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| Open AccessDe novo design of a reversible phosphorylation-dependent switch for membrane targeting
The ability to dynamically control protein-protein interactions and localization of proteins is critical in synthetic biological systems. Here the authors develop a peptide-based molecular switch that regulates dimer formation and lipid membrane targeting via reversible phosphorylation.
- Leon Harrington
- , Jordan M. Fletcher
- & Petra Schwille
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Article
| Open AccessPersistence of viral RNA in lymph nodes in ART-suppressed SIV/SHIV-infected Rhesus Macaques
The existence of HIV reservoir and ongoing replication despite antiretroviral therapy (ART) represents a barrier for cure efforts. Here, using SIV/SHIV-infected rhesus macaque suppressed with ART for one year, the authors characterize multiple lymphoid and non-lymphoid tissues and show that while the viral reservoir exhibits a wide anatomic heterogeneity, persistent viral transcription is mainly restricted to secondary lymphoid organs.
- Anthony M. Cadena
- , John D. Ventura
- & Dan H. Barouch
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Article
| Open AccessKRAS drives immune evasion in a genetic model of pancreatic cancer
Oncogenic KRAS signalling is required for tumor initiation; however KRAS-dependency at advanced stages is less understood. Here, the authors show that, in established KRAS-driven pancreatic cancer, KRAS-ablation does not affect intrinsic tumorigenic capacity but elicits antitumor immune response, highlighting the importance of KRAS-driven immune suppression in tumor maintenance.
- Irene Ischenko
- , Stephen D’Amico
- & Nancy C. Reich
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Article
| Open AccessSingle-cell measurement of plasmid copy number and promoter activity
A quantitative assessment of promoter function can improve the precision of cellular engineering. Here the authors develop a method to simultaneously count plasmid DNA, RNA transcripts and protein expression in single living bacteria.
- Bin Shao
- , Jayan Rammohan
- & Christopher A. Voigt
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Article
| Open AccessKinesin-1 activity recorded in living cells with a precipitating dye
Monitoring the activity of the processive motor protein kinesin-1 in live cells is currently difficult. Here the authors report the fluorogenic small molecule QPD-OTf, a kinesin-1 substrate that causes activity-dependent dye precipitation.
- Simona Angerani
- , Eric Lindberg
- & Nicolas Winssinger
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Article
| Open AccessEndogenous aldehyde accumulation generates genotoxicity and exhaled biomarkers in esophageal adenocarcinoma
Volatile aldehydes can be enriched in esophageal adenocarcinoma patients’ breath. Here, the authors reveal corresponding metabolic changes in EAC tumours, which may be caused by impaired detoxification of endogenous metabolites.
- Stefan Antonowicz
- , Zsolt Bodai
- & George B. Hanna
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Article
| Open AccessA neural m6A/Ythdf pathway is required for learning and memory in Drosophila
Epitranscriptomic modifications can regulate learning and memory. Here, the authors provide proteomic and functional analysis of N6-methyladenosine (m6A)-binding proteins in D. melanogaster and unveil behavioral and regulatory defects for m6A/Ythdf mutants.
- Lijuan Kan
- , Stanislav Ott
- & Eric C. Lai
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Article
| Open AccessMINFLUX nanometer-scale 3D imaging and microsecond-range tracking on a common fluorescence microscope
Minimal photon fluxes (MINFLUX) has enabled molecule-scale resolution in fluorescence microscopy but this had not been shown in standard, broadly applicable microscopy platforms. Here the authors report a solution to allow normal fluorescence microscopy while also providing 1-3 nm 3D resolution.
- Roman Schmidt
- , Tobias Weihs
- & Stefan W. Hell
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Article
| Open AccessPoint-of-care bulk testing for SARS-CoV-2 by combining hybridization capture with improved colorimetric LAMP
Current SARS-CoV-2 diagnostic methods are sensitive yet poorly suited to testing whole communities on a regular basis. Here the authors present Cap-iLAMP that tests gargle lavage samples with an improved colorimetric RT-LAMP.
