Focus 26 January 2021

Biotechnology and methods

Methodology development promotes science advancement. Application of new scientific discoveries to biological processes, organisms, or systems can help to sustainably produce products for healing, feeding, or fueling. This page showcases our recent publications that report methodological or biotechnological advances relevant to biological, biomedical, and agricultural sciences.

Featured articles

Associate toxin-antitoxin with CRISPR-Cas to kill multidrug-resistant pathogens

CRISPR-regulated toxin-antitoxin (CreTA), safeguards CRISPR-Cas immune systems. Here the authors characterize a bacterial CreTA and use this to generate a proof-of-concept antimicrobial strategy, ATTACK, which associates TA and CRISPR-Cas to kill multidrug resistant pathogens.
- Rui Wang
- Xian Shu
- Ming Li
ArticleOpen Access12 Apr 2023 Nature Communications
A roadmap to establish a comprehensive platform for sustainable manufacturing of natural products in yeast

Yeasts, Saccharomyces cerevisiae and Pichia pastoris, are promising chassis for the production of nature products (NPs). Here, the author discusses establishing a comprehensive platform for sustainable production of NPs via system-associated optimization at genetics, temporal controllers, productivity screening, and scalability levels.
- Gita Naseri
PerspectiveOpen Access6 Apr 2023 Nature Communications
Automated optimisation of solubility and conformational stability of antibodies and proteins

Antibodies find key applications in research, diagnostics, and therapeutics, but their development can be impeded by poor stability or solubility. Here the authors developed a computational strategy that enables antibody optimisation, without affecting functionality.
- Angelo Rosace
- Anja Bennett
- Pietro Sormanni
ArticleOpen Access6 Apr 2023 Nature Communications
A comprehensive benchmarking with practical guidelines for cellular deconvolution of spatial transcriptomics

This study comprehensively benchmarks 18 state-of-the-art methods for cellular deconvolution of spatial transcriptomics and provide decision-tree-style guidelines and recommendations for method selection.
- Haoyang Li
- Juexiao Zhou
- Xin Gao
ArticleOpen Access21 Mar 2023 Nature Communications
Limitations of gene editing assessments in human preimplantation embryos

DNA repair in response to DSBs in the preimplantation embryo is hard to analyze. Here the authors show that over 25% of pre-existing heterozygous loci in control single blastomere samples appeared as homozygous after whole genome amplification, therefore, they validated gene editing seen in human embryos in ESCs.
- Dan Liang
- Aleksei Mikhalchenko
- Shoukhrat Mitalipov
ArticleOpen Access7 Mar 2023 Nature Communications
Optical control of PIEZO1 channels

PIEZO proteins are large, mechanically-activated trimeric ion channels. Here the authors report a light-gated mouse PIEZO1 channel, mOP1, whereby an azobenzene-based photoswitch covalently localised at the extracellular apex of a transmembrane helix, rapidly triggers channel gating on light irradiation.
- Francisco Andrés Peralta
- Mélaine Balcon
- Thomas Grutter
ArticleOpen Access7 Mar 2023 Nature Communications
Lantern-shaped flexible RNA origami for Smad4 mRNA delivery and growth suppression of colorectal cancer

mRNA delivery has shown great potential in the treatment of various diseases. Here, the authors develop a lantern-shaped flexible origami for nanolization of single mRNA molecules and demonstrate efficient delivery of Smad4 mRNA, achieving suppression of colorectal cancer tumour growth.
- Muren Hu
- Chang Feng
- Xiaoli Zhu
ArticleOpen Access10 Mar 2023 Nature Communications
Hierarchical graph learning for protein–protein interaction

Despite recent progress, machine learning methods remain inadequate in modeling the natural protein-protein interaction (PPI) hierarchy for PPI prediction. Here, the authors present a double-viewed hierarchical graph learning model, HIGH-PPI, to predict PPIs and extrapolate the molecular details involved.
- Ziqi Gao
- Chenran Jiang
- Jia Li
ArticleOpen Access25 Feb 2023 Nature Communications
A versatile, high-efficiency platform for CRISPR-based gene activation

