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| Open AccessA high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS)
Synthetic promoters can be superior to native ones but the design is challenging without knowledge of gene regulation. Here the authors develop a pipeline that allows for screening a synthetic promoter library to identify high performance promoters in potentially any given cell state of interest.
- Ming-Ru Wu
- , Lior Nissim
- & Timothy K. Lu
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Article
| Open AccessTranscriptome and organellar sequencing highlights the complex origin and diversification of allotetraploid Brassica napus
Despite the economic importance of the allotetraploid crop Brassica napus, our knowledge of its phylogenomic relationships, genetic structure, and diversification is limited. Here, the authors show its complex origin and diversification by analyzing transcriptome and organellar sequencing data.
- Hong An
- , Xinshuai Qi
- & J. Chris Pires
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Article
| Open AccessArtificial coiled coil biomineralisation protein for the synthesis of magnetic nanoparticles
Proteins have been used in the synthesis of magnetic nanoparticles but issues with aggregation limit this application. Here, the authors report on the synthesis of coiled proteins that display the active loop of the natural proteins to avoid aggregation and investigate the application in nanoparticle synthesis.
- Andrea E. Rawlings
- , Lori A. Somner
- & Sarah S. Staniland
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Article
| Open AccessNIR-light-mediated spatially selective triggering of anti-tumor immunity via upconversion nanoparticle-based immunodevices
The use of immunotherapy can be limited by adverse side effects. In this study, the authors designed a nanodevice that spatiotemporally controlled activate immunomodulatory agents at the tumour site upon near-infrared light triggering, thus preventing systemic toxicity with maintained efficacy
- Hongqian Chu
- , Jian Zhao
- & Lele Li
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Article
| Open AccessGenerating viable mice with heritable embryonically lethal mutations using the CRISPR-Cas9 system in two-cell embryos
Roughly 25% of mouse genes are embryonically lethal when knocked out, preventing the generation of viable mouse models. Here the authors use CRISPR-Cas9 to edit one blastomere of a two-cell embryo to generate viable chimeric mice.
- Yi Wu
- , Jing Zhang
- & Songlin Wang
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Article
| Open AccessEfficient base editing for multiple genes and loci in pigs using base editors
Base editors can efficiently produce single nucleotide alterations without requiring a double-strand break. Here the authors show base editing at multiple sites simultaneously in pigs.
- Jingke Xie
- , Weikai Ge
- & Liangxue Lai
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Article
| Open AccessCRISPR-Cas9 fusion to dominant-negative 53BP1 enhances HDR and inhibits NHEJ specifically at Cas9 target sites
Global inhibition of NHEJ factors has been one strategy to improve CRISPR-Cas9 mediated HDR. Here the authors fuse a dominant-negative mutant of 53BP1 to Cas9 to enhance HDR frequency, reduce NHEJ specifically at the Cas9 cut sites, and reduce the toxicity associated with global NHEJ inhibition.
- Rajeswari Jayavaradhan
- , Devin M. Pillis
- & Punam Malik
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Article
| Open AccessA split fluorescent reporter with rapid and reversible complementation
Monitoring protein-protein interactions via bimolecular fluorescence complementation is often limited by the slow kinetics and irreversibility of the complementation. Here the authors introduce a fluorescent reporter for real-time monitoring of reversible interactions based on complementation and binding of an exogenous chromophore.
- Alison G. Tebo
- & Arnaud Gautier
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Article
| Open AccessRegulating intracellular fate of siRNA by endoplasmic reticulum membrane-decorated hybrid nanoplexes
The silencing efficiency of siRNA delivered by non-viral cationic vectors is limited due to endosomal/lysosomal degradation. Here, the authors develop endoplasmic reticulum-coated vesicles as a biomimetic vector for siRNA delivery and show that they improve inhibition of tumor growth in mice in vivo.
- Chong Qiu
- , Hu-Hu Han
- & Qiang Zhang
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Article
| Open AccessGraphene oxide enabled long-term enzymatic transesterification in an anhydrous gas flux
Implementing enzymatic reactions in gas phase has several limitations. Here, the authors report on a method to overcome these using graphene oxide aerogels to immobilize lipase, improve stability/lifetime and investigate the mechanism for improved function.