- Lukas Bokelmann
- , Olaf Nickel
- & Stephan Riesenberg
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Article
| Open AccessPerceptions of the appropriate response to norm violation in 57 societies
Little is known about people’s preferred responses to norm violations across countries. Here, in a study of 57 countries, the authors highlight cultural similarities and differences in people’s perception of the appropriateness of norm violations.
- Kimmo Eriksson
- , Pontus Strimling
- & Paul A. M. Van Lange
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Article
| Open AccessCytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling
Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8+ lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.
- Icia Santos-Zas
- , Jeremie Lemarié
- & Hafid Ait-Oufella
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Article
| Open AccessGermline inherited small RNAs facilitate the clearance of untranslated maternal mRNAs in C. elegans embryos
In animal embryos, maternally deposited mRNAs are degraded by several different mechanisms. Here the authors show that C. elegans embryos inherit antisense pool of small RNAs which are loaded into CSR-1 and cleave complementary maternal mRNAs.
- Piergiuseppe Quarato
- , Meetali Singh
- & Germano Cecere
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Article
| Open AccessThe methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain
The methylation of Histone 3 at Lysine 36 (H3K36) has been implicated in the regulation of transcription and coupled processes such as mRNA splicing. Here the authors show that the histone methyltransferase SETD2 interacts with hnRNP L to mediate the crosstalk between the transcription and splicing machineries.
- Saikat Bhattacharya
- , Michaella J. Levy
- & Jerry L. Workman
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Article
| Open AccessNeuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension
TRPV4 dominant mutations cause neuropathy. Here, the authors show that TRPV4 binds and interacts with RhoA, modulating the actin cytoskeleton. Neuropathy-causing mutations of TRPV4 disrupt this complex, leading to RhoA activation and impairment of neurite extension in cultured cells and flies.
- Brett A. McCray
- , Erika Diehl
- & Charlotte J. Sumner
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Article
| Open AccessTranscriptome and chromatin landscape of iNKT cells are shaped by subset differentiation and antigen exposure
Invariant natural killer T cells are known to be composed of a number of phenotypic and functionally distinct populations. Here the authors use transcriptomic and epigenomic analysis to further characterize the peripheral iNKT compartment before and after antigenic stimulation.
- Mallory Paynich Murray
- , Isaac Engel
- & Mitchell Kronenberg
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Article
| Open AccessEpidermal growth factor receptor signaling uncouples germ cells from the somatic follicular compartment at ovulation
Uncoupling of mature oocytes from somatic granulosa cells is required for their fertilization. Here the authors show that activation of EGFR signalling in granulosa cells during ovulation triggers ERK-dependent loss of filopodia oocyte adhesion, and Arp2/3 mediated retraction of granulosa cell filopodia.
- Laleh Abbassi
- , Stephany El-Hayek
- & Hugh J. Clarke
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Article
| Open AccessEvolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling
The genetic changes that occur in late stage metastatic melanoma are not well delineated. Here, the authors use rapid autopsy samples from metastatic melanoma patients and show that the late stage in the disease is characterised by whole genome doubling and aneuploidy.
- Ismael A. Vergara
- , Christopher P. Mintoff
- & Mark Shackleton
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Article
| Open AccessA multiplexed, automated evolution pipeline enables scalable discovery and characterization of biosensors
Biosensors are key to engineered biological systems. Here the authors demonstrate rapid de novo in vitro evolution of RNA biosensors of small molecules in a fully automated system.
- Brent Townshend
- , Joy S. Xiang
- & Christina D. Smolke
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Article
| Open AccessVirus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis
Checkpoint blocking therapies are used to treat metastatic melanoma, but can have adverse immune-mediated effects, including liver pathology. Here the authors identify an expanded pool of CD4+ effector memory T cells resulting from prior CMV exposure as a risk factor for this adverse effect in these patients.
- James A. Hutchinson
- , Katharina Kronenberg
- & Sebastian Haferkamp
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Article
| Open AccessA chromosome-level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution
Mexican Tetra cavefish have long been of interest in understanding adaptation to severe environmental change. Here the authors present a chromosome-level genome for the proxy-ancestral surface fish, and use CRISPR gene-editing to show the role of the rx3 gene in eye size.
