccessBiased localization of actin binding proteins by actin filament conformation
The assembly of actin filaments into distinct cytoskeletal structures plays a critical role in cell physiology. Here, the authors use a combination of live cell imaging and in vitro single molecule binding measurements to show that tandem calponin homology domains (CH1–CH2) are sensitive to actin filament conformation, biasing their subcellular localization.
- Andrew R. Harris
- , Pamela Jreij
- & Daniel A. Fletcher
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Article
| Open AccessThe Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation
Hop, also known as Stip1 or Sti1, facilitates substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Characterization of proteostasis-related pathways in STIP1 knock-out cell lines reveals that in eukaryotes Stip1 modulates the balance between protein folding and degradation.
- Kaushik Bhattacharya
- , Lorenz Weidenauer
- & Didier Picard
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Article
| Open AccessSpatial proteomics defines the content of trafficking vesicles captured by golgin tethers
The vesicles that transport proteins between intracellular organelles are small, short-lived, and elusive. Here, the authors show that capture of these vesicles through relocalizing tethers to mitochondria allows their contents to be characterised by organelle proteomics.
- John J. H. Shin
- , Oliver M. Crook
- & Sean Munro
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Article
| Open AccessSub-wavelength lateral detection of tissue-approximating masses using an ultrasonic metamaterial lens
Traditional methods for ultrasound detection in biomedical application suffer from limited lateral resolution. Here, the authors show that a phononic metamaterial lens can be used for spatial characterisation of subwavelength objects, even beyond the Fresnel zone of the emitting transducer.
- Ezekiel L. Walker
- , Yuqi Jin
- & Arup Neogi
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Article
| Open AccessEpigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR
PTSD has been associated with DNA methylation of specific loci in the genome, but studies have been limited by small sample sizes. Here, the authors perform a meta-analysis of DNA methylation data from 10 different cohorts and identify CpGs in AHRR that are associated with PTSD.
- Alicia K. Smith
- , Andrew Ratanatharathorn
- & Caroline M. Nievergelt
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Article
| Open AccessAn enhanced isothermal amplification assay for viral detection
Current state-of-the-art diagnostics for infectious diseases are sensitive but require extensive equipment. Here the authors develop an enhanced recombinase polymerase amplification reaction for SARS-CoV-2 that allows for inexpensive and rapid testing with minimal equipment.
- Jason Qian
- , Sarah A. Boswell
- & Michael Springer
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Article
| Open AccessProteomic profiling and genome-wide mapping of O-GlcNAc chromatin-associated proteins reveal an O-GlcNAc-regulated genotoxic stress response
Protein O-GlcNAcylation is involved in regulating gene expression and maintaining cellular homeostasis. Here, the authors develop a chemical reporter-based strategy for the proteomic profiling and genome-wide mapping of genotoxic stress-induced O-GlcNAcylated chromatin-associated proteins.
- Yubo Liu
- , Qiushi Chen
- & Jianing Zhang
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Article
| Open AccessFunctional compensation precedes recovery of tissue mass following acute liver injury
The liver possesses the ability to regenerate following sudden injury. Here, the authors use single-cell RNA-sequencing and in situ transcriptional analyses to identify a new phase of liver regeneration in mice aimed at maintaining essential functions throughout the regenerative process.
- Chad M. Walesky
- , Kellie E. Kolb
- & Wolfram Goessling
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Article
| Open AccessHigh-dimensional super-resolution imaging reveals heterogeneity and dynamics of subcellular lipid membranes
Lipid membranes are heterogeneous and dynamically regulated in cells. Here the authors report a Spectrum and Polarisation Optical Tomography (SPOT) method where they use Nile Red dye to resolve membrane morphology, polarity and phase in cells.
- Karl Zhanghao
- , Wenhui Liu
- & Dayong Jin
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Article
| Open AccessFibronectin-based nanomechanical biosensors to map 3D surface strains in live cells and tissue
The ability to measure strain in cells and tissues in vitro with minimal perturbation and at high spatial resolution has proven challenging. Here the authors develop a fluorescently-labelled fibronectin square lattice mesh that can be applied to the surface of cells and tissues to enable direct quantification and mapping of strain over time.
- Daniel J. Shiwarski
- , Joshua W. Tashman
- & Adam W. Feinberg
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Article
| Open AccessSARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography
Here the authors visualize SARS-CoV-2 infected cells by in situ cryo-electron tomography, delineating the structural organization and conformational changes that occur during virus replication and budding; and provide insight into vRNP architecture and RNA networks in double membrane vesicles.
- Steffen Klein
- , Mirko Cortese
- & Petr Chlanda
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Article
| Open AccessProtein identification by 3D OrbiSIMS to facilitate in situ imaging and depth profiling
Label-free protein characterization at surfaces requires digestion or matrix application prior to mass spectrometry. Here, the authors report the assignment of undigested proteins at surfaces by de novo sequencing and apply the methodology to a protein monolayer biochip and for in situ depth profiling of proteins through human skin.
