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Article
| Open AccessDeep flanking sequence engineering for efficient promoter design using DeepSEED
Designing promoters with desired properties is crucial in synthetic biology. Here, authors introduce DeepSEED, an AI-aided flanking sequence optimisation framework which combines expert knowledge with deep learning techniques to efficiently design promoters in both eukaryotic and prokaryotic cells.
- Pengcheng Zhang
- , Haochen Wang
- & Xiaowo Wang
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Article
| Open AccessBone disease imaging through the near-infrared-II window
Skeletal disorders are commonly diagnosed by X-ray imaging, but the radiation limits its use. Here, the authors show that intravital NIR-II bone imaging is effective in diagnosis of a series of common bone diseases non-invasively in mice.
- Chao Mi
- , Xun Zhang
- & Dayong Jin
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Article
| Open AccessGLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics
Agonists of the glucagon-like peptide-1 receptor are used to treat diabetes and obesity. Here, Wright et al. investigate the subcellular location of the receptor’s signaling events and uncover associations between signaling profiles and adverse drug reactions.
- Shane C. Wright
- , Aikaterini Motso
- & Volker M. Lauschke
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Article
| Open AccessReversible photoregulation of cell-cell adhesions with opto-E-cadherin
Tools for high spatiotemporal control of cell-cell adhesions are lacking. Here, authors propose an optogenetic tool, opto-E-cadherin, that allows reversible control of E-cadherin-mediated cell-cell adhesions with blue light.
- Brice Nzigou Mombo
- , Brent M. Bijonowski
- & Seraphine V. Wegner
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Article
| Open AccessFluorescent sensors for imaging of interstitial calcium
The study of interstitial calcium remains challenging due to scarce methodology. Here, authors present ultra-low affinity genetically encoded fluorescent biosensors for monitoring calcium in intercellular spaces in living tissues.
- Ariel A. Valiente-Gabioud
- , Inés Garteizgogeascoa Suñer
- & Oliver Griesbeck
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Article
| Open AccessEstimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence
The authors used mathematical modeling of human data to study how HIV persists despite suppressive antiretroviral therapy. They found that when latently infected CD4+ T cells proliferate or differentiate, they can create HIV DNA and passage it into other subsets. More mature CD4 cell subsets then clear HIV DNA faster.
- Daniel B. Reeves
- , Charline Bacchus-Souffan
- & Peter W. Hunt
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Article
| Open AccessReactivation of a somatic errantivirus and germline invasion in Drosophila ovaries
Yoth et al. report that some mobile retrovirus-like genetic elements, errantiviruses, pose a threat to genome integrity when reactivated in somatic gonadal tissue, showing that they can infect the oocyte and transpose into the germline genome.
- Marianne Yoth
- , Stéphanie Maupetit-Méhouas
- & Emilie Brasset
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Article
| Open AccessEfficient plant genome engineering using a probiotic sourced CRISPR-Cas9 system
In the field of plant genome engineering, new nucleases with improved editing efficiency and alterative PAM requirements are needed. Here, the authors report a probiotic sourced CRISPR-LrCas9 system with similar PAM requirement to Cas12a and show its high efficiencies in various genome editing applications.
- Zhaohui Zhong
- , Guanqing Liu
- & Yong Zhang
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Article
| Open AccessBiomolecular condensates modulate membrane lipid packing and hydration
Nano-environmental probes and advance imaging microscopy provide deep insight into protein phase separation and the interaction of condensates with membranes, revealing that wetting by condensates can modulate membrane lipid packing and hydration.
- Agustín Mangiarotti
- , Macarena Siri
- & Rumiana Dimova
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Article
| Open AccessGlobal mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions
Many types of RNAs are associated with chromatin. Here the authors identify chromatin-bound RNAs and their binding sites in human embryonic stem cells suggesting that most chromatin-associated RNAs act proximal to their encoding loci and single RNAs are unlikely to alter gene expression.
- Charles Limouse
- , Owen K. Smith
- & Aaron F. Straight
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Article
| Open AccessAll-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ
How ROS diffuse and are cleared between mitochondrial compartments governs oxidative stress and cell signaling. Here, authors map the kinetics of ROS dynamics using optogenetics and discover acute ROS transiently elongates mitochondria.