- Wesley C. Warren
- , Tyler E. Boggs
- & Nicolas Rohner
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Article
| Open AccessLipid regulation of hERG1 channel function
The lipid regulation of mammalian ion channel function has emerged as a fundamental mechanism in the control of electrical signalling and transport specificity. Here, the authors combine molecular dynamics simulations, mutagenesis, and electrophysiology to provide mechanistic insights into how lipophilic molecules alter gating kinetics and K+ currents of hERG1.
- Williams E. Miranda
- , Jiqing Guo
- & Sergei Yu. Noskov
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Article
| Open AccessIntegrative pan cancer analysis reveals epigenomic variation in cancer type and cell specific chromatin domains
The NCI-60 cancer cell line panel covers multiple cancer types but has not been extensively investigated at the epigenetic level. Here, the authors present H3K4me3, H3K27ac, H3K9me3, and H4K20me3 ChIP-Seq analysis of the cell lines, and describe features of chromatin states and integrative analyses of expression, epigenetic and genetic mutation data.
- Lijin K. Gopi
- & Benjamin L. Kidder
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Article
| Open AccessPredictive learning as a network mechanism for extracting low-dimensional latent space representations
Neural networks trained using predictive models generate representations that recover the underlying low-dimensional latent structure in the data. Here, the authors demonstrate that a network trained on a spatial navigation task generates place-related neural activations similar to those observed in the hippocampus and show that these are related to the latent structure.
- Stefano Recanatesi
- , Matthew Farrell
- & Eric Shea-Brown
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Article
| Open AccessImmunogenicity of prime-boost protein subunit vaccine strategies against SARS-CoV-2 in mice and macaques
Current vaccine strategies for SARS-CoV-2 focus on eliciting neutralising antibodies to the spike protein (S), but differences in immunogenicity of full-length S versus receptor binding domain (RBD) only aren’t fully understood. Here, the authors show immunogenicity of different prime-boost strategies with S and/or RBD in mice and macaques.
- Hyon-Xhi Tan
- , Jennifer A. Juno
- & Adam K. Wheatley
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Article
| Open AccessGerm granule dysfunction is a hallmark and mirror of Piwi mutant sterility
Piwi deficiency results in sterility and is associated with transposon expression and genomic instability. Here the authors show that sterility of C. elegans Piwi prg-1 mutant is not associated with transposon-induced DNA damage but is associated with and is phenocopied by dysfunction of germ granules.
- Maya Spichal
- , Bree Heestand
- & Shawn Ahmed
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Article
| Open AccessA critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy
Adult-born granule cells integrate in hippocampal circuitry and contribute to hippocampal function. Here, the authors show that a critical period of neuronal activity regulates aberrant neurogenesis to rewire hippocampal circuitry and drive seizures in a mouse model of epilepsy.
- Zane R. Lybrand
- , Sonal Goswami
- & Jenny Hsieh
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Article
| Open AccessSomatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours
Malignant rhabdoid tumours (MRT) have been suggested to originate in the ectoderm-derived neural crest. Here, the authors analyse MRTs using phylogenetics, scRNA-seq, and patient-derived organoids; they find evidence for an MRT origin in the neural crest lineage and suggest differentiation treatment with HDAC/mTOR inhibitors.
- Lars Custers
- , Eleonora Khabirova
- & Jarno Drost
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Article
| Open AccesspHmScarlet is a pH-sensitive red fluorescent protein to monitor exocytosis docking and fusion steps
A number of pH-sensitive fluorescent proteins exist which enable monitoring of some but not all steps of exocytosis. Here the authors engineer a bright, photostable red pH-sensitive fluorescent protein, pHmScarlet, to allow visualisation of the docking and fusion events of exocytosis.
- Anyuan Liu
- , Xiaoshuai Huang
- & Pingyong Xu
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Article
| Open AccessStaphylococcus aureus induces an itaconate-dominated immunometabolic response that drives biofilm formation
The authors show that the pathogen Staphylococcus aureus induces a distinct airway immunometabolic response, dominated by release of itaconate. This metabolite, in turn, potentiates extracellular polysaccharide synthesis and biofilm formation in S. aureus, which may facilitate chronic infection.