- Weina Xu
- , Zhongwang Fu
- & Zheng Liu
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Article
| Open AccessRegulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters
Chimeric antigen receptor (CAR) T cell anti-cancer therapies might result in toxic side effects. Here the authors present a strategy based on the modulation of CAR T cells via administration of a bispecific adapter that target them to cancer cells, resulting in diminished CAR-T cells toxicity and enhanced solid tumor eradication.
- Yong Gu Lee
- , Haiyan Chu
- & Philip S. Low
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Article
| Open AccessProgrammable mutually exclusive alternative splicing for generating RNA and protein diversity
Alternative splicing expands the genetic coding capacity and proteomic diversity of the cell. Here the authors create a synthetic biology platform for regulating four programmable exons in modular transcription factors.
- Melina Mathur
- , Cameron M. Kim
- & Christina D. Smolke
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Article
| Open AccessChromatin interaction maps reveal genetic regulation for quantitative traits in maize
Spatial organization of regulatory elements and its impact on gene expression in plants remain unclear. Here, the authors construct maize chromatin interaction maps using chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) and show their associations with gene expression and agronomic traits.
- Yong Peng
- , Dan Xiong
- & Xingwang Li
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Article
| Open AccessLong-range interactions between proximal and distal regulatory regions in maize
Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) can discover specific protein-centered chromatin interactions in high resolution. Here, the authors use ChIA-PET to reveal the complex and dynamic interactions between proximal and distal regulatory regions of genes in maize.
- En Li
- , Han Liu
- & Jinsheng Lai
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Article
| Open AccessCOMPASS for rapid combinatorial optimization of biochemical pathways based on artificial transcription factors
Metabolic engineering requires the balancing of gene expression to obtain optimal output. Here the authors present COMPASS – COMbinatorial Pathway ASSembly – which uses plant-derived artificial transcription factors and cloning of thousands of DNA constructs in parallel to rapidly optimise pathways.
- Gita Naseri
- , Jessica Behrend
- & Bernd Mueller-Roeber
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Article
| Open AccessSimulating multiple faceted variability in single cell RNA sequencing
Simulated single cell RNA sequencing data is useful for method development and comparison. Here, the authors developed SymSim, a simulator that explicitly models the main factors of variation in single cell data.
- Xiuwei Zhang
- , Chenling Xu
- & Nir Yosef
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Article
| Open AccessHypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies
In vitro blood-brain barrier (BBB) models do not fully recapitulate the in vivo barrier function. Here the authors develop an organ-on-a-chip BBB model using iPS-derived human brain endothelial cells differentiated under hypoxia, primary human pericytes and astrocytes, which maintains in vivo-like BBB barrier and shuttling functions for a week.
- Tae-Eun Park
- , Nur Mustafaoglu
- & Donald E. Ingber
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Article
| Open AccessVariation of a major facilitator superfamily gene contributes to differential cadmium accumulation between rice subspecies
Grain of indica rice accumulates more toxic cadmium (Cd) than japonica, but the underlying genetic basis is unclear. Here, the authors show that natural variation of OsCd1 contributes to divergence in grain Cd accumulation and transferring japonica allele to indica rice leads to reduced Cd accumulation.
- Huili Yan
- , Wenxiu Xu
- & Zhenyan He
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Article
| Open AccessAn asymmetric allelic interaction drives allele transmission bias in interspecific rice hybrids
Our limited understanding of the hybrid sterility (HS) mechanism in Asian–African rice hybrids hampers utilization of the interspecific heterosis for rice production. Here, the authors identify S1-mediated HS-related tripartite gamete killer-protector system, and explore their evolutionary relationship.
- Yongyao Xie
- , Jintao Tang
- & Letian Chen
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Article
| Open AccessVibrio sp. dhg as a platform for the biorefinery of brown macroalgae
Brown macroalgae is a good candidate feedstock for biorefinery, but the major carbohydrate alginate cannot be digested by current industrial microbes. Here, the authors isolate Vibrio sp. dhg and engineer it to produce value-added biochemicals from alginate using newly developed genetic tools.