- Shon A. Koren
- , Nada Ahmed Selim
- & Andrew P. Wojtovich
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Article
| Open AccessFEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins
When and how microglia engulf synapses and myelin is still unclear. Here, the authors provide a suite of flow cytometry-based approaches to quantify engulfment, paving the way for high-throughput assessment of microglial function in health and disease.
- Lasse Dissing-Olesen
- , Alec J. Walker
- & Beth Stevens
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Article
| Open AccessPrevious infection with seasonal coronaviruses does not protect male Syrian hamsters from challenge with SARS-CoV-2
Here, the authors analysed immune response to two consecutive coronavirus infections and observed that hamsters infected with seasonal coronaviruses were not protected from COVID-19 despite cross-reactive antibodies. Antiviral and germinal center B cell responses were suppressed but not during SARS-CoV-2 variant infections.
- Magen E. Francis
- , Ethan B. Jansen
- & Alyson A. Kelvin
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Article
| Open AccessTracing immune cells around biomaterials with spatial anchors during large-scale wound regeneration
Skin scarring devoid of dermal appendages has unfavorable effects on aesthetic and physiological functions. Here, the authors present a treatment based on extracellular matrix scaffolds and perform multimodal analysis to highlight the role of Tregs recruited by the biomaterial in mitigating tissue fibrous by suppressing excessive inflammation.
- Yang Yang
- , Chenyu Chu
- & Yili Qu
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Article
| Open AccessDeep learning-enabled realistic virtual histology with ultraviolet photoacoustic remote sensing microscopy
Oncologic tumour resection is not fully accurate. Here the authors report a label-free virtual histological imaging method based on a non-contact, reflection-mode ultraviolet photoacoustic remote sensing and scattering microscope, combined with unsupervised deep learning using a cycle-consistent GAN.
- Matthew T. Martell
- , Nathaniel J. M. Haven
- & Roger J. Zemp
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Article
| Open AccessMaintenance of pluripotency-like signature in the entire ectoderm leads to neural crest stem cell potential
How the neural crest gains its pluripotency-like stem cell potential is unclear. Here, the authors show that the entire post-gastrula ectoderm maintains expression of pluripotency genes, leading to the high stem cell capacity in the neural crest.
- Ceren Pajanoja
- , Jenny Hsin
- & Laura Kerosuo
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Article
| Open AccessEpigenomic analysis of formalin-fixed paraffin-embedded samples by CUT&Tag
Conducting epigenomic studies on FFPE samples is traditionally challenging due to chromatin damage caused due to exposure to formaldehyde. Here, the authors show that an optimisation of their previous CUTAC method allows the production of high-resolution maps of regulatory elements from FFPE samples.
- Steven Henikoff
- , Jorja G. Henikoff
- & Eric C. Holland
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Article
| Open AccessSeasonal pigment fluctuation in diploid and polyploid Arabidopsis revealed by machine learning-based phenotyping method PlantServation
Long-term monitoring of plants in field fluctuating environments remains challenging. Here, the authors develop PlantServation, a machine learning-based phenotyping method, and estimate environmental and genotypic effects on the pigment anthocyanin content of diploid and polyploid Arabidopsis.
- Reiko Akiyama
- , Takao Goto
- & Kentaro K. Shimizu
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Article
| Open AccessmRNA vaccines encoding fusion proteins of monkeypox virus antigens protect mice from vaccinia virus challenge
The authors report mRNA vaccines encoding a fusion protein of MPXV A35R extracellular domain and full-length M1R and observe improved anti-M1R antibody response. The vaccines show enhanced active and passive protection in female mice challenged with a lethal dose of vaccinia virus.
- Fujun Hou
- , Yuntao Zhang
- & Xiaoming Yang
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Article
| Open AccessDistinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor
Genetically encoded dopamine sensors have emerged as an alternative to voltammetry for in vivo dopamine measurements. Here, the authors compare these two methods directly, and document dopamine responses during Pavlovian conditioning across the striatum.
