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| Open AccessLogical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes
Descriptive data in biomedical research are expanding rapidly, but functional validation methods lag behind. Here, authors present Logical Synthetic cis-regulatory DNA, a framework to design reporters that mark cellular states and pathways, showcasing its applicability to complex phenotypic states.
- Carlos Company
- , Matthias Jürgen Schmitt
- & Gaetano Gargiulo
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Article
| Open AccessMechanically resilient hybrid aerogels containing fibers of dual-scale sizes and knotty networks for tissue regeneration
Aerogels are suitable for soft tissue engineering, but often come with brittleness. Here the authors develop a hybrid aerogel with micro- and nanofiber networks that optimizes tensile moduli and fracture energies and show that these materials are super-elastic, fostering rapid tissue ingrowth and allowing minimally invasive procedures.
- S. M. Shatil Shahriar
- , Alec D. McCarthy
- & Jingwei Xie
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Article
| Open AccessThe impacts of active and self-supervised learning on efficient annotation of single-cell expression data
Cell type annotation for single-cell data is challenging. Here, authors explore active and self-supervised learning and introduce adaptive reweighting as a tailored heuristic, demonstrating competitive performance and showing that incorporating prior knowledge enhances cell type annotation accuracy.
- Michael J. Geuenich
- , Dae-won Gong
- & Kieran R. Campbell
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Article
| Open AccessMicropillar arrays, wide window acquisition and AI-based data analysis improve comprehensiveness in multiple proteomic applications
Obtaining a comprehensive proteomic profile for complex samples is still an elusive task. Here, the authors present an LC-MS/MS workflow including micropillar arrays, wide isolation windows and AI-based data analysis to boost proteomic coverage and throughput for multiple proteomic samples.
- Manuel Matzinger
- , Anna Schmücker
- & Rupert L. Mayer
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Article
| Open AccessSystems engineering of Escherichia coli for high-level glutarate production from glucose
Glutarate is a platform chemical widely used in the production of polyesters and polyamindes. Here, the authors design the shortest and thermodynamically favorable pathway, and increase glutarate production from glucose through systematic engineering of E. coli.
- Zhilan Zhang
- , Ruyin Chu
- & Cong Gao
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Article
| Open AccessTuning oxidant and antioxidant activities of ceria by anchoring copper single-site for antibacterial application
Nanozymes used for antibacterial therapy conventionally have complex catalytic activities that cause multiple pathways in parallel and unwanted outcome. Here, the authors report a Cu-CeO2 single site nanozyme in which Cu single site modification can enhance the peroxidase-like activity and inhibit the hydroxyl radical antioxidant capacity of CeO2 to optimise the antibacterial effects.
- Peng Jiang
- , Ludan Zhang
- & Yuguang Wang
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Article
| Open AccessA sequence-aware merger of genomic structural variations at population scale
Existing tools for structural variations (SVs) calling and merging often lead to fragmented SVs and the potential of introducing unnecessary errors. Here, the authors report the PanPop pipeline to address these issues by implementing sequence-aware SV merging algorithm to efficiently merge SVs of various types.
- Zeyu Zheng
- , Mingjia Zhu
- & Yongzhi Yang
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Article
| Open AccessAnti-CRISPR Anopheles mosquitoes inhibit gene drive spread under challenging behavioural conditions in large cages
CRISPR-based gene drives have the potential to spread within populations and are considered as promising vector control tools. Here the authors show an anti-drive mosquito strain that prevents the spread and collapse of a population suppression gene drive in laboratory Anopheles mosquito large cage trials in complex ecological and behavioral conditions.
- Rocco D’Amato
- , Chrysanthi Taxiarchi
- & Ruth Müller
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Article
| Open AccessMultiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo
Dysregulation of alternative polyadenylation (APA) is associated with poor prognosis in cancer but its functional role is less clear. Here, the authors develop a CRISPR-Cas9- based screen to determine the effects of different APA events on melanoma growth in mouse models.
- Austin M. Gabel
- , Andrea E. Belleville
- & Robert K. Bradley
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Article
| Open AccessBacterial protoplast-derived nanovesicles carrying CRISPR-Cas9 tools re-educate tumor-associated macrophages for enhanced cancer immunotherapy
CRISPR-Cas9 genome editing systems have great potential in cancer therapy. Here the authors report a gene-editing delivery system using functionalized nanovesicles derived from E. coli protoplasts to encapsulate Cas9-sgRNA ribonucleoprotein for the selective targeting of Pik3cg in tumor associated macrophages.