- Anna M. Kotowska
- , Gustavo F. Trindade
- & David J. Scurr
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Article
| Open AccessDocking sites inside Cas9 for adenine base editing diversification and RNA off-target elimination
Current SpCas9 adenine base editors that minimise RNA off-target activities have constrained editing windows. Here the authors use domain insertion of TadA into Cas9 to narrow, expand or shift the editing window with RNA off-target minimization simultaneously
- Shuo Li
- , Bo Yuan
- & Tian-Lin Cheng
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Article
| Open AccessAutomatic classification and segmentation of single-molecule fluorescence time traces with deep learning
Traces from single-molecule fluorescence microscopy (SMFM) experiments exhibit photophysical artifacts that typically make analysis time-consuming. Here, the authors have developed an easily accessible software, AutoSiM, for two distinct applications of deep learning to the efficient processing of SMFM time traces.
- Jieming Li
- , Leyou Zhang
- & Nils G. Walter
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Article
| Open AccessImmune suppression in the early stage of COVID-19 disease
How COVID-19 pathology differs from other drivers of pneumonia is unclear. Here the authors analyze urine from patients with COVID-19 and identify an immunosuppressive protein expression pattern that is distinct from the pattern in healthy individuals or patients with non-COVID-19 pneumonia.
- Wenmin Tian
- , Nan Zhang
- & Catherine C. L. Wong
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Article
| Open AccessPlant hairy roots enable high throughput identification of antimicrobials against Candidatus Liberibacter spp.
The putative causal agent of citrus greening Candidatus Liberibacter asiaticus (CLas) cannot be cultured, which hampers finding new therapies to control this devastating disease. Here, the authors show that hairy roots support CLas propagation and enable high throughput antimicrobial screening.
- Sonia Irigoyen
- , Manikandan Ramasamy
- & Kranthi K. Mandadi
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Article
| Open AccessVav2 catalysis-dependent pathways contribute to skeletal muscle growth and metabolic homeostasis
Skeletal muscle plays a key role in regulating systemic glucose and metabolic homeostasis. Here, the authors show that the catalytic activity of Vav2, an activator of Rho GTPases, modulates those processes by favoring the responsiveness of this tissue to insulin and related factors.
- Sonia Rodríguez-Fdez
- , L. Francisco Lorenzo-Martín
- & Xosé R. Bustelo
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Article
| Open AccessComputer vision for pattern detection in chromosome contact maps
Chromatin loops bridging distant loci within chromosomes can be detected by a variety of techniques such as Hi-C. Here the authors present Chromosight, an algorithm applied on mammalian, bacterial, viral and yeast genomes, able to detect various types of pattern in chromosome contact maps, including chromosomal loops.
- Cyril Matthey-Doret
- , Lyam Baudry
- & Axel Cournac
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Article
| Open AccessMicrobiota-directed fibre activates both targeted and secondary metabolic shifts in the distal gut
Here, the authors tailor an acetylated galactoglucomannan (AcGGM) fibre from spruce wood to specifically enrich Roseburia and Faecalibacterium - beneficial species which have the enzymatic machinery to breakdown the fibre and generate butyrate. They subsequently perform a piglet feeding trial, metagenomics and metaproteomics, together showing that AcGGM-fed pigs exhibit not only increased Roseburia and Faecalibacterium populations with AcGGM-specific mannan-specific esterases, but also secondary metabolic pathways.
- Leszek Michalak
- , John Christian Gaby
- & Bjørge Westereng
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Article
| Open AccessNative mass spectrometry reveals the initial binding events of HIV-1 rev to RRE stem II RNA
The HIV-1 RNA-binding protein rev facilitates nuclear export of viral RNA. Here, the authors use native mass spectrometry to study the interactions between rev-derived peptides and rev response elements of HIV-1 RNA, providing mechanistic insights into rev recognition and recruitment.
- Eva-Maria Schneeberger
- , Matthias Halper
- & Kathrin Breuker
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Article
| Open AccessA computational method for detection of ligand-binding proteins from dose range thermal proteome profiles
2D-thermal proteome profiling (2D-TPP) is a powerful assay for probing interactions of proteins with small molecules in their native context. Here the authors provide a statistical method for false discovery rate controlled analysis for 2D-TPP applications.
- Nils Kurzawa
- , Isabelle Becher
- & Mikhail M. Savitski
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Article
| Open AccessA convolutional neural network segments yeast microscopy images with high accuracy
Current cell segmentation methods for Saccharomyces cerevisiae face challenges under a variety of standard experimental and imaging conditions. Here the authors develop a convolutional neural network for accurate, label-free cell segmentation.
- Nicola Dietler
- , Matthias Minder
- & Sahand Jamal Rahi
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Article
| Open AccessQuantitative and multiplexed chemical-genetic phenotyping in mammalian cells with QMAP-Seq
Identifying chemical-genetic interactions in mammalian cells is limited to low-throughput or computational methods. Here, the authors present QMAP-Seq, a broadly accessible and scalable approach that uses NGS for pooled high-throughput chemical-genetic profiling in mammalian cells.
- Sonia Brockway
- , Geng Wang
- & Marc L. Mendillo
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