- Armando G. Salinas
- , Jeong Oen Lee
- & David M. Lovinger
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Article
| Open AccessSEPepQuant enhances the detection of possible isoform regulations in shotgun proteomics
Protein isoform quantification in shotgun proteomics is challenging due to the mapping of many peptides to multiple protein isoforms. Here, the authors present a computational method SEPepQuant and demonstrate its utility in revealing protein isoform level regulation in shotgun proteomics.
- Yongchao Dou
- , Yuejia Liu
- & Bing Zhang
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Article
| Open AccessA robust normalized local filter to estimate compositional heterogeneity directly from cryo-EM maps
Heterogeneity in structural biology data includes potentially valuable information about binding and dynamics. Here, the authors devise, validate and demonstrate a method to quantify local heterogeneity in 3D reconstructions.
- Björn O. Forsberg
- , Pranav N. M. Shah
- & Alister Burt
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Article
| Open AccessPlasma metabolomic profiles associated with mortality and longevity in a prospective analysis of 13,512 individuals
The metabolic alterations underpinning aging processes and mortality in humans are not well understood. Here, the authors show that differences in levels of nucleosides, amino acids, and several lipid subclasses can predict mortality and longevity.
- Fenglei Wang
- , Anne-Julie Tessier
- & Marta Guasch-Ferré
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Article
| Open AccessPolyamine detergents tailored for native mass spectrometry studies of membrane proteins
Native mass spectrometry of membrane proteins in commonly used detergents are not ideal for preserving non-covalent interactions. Here, the authors develop new detergents for native MS of intact membrane proteins, opening new opportunities to study membrane proteins in various detergents.
- Yun Zhu
- , Bo-Ji Peng
- & Arthur Laganowsky
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Article
| Open AccessOptimized virtual optical waveguides enhance light throughput in scattering media
Virtual optical waveguide can be potentially utilised in variety of applications that require in situ light steering yet the efficacy is still unclear. Here, the authors show that ultrasonically-sculpted virtual gradient-index waveguides are effective in guiding and confining light inside tissue and other scattering media, and significantly outperform external lenses at this task.
- Adithya Pediredla
- , Matteo Giuseppe Scopelliti
- & Ioannis Gkioulekas
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Article
| Open AccessSHIELD: a platform for high-throughput screening of barrier-type DNA elements in human cells
Chromatin boundary elements are hard to define and characterize. Here the authors report Site-specific Heterochromatin Insertion of Elements at Lamina-associated Domains (SHIELD) for high-throughput screening of barrier-type DNA elements in human cells.
- Meng Zhang
- , Mary Elisabeth Ehmann
- & Huimin Zhao
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Article
| Open AccessHigh-efficiency green management of potato late blight by a self-assembled multicomponent nano-bioprotectant
Unlike the other plant pathogens, Phytophtora infestans, the causative pathogen of potato late blight, can hardly take up dsRNA, which is a key obstacle in using dsRNA for disease control. Here, the authors design a self-assembled multicomponent nano-bioprotectant for potato late blight management.
- Yuxi Wang
- , Mingshan Li
- & Xiaodan Wang
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Article
| Open AccessMetabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection
Gauging the in vivo metabolism of immune cells at the single-cell level has proven challenging. Here the authors use spectral flow cytometry to investigate metabolic profiles in tissue-resident macrophages from several organs and changes in response to helminth infection.
- Graham A. Heieis
- , Thiago A. Patente
- & Bart Everts
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Article
| Open AccessA magneto-activated nanoscale cytometry platform for molecular profiling of small extracellular vesicles
Exosomal PD-L1 (exoPD-L1) is a biomarker predicting immunotherapeutic responses. Here the authors report NanoEPIC, a nanoscale cytometry platform that enables phenotypic sorting and exoPD-L1 profiling from blood plasma by using magnetic-activated ranking to differentiate exosomal subpopulations.