The generation of CRISPR-mediated transcriptional activation (CRISPRa)-competent cell lines pose significant technical challenges. Here the authors report a platform for production of CRISPRa-ready cell populations which they combine with optimised expressed and synthetic gRNA scaffolds to enhance functionality.
- Amy J. Heidersbach
- Kristel M. Dorighi
- Benjamin Haley
ArticleOpen Access17 Feb 2023 Nature Communications
Community science designed ribosomes with beneficial phenotypes

While the ribosome has been harnessed for synthetic biology, designing ribosomes has remained challenging. Here, the authors demonstrate a community science approach for rational design of ribosomes with beneficial properties.
- Antje Krüger
- Andrew M. Watkins
- Michael C. Jewett
ArticleOpen Access21 Feb 2023 Nature Communications
Batch alignment of single-cell transcriptomics data using deep metric learning

The increasing scale of single-cell RNA-seq studies presents new challenge for integrating datasets from different batches. Here, the authors develop scDML, a tool that simultaneously removes batch effects, improves clustering performance, recovers true cell types, and scales well to large datasets.
- Xiaokang Yu
- Xinyi Xu
- Xiangjie Li
ArticleOpen Access21 Feb 2023 Nature Communications
Systematically attenuating DNA targeting enables CRISPR-driven editing in bacteria

Genome editing in bacteria normally requires efficient recombination and high transformation efficiencies, which often isn’t. Here the authors report that systematically attenuating DNA targeting activity enables RecA-mediated repair in different bacteria, allowing chromosomal cleavage to drive editing.
- Daphne Collias
- Elena Vialetto
- Chase L. Beisel
ArticleOpen Access8 Feb 2023 Nature Communications
Highly efficient and robust π-FISH rainbow for multiplexed in situ detection of diverse biomolecules

Fluorescence in situ hybridization (FISH) methods with high sensitivity are needed. Here the authors develop multiplex πFISH rainbow to detect a range of biomolecules; they also combine this with the hybridization chain reaction to develop πFISH+ technology for short nucleic acid fragment detection.
- Yingfeng Tao
- Xiaoliu Zhou
- Gang Cao
ArticleOpen Access27 Jan 2023 Nature Communications
Transformer for one stop interpretable cell type annotation

Developing computational tools for interpretable cell type annotation in scRNA-seq data remains challenging. Here the authors propose a Transformer-based model for interpretable annotation transfer using biologically understandable entities, and demonstrate its performance on large or atlas datasets.
- Jiawei Chen
- Hao Xu
- Jing-Dong J. Han
ArticleOpen Access14 Jan 2023 Nature Communications
Spatially resolved transcriptomic profiling of degraded and challenging fresh frozen samples

Spatial transcriptomics relies on RNA quality, which is variable and dependent on sample handling, storage, and/or intrinsic factors. Here, authors present a genome-wide spatial gene expression profiling method called RNA Rescue Spatial Transcriptomics (RRST), designed for the analysis of moderate to low quality fresh frozen tissue samples and demonstrate its robustness on 7 different tissue types.
- Reza Mirzazadeh
- Zaneta Andrusivova
- Joakim Lundeberg
ArticleOpen Access31 Jan 2023 Nature Communications
scMoMaT jointly performs single cell mosaic integration and multi-modal bio-marker detection

Many methods for single cell data integration have been developed, though mosaic integration remains challenging. Here the authors present scMoMaT, a mosaic integration method for single cell multi-modality data from multiple batches, that jointly learns cell representations and marker features across modalities for different cell clusters, to interpret the cell clusters from different modalities.
- Ziqi Zhang
- Haoran Sun
- Xiuwei Zhang
ArticleOpen Access24 Jan 2023 Nature Communications
Differential sensing with arrays of de novo designed peptide assemblies

