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Article
| Open AccessEnhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys
Targeted drug delivery in vivo is a complex challenge, and understanding the characteristics that define the behavior of delivery vehicles in vivo is vital for advancing delivery vehicle design. Here the authors use a library of polymeric delivery vehicles and high-throughput tools to study the structure-function relationships guiding the physiological fate of nanomedicines.
- Alexandra S. Piotrowski-Daspit
- , Laura G. Bracaglia
- & W. Mark Saltzman
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Article
| Open AccessHigh-throughput mechanical phenotyping and transcriptomics of single cells
The molecular system regulating cell surface mechanics remains largely unexplored at single-cell resolution. Here, the authors report a high-throughput single-cell assay, ELASTomics, which integrates mechanical phenotyping with unbiased transcriptomics.
- Akifumi Shiomi
- , Taikopaul Kaneko
- & Hirofumi Shintaku
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Article
| Open AccessSer/Leu-swapped cell-free translation system constructed with natural/in vitro transcribed-hybrid tRNA set
The use of orthogonal genetic code can help to prevent the escape of hazardous genes through horizontal gene transfer. Here, the authors develop a cell-free translation system with the Ser/Leu-swapped genetic code using a hybrid tRNA set and show its application in enhancing the production of superfolder GFP.
- Tomoshige Fujino
- , Ryogo Sonoda
- & Hiroshi Murakami
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Article
| Open AccessMechanically robust and personalized silk fibroin-magnesium composite scaffolds with water-responsive shape-memory for irregular bone regeneration
The regeneration of critical-size bone defects, especially those with irregular shapes, remains a clinical challenge. Here, the authors report a shape-memory, tailorable, self-adaptive and bioactive silk fibroin/magnesium composite scaffold that can quickly match irregular defects by simple trimming and lead to good interface integration.
- Zhinan Mao
- , Xuewei Bi
- & Yufeng Zheng
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Article
| Open AccessGRouNdGAN: GRN-guided simulation of single-cell RNA-seq data using causal generative adversarial networks
Benchmarking GRN inference methods remains a challenge. Here, authors present GRouNdGAN, a causal generative model that imposes a user-defined GRN in its architecture to simulate realistic single-cell data, bridging the gap between synthetic and biological data benchmarks of GRN inference methods.
- Yazdan Zinati
- , Abdulrahman Takiddeen
- & Amin Emad
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Article
| Open AccessEnzyme-assisted high throughput sequencing of an expanded genetic alphabet at single base resolution
The expansion of the genetic code with synthetic nucleotides has broadened our ability to evolve DNA as a functional material, but we lack analytical tools for the expanded alphabet. Here the authors demonstrate an enzyme-assisted method for the sequencing of six-letter DNA.
- Bang Wang
- , Kevin M. Bradley
- & Steven A. Benner
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Article
| Open AccessTransfer learning enables identification of multiple types of RNA modifications using nanopore direct RNA sequencing
Simultaneous profiling of multiple RNA modifications is a promising yet understudied field of research. Here, authors develop a transferable deep learning framework capable of detecting multiple types of RNA modifications in single nanopore sequencing sample.
- You Wu
- , Wenna Shao
- & Xiang Yu
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Article
| Open AccessTargeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy
Efforts to apply targeted protein degradation for antibiotic development are limited by our understanding of prokaryotic protein degradation. Here, the authors establish a chemical-genetic platform and predictive model to determine the degradation potential of essential mycobacterial proteins.
- Harim I. Won
- , Samuel Zinga
- & Junhao Zhu
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Article
| Open AccessA cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys
As demand for organ transplants exceeds availability there has been an unmet need to extend preservation of deceased donor kidneys. Here, the authors show that a cell-free nutrient-supplemented perfusate allows 4-day preservation of human kidneys using spatially resolved lipidomics and metabolomics.
- Marlon J. A. de Haan
- , Marleen E. Jacobs
- & Ton J. Rabelink
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Article
| Open AccessEnhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways
Precise genome editing is crucial. Here the authors demonstrate that dual inhibition of p53-mediated cell death and distinct activation of the DNA damage repair system upon DNA damage by cytosine base editor (CBE) or prime editor (PE) additively enhanced editing efficiency in hPSCs.