- Kangfu Chen
- , Bill T. V. Duong
- & Shana O. Kelley
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Article
| Open AccesstgCRISPRi: efficient gene knock-down using truncated gRNAs and catalytically active Cas9
CRISPRi is used for gene silencing in mammalian cells. Here the authors report a gene-suppression/activation strategy using active Cas9 complexed with truncated gRNAs (tgCRISPRi/a) without causing DNA cleavage: they use this to repress or activate expression of several target genes throughout somatic tissues in Drosophila melanogaster.
- Ankush Auradkar
- , Annabel Guichard
- & Ethan Bier
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Article
| Open AccessA split and inducible adenine base editor for precise in vivo base editing
TadA deaminases widely used in many base editors lack post-translational control in cells. Here the authors report a split adenine base editor (sABE) using chemically induced dimerisation (CID) to control the catalytic activity of TadA8e and show this can be used for PCSK9 gene editing in the mouse liver.
- Hongzhi Zeng
- , Qichen Yuan
- & Xue Gao
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Article
| Open AccessA strategy for Cas13 miniaturization based on the structure and AlphaFold
Small Cas enzymes are required for therapeutic use. Here the authors report an Interaction, Dynamics and Conservation (IDC) strategy for protein miniaturisation and use this to generate five compact variants of Cas13 based on a combination of IDC strategy and AlphaFold2.
- Feiyu Zhao
- , Tao Zhang
- & Zhanjun Li
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Article
| Open AccessHeterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam
Here, the reaction of the suicide inhibitor sulbactam with the M. tuberculosis β-lactamase (BlaC) is investigated with time-resolved crystallography. Singular Value Decomposition is implemented to extract kinetic information despite changes in unit cell parameters during the time-course of the reaction.
- Tek Narsingh Malla
- , Kara Zielinski
- & Marius Schmidt
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Article
| Open AccessEpigenome-wide association analysis of infant bronchiolitis severity: a multicenter prospective cohort study
DNA methylation patterns that are associated with disease can reveal genes involved in disease etiology. Here, the authors identify blood DNA methylation signatures that are associated with bronchiolitis severity and play important roles in tissues, cells, and pathways.
- Zhaozhong Zhu
- , Yijun Li
- & Kohei Hasegawa
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Article
| Open AccessVisualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography
Antimicrobial peptide mechanism of membrane disruption have not been fully characterized at the cellular level. Here, authors use cryo-electron tomography and AFM to directly visualize the disruption of the outer and inner membranes of Escherichia coli by a de novo-designed peptide.
- Eric H.-L. Chen
- , Chun-Hsiung Wang
- & Rita P.-Y. Chen
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Article
| Open AccessA Type II-B Cas9 nuclease with minimized off-targets and reduced chromosomal translocations in vivo
SpCas9 unintended editing is a major concern. Here the authors report an off-target method using Duplex Sequencing with increased sensitivity for Cas9 mutation detection; they also identify a Cas9 variant of the II-B subfamily with intrinsic high fidelity (PsCas9) and see improved specificity.
- Burcu Bestas
- , Sandra Wimberger
- & Marcello Maresca
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Article
| Open AccessOptogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy
Optogenetics makes use of light-sensitive proteins to control biological processes using light. Here, the authors present an optogenetic system that regulates the cGAS/STING pathway remotely and demonstrate its efficacy in murine tumour models.
- Yaling Dou
- , Rui Chen
- & Yun Huang
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Article
| Open AccessSingle cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A
The mechanism and disease-relevance of pancreatic b-cell heterogeneity remains elusive. Here the authors show that variable HNF1A-FXYD2 activity drives single b-cell heterogeneity at transcriptomic, epigenomic, and electro-physiological levels, which strongly mark the progression of type 2 diabetes.
- Chen Weng
- , Anniya Gu
- & Yan Li
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Article
| Open AccessA deep learning-based stripe self-correction method for stitched microscopic images
Image stitching in fluorescence microscopy can be a hindrance to image quality and to downstream quantitative analyses. Here, the authors propose a deep learning-based stripe self-correction method that corrects diverse stripes and artifacts for stitched microscopic images.