Differential sensing aims to mimic senses such as taste and smell through the use of synthetic receptors. Here, the authors show that arrays of de novo designed peptide assemblies can be used as sensor components to distinguish various analytes and complex mixtures.
- William M. Dawson
- Kathryn L. Shelley
- Derek N. Woolfson
ArticleOpen Access24 Jan 2023 Nature Communications
Achieving single nucleotide sensitivity in direct hybridization genome imaging

Visualisation of point mutations in situ is informative for studying genetic diseases. Here the authors report single guide genome oligopaint via local denaturation fluorescence in situ hybridisation, sgGOLDFISH, a direct hybridisation genome imaging method with single-nucleotide sensitivity.
- Yanbo Wang
- W. Taylor Cottle
- Taekjip Ha
ArticleOpen Access15 Dec 2022 Nature Communications
Large-scale perfused tissues via synthetic 3D soft microfluidics

Bioengineering live tissues has remained challenging due to limited nutrient exchange in the growing tissues. Here, the authors have developed micro-perfused 2-photon printing of 3D microfluidics, to engineer large-scale, viable and functional neural and hepatic 3D tissues.
- Sergei Grebenyuk
- Abdel Rahman Abdel Fattah
- Adrian Ranga
ArticleOpen Access12 Jan 2023 Nature Communications
Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis

Gene delivery to fibroblasts for liver fibrosis treatment remains challenging. Here the authors develop a combinatorial library of ligand-tethered lipidoids via a modular synthetic method and adopt a 2-round screening strategy to identify lipidoids for potent and selective gene delivery to fibroblasts.
- Xuexiang Han
- Ningqiang Gong
- Michael J. Mitchell
ArticleOpen Access17 Jan 2023 Nature Communications
Engineering inducible biomolecular assemblies for genome imaging and manipulation in living cells

Imaging non-repetitive loci in living cells remains challenging. Here, the authors engineered an inducible system whereby biomolecular assemblies can be guided to specific genomic loci by a nuclease-defective Cas9, allowing the simultaneous imaging and manipulation of the loci.
- Qin Peng
- Ziliang Huang
- Yingxiao Wang
ArticleOpen Access24 Dec 2022 Nature Communications
Bioprinting microporous functional living materials from protein-based core-shell microgels

Extrusion bioprinting can be used to produce living materials but controlling cell microenvironments is challenging. Here, the authors use a type of core-shell microgel ink that decouples cell culture from material processing to produce functional materials with a range of potential applications.
- Yangteng Ou
- Shixiang Cao
- Tuomas P. J. Knowles
ArticleOpen Access19 Jan 2023 Nature Communications
Gene activation guided by nascent RNA-bound transcription factors

Gene activation methods are valuable for studying gene functions and may have potential applications in bioengineering and medicine. Here the authors developed Narta technology to achieve gene activation by recruiting artificial transcription factors to transcription sites through nascent RNAs of the target gene.
- Ying Liang
- Haiyue Xu
- Baohui Chen
ArticleOpen Access28 Nov 2022 Nature Communications
Bead-jet printing enabled sparse mesenchymal stem cell patterning augments skeletal muscle and hair follicle regeneration

Current mesenchymal stem cell (MSC) transplantation practices are limited by the loss or reduced performance of MSCs. Here the authors develop a bead-jet printer for intraoperative formulation and printing of MSCs-laden Matrigel beads to improve skeletal muscle and hair follicle regeneration.
- Yuanxiong Cao
- Jiayi Tan
- Shaohua Ma
ArticleOpen Access3 Dec 2022 Nature Communications
A unified computational framework for single-cell data integration with optimal transport

Integrating heterogeneous single-cell multi-omics as well as spatially resolved transcriptomic data remains a major challenge. Here the authors report a unified single-cell data integration framework using an unbalanced optimal transport-based deep network.
- Kai Cao
- Qiyu Gong
- Lin Wan
ArticleOpen Access1 Dec 2022 Nature Communications
High-throughput robust single-cell DNA methylation profiling with sciMETv2