- Hyun Gyu Lim
- , Dong Hun Kwak
- & Gyoo Yeol Jung
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Article
| Open AccessTerminator-free template-independent enzymatic DNA synthesis for digital information storage
Adoption of DNA as a data storage medium could be accelerated with specialized synthesis processes and codecs. The authors describe TdT-mediated DNA synthesis in which data is stored in transitions between non-identical nucleotides and the use of synchronization markers to provide error tolerance.
- Henry H. Lee
- , Reza Kalhor
- & George M. Church
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Article
| Open AccessThe viral protein corona directs viral pathogenesis and amyloid aggregation
The protein corona around artificial nanoparticles is known to influence activity and biological fate, the formation around viruses is less well understood. Here, the authors observe the formation of protein corona on viruses and study the effects this corona has on viral infectivity and on amyloid protein assembly.
- Kariem Ezzat
- , Maria Pernemalm
- & Samir EL Andaloussi
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Article
| Open AccessDevelopment of an immunodeficient pig model allowing long-term accommodation of artificial human vascular tubes
The development of tissue-engineered vascular grafts heavily relies on the availability of large animal models that allow long-term assessment of graft patency. Here Itoh et al. propose a novel model of immunodeficient pigs that allows long-term accommodation of human cell-derived three-dimensional bioprinted vascular tubes.
- Manabu Itoh
- , Yosuke Mukae
- & Eiji Kobayashi
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Article
| Open AccessOptimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
Agonistic 4-1BB antibodies developed for cancer immunotherapy have suffered from either hepatotoxicity or insufficient anti-cancer activity. Here the authors determine the contribution of FcγR binding and agonistic strength to these outcomes, and engineer a 4-1BB antibody with potent anti-tumor effect and no liver toxicity in mice.
- Xinyue Qi
- , Fanlin Li
- & Xuanming Yang
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Article
| Open AccessDNA-templated synthesis of biomimetic cell wall for nanoencapsulation and protection of mammalian cells
The creation of protective barriers around cells is of interest for a range of applications. Here, the authors report on the creation of DNA templated alginate-polylysine biomimetic cell walls for encapsulating and shielding cells, demonstrating protection against physical assaults and immune reactions.
- Peng Shi
- , Nan Zhao
- & Yong Wang
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Article
| Open AccessFunctional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening
Gene fusions are observed in many cancers but their link to tumour fitness is largely unknown. Here, transcriptomic analysis combined with pharmacological and CRISPR-Cas9 screening of cancer cell lines was used to evaluate the functional linkage between fusions and tumour fitness.
- Gabriele Picco
- , Elisabeth D. Chen
- & Mathew J. Garnett
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Article
| Open AccessHydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells
Transcriptome analysis of circulating tumor cells (CTCs) provides insights into monitoring target therapeutics and underlying tumor metastasis. Here the authors present Hydro-Seq, a contamination-free high-throughput hydrodynamic scRNA-seq barcoding technique for rare CTCs.
- Yu-Heng Cheng
- , Yu-Chih Chen
- & Euisik Yoon
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Article
| Open AccessPreclinical safety study of a combined therapeutic bone wound dressing for osteoarticular regeneration
Arthroplasty is the main clinical option for the treatment of osteoarticular lesions, but has limited efficacy. Here, the authors use a wound dressing with autologous mesenchymal stromal cells, functionalised for local BMP2 delivery, and show feasibility and safety in standardised preclinical tests in animal models, suggesting suitability for use in clinical trials.
- Laetitia Keller
- , Luc Pijnenburg
- & Nadia Benkirane-Jessel
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Article
| Open AccessA strongly adhesive hemostatic hydrogel for the repair of arterial and heart bleeds
Uncontrollable bleeding is a major problem in surgery and after trauma. Here the authors design a photo-reactive adhesive that mimics the composition of connective tissue and is able to stop high pressure bleeding within half a minute.
- Yi Hong
- , Feifei Zhou
- & Hongwei Ouyang
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Article
| Open AccessSuppression of a broad spectrum of liver autoimmune pathologies by single peptide-MHC-based nanomedicines
Immune response against tissue-specific antigens is a hallmark of autoimmunity. Here the authors show that a single autoantigen-based nanomedicine can ameliorate pathology in a broad range of liver autoimmunity models without impairing host defenses, suggesting organ-wide tolerization.
