Featured
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Article
| Open AccessA deep learning model for predicting next-generation sequencing depth from DNA sequence
DNA probes used in next generation sequencing (NGS) have variable hybridisation kinetics, resulting in non-uniform coverage. Here, the authors develop a deep learning model to predict NGS depth using DNA probe sequences and apply to human and non-human sequencing panels.
- Jinny X. Zhang
- , Boyan Yordanov
- & David Yu Zhang
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Article
| Open AccessSARS-CoV-2 antibody dynamics and transmission from community-wide serological testing in the Italian municipality of Vo’
Vo’, Italy, is a unique setting for studying SARS-CoV-2 antibody dynamics because mass testing was conducted there early in the pandemic. Here, the authors perform two follow-up serological surveys and estimate seroprevalence, the extent of within-household transmission, and the impact of contact tracing.
- Ilaria Dorigatti
- , Enrico Lavezzo
- & Andrea Crisanti
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Article
| Open AccessTowards omics-based predictions of planktonic functional composition from environmental data
Advances in omics approaches could enable quantitative predictions of microbial functional composition. Here the authors re-analyze 885 metagenome-assembled genomes from Tara Oceans, and use a network approach to quantify protein functional clusters and explore their biogeography.
- Emile Faure
- , Sakina-Dorothée Ayata
- & Lucie Bittner
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Article
| Open AccessSi-C is a method for inferring super-resolution intact genome structure from single-cell Hi-C data
Constructing valid super-resolution intact genome 3D structures from single-cell Hi-C data is essential in investigating chromosome folding. Here the authors develop a method that makes it possible to visualize and investigate chromosome folding in individual cells at the genome scale
- Luming Meng
- , Chenxi Wang
- & Qiong Luo
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Article
| Open AccessAdvancing diagnostic performance and clinical usability of neural networks via adversarial training and dual batch normalization
Unmasking the decision making process of machine learning models is essential for implementing diagnostic support systems in clinical practice. Here, the authors demonstrate that adversarially trained models can significantly enhance the usability of pathology detection as compared to their standard counterparts.
- Tianyu Han
- , Sven Nebelung
- & Daniel Truhn
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Article
| Open AccessChronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity
Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients.
- Linh T. Bui
- , Nichelle I. Winters
- & Laure Emmanuelle Zaragosi
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Article
| Open AccessLineage-specific protection and immune imprinting shape the age distributions of influenza B cases
The earliest infections with influenza A shape the immune responses to future infections, but it is not known if this phenomenon applies to influenza B. Here, the authors use influenza B case data from New Zealand and find evidence for both lineage-specific and imprinting protection.
- Marcos C. Vieira
- , Celeste M. Donato
- & Sarah Cobey
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Article
| Open AccessData storage using peptide sequences
Finding durable, high-density media for data storage is necessary to support the ever-expanding generation of digital data. Here, the authors use peptide sequences to store digital data and retrieve them using tandem mass spectrometry, proving that peptides can be used as a storage medium.
- Cheuk Chi A. Ng
- , Wai Man Tam
- & Zhong-Ping Yao
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Article
| Open AccessArtificial intelligence guided discovery of a barrier-protective therapy in inflammatory bowel disease
Traditional drug discovery process use differential, Bayesian and other network based approaches. We developed a Boolean approach for building disease maps and prioritizing pre-clinical models to discover a first-in-class therapy to restore and protect the leaky gut barrier in inflammatory bowel disease.
- Debashis Sahoo
- , Lee Swanson
- & Pradipta Ghosh
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Article
| Open AccessProfiling variable-number tandem repeat variation across populations using repeat-pangenome graphs
Variable number tandem repeats (VNTRs) are difficult to analyze by short-read sequencing in disease studies. Here, the authors describe a VNTR mapping strategy for short-read analyses using a repeat pangenome graph. This method will help elucidate the contribution of VNTRs to diversity and disease.
- Tsung-Yu Lu
- , Katherine M. Munson
- & Mark J. P. Chaisson
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Article
| Open AccessA clinical deep learning framework for continually learning from cardiac signals across diseases, time, modalities, and institutions
Deep learning algorithms trained on data streamed temporally from different clinical sites and from a multitude of physiological sensors are generally affected by a degradation in performance. To mitigate this, the authors propose a continual learning strategy that employs a replay buffer.
- Dani Kiyasseh
- , Tingting Zhu
- & David Clifton
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Article
| Open AccessMultiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer
Mutations in 5’ untranslated regions (UTRs) have a functional role in gene expression in cancer. Here, the authors develop a sequencing-based high throughput functional assay named PLUMAGE and show the effects of these mutations on gene expression and their association with clinical outcomes in prostate cancer.