Despite the importance of DNA methylation, accessible and high-throughput methods to profile methylation at the single-cell level are lacking. Here, the authors present sciMETv2, a high-throughput workflow that provides high-quality single-cell methylomes in a robust and simple workflow.
- Ruth V. Nichols
- Brendan L. O’Connell
- Andrew C. Adey
ArticleOpen Access9 Dec 2022 Nature Communications
Adenine base editing efficiently restores the function of Fanconi anemia hematopoietic stem and progenitor cells

Fanconi Anemia (FA) is caused by deficiencies in DNA repair, making it hard to correct. Here the authors report a therapeutic base editing strategy to address two of the most prevalent FANCA mutations in patient hematopoietic stem and progenitor cells.
- Sebastian M. Siegner
- Laura Ugalde
- Jacob E. Corn
ArticleOpen Access12 Nov 2022 Nature Communications
Metabolite annotation from knowns to unknowns through knowledge-guided multi-layer metabolic networking

Unknown metabolite annotation is a grand challenge in untargeted metabolomics. Here, the authors develop knowledge-guided multi-layer networking (KGMN) to enable global metabolite annotation from knowns to unknowns in untargeted metabolomics.
- Zhiwei Zhou
- Mingdu Luo
- Zheng-Jiang Zhu
ArticleOpen Access4 Nov 2022 Nature Communications
De novo analysis of bulk RNA-seq data at spatially resolved single-cell resolution

Current methods to reanalyze bulk RNA-seq at spatially resolved single-cell resolution have limitations. Here, the authors develop Bulk2Space, a spatial deconvolution algorithm using single-cell and spatial transcriptomics as references, providing new insights into spatial heterogeneity within bulk tissue.
- Jie Liao
- Jingyang Qian
- Xiaohui Fan
ArticleOpen Access30 Oct 2022 Nature Communications
Wireless theranostic smart contact lens for monitoring and control of intraocular pressure in glaucoma

Glaucoma is an irreversible ocular disease that may lead to vision loss. Here the authors develop a theranostic smart contact lens with an intraocular pressure sensor, a flexible drug delivery system, wireless power and communication systems and an application specific integrated circuit chip for both monitoring and control of intraocular pressure in glaucoma induced rabbits.
- Tae Yeon Kim
- Jee Won Mok
- Sei Kwang Hahn
ArticleOpen Access10 Nov 2022 Nature Communications
Absolute protein quantification using fluorescence measurements with FPCountR

A challenge in synthetic biology is the empirical characterisation of genetic parts. Here the authors present FPCountR, a validated method and accompanying R package that enables the precise quantification of fluorescent protein reporters per bacterial cell to be enumerated in ‘proteins per cell’ or nanomolar units without requiring protein purification.
- Eszter Csibra
- Guy-Bart Stan
ArticleOpen Access3 Nov 2022 Nature Communications
A genetically encoded fluorescent biosensor for detecting itaconate with subcellular resolution in living macrophages

Itaconate has been identified as an immunomodulatory metabolite produced by activated macrophages, but methods for detecting itaconate in live cells are lacking. Here, the authors develop a fluorescent biosensor named BioITA for detecting itaconate in subcellular compartments of living macrophages.
- Pengkai Sun
- Zhenxing Zhang
- Xinjian Li
ArticleOpen Access4 Nov 2022 Nature Communications
FRET-FISH probes chromatin compaction at individual genomic loci in single cells

Chromatin compaction affects many nuclear processes yet compaction levels at individual genomic loci have been notoriously difficult to assess. Here, Ana Mota and co-authors from the Bienko-Crosetto Lab present FRET-FISH for probing chromatin compaction at selected loci in single cells.
- Ana Mota
- Szymon Berezicki
- Magda Bienko
ArticleOpen Access5 Nov 2022 Nature Communications
Microfluidic space coding for multiplexed nucleic acid detection via CRISPR-Cas12a and recombinase polymerase amplification

