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Article
| Open AccessEpiScanpy: integrated single-cell epigenomic analysis
The authors present epiScanpy: a computational framework for the analysis of single-cell epigenomic data, both ATAC-seq and DNA methylation data, with examples for clustering, cell type identification, trajectory learning and atlas integration - and show its performance in distinguishing cell types.
- Anna Danese
- , Maria L. Richter
- & Maria Colomé-Tatché
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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 AccessPredicting post-operative right ventricular failure using video-based deep learning
The echocardiogram allows for a comprehensive assessment of the cardiac musculature and valves, but its rich temporally resolved data remain underutilized. Here, the authors develop a video AI system trained to predict post-operative right ventricular failure.
- Rohan Shad
- , Nicolas Quach
- & William Hiesinger
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Article
| Open AccessA pre-registered short-term forecasting study of COVID-19 in Germany and Poland during the second wave
Forecasting models have been used extensively to inform decision making during the COVID-19 pandemic. In this preregistered and prospective study, the authors evaluated 14 short-term models for Germany and Poland, finding considerable heterogeneity in predictions and highlighting the benefits of combined forecasts.
- J. Bracher
- , D. Wolffram
- & Frost Tianjian Xu
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Article
| Open AccessCopy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma
Chromothripsis is associated with unfavourable outcomes in multiple myeloma (MM), but its detection usually requires whole genome sequencing. Here the authors develop an approach to detect chromothripsis in MM based on copy-number signatures that also works with whole exome sequencing data.
- Kylee H. Maclachlan
- , Even H. Rustad
- & Francesco Maura
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Article
| Open AccessPredicting base editing outcomes with an attention-based deep learning algorithm trained on high-throughput target library screens
Base editors enable precise genetic alterations but vary in efficiency at different loci. Here the authors analyse ABEs and CBEs at over 28,000 integrated sequences to train BE-DICT, a machine learning model capable of predicting base editing outcomes.
- Kim F. Marquart
- , Ahmed Allam
- & Gerald Schwank
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Article
| Open AccessGlobal spread of Salmonella Enteritidis via centralized sourcing and international trade of poultry breeding stocks
Salmonella enterica serotype Enteritidis is a pathogen of poultry that can cause outbreaks in humans. Here the authors use genomic and trade data to investigate a pandemic in the 1980s, finding evidence that international trade of breeding stocks led to global spread of the pathogen.
- Shaoting Li
- , Yingshu He
- & Xiangyu Deng
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Article
| Open AccessEvidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans
Duplications of gene segments can allow novel physiological adaptations to evolve. A detailed analysis of the TCAF gene family in primates and archaic humans suggest rapid duplication and diversification in this gene family is associated with cold or dietary adaptations.
- PingHsun Hsieh
- , Vy Dang
- & Evan E. Eichler
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Article
| Open AccessThe landscape of alternative polyadenylation in single cells of the developing mouse embryo
Alternative polyadenylation regulates localization, half-life and translation of mRNA isoforms. Here the authors investigate alternative polyadenylation using single cell RNA sequencing data from mouse embryos and identify 3’-UTR isoforms that are regulated across cell types and developmental time.
- Vikram Agarwal
- , Sereno Lopez-Darwin
- & Jay Shendure
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Article
| Open AccessComprehensive characterization of 536 patient-derived xenograft models prioritizes candidates for targeted treatment
Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.
- Hua Sun
- , Song Cao
- & Li Ding
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Article
| Open AccessMulti-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases
Alcohol use disorder and drinks per week both have been studied genetically and have different correlations with psychiatric diseases. Here the authors integrate multi-omics data to identify unique and shared variants, genes and pathways for alcohol use disorder and drinks per week.
- Manav Kapoor
- , Michael J. Chao
- & Alison Goate
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Article
| Open AccessThe regulatory impact of RNA-binding proteins on microRNA targeting
miRNAs are loaded into Argonaute protein and repress complementary mRNA targets. Here the authors show the unappreciated role of RNA binding proteins for efficient miRNA targeting and expand the current understanding of miRNA targeting.
- Sukjun Kim
- , Soyoung Kim
- & Daehyun Baek
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Article
| Open AccessThe antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter
Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.
- Per Plenge
- , Dongxue Yang
- & Claus J. Loland
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Article
| Open AccessThe risk of indoor sports and culture events for the transmission of COVID-19
Mass gathering events represent a risk for transmission of SARS-CoV-2. Here, the authors describe an experimental indoor test event in which individual contacts were measured and use aerosol and epidemiological modelling to evaluate transmission risks of different types of restrictions in the arena.