- Ju-Chan Park
- , Yun-Jeong Kim
- & Hyuk-Jin Cha
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Article
| Open AccessRegulation of cerebral blood flow boosts precise brain targeting of vinpocetine-derived ionizable-lipidoid nanoparticles
Despite advances in active drug-targeting for blood-brain barrier penetration, challenges related to brain biodistribution, and drug accumulation persist. Here the authors show a molecular library design centered on cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system inspired by the neuroprotective properties of vinpocetine.
- Xufei Bian
- , Ling Yang
- & Chong Li
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Article
| Open AccessAn integrated technology for quantitative wide mutational scanning of human antibody Fab libraries
Limited experimental platforms exist for assessing quantitative sequence-function relationships for multiple antibodies. Here, authors develop a deep-sequencing based technology called MAGMA-seq, that determines the quantitative properties of antibody libraries.
- Brian M. Petersen
- , Monica B. Kirby
- & Timothy A. Whitehead
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Article
| Open AccessDiscovering allatostatin type-C receptor specific agonists
Pesticides safeguard crops against pest infestations and mitigate associated risks. In this work, the authors develop a pesticide targeting AlstR-C of T.pityocampa pests, showing promising results without harming other insects, and advancing the development of GPCR-targeted pesticides for insect control.
- Kübra Kahveci
- , Mustafa Barbaros Düzgün
- & Necla Birgul Iyison
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Article
| Open AccessMultiplexed bulk and single-cell RNA-seq hybrid enables cost-efficient disease modeling with chimeric organoids
IPSC-derived organoids model diseases. Multiplexed coculture and demultiplexing natural genetic barcodes aid in studying genetic effects. Here, authors introduce Vireo-bulk to deconvolve bulk RNA-seq data, quantify donor abundance and identify differentially expressed genes.
- Chen Cheng
- , Gang Wang
- & Jin Zhang
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Matters Arising
| Open AccessReply to: Technical challenges of studying the impact of plasma components on the efficacy of lipid nanoparticles for vaccine and therapeutic applications
- Kai Liu
- , Elisa Lázaro-Ibáñez
- & Alan Sabirsh
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Article
| Open AccessA genetically encoded biosensor to monitor dynamic changes of c-di-GMP with high temporal resolution
The ubiquitous second messenger c-di-GMP regulates many biological processes in bacteria, including cell cycle, motility, virulence and biofilm formation. Here, Kaczmarczyk et al. develop a c-di-GMP biosensor that enables dynamic real-time tracking of c-di-GMP levels in individual living cells.
- Andreas Kaczmarczyk
- , Simon van Vliet
- & Urs Jenal
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Article
| Open AccessPrediction of m6A and m5C at single-molecule resolution reveals a transcriptome-wide co-occurrence of RNA modifications
The epitranscriptome holds many unexplored RNA functions, but detecting multiple modifications from one sample remains challenging. Here, authors devise a strategy combining AI and nanopore sequencing to uncover a transcriptome-wide co-occurrence of two modification types in individual RNA molecules.
- P Acera Mateos
- , A J Sethi
- & E Eyras
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Article
| Open AccessEngineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding
Direct oral anticoagulants (DOACs) targeting factor Xa that are used to prevent or treat thromboembolic disorders carry the risk of uncontrolled bleeding. Here, the authors present the computational design and evaluation of factor Xa-variants which can be used to reduce DOAC-associated bleeding.
- Wojciech Jankowski
- , Stepan S. Surov
- & Zuben E. Sauna
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Article
| Open AccessNetwork-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis
Aberrant signalling pathway activity is relevant for tumour growth and resistance to therapy, but remains hard to understand and target. Here, the authors develop VESPA, a phosphoproteomics-based machine learning algorithm that can elucidate response and adaptation to drug perturbations in cancer signalling pathways.
- George Rosenberger
- , Wenxue Li
- & Andrea Califano
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Review Article
| Open AccessCritical learning from industrial catalysis for nanocatalytic medicine
The knowledge gained from industrial catalysis benefits advancements of nanocatalytic medicines. Here the authors review the similarities, differences and connections in catalytic reactions between industrial and medical applications to support deep understanding and rational design of nanocatalytic medicines.