- Mingming Zhao
- , Xiaohui Cheng
- & Junfeng Zhang
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Article
| Open AccessDeepFocus: fast focus and astigmatism correction for electron microscopy
High-throughput electron microscopy demands minimal human intervention and high image quality. Here, authors introduce DeepFocus, a data-driven method for aberration correction in electron microscopy, robust for low SNR images, fast and easily adaptable to microscopes and samples. Peer Review Information: Nature Communications thanks Yang Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
- P. J. Schubert
- , R. Saxena
- & J. Kornfeld
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Article
| Open AccessTwo way workable microchanneled hydrogel suture to diagnose, treat and monitor the infarcted heart
Myocardial infarction can lead to malignant arrhythmia and myocardial remodeling. Here, the authors report a microchanneled hydrogel suture for two-way signal communication, pumping drugs on demand, and cardiac repair.
- Fangchao Xue
- , Shanlan Zhao
- & Wen Zeng
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Article
| Open AccessUtility of long-read sequencing for All of Us
Using All of Us pilot data, the authors compared short- and long-read performance across medically relevant genes and showcased the utility of long reads to improve variant detection and phasing in easy and hard to resolve medically relevant genes.
- M. Mahmoud
- , Y. Huang
- & F. J. Sedlazeck
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Article
| Open AccessNuclear and cytoplasmic specific RNA binding proteome enrichment and its changes upon ferroptosis induction
The reported assay shows a subcellular-specific RNA labeling method for efficient enrichment and deep profiling of nuclear and cytoplasmic RBPs, the authors apply this to investigate changes of subcellular-specific RBP-RNA interactions in ferroptosis.
- Haofan Sun
- , Bin Fu
- & Weijie Qin
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Article
| Open AccessSemi-supervised integration of single-cell transcriptomics data
Batch effects hinder multi-sample single-cell data analyses. Here, authors present STACAS, a scalable single-cell RNA-seq data integration tool that uses prior cell type knowledge to preserve biological variability, demonstrating robustness to noisy input cell type labels.
- Massimo Andreatta
- , Léonard Hérault
- & Santiago J. Carmona
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Article
| Open AccessCatalytic carbon–carbon bond cleavage in lignin via manganese–zirconium-mediated autoxidation
Efforts to produce aromatic monomers through catalytic lignin depolymerization were focused on aryl–ether bond cleavage, while the carbon–carbon bonds of a large fraction of aromatic monomers in lignin are difficult to cleave. Here, the authors report a catalytic autoxidation method using manganese and zirconium salts as catalysts to cleave the C–C bonds in lignin-derived dimers and oligomers from pine and poplar.
- Chad T. Palumbo
- , Nina X. Gu
- & Gregg T. Beckham
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Article
| Open AccessEngineering a transposon-associated TnpB-ωRNA system for efficient gene editing and phenotypic correction of a tyrosinaemia mouse model
Miniature gene editing tools are highly desired for efficient in vivo delivery and disease treatment. Here, the authors reported engineering hypercompact TnpB-ωRNA for robust gene editing with minimal off-target effect in cultured cells and use it to rescue fatal genetic liver disease in a tyrosinaemia mouse model.
- Zhifang Li
- , Ruochen Guo
- & Chunlong Xu
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Article
| Open AccessIn-situ-sprayed therapeutic hydrogel for oxygen-actuated Janus regulation of postsurgical tumor recurrence/metastasis and wound healing
Surgery is a primary therapeutic modality for treating melanoma, but it is challenging to tackle tumor recurrence/metastasis and postsurgical wounds. Here the authors report a sprayable hydrogel capable of long-lasting and controllable oxygen supply for preventing tumor recurrence/metastasis and simultaneously promoting wound healing during the postsurgical treatment of melanoma.
- Shuiling Chen
- , Yang Luo
- & Shaobing Zhou
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Article
| Open AccessChemically-defined and scalable culture system for intestinal stem cells derived from human intestinal organoids
Challenges in reproducibility and large-scale expansion limit the current applicability of human intestinal organoids. Here, the authors present a feeder-free, chemically-defined culture method for enrichment of intestinal stem cells isolated from 3D human intestinal organoids.