- Stefan Moritz
- , Cornelia Gottschick
- & Rafael Mikolajczyk
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Article
| Open AccessGenome dependent Cas9/gRNA search time underlies sequence dependent gRNA activity
The link between gRNA sequence and Cas9 activity is well established but the mechanism underlying this relationship is not well understood. Here the authors show that gRNA sequence primarily influences activity by dictating the time it takes for Cas9 to find the target site in a species-specific manner.
- E. A. Moreb
- & M. D. Lynch
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Article
| Open AccessImproving fragment-based ab initio protein structure assembly using low-accuracy contact-map predictions
Predicting protein structure from sequence is still not possible for all proteins. Here, the authors introduce a method that integrates deep learning and information about protein co-evolution to guide the prediction of non-homologous protein structures with greater accuracy.
- S. M. Mortuza
- , Wei Zheng
- & Yang Zhang
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Article
| Open AccessCorrecting for sparsity and interdependence in glycomics by accounting for glycan biosynthesis
Glycomics can uncover important molecular changes but measured glycans are highly interconnected and incompatible with common statistical methods, introducing pitfalls during analysis. Here, the authors develop an approach to identify glycan dependencies across samples to facilitate comparative glycomics.
- Bokan Bao
- , Benjamin P. Kellman
- & Nathan E. Lewis
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Article
| Open AccessA hierarchical approach to removal of unwanted variation for large-scale metabolomics data
Mass spectrometry-based metabolomics is a powerful method for profiling large clinical cohorts but batch variations can obscure biologically meaningful differences. Here, the authors develop a computational workflow that removes unwanted data variation while preserving biologically relevant information.
- Taiyun Kim
- , Owen Tang
- & Jean Yee Hwa Yang
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Article
| Open AccessHigh COVID-19 transmission potential associated with re-opening universities can be mitigated with layered interventions
Reopening of universities to students following COVID-19 restrictions risks increased transmission due to high numbers of social contacts and the potential for asymptomatic transmission. Here, the authors use a mathematical model with social contact data to estimate the impacts of reopening a typical non-campus based university in the UK.
- Ellen Brooks-Pollock
- , Hannah Christensen
- & Leon Danon
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Article
| Open AccessLineageOT is a unified framework for lineage tracing and trajectory inference
Lineage tracing and snapshots of transcriptional state at the single-cell level are powerful, complementary tools for studying development. Here, the authors propose a mathematical method combining lineage tracing with trajectory inference to improve our understanding of development.
- Aden Forrow
- & Geoffrey Schiebinger
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Article
| Open AccessInteracting evolutionary pressures drive mutation dynamics and health outcomes in aging blood
Age-related clonal hematopoiesis is associated with risk for diseases like acute myeloid leukemia (AML), yet it is unclear why some individuals do not progress despite having AML driver mutations. Here, the authors use deep learning and population genetics models to investigate how the interplay of positive and negative selection influences AML progression.
- Kimberly Skead
- , Armande Ang Houle
- & Philip Awadalla
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Article
| Open AccessTopological isolation of developmental regulators in mammalian genomes
The phenotypic consequence of 3D genome boundary disruption on developmental processes remains insufficiently understood. Here, the authors show that perturbation of a SOX17 boundary in human pluripotent stem cells interferes with proper differentiation and that germline variations affecting such boundaries are subject to selection, resulting in underrepresentation in the human population.
- Hua-Jun Wu
- , Alexandro Landshammer
- & Franziska Michor
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Article
| Open AccessDeep learning-based transformation of H&E stained tissues into special stains
Performing multiple histological stains on a biopsy can be costly and time consuming. Here the authors present a method for the digital transformation of H&E stained tissue into special stains (e.g., PAS, Masson’s Trichrome and Jones silver stain), and demonstrate that it improves diagnoses over the use of H&E only.
- Kevin de Haan
- , Yijie Zhang
- & Aydogan Ozcan
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Article
| Open AccessA last-in first-out stack data structure implemented in DNA
DNA is becoming increasingly used as a medium to store non-genetic information. Here the authors present a dynamic stack data structure implemented as a DNA polymer chemistry able to record and retrieve signals in a last-in first-out order.
- Annunziata Lopiccolo
- , Ben Shirt-Ediss
- & Natalio Krasnogor
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Article
| Open AccessThe molecular basis, genetic control and pleiotropic effects of local gene co-expression
Local gene co-expression is found throughout the genome, but systematic analysis of these co-expressed genes is needed. Here, the authors identify local co-expressed genes in 49 tissues and characterize the genetic variants which may affect their expression and contribute to disease.
