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| 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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Article
| Open AccessX-ray-activated polymerization expanding the frontiers of deep-tissue hydrogel formation
Photo-crosslinking polymerization facilitates precise control of hydrogel formation for various applications including tissue engineering, but most existing photo-crosslinking methods fail to achieve deep-tissue penetration, especially within bone structures. Here the authors report a strategy of low-dose X-ray-activated polymerization that enables deep-tissue hydrogel formation.
- Hailei Zhang
- , Boyan Tang
- & Gang Han
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Article
| Open AccessA modular and synthetic biosynthesis platform for de novo production of diverse halogenated tryptophan-derived molecules
De novo fermentation and synthetic pathway construction for halogen-containing molecules remain relatively underexplored. Here, the authors report a mix-and-match co-culture platform to de novo generate a large array of halogenated tryptophan derivatives in E. coli from glucose.
- Kevin B. Reed
- , Sierra M. Brooks
- & Hal S. Alper
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Article
| Open AccessMultiscale architecture design of 3D printed biodegradable Zn-based porous scaffolds for immunomodulatory osteogenesis
Rapid degradation inducing overdose toxicity remains challenging in porous biodegradable bone scaffolds. Here the authors present multiscale architecture design on ZnLi scaffolds with 90% porosity orchestrates immune responses and subsequent bone regeneration.
- Shuang Li
- , Hongtao Yang
- & Yufeng Zheng
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Article
| Open AccessHydrophobic mismatch drives self-organization of designer proteins into synthetic membranes
The organization of membrane proteins is critical to cellular function. Here the authors explore how computational protein design, MD simulation, and cell-free systems can be combined to elucidate how membrane-protein hydrophobic mismatch affects protein folding and organization in synthetic lipid membranes.
- Justin A. Peruzzi
- , Jan Steinkühler
- & Neha P. Kamat
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Article
| Open AccessKSNP: a fast de Bruijn graph-based haplotyping tool approaching data-in time cost
Haplotyping is the process of distinguishing alleles inherited together on a chromosome, a crucial step in assembling and interpreting genome sequences. Here, the authors present a computationally efficient haplotype assembly tool for long read sequencing data.
- Qian Zhou
- , Fahu Ji
- & Jue Ruan
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Article
| Open AccessComplex activity and short-term plasticity of human cerebral organoids reciprocally connected with axons
Connecting cerebral organoids with an axon bundle models inter-regional projections and enhances neural activity. Optogenetic stimulation induces short-term plasticity, offering insights into macroscopic circuit development and functionality.
- Tatsuya Osaki
- , Tomoya Duenki
- & Yoshiho Ikeuchi
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Article
| Open AccessscButterfly: a versatile single-cell cross-modality translation method via dual-aligned variational autoencoders
Technical limitations of simultaneously multi-omics profiling lead to highly noisy multi-modal data and substantial costs. Here, authors proposed a versatile framework and data augmentation schemes, capable of single-cell cross-modality translation and multiple extensive applications.
- Yichuan Cao
- , Xiamiao Zhao
- & Shengquan Chen
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Article
| Open AccessContext-aware deep learning enables high-efficacy localization of high concentration microbubbles for super-resolution ultrasound localization microscopy
Ultrasound localisation microscopy enables deep tissue microvascular imaging. Here, authors introduce LOCA-ULM, a deep learning pipeline enhancing localisation accuracy in high microbubble concentrations. LOCA-ULM reveals dense cerebrovascular networks and enhances the sensitivity of functional ULM.
- YiRang Shin
- , Matthew R. Lowerison
- & Pengfei Song
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Article
| Open AccessThe CRISPR-Cas13a Gemini System for noncontiguous target RNA activation
CRISPR-Cas13a based methods currently use contiguous target RNA activation, which only enables single-target detection or editing. Here the authors propose a noncontiguous target RNA activation approach which can provide rapid, simultaneous and sensitive detection of two RNAs in a single readout, as well as parallel dual transgene knockdown.