- Yiting Lim
- , Sonali Arora
- & Andrew C. Hsieh
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Article
| Open AccessSensitive detection of tumor mutations from blood and its application to immunotherapy prognosis
It is possible to call single-nucleotide variant (SNV) in cell-free DNA (cfDNA), but the accuracy of detection is often affected by low tumour cfDNA content. Here, the authors develop a method, cfSNV, and show that it can be used even for medium-coverage whole exome sequencing of cfDNA.
- Shuo Li
- , Zorawar S. Noor
- & Xianghong Jasmine Zhou
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Article
| Open AccessFractional response analysis reveals logarithmic cytokine responses in cellular populations
Our ability to interpret single-cell multivariate signaling responses is still limited. Here the authors introduce fractional response analysis (FRA), involving fractional cell counting, capable of deconvoluting heterogeneous multivariate responses of cellular populations.
- Karol Nienałtowski
- , Rachel E. Rigby
- & Michał Komorowski
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Article
| Open AccessGapClust is a light-weight approach distinguishing rare cells from voluminous single cell expression profiles
While rare cell type identification is indispensable in single cell studies, powerful tools with high detection accuracy and computational efficiency are still lacking. Here, the authors propose a light-weight algorithm which can distinguish rare cell types from voluminous single cell expression profiles.
- Botao Fa
- , Ting Wei
- & Zhangsheng Yu
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Matters Arising
| Open AccessRe-evaluating the evidence for a universal genetic boundary among microbial species
- Connor S. Murray
- , Yingnan Gao
- & Martin Wu
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Matters Arising
| Open AccessReply to: “Re-evaluating the evidence for a universal genetic boundary among microbial species”
- Luis M. Rodriguez-R
- , Chirag Jain
- & Konstantinos T. Konstantinidis
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Article
| Open AccessImproved genetic prediction of complex traits from individual-level data or summary statistics
Existing genetic prediction tools typically assume that genetic variants contribute equally towards the phenotype. The authors develop eight prediction tools that allow the user to specify the heritability model, and show that these tools enable substantially improved prediction of complex traits.
- Qianqian Zhang
- , Florian Privé
- & Doug Speed
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Article
| Open AccessA genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex
Klebsiella pneumoniae is a pathogen of increasing public health concern and antimicrobial resistance is becoming more prevalent. Here, the authors describe a K. pneumoniae genotyping tool, Kleborate, that can be used to identify lineages and detect antimicrobial resistance and virulence loci.
- Margaret M. C. Lam
- , Ryan R. Wick
- & Kathryn E. Holt
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Article
| Open AccessCoordination of endothelial cell positioning and fate specification by the epicardium
It remains unclear how spatial information controls endothelial cell identity and behavior in the developing heart. Here the authors perform single cell RNA sequencing at key developmental timepoints in mice to interrogate cellular contributions to coronary vessel patterning and maturation in the epicardium.
- Pearl Quijada
- , Michael A. Trembley
- & Eric M. Small
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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 AccessChromatin states shaped by an epigenetic code confer regenerative potential to the mouse liver
Few studies have provided functional analysis of the epigenetic landscape in the regenerating liver. Here the authors define chromatin states in the quiescent vs. regenerating mouse liver through integration of genome wide profiles of DNA methylation, histone modifications, and chromatin accessibility, identifying H3K27me3 as an epigenetic mark conferring regenerative potential.
- Chi Zhang
- , Filippo Macchi
- & Kirsten C. Sadler
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Article
| Open AccessThe T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival
Precision medicine needs prognostic markers to select the patients that will benefit more from targeted therapy. Authors show here that high level of baseline T cell receptor diversity is an indicator of favourable prognosis in multiple cancer types, and monoclonal expansion of T-cells correlates with good response to immune checkpoint blockade therapy in metastatic melanoma patients.
- Sara Valpione
- , Piyushkumar A. Mundra
- & Richard Marais
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Article
| Open AccessAttention-based multi-label neural networks for integrated prediction and interpretation of twelve widely occurring RNA modifications
RNA modifications appear to play a role in determining RNA structure and function. Here, the authors develop a deep learning model that predicts the location of 12 RNA modifications using primary sequence, and show that several modifications are associated, which suggests dependencies between them.
- Zitao Song
- , Daiyun Huang
- & Jia Meng
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Article
| Open AccessOrganization of the inputs and outputs of the mouse superior colliculus
The superior colliculus (SC) receives diverse cortical inputs to drive many behaviors. Here, based on comprehensive mapping of cortico-tectal projections, the authors refined the superior colliculus into medial, centromedial, centrolateral, and lateral zones, and characterized the input-output connectivity and morphology of neurons in each zone that serve the role of SC in goal-directed behaviors.