- Ohman Kwon
- , Hana Lee
- & Mi-Young Son
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Article
| Open AccessNon-invasive transdermal delivery of biomacromolecules with fluorocarbon-modified chitosan for melanoma immunotherapy and viral vaccines
Different approaches have been described for the transdermal delivery of drugs. Here the authors report the design of a fluorocarbon modified chitosan-based non-invasive transdermal platform for the delivery of biomacromolecules, such as viral antigens for vaccines or immune checkpoint inhibitors for melanoma immunotherapy.
- Wenjun Zhu
- , Ting Wei
- & Zhuang Liu
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Article
| Open AccessLarge-scale genomic rearrangements boost SCRaMbLE in Saccharomyces cerevisiae
Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution (SCRaMbLE) is a promising tool to study genomic rearrangements. Here the authors present an engineered yeast strain with 83 sparsely distributed loxPsym sites across the genome can genrerate large-scale genomic rearrangements, which benefits cell fitness under stress and boosts the SCRaMbLE system when combined with synthetic chromosomes.
- Li Cheng
- , Shijun Zhao
- & Junbiao Dai
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Article
| Open AccessCompositional and temporal division of labor modulates mixed sugar fermentation by an engineered yeast consortium
Synthetic microbial communities are suitable for mixed substrates fermentation and long metabolic pathway engineering. Here, the authors combine fermentation experiments with mathematical modeling to reveal the effect of compositional and temporal changes on division of labor in cellulosic ethanol production using two yeast strains.
- Jonghyeok Shin
- , Siqi Liao
- & Yong-Su Jin
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Article
| Open AccessSiFT: uncovering hidden biological processes by probabilistic filtering of single-cell data
Cells simultaneously encode multiple signals, some harder to recover. Here, authors introduce SiFT (Signal FilTering), a kernel-based projection method, revealing underlying biological processes in single-cell data.
- Zoe Piran
- & Mor Nitzan
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Article
| Open AccessA multiplexed, confinable CRISPR/Cas9 gene drive can propagate in caged Aedes aegypti populations
Aedes aegypti is the main vector of several major pathogens including dengue, Zika and chikungunya viruses. Here the authors find that a CRISPR/Cas9 based split gene drive in Aedes aegypti could successfully bias inheritance up to 89% over successive generations in a multi-cage trial with further deep sequencing suggesting that the multiplexing design could mitigate resistance allele formation.
- Michelle A. E. Anderson
- , Estela Gonzalez
- & Luke Alphey
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Article
| Open AccessA drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues
The efficacy of drug-eluting stents remains limited due to delayed reendothelialization, impaired intimal remodeling, and potentially increased late restenosis. Here the authors propose a one-produces-multi stent coating, a drug-free strategy that supports in situ healing of vascular tissues, as demonstrated in rabbit and porcine models.
- Haoshuang Wu
- , Li Yang
- & Yunbing Wang
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Article
| Open AccessLNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing
Adipose stem cells are promising therapeutic agents in tissue regeneration. Here the authors develop a lipid nanoparticle/RNA engineering platform to enhance the protein production of these cells, which demonstrate superior healing efficacy in a mouse model of diabetic cutaneous wounds.
- Yonger Xue
- , Yuebao Zhang
- & Yizhou Dong
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Article
| Open AccessRapid and visual identification of β-lactamase subtypes for precision antibiotic therapy
The rapid identification of drug-resistant bacteria is vital for effective treatment and to avoid antibiotic misuse. Here authors report a paper-based sensor which utilises chromogenic carbapenem and cephalosporin substrates for the identification and discrimination of β-lactamase subtypes.
- Wenshuai Li
- , Jingqi Li
- & Dingbin Liu
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Article
| Open AccessRational strain design with minimal phenotype perturbation
No consensus exists on the computationally tractable use of dynamic models for strain design. To tackle this, the authors report a framework, nonlinear-dynamic-model-assisted rational metabolic engineering design, for efficiently designing robust, artificially engineered cellular organisms.
- Bharath Narayanan
- , Daniel Weilandt
- & Vassily Hatzimanikatis
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Article
| Open AccessDNA mechanocapsules for programmable piconewton responsive drug delivery
The mechanical dysregulation of cells is associated with several diseases and strategies to deliver drugs based on the “mechanical phenotype” of a cell are desirable. Here, the authors design and characterize DNA mechanocapsules comprised of DNA tetrahedrons that are force responsive, and showed they can encapsulate macromolecular cargo and release it upon application of force.