- Zhaokui Jin
- , Lingdong Jiang
- & Qianjun He
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Article
| Open AccessA quantitative gibberellin signaling biosensor reveals a role for gibberellins in internode specification at the shoot apical meristem
Engineering of a biosensor allows the authors to map the signaling activity of the phytohormones gibberellins (GAs) and to show that GAs orient cell division at the shoot apex to establish the organization in parallel cell files of plant stems.
- Bihai Shi
- , Amelia Felipo-Benavent
- & Teva Vernoux
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Article
| Open AccessNative N-glycome profiling of single cells and ng-level blood isolates using label-free capillary electrophoresis-mass spectrometry
Single-cell manipulation and processing techniques and improvements in mass spectrometry sensitivity make single-cell proteomic profiling feasible. This study presents a label-free approach for the characterisation of native N-glycans of single mammalian cells and ng-level blood isolates, demonstrating the potential to detect cell surface glycome changes at the single-cell level in health or disease.
- Anne-Lise Marie
- , Yunfan Gao
- & Alexander R. Ivanov
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Article
| Open AccessPrecise immunofluorescence canceling for highly multiplexed imaging to capture specific cell states
Multiplexed imaging to study cellular pathways can be hampered by lack of antibody specificity, especially when assessing signal activation. Here, the authors present Precise Emission Canceling Antibodies (PECAbs), which enable high-specificity sequential imaging and the study of signaling pathways.
- Kosuke Tomimatsu
- , Takeru Fujii
- & Yasuyuki Ohkawa
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Article
| Open AccesstauFisher predicts circadian time from a single sample of bulk and single-cell pseudobulk transcriptomic data
There is a need to determine circadian time in gene expression datasets. Here, authors built tauFisher, a pipeline that predicts circadian time labels from single transcriptomic samples. tauFisher will be useful for determining body clock time in circadian medicine and for research.
- Junyan Duan
- , Michelle N. Ngo
- & Bogi Andersen
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Article
| Open AccessTargeted delivery of the probiotic Saccharomyces boulardii to the extracellular matrix enhances gut residence time and recovery in murine colitis
In this study, the authors engineered a targeted Saccharomyces boulardii probiotic yeast platform, showing it exhibits high adherence to extracellular matrix proteins, resulting in longer gut residence, higher colon concentrations, and enhanced recovery in murine colitis.
- Mairead K. Heavey
- , Anthony Hazelton
- & Juliane Nguyen
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Article
| Open AccessIn vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment
Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal degenerative disease without approved therapeutic drug. Here, the authors show a promising CRISPR/Cas9 mediated homology-independent targeted integration therapy in patient derived cells and humanized mice carrying BCD mutations.
- Xiang Meng
- , Ruixuan Jia
- & Liping Yang
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Article
| Open AccessAn adeno-associated virus variant enabling efficient ocular-directed gene delivery across species
In non-human primates, rAAVs are delivered through suprachoroidal injection at a high dose to achieve optimal efficacy. Here, the authors present a novel AAV capsid (AAVv128) that significantly improved the transduction efficiency in photoreceptor and retinal pigment epithelial cells across species.
- Shuang Luo
- , Hao Jiang
- & Xun Sun
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Article
| Open AccessBiosynthetic production of anticoagulant heparin polysaccharides through metabolic and sulfotransferases engineering strategies
Microbial heparin bioproduction is hampered by the difficulty of recombinant expression of active heparan sulfate N-deacetylase/N-sulfotransferase. Here, the authors solve the problem by developing a cellular system-based semisynthetic strategy and achieve the production of active heparin by engineered E. coli.
- Jian-Qun Deng
- , Yi Li
- & Ju-Zheng Sheng
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Article
| Open AccessCell-penetrating protein-recognizing polymeric nanoparticles through dynamic covalent chemistry and double imprinting
Molecular recognition of proteins is essential for achieving their biological functions but it is challenging to prepare selective protein-binding materials. Here the authors report a method that combines dynamic covalent chemistry and double molecular imprinting to construct protein-recognizing nanoparticles capable of specific inhibition of protein–protein interactions.
- Avijit Ghosh
- , Mansi Sharma
- & Yan Zhao
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Article
| Open AccessSynthetic intrinsically disordered protein fusion tags that enhance protein solubility
Insoluble protein expression continues to be a bottleneck for biotechnology. Here, Chilkoti and colleagues report a method for generating and identifying hypersoluble intrinsically disordered protein fusion tags to improve soluble protein expression and rescue protein function.