Fast, low-cost and multiplexed nucleic acid detection is challenging. Here the authors report a strategy that couples microfluidic space coding, CRISPRCas12a, and multiplex RPA for the rapid detection of up to 30 targets with only one fluorescent probe.
- Zhichen Xu
- Dongjuan Chen
- Maili Liu
ArticleOpen Access29 Oct 2022 Nature Communications
A comprehensive Bioconductor ecosystem for the design of CRISPR guide RNAs across nucleases and technologies

The success of CRISPR experiments relies on the choice of gRNA. Here the authors report crisprVerse, which enables efficient gRNA design and annotation for methods including CRISPRko, CRISPRa, CRISPRi, CRISPRbe and CRISPRkd, enabled for RNA- and DNA-targeting nucleases, including Cas9, Cas12 and Cas13.
- Luke Hoberecht
- Pirunthan Perampalam
- Jean-Philippe Fortin
ArticleOpen Access2 Nov 2022 Nature Communications
A doxycycline- and light-inducible Cre recombinase mouse model for optogenetic genome editing

Achieving spatial control of gene expression is important. Here the authors report an optimised photoactivatable Cre recombinase system, doxycycline- and light-inducible Cre recombinase (DiLiCre), and generate a DiLiCre mouse line which they use for mutagenesis in vivo and positional cell-tracing.
- Miguel Vizoso
- Colin E. J. Pritchard
- Jacco van Rheenen
ArticleOpen Access28 Oct 2022 Nature Communications
Binary-FRET reveals transient excited-state structure associated with activity-dependent CaMKII - NR2B binding and adaptation

FRET can be used to study conformational changes and protein-protein interactions. Here the authors report Binary-FRET for monitoring two FRET reactions, one encoded in the fluorescence lifetime of the donor, another encoded in its anisotropy, and monitor the dynamics of CaMKII and its interaction with NR2B.
- Tuan A. Nguyen
- Henry L. Puhl III
- Steven S. Vogel
ArticleOpen Access25 Oct 2022 Nature Communications
Cell-specific bioorthogonal tagging of glycoproteins

Changes in glycoprotein expression are correlates of disease, but secreted glycoproteins cannot be accurately traced to their cell line of origin. Here, the authors develop a strategy to chemically tag and profile glycoproteins in a cell line-specific manner in co-culture systems and in vivo.
- Anna Cioce
- Beatriz Calle
- Benjamin Schumann
ArticleOpen Access25 Oct 2022 Nature Communications
Engineered helicase replaces thermocycler in DNA amplification while retaining desired PCR characteristics

PCR is an essential method for the amplification and manipulation of nucleic acids, but the requirement for a thermocycler limits access. Here, authors engineer a helicase to replace the heating step of PCR with enzymatic unwinding, allowing the isothermal amplification of fragments up to 6 kb.
- Momčilo Gavrilov
- Joshua Y. C. Yang
- Taekjip Ha
ArticleOpen Access23 Oct 2022 Nature Communications
A universal glycoenzyme biosynthesis pipeline that enables efficient cell-free remodeling of glycans

Access to glycoenzymes for basic and applied research is limited by difficulties with their recombinant expression. Here, the authors describe a universal strategy for converting membrane-bound glycosyltransferases into water-soluble biocatalysts, which are expressed at high levels with retention of activity.
- Thapakorn Jaroentomeechai
- Yong Hyun Kwon
- Matthew P. DeLisa
ArticleOpen Access24 Oct 2022 Nature Communications
A predictive computational platform for optimizing the design of bioartificial pancreas devices

Transplanting encapsulated insulin-producing cells may achieve a functional cure for type 1 diabetes, but efficacy is constrained by mass transfer limits. Here, the authors report a dynamic computational platform to investigate the therapeutic potency of such programmable bioartificial pancreas devices.
- Alexander U. Ernst
- Long-Hai Wang
- Minglin Ma
ArticleOpen Access13 Oct 2022 Nature Communications
Cell-specific regulation of gene expression using splicing-dependent frameshifting