- Hongrui Zhao
- , Yan Sheng
- & Jiaming Hu
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Article
| Open AccessVISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
VISTA is a pH-dependent inhibitory checkpoint for T-cells that is abundant on myeloid lineage cells and antagonists of VISTA may successfully reinvigorate anti-tumour immunity. Here, the authors show that the antibody SNS-101, which is currently being investigated in humans in a clinical trial, is characterized by pH-sensitivity that endows it with favorable pharmacokinetic and safety profiles, and enhanced therapeutic effect when combined with PD-1 checkpoint inhibitors.
- Thomas Thisted
- , F. Donelson Smith
- & Edward H. van der Horst
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Article
| Open AccessEarly detection of emerging viral variants through analysis of community structure of coordinated substitution networks
Rise of new viral strains is a major public health challenge, demanding advanced detection and forecasting methods. This study shows how examining communities within networks of viral mutations enables early detection of emerging strains.
- Fatemeh Mohebbi
- , Alex Zelikovsky
- & Pavel Skums
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Article
| Open AccessPianno: a probabilistic framework automating semantic annotation for spatial transcriptomics
Recognising spatial spots’ biological identity in spatial transcriptomics remains a challenge. Here, authors introduce Pianno, a tool that helps annotate the biological structures or cell-type constructions across diverse tissues, offering new perspectives on understanding spatial transcriptomics.
- Yuqiu Zhou
- , Wei He
- & Ying Zhu
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Article
| Open AccessBiomimetic NIR-II fluorescent proteins created from chemogenic protein-seeking dyes for multicolor deep-tissue bioimaging
Near-infrared-I/II fluorescent proteins (NIR-I/II FPs) are crucial for in vivo imaging, but their availability is still scarce. Here, the authors make use of protein-seeking NIR-II dyes as chromophores, which covalently bind to tag proteins and thus creating biomimetic NIR-II FPs.
- Jiajun Xu
- , Ningning Zhu
- & Shoujun Zhu
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Article
| Open AccessPLMSearch: Protein language model powers accurate and fast sequence search for remote homology
Homologous protein search is one of the most commonly used methods for protein analysis. Here, authors propose PLMSearch, a search method that takes only sequences as input and can search millions of protein pairs in seconds while maintaining sensitivity comparable to SOTA structure search methods.
- Wei Liu
- , Ziye Wang
- & Shanfeng Zhu
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Article
| Open AccessCell surface patching via CXCR4-targeted nanothreads for cancer metastasis inhibition
CXCR4-targeted therapies have been proposed for the treatment of cancer metastasis. Here the authors propose a CXCR4-targeted strategy based on interactable polymer nanothreads, showing inhibition of metastasis in preclinical cancer models.
- Minglu Zhou
- , Chendong Liu
- & Lian Li
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Article
| Open AccessMicrointerfaces in biopolymer-based bicontinuous hydrogels guide rapid 3D cell migration
Extracellular microinterfaces provide cells with migration tracks in vivo. Here, the authors introduce these microtracks into bicontinuous hydrogels to elicit rapid cell migration in 3-dimensional contexts.
- Karen L. Xu
- , Nikolas Di Caprio
- & Jason A. Burdick
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Article
| Open AccessGene-expression memory-based prediction of cell lineages from scRNA-seq datasets
Combining experimental lineage tracing with single cell transcriptomics is technically demanding. Here, authors present GEMLI, a computational tool to annotate cell lineages in single cell RNA sequencing data solely based on gene expression.
- A. S. Eisele
- , M. Tarbier
- & D. M. Suter
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Article
| Open AccessDELVE: feature selection for preserving biological trajectories in single-cell data
Characteristic genes or proteins driving continuous biological processes are difficult to uncover from noisy single-cell data. Here, authors present DELVE, an unsupervised feature selection method to identify core molecular features driving cell fate decisions.
- Jolene S. Ranek
- , Wayne Stallaert
- & Jeremy E. Purvis
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Article
| Open AccessBioorthogonal photocatalytic proximity labeling in primary living samples
Studying subcellular proteomes in primary living cells is crucial for understanding health and disease. Here, the authors introduce CAT-S, a non-genetic method based on photocatalysis, enabling in situ deciphering of mitochondrial proteomes in primary cells from mouse tissues and human blood.