- Nicholas C. Tang
- , Jonathan C. Su
- & Ashutosh Chilkoti
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Article
| Open AccessSkin graft with dermis and appendages generated in vivo by cell competition
Skin substitutes generated by tissue engineering have limited properties. Here, authors established niche encroachment method. Cell competition enabled skin organogenesis from allogeneic and xenogeneic stem cells on p63 knockout embryos, resulting in a complete skin graft on dermis with hair.
- Hisato Nagano
- , Naoaki Mizuno
- & Hiromitsu Nakauchi
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Perspective
| Open AccessEngineering is evolution: a perspective on design processes to engineer biology
Evolutionary and rational design approaches are commonly used to engineer biological systems but are typically seen at odds with each other. In this perspective the authors argue for the concept of an evolutionary design spectrum to help unify and compare these design methodologies to support more effective biological engineering.
- Simeon D. Castle
- , Michiel Stock
- & Thomas E. Gorochowski
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Article
| Open AccessDiscovering a mitochondrion-localized BAHD acyltransferase involved in calystegine biosynthesis and engineering the production of 3β-tigloyloxytropane
A mitochondrion-localised BAHD acyltransferase (3β-tigloyloxytropane synthase, TS) from Atropa belladonna is responsible for the formation of 3β-tigloyloxytropane, the key intermediate in calystegine biosynthesis.
- Junlan Zeng
- , Xiaoqiang Liu
- & Zhihua Liao
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Article
| Open AccessA vascularized breast cancer spheroid platform for the ranked evaluation of tumor microenvironment-targeted drugs by light sheet fluorescence microscopy
Assessing tumour microenvironment-targeted drug candidates remains challenging. Here, the authors develop a comprehensive screening platform that allows for monitoring, quantifying, and ranking drug-induced effects in self-organizing, vascularized tumour spheroids.
- David Ascheid
- , Magdalena Baumann
- & Erik Henke
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Article
| Open AccessThe hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies
Here, the authors elongated the hinge structure of IgG1 monoclonal antibodies. The modified IgG1-IgG3 hybrid subclass showed enhanced Fc-mediated function compared to IgG1 in two distinct biological systems, Streptococcus pyogenes and SARS-CoV-2.
- Arman Izadi
- , Yasaman Karami
- & Pontus Nordenfelt
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Article
| Open AccessscLENS: data-driven signal detection for unbiased scRNA-seq data analysis
Single-cell RNA sequencing data analysis is limited by noise and high dimensionality. Here, authors present scLENS, a tool that automates accurate signal detection without manual input, particularly in complex datasets.
- Hyun Kim
- , Won Chang
- & Jae Kyoung Kim
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Article
| Open AccessEfficient gene knockout and genetic interaction screening using the in4mer CRISPR/Cas12a multiplex knockout platform
Paralog synthetic lethals have been assessed with multiple CRISPR-based methods, but systematic comparison among these platforms is unavailable. Here, the authors systematically compare combinatorial perturbation platforms and establish the in4mer CRISPR/Cas12a multiplex knockout platform.
- Nazanin Esmaeili Anvar
- , Chenchu Lin
- & Traver Hart
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Article
| Open AccessStimulus-responsive assembly of nonviral nucleocapsids
A stimulus-responsive approach for recapitulating nonviral nucleocapsid assembly on demand under controlled conditions provides a robust platform for applications in synthetic biology and mRNA nanomedicine.
- Mao Hori
- , Angela Steinauer
- & Donald Hilvert
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Article
| Open AccessA mechanical-assisted post-bioprinting strategy for challenging bone defects repair
Bioprinting has revitalized tissue regeneration efforts, yet challenges persist due to cell damage during fabrication and mechanical instability of printed scaffolds. Here, the authors develop a mechanical-assisted post-bioprinting strategy for loading cells into hollow scaffolds that effectively repair challenging bone defects.
- Jirong Yang
- , Zhigang Chen
- & Changshun Ruan
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Article
| Open AccessUnravelling and reconstructing the biosynthetic pathway of bergenin
Bergenin is a rare C-glycoside of 4-O-methyl gallic acid with multiple pharmacological properties. Here, the authors report the elucidation of the biosynthetic pathway of bergenin in Ardisia japonica and its bioproduction by engineered E. coli.