Precise and reliable gene delivery remains technically challenging. Here, the authors show that rationally designed frameshifting splicing can be used to express genes only in targeted cell types, with the potential to enhance the specificity AAV gene delivery.
- Jonathan P. Ling
- Alexei M. Bygrave
- Seth Blackshaw
ArticleOpen Access1 Oct 2022 Nature Communications
Wax worm saliva and the enzymes therein are the key to polyethylene degradation by Galleria mellonella

The crucial first step in the biodegradation of polyethylene plastic is oxidation of the polymer. This has traditionally required abiotic pre-treatment, but now Bertocchini and colleagues report two wax worm enzymes capable of catalyzing this oxidation and subsequent degradation at room temperature.
- A. Sanluis-Verdes
- P. Colomer-Vidal
- F. Bertocchini
ArticleOpen Access4 Oct 2022 Nature Communications
Complex genomic patterns of abasic sites in mammalian DNA revealed by a high-resolution SSiNGLe-AP method

Abasic (AP) sites represent a prominent type of DNA damage, yet the genomics of this lesion remains unexplored. Here, the authors report a method to map such sites at the nucleotide level in complex genomes and use it to extract complex age- and tissue-dependent patterns of AP sites in mammals.
- Ye Cai
- Huifen Cao
- Philipp Kapranov
ArticleOpen Access5 Oct 2022 Nature Communications
A method for multiplexed full-length single-molecule sequencing of the human mitochondrial genome

Accurate analysis of mitochondrial DNA is important for mitochondrial disease clinical research and diagnostics. Here, authors present a method using Cas9 cleavage, nanopore sequencing and a custom pipeline to identify pathogenic variants, deletions and accurately quantify heteroplasmy to below 1%.
- Ieva Keraite
- Philipp Becker
- Ivo Glynne Gut
ArticleOpen Access6 Oct 2022 Nature Communications
A blind benchmark of analysis tools to infer kinetic rate constants from single-molecule FRET trajectories

The ability to infer quantitative kinetic information from single-molecule FRET (smFRET) data can be challenging. Here the authors perform a blind benchmark study assessing different analysis tools used to infer kinetic rate constants from smFRET trajectories, testing on simulated and experimental data.
- Markus Götz
- Anders Barth
- Sonja Schmid
ArticleOpen Access14 Sep 2022 Nature Communications
Biosynthesis of plant hemostatic dencichine in Escherichia coli

Biosynthetic pathway of dencichine, a plant derived nature product that has found various pharmacological applications, is still elusive. Here, the authors design artificial pathways through retro-biosynthesis approaches and achieve its efficient production in E. coli by systematic metabolic and enzymatic engineering.
- Wenna Li
- Zhao Zhou
- Qipeng Yuan
ArticleOpen Access19 Sep 2022 Nature Communications
Smart soft contact lenses for continuous 24-hour monitoring of intraocular pressure in glaucoma care

Continuous monitoring of intraocular pressure remains a grand challenge in glaucoma care. Here the authors develop smart soft contact lenses for continuous 24-hour monitoring of intraocular pressure in human eyes, even during sleep.
- Jinyuan Zhang
- Kyunghun Kim
- Chi Hwan Lee
ArticleOpen Access20 Sep 2022 Nature Communications
Screening microbially produced Δ⁹-tetrahydrocannabinol using a yeast biosensor workflow

Microbial production of cannabinoids promises a cheaper and more sustainable route to these important therapeutic molecules, but strain improvement and screening is challenging. Here, the authors develop a yeast-based Δ9-tetrahydrocannabinol (THC) biosensor for screening microbial mutant libraries.
- William M. Shaw
- Yunfeng Zhang
- Tom Ellis
ArticleOpen Access20 Sep 2022 Nature Communications

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