- Ziqi Liu
- , Fuhu Guo
- & Xinyuan Fan
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Article
| Open AccessRegulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus
Systemic Lupus Erythematosus (SLE) is a chronic and progressive autoimmune disease characterized by abnormally activated B cells causing organ damage. Here authors introduce an adoptive cell therapy involving regulatory T cells overexpressing FoxP3 and harboring an anti-CD19 CAR to inhibit pathological B cells and thus tissue-harming autoimmunity in a humanized mouse model.
- M. Doglio
- , A. Ugolini
- & C. Bonini
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Article
| Open AccessSilk fibroin hydrogel adhesive enables sealed-tight reconstruction of meniscus tears
Suture repair is the current clinical treatment for meniscus tears, but inaccessible tears in company with re-tears susceptibility remain unresolved. Here the authors address these issues by developing a meniscus adhesive-based strategy for the seamless and dense reconstruction of torn meniscus.
- Xihao Pan
- , Rui Li
- & Hongwei Ouyang
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Article
| Open AccessA dual diffusion model enables 3D molecule generation and lead optimization based on target pockets
Structure-based generative chemistry is crucial in computer-aided drug discovery. Here, authors propose PMDM, a conditional generative model for 3D molecule generation tailored to specific targets. Extensive experiments demonstrate that PMDM can effectively generate rational bioactive molecules
- Lei Huang
- , Tingyang Xu
- & Hengtong Zhang
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Article
| Open AccessPredicting and improving complex beer flavor through machine learning
Perception and appreciation of food flavour depends on many factors, posing a challenge for effective prediction. Here, the authors combine extensive chemical and sensory analyses of 250 commercial Belgian beers to train machine learning models that enable flavour and consumer appreciation prediction.
- Michiel Schreurs
- , Supinya Piampongsant
- & Kevin J. Verstrepen
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Article
| Open AccessSynthetically-primed adaptation of Pseudomonas putida to a non-native substrate D-xylose
Pseudomonas putida is becoming a host of choice for the valorization of lignocellulosic substrates. Here, the authors provide insight into the adaptation of this bacterium to the non-native substrate D-xylose, enabled by metabolic engineering and adaptive laboratory evolution.
- Pavel Dvořák
- , Barbora Burýšková
- & Martin Benešík
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Article
| Open AccessFunctional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair
Here the authors describe a functional screening platform in human stem cells to identify and optimize protein-based gene editing additives that increase homologous directed recombination and have potential to improve gene therapy workflows.
- Juan A. Perez-Bermejo
- , Oghene Efagene
- & Kristen L. Seim
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Article
| Open AccessDevelopmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier
DNA double-strand breaks (DSBs) are repaired by a hierarchically regulated network of pathways. Here, authors develop ICP for deciphering somatic DSB repair patterns in multicellular organisms and discover developmental regulation in flies and mosquitoes, enabling tracking of mutant alleles and interhomolog copying of gene cassettes.
- Zhiqian Li
- , Lang You
- & Ethan Bier
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Article
| Open AccessVersatile human cardiac tissues engineered with perfusable heart extracellular microenvironment for biomedical applications
The application of engineered cardiac tissues is limited due to their immaturity and lack of functionality. Here, the authors develop an integrated culture platform featuring heart extracellular matrix cultured in a microfluidic chip to facilitate cardiac tissue development for versatile biomedical applications.
- Sungjin Min
- , Suran Kim
- & Seung-Woo Cho
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Article
| Open AccessA let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility
The authors pioneered the iPSC-derived platelet transfusion in human. Here they employ miRNA switches, identifying RALB as a determinant of immune megakaryocytes and a marker for quality control, advancing standardization of iPSC-platelet production.
- Si Jing Chen
- , Kazuya Hashimoto
- & Koji Eto
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Review Article
| Open AccessArtificial cells for in vivo biomedical applications through red blood cell biomimicry
Despite the enormous progress in the field of giant lipid vesicles, their use for in vivo biomedical applications is limited. Here, the authors discuss red blood cells as inspiration for enhancing those vesicles, investigating the required cellular features and the corresponding technical hurdles.
- Jorik Waeterschoot
- , Willemien Gosselé
- & Xavier Casadevall i Solvas
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Article
| Open AccessA universal molecular control for DNA, mRNA and protein expression
Multi-omics analyses powerfully combine gene expression and translation, however no available controls can be used across these techniques. Here the authors develop pREF, a universal control construct designed for use in DNA, RNA and protein analyses.