- Shu Wang
- , Xiaoxiang Liu
- & Jianxin Chen
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Article
| Open AccessSystematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation
During preclinical drug development, the ability of cancer cell lines to faithfully model human disease is important for identifying potential therapeutic strategies. Here, using transcriptomic datasets of over 1000 cell lines, the authors evaluate how representative each line is of its cancer type and present their cell line selection tool.
- Han Jin
- , Cheng Zhang
- & Adil Mardinoglu
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Article
| Open AccessLocating causal hubs of memory consolidation in spontaneous brain network in male mice
How long-lasting memory is formed remains incompletely understood. Here, using fMRI and hub silencing, the authors discovered causal network hubs that are instrumental in consolidating memory and contributing to network reorganization.
- Zengmin Li
- , Dilsher Athwal
- & Kai-Hsiang Chuang
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Article
| Open AccessProgrammable RNA detection with CRISPR-Cas12a
Cas12a is widely used in diagnostic platforms. Here the authors show that Cas12a can be programmed to directly detect RNA substrates, this is due to the 3’-end of the crRNA tolerating both RNA and DNA substrates: they use this to report a method, SAHARA, to detect RNA sequences.
- Santosh R. Rananaware
- , Emma K. Vesco
- & Piyush K. Jain
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Article
| Open AccessDemonstrating paths for unlocking the value of cloud genomics through cross cohort analysis
The emergence of large-scale genomics projects has led to genetic studies across cohorts. Here, the authors conduct genome-wide association studies meta-analyzing in trusted research environments or pooling together and find similar, but not identical results.
- Nicole Deflaux
- , Margaret Sunitha Selvaraj
- & Alexander G. Bick
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Article
| Open AccessCRUSTY: a versatile web platform for the rapid analysis and visualization of high-dimensional flow cytometry data
CRUSTY is an interactive webtool for flow cytometry data analysis, offering popular algorithms and visualizations, and generating publication-quality figures in minutes. It enables users without bioinformatics expertize to mine complex datasets, supports real-time exploration, and is freely available online.
- Simone Puccio
- , Giorgio Grillo
- & Enrico Lugli
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Article
| Open AccessLrig1-expression confers suppressive function to CD4+ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis
Regulatory T cells, and to certain extent other T cell subsets, limit the immune response to avoid harmful inflammation and tissue damage. Here authors identify a surface molecule, Lrig1, that is directly responsible for the suppressive function in regulatory T cells and in Il-17-producing helper T cells.
- Jae-Seung Moon
- , Chun-Chang Ho
- & Sang-Kyou Lee
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Article
| Open AccessEnhancing photosynthetic CO2 fixation by assembling metal-organic frameworks on Chlorella pyrenoidosa
Concentrating CO2 around Rubisco is critical to improve photosynthetic efficiency for biomass yield. Here, the authors report the self-assembly of metal-organic frameworks (MOFs) on the surface of green alga Chlorella pyrenoidosa to enhance the photosynthetic carbon fixation.
- Dingyi Li
- , Hong Dong
- & Can Li
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Article
| Open AccessTranscranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans
The neural mechanisms underlying transcranial ultrasound stimulation (TUS) in humans are not well understood. Here, the authors show that theta-burst stimulation reduces gamma-aminobutyric acid (GABA) levels in the posterior cingulate cortex, as well as increasing functional connectivity in the anterior and posterior cingulate cortex.
- Siti N. Yaakub
- , Tristan A. White
- & Elsa F. Fouragnan
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Article
| Open AccessNext generation synthetic memory via intercepting recombinase function
Memory is a basic tenet of intelligent biological systems. Here the authors engineered a programmable and expandable iteration of recombinase-based synthetic memory (interception) that functions post-translation, resulting in faster recombination.
- Andrew E. Short
- , Dowan Kim
- & Corey J. Wilson
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Article
| Open AccessFeasibility of an implantable bioreactor for renal cell therapy using silicon nanopore membranes
An implantable bioartificial kidney with a cell-containing bioreactor could be used to treat end-stage renal disease. Here the authors demonstrate the feasibility of an implantable bioreactor by maintaining human cell viability and functionality after implantation in a xenograft model.
- Eun Jung Kim
- , Caressa Chen
- & Shuvo Roy
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