- Channakeshava Sokke Umeshappa
- , Santiswarup Singha
- & Pere Santamaria
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Review Article
| Open AccessSynthetic biology strategies for microbial biosynthesis of plant natural products
Engineering microbial cell factories for the production of useful plant natural products (PNPs) is a resource-conserving and environmentally-friendly synthesis route. Here, the authors review recent developments that enable engineering of hosts, pathways, and enzymes to make PNPs and PNP derivatives.
- Aaron Cravens
- , James Payne
- & Christina D. Smolke
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Comment
| Open AccessBuilding a global alliance of biofoundries
Biofoundries provide an integrated infrastructure to enable the rapid design, construction, and testing of genetically reprogrammed organisms for biotechnology applications and research. Many biofoundries are being built and a Global Biofoundry Alliance has recently been established to coordinate activities worldwide.
- Nathan Hillson
- , Mark Caddick
- & Paul S. Freemont
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Article
| Open AccessNanopore blockade sensors for ultrasensitive detection of proteins in complex biological samples
Nanopore sensors have long analysis times when analytes are at low concentration and non-specific signals in complex media. Here the authors use antibody-modified magnetic nanoparticles to detect prostate-specific antigen at sub-femtomolar concentrations in blood.
- Kyloon Chuah
- , Yanfang Wu
- & J. Justin Gooding
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Article
| Open AccessSynthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response
Supraphysiological T cell activation by chimeric antigen receptor (CAR) contributes to T cell exhaustion and adverse events in CAR T cell therapies. Here the authors engineer a synthetic antigen receptor that integrates into the endogenous TCR complex, preserving natural regulatory circuits and achieving improved performance in mouse tumor models.
- Patrick A. Baeuerle
- , Jian Ding
- & Robert Hofmeister
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Article
| Open AccessMicroclot array elastometry for integrated measurement of thrombus formation and clot biomechanics under fluid shear
Blood clotting is a complex process involving platelet adhesion and clot stiffening. Here the authors present a microfluidic system to recapitulate the dynamic changes in clot mechanics under physiological shear.
- Zhaowei Chen
- , Jiankai Lu
- & Ruogang Zhao
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Article
| Open AccessA generic approach towards afterglow luminescent nanoparticles for ultrasensitive in vivo imaging
Afterglow luminescence is used to reduce background noise and increase sensitivity; however, biocompatible afterglow materials are limited. Here, the authors report on an approach to turn standard optical agents into afterglow nanoparticles and demonstrate the application in tumour imagining in vivo.
- Yuyan Jiang
- , Jiaguo Huang
- & Kanyi Pu
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Article
| Open AccessRapid evaluation of bioactive Ti-based surfaces using an in vitro titration method
In vitro testing of implant materials bioactivity is important and the current methods take time. Here, the authors report on the development of a faster titration based method for assessing the mineralization activity of materials and validate the method in vitro and in vivo using titanium surfaces.
- Weitian Zhao
- , David Michalik
- & Paul Bowen
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Article
| Open AccessMechanism-based tuning of insect 3,4-dihydroxyphenylacetaldehyde synthase for synthetic bioproduction of benzylisoquinoline alkaloids
Bioproduction of tetrahydropapaveroline (THP) is limited by the specificity of monoamine oxidase (MAO). Here, the authors identify an insect 3,4-dihydroxyphenylacetaldehyde synthase (DHPAAS) that can bypass MAO for direct aldehyde production and demonstrate bifunctional switching of DHPAAS for efficient THP production.
- Christopher J. Vavricka
- , Takanobu Yoshida
- & Akihiko Kondo
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Article
| Open AccessThe glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells
Lysosomal replacement enzymes are taken up by cell surface receptors that recognize glycans, the effects of different glycan features are unknown. Here the authors present a gene engineering screen in CHO cells that allows custom N-glycan-decorated enzymes with improved circulation time and organ distribution.