- Helen M. Gunter
- , Scott E. Youlten
- & Tim R. Mercer
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Article
| Open AccessMapping human tissues with highly multiplexed RNA in situ hybridization
Application of multiplexed RNA in situ mapping techniques to human tissues remains challenging. Here, the authors report DART-FISH, a padlock probe-based technology capable of profiling large numbers of genes in centimetre-sized human tissue sections.
- Kian Kalhor
- , Chien-Ju Chen
- & Kun Zhang
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Article
| Open AccessAutologous cell transplantation for treatment of colorectal aganglionosis in mice
Neurointestinal diseases cause significant morbidity and effective treatments are lacking. Here, authors perform autologous cell transplantation of enteric neural stem cells in a mouse model of colonic aganglionosis and report restoration of colonic contractile activity.
- Weikang Pan
- , Ahmed A. Rahman
- & Ryo Hotta
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Article
| Open AccessExemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial
Intrinsic and acquired resistances to CDK4/6 inhibitors have been described in patients with breast cancer. Here the authors report the results from a phase I/II clinical trial of the aromatase inhibitor exemestane plus everolimus (mTOR inhibitor) and palbociclib (CDK4/6i) in patients with metastatic breast cancer, assessing safety, clinical efficacy, as well as genomic and transcriptomic determinants of resistance.
- Jorge Gómez Tejeda Zañudo
- , Romualdo Barroso-Sousa
- & Nikhil Wagle
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Article
| Open AccessEngineering intelligent chassis cells via recombinase-based MEMORY circuits
The unification of decision-making, communication, and memory would enable the programming of intelligent biotic systems. Here, the authors achieve this goal by engineering E. coli chassis cells with an array of inducible recombinases that mediate diverse genetic programs.
- Brian D. Huang
- , Dowan Kim
- & Corey J. Wilson
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Article
| Open AccessSpyMask enables combinatorial assembly of bispecific binders
Bispecific antibody architecture is often important for function but rarely optimized. Here, authors present a modular approach to assemble bispecifics in varied formats using a SpyTag/SpyCatcher approach called SpyMask, and build anti-HER2 bispecifics whose activities depend on binder orientation and bispecific geometry.
- Claudia L. Driscoll
- , Anthony H. Keeble
- & Mark R. Howarth
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Article
| Open AccessTargeted metagenomics reveals association between severity and pathogen co-detection in infants with respiratory syncytial virus
The impact of other pathogens on disease outcome was studied in European infants with RSV infection. Additional viruses were commonly co-detected during infection but were weakly linked to severity. However, presence of Haemophilus bacteria strongly associated with severe cases.
- Gu-Lung Lin
- , Simon B. Drysdale
- & Andrew J. Pollard
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Article
| Open AccessHighly sensitive spatial transcriptomics using FISHnCHIPs of multiple co-expressed genes
Leveraging the fact that eukaryotic genomes are organized into gene modules, FISHnCHIPs images multiple co-expressed genes simultaneously for sensitive and high throughput profiling of gene programs and cell types in tissues.
- Xinrui Zhou
- , Wan Yi Seow
- & Kok Hao Chen
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Article
| Open AccessProinflammatory polarization of engineered heat-inducible macrophages reprogram the tumor immune microenvironment during cancer immunotherapy
Alternatively activated macrophages have a pivotal role in resolving inflammation but in the tumour microenvironment they are immunosuppressive. Here author show that adoptively transferred engineered macrophages harbouring a heat-inducible genetic switch can resist the polarizing effect of the tumour microenvironment, and do not only remain pro-inflammatory themselves but also re-polarise the endogenous macrophages upon controlled warming with a purpose-made device.
- Yanan Xue
- , Xiaojie Yan
- & Yuan Ping
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Article
| Open AccessBiosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol
Despite intensive investigation, stepwise reactions from diol to Taxol tetracyclic core skeleton remain unclear. Here, authors fill this gap by identifying two P450s and confirming the reaction order.
- Chengshuai Yang
- , Yan Wang
- & Zhihua Zhou
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