- Diogo M. Ribeiro
- , Simone Rubinacci
- & Olivier Delaneau
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Article
| Open AccessAutomatic detection of 39 fundus diseases and conditions in retinal photographs using deep neural networks
Systems for automatic detection of a single disease may miss other important conditions. Here, the authors show a deep learning platform can detect 39 common retinal diseases and conditions.
- Ling-Ping Cen
- , Jie Ji
- & Mingzhi Zhang
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Article
| Open AccessTracking the introduction and spread of SARS-CoV-2 in coastal Kenya
SARS-CoV-2 was first detected in Kenya in March 2020 and there was evidence of local transmission in the following months. Here, the authors characterise the early stages of the epidemic in coastal Kenya using phylogenetics and find evidence of multiple strain importations from international points of entry.
- George Githinji
- , Zaydah R. de Laurent
- & Charles N. Agoti
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Article
| Open AccessThe structural dynamics of macropinosome formation and PI3-kinase-mediated sealing revealed by lattice light sheet microscopy
Macropinocytosis is a cellular process for the uptake of extracellular fluid. Here, the authors use lattice light sheet microscopy to examine the spatial dynamics of the plasma membrane, PI3K activity, and structural differences of various macrophage cell types during macropinocytosis.
- Shayne E. Quinn
- , Lu Huang
- & Brandon L. Scott
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Article
| Open AccessIceR improves proteome coverage and data completeness in global and single-cell proteomics
Label-free quantitative proteomics by data dependent acquisition offers high protein identification rates but is often limited by missing values. Here, the authors develop a quantification workflow that substantially reduces missing values while maintaining high identification rates and quantification accuracy.
- Mathias Kalxdorf
- , Torsten Müller
- & Jeroen Krijgsveld
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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 AccessDetection and characterization of the SARS-CoV-2 lineage B.1.526 in New York
West and colleagues develop the Variant Database software tool for examination of changing Spike mutations in SARS-CoV-2 genomes. The authors use this to detect emerging lineages of SARS-CoV-2 in New York and report the rapid spread of the B.1.526 lineage in the city.
- Anthony P. West Jr.
- , Joel O. Wertheim
- & Pamela J. Bjorkman
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Matters Arising
| Open AccessQuality control requirements for the correct annotation of lipidomics data
- Harald C. Köfeler
- , Thomas O. Eichmann
- & Kim Ekroos
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Matters Arising
| Open AccessReply to “Quality control requirements for the correct annotation of lipidomics data”
- Catherine G. Vasilopoulou
- , Karolina Sulek
- & Florian Meier
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Article
| Open AccessGenomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer
The progression from biliary tract intraepithelial neoplasia (BilIN) to gallbladder carcinoma (GBC) remains unclear. Here the authors use genomics to analyze coexisting GBC lesions, low-grade and high-grade BilINs, revealing two distinct evolutionary paths for GBC development.
- Jianzhen Lin
- , Xinxin Peng
- & Han Liang
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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 AccessSc-compReg enables the comparison of gene regulatory networks between conditions using single-cell data
Changes in cell state underlie the difference between health and disease. Here, the authors propose a computational framework for the integration of gene expression and chromatin-accessibility data from single cells to identify differences in gene regulation in cell types across two conditions.
- Zhana Duren
- , Wenhui Sophia Lu
- & Wing Hung Wong
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Article
| Open AccessAn extended reconstruction of human gut microbiota metabolism of dietary compounds
The interplay between human diet and the gut microbiome is complex. Here, the authors present a model of human-microbiome interaction that can predict how phenolic compounds are metabolized by the human gut microbiome, identifying diet-specific metabolites in children of varied clinical conditions.
- Telmo Blasco
- , Sergio Pérez-Burillo
- & Francisco J. Planes
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Article
| Open AccessActivation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design
G protein-coupled receptors (GPCRs) are a critical target in modern drug development across a wide range of indications. Here the authors provide a comprehensive characterization of a typical GPCR, the angiotensin II (AngII) type 1 receptor (AT1R), and provide insight into its activation mechanism that suggest avenues for the design of allosteric GPCR modulators.