- Arventh Velusamy
- , Radhika Sharma
- & Khalid Salaita
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Article
| Open AccessProgrammable RNA base editing with photoactivatable CRISPR-Cas13
Cas13 systems suffer from a lack of spatiotemporal control. Here the authors report paCas13, a light-inducible Cas13 system created by fusing Magnet with fragment pairs; they also report padCas13, a light-inducible base-editing system by fusing ADAR2 to catalytically inactive paCas13 fragments.
- Jeonghye Yu
- , Jongpil Shin
- & Won Do Heo
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| Open AccessA bumpy road ahead for genetic biocontainment
While the research community continues to develop novel proposals for intrinsic biocontainment of genetically engineered organisms, translation to real-world deployment faces several challenges.
- Dalton R. George
- , Mark Danciu
- & Emma K. Frow
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Article
| Open AccessInterindividual- and blood-correlated sweat phenylalanine multimodal analytical biochips for tracking exercise metabolism
The in-depth study on the sweat–blood partitioning mechanisms of amino acids is promising for noninvasive metabolic monitoring. Here, the authors develop a wearable biochip for sweat phenylalanine multimodal analysis aimed at tracking exercise metabolic risk and exploring the sweat–blood correlation.
- Bowen Zhong
- , Xiaokun Qin
- & Lili Wang
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Article
| Open Accessi-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists
In contrast to their clinical success as inhibitors and targeting agents, antibodies have generally been ineffective as receptor agonists. Here, Romei et al. leverage a natural homotypic interface to tune antibody geometry, enabling optimization of agonist activity for multiple therapeutic targets.
- Matthew G. Romei
- , Brandon Leonard
- & Greg A. Lazar
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Article
| Open AccessEngineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
There is an unmet medical need for the detection and treatment of early adenomas to prevent their progression to malignant disease. Here the authors show that orally administered E. coli Nissle 1917 can selectively colonize adenomas in mouse models and in patients as a detection tool, as well as deliver immunotherapeutics for colorectal neoplasia treatment.
- Candice R. Gurbatri
- , Georgette A. Radford
- & Tal Danino
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Article
| Open AccessDual electrical stimulation at spinal-muscular interface reconstructs spinal sensorimotor circuits after spinal cord injury
Electrical signals with characteristic parameters for reconstructing neural circuits remain incompletely understood, limiting the therapeutic potential of electrical neuromodulation techniques. Here, the authors demonstrate that dual electrical stimulation at 10–20 Hz rebuilds the spinal sensorimotor neural circuit after spinal cord injury, indicating the characteristic signals of circuit remodeling.
- Kai Zhou
- , Wei Wei
- & Yaobo Liu
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Article
| Open AccessSoluble and multivalent Jag1 DNA origami nanopatterns activate Notch without pulling force
The Notch receptor is known to be activated by a pulling force, but whether it is strictly required remains to be clarified. Here, the authors demonstrate activation of Notch through soluble multivalent DNA origami constructs, showing effects in neuroepithelial-like stem cells.
- Ioanna Smyrlaki
- , Ferenc Fördős
- & Björn Högberg
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Article
| Open AccessNanoparticle-based DNA vaccine protects against SARS-CoV-2 variants in female preclinical models
Here the authors screen different lipid nanoparticle (LNP) formulations for intramuscular delivery of plasmid DNA and uptake by antigen-presenting cells. The lead LNP exhibits immunogenicity and protection in small animal models that is comparable to approved SARS-CoV-2 mRNA vaccine formulations.
- Lays Cordeiro Guimaraes
- , Pedro Augusto Carvalho Costa
- & Pedro Pires Goulart Guimaraes
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Article
| Open AccessPROST: quantitative identification of spatially variable genes and domain detection in spatial transcriptomics
Understanding biological mechanisms requires a thorough exploration of spatiotemporal transcriptional patterns in complex tissues. Here, authors present PROST to quantify spatial gene expression patterns and detect spatial domains using spatial transcriptomics data of varying resolutions.
- Yuchen Liang
- , Guowei Shi
- & Zhonghui Tang
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Article
| Open AccessFlexible, scalable, high channel count stereo-electrode for recording in the human brain
Electrodes available for deep brain recording and stimulation have a number of limitations. Here the authors describe a thin-film depth electrode that may offer improved spatial and temporal resolution for recording brain activity.