- Ruiqi Yan
- , Binghan Xie
- & Lin Yang
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Article
| Open AccessControl of polymers’ amorphous-crystalline transition enables miniaturization and multifunctional integration for hydrogel bioelectronics
Soft elastic materials could be useful in the fabrication of brain-machine interfaces, but achieving the desirable material properties can be challenging. Here, the authors report control of the amorphous-crystalline transition of polymers to alter hydrogel properties and monitor mouse behaviour.
- Sizhe Huang
- , Xinyue Liu
- & Siyuan Rao
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Perspective
| Open AccessAutomated in vivo enzyme engineering accelerates biocatalyst optimization
Achieving cost-competitive bio-based processes requires development of stable and selective biocatalysts. In this Perspective, the authors propose an integrated solution combining growth-coupled selection with machine learning and automated workflows to accelerate development pipelines.
- Enrico Orsi
- , Lennart Schada von Borzyskowski
- & Steffen N. Lindner
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Article
| Open AccessCoCas9 is a compact nuclease from the human microbiome for efficient and precise genome editing
Cas9 nucleases hold clinical significance for genome editing therapies. Here the authors characterize CoCas9, a compact, efficient and precise Cas9 from the human microbiome, and show that delivery via AAV vectors enables efficient editing in the mouse retina, expanding the genome editing toolbox.
- Eleonora Pedrazzoli
- , Michele Demozzi
- & Anna Cereseto
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Article
| Open AccessStructural and biochemical analysis of family 92 carbohydrate-binding modules uncovers multivalent binding to β-glucans
Carbohydrate binding modules (CBMs) are non-catalytic domains found within multi-modular carbohydrate-active enzymes like glycoside hydrolases. Here, the authors show the crystal structures of two CBM family 92 members, which use three different surface binding sites to bind to β-glucans.
- Meng-Shu Hao
- , Scott Mazurkewich
- & Lauren S. McKee
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Article
| Open AccessIntegrating taxonomic signals from MAGs and contigs improves read annotation and taxonomic profiling of metagenomes
Metagenomic taxonomic profiling usually relies either on reads or assembled contigs/MAGs. Here, authors present RAT, a tool that integrates taxonomic signals from reads, contigs, and MAGs into one profile with high precision and sensitivity. RAT provides a comprehensive view of the microbiome.
- Ernestina Hauptfeld
- , Nikolaos Pappas
- & F. A. Bastiaan von Meijenfeldt
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Article
| Open AccessA patient-specific lung cancer assembloid model with heterogeneous tumor microenvironments
Realistic tumour models are critical for the development of clinically relevant treatments. Here, the authors develop a lung cancer assembloid model which recapitulates key components of the primary tumour, and can be used to predict clinical outcome.
- Yanmei Zhang
- , Qifan Hu
- & Zhuo Xiong
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Article
| Open AccessLocal environment in biomolecular condensates modulates enzymatic activity across length scales
Here, the authors show that biomolecular condensates can enhance enzymatic rates by creating distinct solvent environments compared to the surrounding solution, and this emergent property can manifest within assemblies as small as nanometers.
- Marcos Gil-Garcia
- , Ana I. Benítez-Mateos
- & Paolo Arosio
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Article
| Open AccessEngineering a synthetic gene circuit for high-performance inducible expression in mammalian systems
Inducible gene expression systems can be used to control the expression of a gene of interest by means of small molecules. Here the authors present CASwitch, a synthetic gene circuit platform enhancing inducible gene expression systems by reducing leakiness and boosting fold induction, for real world applications like gene therapy vector production and biosensors.
- Giuliano De Carluccio
- , Virginia Fusco
- & Diego di Bernardo
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Article
| Open AccessThe physiological interactome of TCR-like antibody therapeutics in human tissues
The use of bispecific antibodies to target tumour-specific epitopes presented by MHC molecules in tumour tissue is a promising avenue for cancer immunotherapy. Here the authors use a mass-spectrometry guided analysis to identify off-target MHC-peptide complexes that bind to TCR-like antibodies next to the target peptide, enabling a novel approach to monitoring of antibody specificity during clinical maturation and development.
- Estelle Marrer-Berger
- , Annalisa Nicastri
- & Nicola Ternette
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