- Shaoyong Lu
- , Xinheng He
- & Jian Zhang
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Article
| Open AccessReversible gene silencing through frameshift indels and frameshift scars provide adaptive plasticity for Mycobacterium tuberculosis
Bacterial adaptation through frame-shifting insertions and deletions (indels) could be reversed by secondary introduction of a frame-restoring indel. Here, the authors develop ScarTrek, a program that scans genomic data for different indels, and analyze 5977 clinical M. tuberculosis isolates for indel frequency.
- Aditi Gupta
- & David Alland
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Article
| Open AccessGIANA allows computationally-efficient TCR clustering and multi-disease repertoire classification by isometric transformation
Grouping T-cell receptors (TCRs) by sequence similarity could lead to new immunological insights. Here, the authors propose a tool that allows the rapid clustering of millions of TCR sequences, identifying TCRs potentially associated with the response to cancer, infectious and autoimmune diseases.
- Hongyi Zhang
- , Xiaowei Zhan
- & Bo Li
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Article
| Open AccessNon-invasive hydrodynamic imaging in plant roots at cellular resolution
Existing methods for non-invasively monitoring water flow in plants have limited spatial/temporal resolution. Here, the authors report that Raman microspectroscopy, complemented by hydrodynamic modelling, can monitor hydrodynamics within living root tissues at cell- and sub-second-scale resolutions.
- Flavius C. Pascut
- , Valentin Couvreur
- & Kevin F. Webb
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Article
| Open AccessHaploinsufficiency of SF3B2 causes craniofacial microsomia
Despite being a common congenital facial anomaly, the genetic etiology of craniofacial microsomia (CFM) is not well understood. Here, the authors use exome and genome sequencing of 146 individuals with CFM to identify haploinsufficient variants in SF3B2 as a prevalent underlying cause.
- Andrew T. Timberlake
- , Casey Griffin
- & Daniela V. Luquetti
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Article
| Open AccessDiffusion-mediated HEI10 coarsening can explain meiotic crossover positioning in Arabidopsis
Crossover numbers and positions are tightly controlled but the mechanism involved is still obscure. Here, the authors, using quantitative super-resolution cytogenetics and mathematical modelling, show that diffusion mediated coarsening of HEI10, an E3-ligase domain containing protein, may explain meiotic crossover positioning in Arabidopsis.
- Chris Morgan
- , John A. Fozard
- & Martin Howard
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Article
| Open AccessIdentification of the cross-strand chimeric RNAs generated by fusions of bi-directional transcripts
Gene fusion, trans-splicing or transcription read-through contributes to generation of chimeric RNA. Here the authors develop a pipeline to identify non-canonical type of chimeric RNAs called cross-strand chimeric RNA (cscRNA), which are fused between two precursor RNAs transcribed from the opposite DNA strands.
- Yuting Wang
- , Qin Zou
- & Xuerui Yang
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Article
| Open AccessHeatstroke predictions by machine learning, weather information, and an all-population registry for 12-hour heatstroke alerts
In the context of climate change, heatstroke is expected to become an increasingly relevant public health concern. Here, the authors develop and validate prediction models for the number of all heatstroke cases in different cities in Japan.
- Soshiro Ogata
- , Misa Takegami
- & Kunihiro Nishimura
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Article
| Open AccessSuper enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis
Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.
- Mengfei Liu
- , Sheng Cao
- & Vijay H. Shah
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Article
| Open AccessImpact of tiered restrictions on human activities and the epidemiology of the second wave of COVID-19 in Italy
Italy introduced a system of tiered SARS-CoV-2 control measures in November 2020. Here, the authors quantify the effect of these measures on SARS-CoV-2 transmissibility and hospitalisation, and find reductions across all tiers with the greatest impacts associated with the most restrictive level.
- Mattia Manica
- , Giorgio Guzzetta
- & Stefano Merler
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Article
| Open AccessInsulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans
How phosphorylation mediated by Insulin/IGF-1 Signaling kinases regulates lifespan remains unclear. Here the authors perform a large-scale quantitative phosphoproteomic analysis of wildtype and IIS mutant C. elegans strains to reveal detailed functional insights into longevity.
- Wen-Jun Li
- , Chen-Wei Wang
- & Meng-Qiu Dong
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Article
| Open AccessStrainberry: automated strain separation in low-complexity metagenomes using long reads
Existing long-read de novo assembly methods can partially, but not completely, separate strains. Here, the authors develop Strainberry, a metagenome assembly bioinformatic pipeline that exclusively uses longread data to accurately separate and reconstruct strain genomes from single-sample low-complexity microbiomes.
- Riccardo Vicedomini
- , Christopher Quince
- & Rayan Chikhi
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