- Keundong Lee
- , Angelique C. Paulk
- & Shadi. A. Dayeh
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Article
| Open AccessEmbryos assist morphogenesis of others through calcium and ATP signaling mechanisms in collective teratogen resistance
The collective activity of cells enables embryos to overcome various perturbations. Here, authors show that at the higher (population) level, embryos also communicate. This enables larger groups to resist chemical and molecular-genetic teratogens.
- Angela Tung
- , Megan M. Sperry
- & Michael Levin
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Article
| Open AccessAntibody-dependent enhancement of toxicity of myotoxin II from Bothrops asper
The recent emergence of monoclonal antibodies able to neutralize snake toxins have revolutionized the approach of developing novel therapies to treat snakebite envenoming, at least in animal models. Here, the authors show antibody-dependent enhancement of toxicity (ADET) for a toxin derived from snake venom and highlight the importance of this phenomenon when testing therapeutic antibodies against snake venoms in animal models.
- Christoffer V. Sørensen
- , Julián Fernández
- & Andreas H. Laustsen
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Article
| Open AccessEnhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation
Achieving targeted drug delivery for calcified aortic valve is challenging. Here, the authors find that protease activated receptor 2 (PAR2) is up-regulated on calcified valves and develop a magnetic nanocarrier functionalized with PAR2-targeting peptide for dual-active drug delivery.
- Jinyong Chen
- , Tanchen Ren
- & Xianbao Liu
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Article
| Open AccessReprogramming mechanism dissection and trophoblast replacement application in monkey somatic cell nuclear transfer
Somatic cloning of rhesus monkey has not been successful until now. Here, authors report epigenetic abnormalities in SCNT embryos and placentas and develop a trophoblast replacement method that enables them to successful clone of a healthy male rhesus monkey.
- Zhaodi Liao
- , Jixiang Zhang
- & Qiang Sun
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Article
| Open AccessFlexible switch matrix addressable electrode arrays with organic electrochemical transistor and pn diode technology
Organic neural implants hold considerable promise for biocompatible neural interfaces. Here, the authors employ polymer-based organic electrochemical diodes and transistors to develop neuron-sized complex circuits, enabling multiplexing without crosstalk and demonstrate that, when integrated onto ultra-thin plastic, these circuits achieve high performance while maintaining minimal invasiveness.
- Ilke Uguz
- , David Ohayon
- & Kenneth L. Shepard
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Article
| Open AccessA self-powered intracardiac pacemaker in swine model
Harvesting biomechanical energy from cardiac motion is an attractive power source for implantable bioelectronic devices. Here, the authors report a battery-free, transcatheter, self-powered intracardiac pacemaker for the treatment of arrhythmia in large animal models.
- Zhuo Liu
- , Yiran Hu
- & Zhong Lin Wang
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Article
| Open AccessDigital automation of transdermal drug delivery with high spatiotemporal resolution
Microneedle patches that can actively address individual needles are challenging to realize. Here, the authors introduce a spatiotemporal on-demand patch for precise and personalized drug delivery, utilizing electrically triggered control with drug-loaded microneedles and biocompatible metallic membranes.
- Yihang Wang
- , Zeka Chen
- & Wubin Bai
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Article
| Open AccessBIDCell: Biologically-informed self-supervised learning for segmentation of subcellular spatial transcriptomics data
Subcellular in situ spatial transcriptomics offers the promise to address biological problems that were previously inaccessible but requires accurate cell segmentation to uncover insights. Here, authors present BIDCell, a biologically informed, deep learning-based cell segmentation framework.
- Xiaohang Fu
- , Yingxin Lin
- & Jean Y. H. Yang
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Article
| Open AccessDirect RNA sequencing coupled with adaptive sampling enriches RNAs of interest in the transcriptome
It can be difficult to find rare transcripts when sequencing a transcriptome. Here the authors show adaptive sampling on direct RNA runs to increase the likelihood of finding less frequent ones while selectively ejecting the higher-abundance transcripts.
- Jiaxu Wang
- , Lin Yang
- & Yue Wan
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Article
| Open AccessDe novo biosynthesis of antiarrhythmic alkaloid ajmaline
Ajmaline is an antiarrhythmic monoterpenoid indole alkaloid produced by the root of Rauwolfia serpentina. Here, the authors complete the ajmaline biosynthetic pathway by identifying two reductases and two esterases, and achieve the de novo ajmaline biosynthesis by engineering Baker’s yeast.
- Jun Guo
- , Di Gao
- & Yang Qu
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