- Weihua Tian
- , Zilu Ye
- & Zhang Yang
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Article
| Open AccessRed-shifting mutation of light-driven sodium-pump rhodopsin
Microbial rhodopsins are photoreceptive and widely used in optogenetics for which they should preferable function with longer-wavelength light. Here, authors achieve a 40-nm red-shift in the absorption wavelength of a sodium-pump rhodopsin (KR2) by altering the distribution of the retinal chromophore.
- Keiichi Inoue
- , María del Carmen Marín
- & Hideki Kandori
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Article
| Open AccessDevelopment and application of a high-content virion display human GPCR array
G protein-coupled receptors (GPCRs) are important targets for drug discovery. Here, the authors develop a Virion Display array of 315 functional non-odorant GPCRs, providing a platform for high-throughput, unbiased screening for small molecule drugs, affinity reagents, and microbial interactions.
- Guan-Da Syu
- , Shih-Chin Wang
- & Heng Zhu
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Article
| Open AccessCUT&Tag for efficient epigenomic profiling of small samples and single cells
Understanding gene regulation will require mapping specific chromain features in a small number of cells at high resolution. Here the authors describe CUT&Tag, which uses antibody-mediated tethering of Tn5 transposase to a chromatin protein to generate high resolution libraries.
- Hatice S. Kaya-Okur
- , Steven J. Wu
- & Steven Henikoff
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Article
| Open AccessNear physiological spectral selectivity of cochlear optogenetics
Cochlear implant spectral resolution is limited by current spread from each stimulation electrode. Here the authors compare optogenetic, electric and acoustic stimulation in gerbils and demonstrate improved spectral resolution of optogenetic over conventional electric stimulation.
- Alexander Dieter
- , Carlos J. Duque-Afonso
- & Tobias Moser
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Article
| Open AccessDNA-enabled rational design of fluorescence-Raman bimodal nanoprobes for cancer imaging and therapy
Currently available Raman scanners are limited in speed to acquire images of clinically relevant sizes in cancer imaging. Here, the authors developed a DNA based design principle for Raman-Fluorescence bimodal nanoparticles and demonstrate real-time, high precision image-guided tumor resections and photothermal ablation of cancer.
- Suchetan Pal
- , Angana Ray
- & Moritz F. Kircher
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Article
| Open AccessHigh-resolution specificity profiling and off-target prediction for site-specific DNA recombinases
The development of site-specific recombinases as genome editing tools is limited by the difficulty of altering their DNA sequence specificity. Here the authors present Rec-seq, a method for identifying specificity determinants and off-target substrates of recombinases in an unbiased manner.
- Jeffrey L. Bessen
- , Lena K. Afeyan
- & David R. Liu
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Article
| Open AccessNatural variation of OsGluA2 is involved in grain protein content regulation in rice
Grain protein content determines rice nutrition quality. Here, the authors show that a single nucleotide polymorphism in the promoter region of OsGluA2, encoding a glutelin type-A2 precursor, is responsible for glutelin content difference between the indica and japonica rice subspecies.
- Yihao Yang
- , Min Guo
- & Changjie Yan
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Article
| Open AccessIn vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers
Nanoparticle delivery of siRNA has problems with penetration and off target accumulation. Here, the authors report on the development of Y-shaped block catiomers which dynamically wrap around siRNA; demonstrate increased circulation times and delivery into hard to reach brain and pancreas tumour models.
- Sumiyo Watanabe
- , Kotaro Hayashi
- & Kazunori Kataoka
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Article
| Open AccessSingle-cell trajectories reconstruction, exploration and mapping of omics data with STREAM
The increasing accessibility of single cell omics technologies beyond transcriptomics demands parallel advances in analysis. Here, the authors introduce STREAM, a pipeline for reconstruction and visualization of differentiation trajectories from both single-cell RNA-seq and ATAC-seq data.
- Huidong Chen
- , Luca Albergante
- & Luca Pinello
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Article
| Open AccessArtificial cell membrane binding thrombin constructs drive in situ fibrin hydrogel formation
The incorporation of cells into tissue engineering scaffolds can be a major challenge. Here, the authors report on anchoring thrombin to cell membranes for the in situ formation of fibrin scaffolds around the modified cells, demonstrate scaffold formation in vitro and show cell survival in vivo.
- Robert C. Deller
- , Thomas Richardson
- & Adam W. Perriman
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