- Nora L. Benavidez
- , Michael S. Bienkowski
- & Hong-Wei Dong
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Article
| Open AccessDivide-and-conquer: machine-learning integrates mammalian and viral traits with network features to predict virus-mammal associations
A more comprehensive map of viral host ranges can help identify and mitigate zoonotic and animal-disease risks. A divide-and-conquer approach which separates viral, mammalian and network features predicts over 20,000 unknown associations between known viruses and susceptible mammalian species.
- Maya Wardeh
- , Marcus S. C. Blagrove
- & Matthew Baylis
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Article
| Open AccessA genetically encoded anti-CRISPR protein constrains gene drive spread and prevents population suppression
Technologies that can halt the spread of gene drives would be highly useful in controlling or reverting their effect. Here the authors use the anti-CRISPR protein AcrIIA4 to inactivate drives in A. gambiae.
- Chrysanthi Taxiarchi
- , Andrea Beaghton
- & Andrea Crisanti
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Article
| Open AccessSpearheading future omics analyses using dyngen, a multi-modal simulator of single cells
To benchmark single cell bioinformatics tools, data simulators can provide a robust ground truth. Here the authors present dyngen, a multi-modal simulator, and apply it to aligning cell developmental trajectories, cell-specific regulatory network inference and estimation of RNA velocity.
- Robrecht Cannoodt
- , Wouter Saelens
- & Yvan Saeys
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Article
| Open AccessBioactivity descriptors for uncharacterized chemical compounds
Small molecules bioactivity descriptors are enriched representations of compounds, reaching beyond chemical structures and capturing their known biological properties. Here the authors present a collection of deep neural networks able to infer bioactivity signatures for any compound of interest, even when little or no experimental information is available for them.
- Martino Bertoni
- , Miquel Duran-Frigola
- & Patrick Aloy
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Article
| Open AccessResidue 6.43 defines receptor function in class F GPCRs
The class Frizzled of G protein-coupled receptors (GPCRs) consist of ten Frizzled (FZD1-10) subtypes and Smoothened (SMO). Here the Schulte laboratory demonstrates that FZDs differ substantially from SMO in receptor activation-associated conformational changes, while SMO manifests a preference for a straight TM6, the TM6 of FZDs is kinked upon activation.
- Ainoleena Turku
- , Hannes Schihada
- & Gunnar Schulte
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Article
| Open AccessRole of backbone strain in de novo design of complex α/β protein structures
The authors show that consideration of global backbone strain enables successful de novo design of larger αβ-proteins with five- and six- stranded β-sheets flanked by α-helices.
- Nobuyasu Koga
- , Rie Koga
- & David Baker
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Review Article
| Open AccessMining and unearthing hidden biosynthetic potential
Natural products are an important source of bioactive compounds and have versatile applications in different fields, but their discovery is challenging. Here, the authors review the recent developments in genome mining for discovery of natural products, focusing on compounds from unconventional microorganisms and microbiomes.
- Kirstin Scherlach
- & Christian Hertweck
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Article
| Open AccessTumor-associated hematopoietic stem and progenitor cells positively linked to glioblastoma progression
A deeper knowledge of the immune cell profile within the brain cancer tumor microenvironment (TM) could identify targets to improve immunotherapy efficacy. Here, in glioblastoma, the authors find haematopoietic stem and progenitor cells in the TM, which are associated with poor prognosis and increased immunosuppression.
- I-Na Lu
- , Celia Dobersalske
- & Igor Cima
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Article
| Open AccessComprehensive identification of transposable element insertions using multiple sequencing technologies
Identification of transposable element (TE) insertions from whole genome sequencing data remains challenging. Here the authors developed a comprehensive TE insertion detection algorithm xTea that can be applied to both short-read and long-read sequencing data.
- Chong Chu
- , Rebeca Borges-Monroy
- & Peter J. Park
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Article
| Open AccessscGCN is a graph convolutional networks algorithm for knowledge transfer in single cell omics
Making sense of the rapidly growing single-cell omics datasets available is limited by difficulties in leveraging disparate datasets in analyses. Here, the authors present scGCN, a graph based convolutional network to allow effective knowledge transfer across omics datasets.
- Qianqian Song
- , Jing Su
- & Wei Zhang
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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 catalog of the diversity and ubiquity of bacterial microcompartments
Bacterial microcompartments (BMCs) are organelles consisting of a protein shell in which certain metabolic reactions take place separated from the cytoplasm. Here, Sutter et al. present a comprehensive catalog of BMC loci, substantially expanding the number of known BMCs and describing distinct types and compartmentalized reactions.
- Markus Sutter
- , Matthew R. Melnicki
- & Cheryl A. Kerfeld
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Article
| Open AccessSystematic detection of functional proteoform groups from bottom-up proteomic datasets
Many proteins exist in various proteoforms but detecting these variants by bottom-up proteomics remains difficult. Here, the authors present a computational approach based on peptide correlation analysis to identify and characterize proteoforms from bottom-up proteomics data.
- Isabell Bludau
- , Max Frank
- & Ruedi Aebersold
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Article
| Open AccessPreventing corneal blindness caused by keratitis using artificial intelligence
Keratitis is the main cause of corneal blindness worldwide, but most vision loss caused by keratitis can be avoidable via early detection and treatment, which are challenging in resource-limited settings. Here, the authors develop a deep learning system for the automated classification of keratitis and other cornea abnormalities.
- Zhongwen Li
- , Jiewei Jiang
- & Wei Chen
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Article
| Open Accessα-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity
α-Synuclein (αS) aggregation is a driver of several neurodegenerative disorders. Here, the authors identify a class of peptides that bind toxic αS oligomers and amyloid fibrils but not monomeric functional protein, and prevent further αS aggregation and associated cell damage.
- Jaime Santos
- , Pablo Gracia
- & Salvador Ventura
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Article
| Open AccessMachine learning differentiates enzymatic and non-enzymatic metals in proteins
The authors generate the largest structural dataset of enzymatic and non-enzymatic metalloprotein sites to date. They use this dataset to train a decision-tree ensemble machine learning algorithm that allows them to distinguish between catalytic and non-catalytic metal sites. The computational model described here could also be useful for the identification of new enzymatic mechanisms and de novo enzyme design.
- Ryan Feehan
- , Meghan W. Franklin
- & Joanna S. G. Slusky
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Article
| Open AccessSingle-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human fibrotic skin diseases
Fibroblasts are found to be heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. Here the authors employ scRNA-seq to explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases.
- Cheng-Cheng Deng
- , Yong-Fei Hu
- & Bin Yang
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Article
| Open AccessModel-based prediction of spatial gene expression via generative linear mapping
Single cell RNA-seq loses spatial information of gene expression in multicellular systems because tissue must be dissociated. Here, the authors show the spatial gene expression profiles can be both accurately and robustly reconstructed by a new computational method using a generative linear mapping, Perler.
- Yasushi Okochi
- , Shunta Sakaguchi
- & Honda Naoki
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Article
| Open AccessMolDiscovery: learning mass spectrometry fragmentation of small molecules
A large number of mass spectra from different samples have been collected, and to identify small molecules from these spectra, database searches are needed, which is challenging. Here, the authors report molDiscovery, a mass spectral database search method that uses an algorithm to generate mass spectrometry fragmentations and learns a probabilistic model to match small molecules with their mass spectra.
- Liu Cao
- , Mustafa Guler
- & Hosein Mohimani
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Article
| Open AccessControlling the pandemic during the SARS-CoV-2 vaccination rollout
Despite the consensus that mass vaccination against SARS-CoV-2 will ultimately end the pandemic, it is not clear when and which control measures can be relaxed during the rollout of vaccination programmes. Here, the authors investigate relaxation scenarios using an age-structured transmission model that has been fitted to data for Portugal.
- João Viana
- , Christiaan H. van Dorp
- & Ganna Rozhnova
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Article
| Open AccessLearning mutational signatures and their multidimensional genomic properties with TensorSignatures
Currently available tools for the analysis of mutational signatures do not make use of all possible genomic properties aside from mutation patterns. Here the authors present TensorSignatures, an efficient framework that jointly infers mutational signatures and their genomic determinants.
- Harald Vöhringer
- , Arne Van Hoeck
- & Moritz Gerstung
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Article
| Open AccessIntegrated analysis of Xist upregulation and X-chromosome inactivation with single-cell and single-allele resolution
X-chromosome inactivation (XCI) ensures dosage compensation between the sexes. Here the authors perform allele-specific single-cell RNA sequencing in differentiating mouse embryonic stem cells to provide a detailed profile of the onset of XCI.
- Guido Pacini
- , Ilona Dunkel
- & Edda G. Schulz
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Article
| Open AccessInsights into household transmission of SARS-CoV-2 from a population-based serological survey
Household-based studies can provide insights into SARS-CoV-2 transmission. Here, the authors fit transmission models to serological data from Geneva, Switzerland, and estimate that the risk of infection from single household exposure (17.3%) was higher than for extra-household exposure (5.1%).
- Qifang Bi
- , Justin Lessler
- & Didier Trono
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Article
| Open AccessChildren’s exploratory play tracks the discriminability of hypotheses
People can infer unobserved causes of perceptual data (e.g. the contents of a box from the sound made by shaking it). Here the authors show that children compare what they hear with what they would have heard given other causes, and explore longer when the heard and imagined sounds are hard to discriminate.
- Max H. Siegel
- , Rachel W. Magid
- & Laura E. Schulz
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