- Kira L. Tomlinson
- , Tania Wong Fok Lung
- & Sebastián A. Riquelme
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Article
| Open AccessGlobal profiling of distinct cysteine redox forms reveals wide-ranging redox regulation in C. elegans
Reversible cysteine oxidative modifications have emerged as important mechanisms that alter protein function. Here the authors globally assess the cysteine reactivity and an array of cysteine oxidative modifications in C. elegans, providing insights into redox signaling at the organismal level.
- Jin Meng
- , Ling Fu
- & Jing Yang
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Article
| Open AccessEvolution of combinatorial diversity in trans-acyltransferase polyketide synthase assembly lines across bacteria
Trans-acyltransferase polyketide synthases are multimodular enzymes that synthesise diverse polyketides. Here, the authors present an algorithm for the global study of their diversity, showing exchange of conserved consecutive modules as a driver of diversification, and guiding the discovery of polyketides.
- Eric J. N. Helfrich
- , Reiko Ueoka
- & Marnix H. Medema
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Article
| Open AccessATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking
The molecular mechanisms mediating nociception are unclear. Here, the authors show that the Activating Transcription Factor 4 (ATF4) is important for the response to heat nociception in mice and ATF4 role in mediating protein trafficking in dorsal root ganglion neurons.
- Man-Xiu Xie
- , Xian-Ying Cao
- & Xiao-Long Zhang
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Article
| Open AccessA scalable unified framework of total and allele-specific counts for cis-QTL, fine-mapping, and prediction
Methods for eQTL mapping from total and allele-specific gene expression typically are too computationally heavy to apply to large scale studies. Here, the authors describe a computationally efficient method to identify eQTLs, fine-map and predict expression from total and allele-specific gene expression
- Yanyu Liang
- , François Aguet
- & Hae Kyung Im
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Article
| Open AccessReversible thermal regulation for bifunctional dynamic control of gene expression in Escherichia coli
Genetic circuits can be built with bifunctional dynamic regulation of gene expression. Here the authors design a thermosensitive switch for spatial and temporal control of colony pattern, cell shape and polymer production.
- Xuan Wang
- , Jia-Ning Han
- & Guo-Qiang Chen
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Article
| Open AccessInter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling
The inter- and intra-tumor heterogeneity of metastatic prostate cancer (mPC) is underexplored. Here the authors use Digital Spatial Profiling to study gene and protein expression heterogeneity in 27 mPC patients, finding variation in associated pathways and potential immunotherapy targets.
- Lauren Brady
- , Michelle Kriner
- & Peter S. Nelson
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Article
| Open AccessAntagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging
Sarcopenia is the age-associated functional decline and atrophy of muscle fibers, and it has been proposed that it might be counteracted by inducing myofiber hypertrophy. Here, the authors show that expression levels of the ubiquitin ligase UBR4 are increased with ageing, and that whilst its genetic ablation rescues muscle atrophy, it is also associated with reduced protein quality and impaired force production in Drosophila and mouse models.
- Liam C. Hunt
- , Bronwen Schadeberg
- & Fabio Demontis
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Article
| Open AccessA multiplexed, next generation sequencing platform for high-throughput detection of SARS-CoV-2
Wide-spread outbreaks of pathogens require high intensity testing to manage. Here, the authors present C19-SPAR-Seq, a scalable and automated platform to analyse tens of thousands of SARS-CoV-2 patient samples in a single run.
- Marie-Ming Aynaud
- , J. Javier Hernandez
- & Jeffrey L. Wrana
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Article
| Open AccessPharmacological rescue in patient iPSC and mouse models with a rare DISC1 mutation
Previous work has shown in iPSC derived neurons that synaptic impairments are associated with a 4bp DISC1 deletion. Here the authors demonstrate a role for the PDE4 signalling pathway in these synaptic impairments.
- Nam-Shik Kim
- , Zhexing Wen
- & Guo-li Ming
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Article
| Open AccessT-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors
There is an urgent need to discover blood-based biomarkers to predict response to immune checkpoint inhibitors (ICI). Here the authors show that effective ICI therapy correlates with increased frequency of circulating CX3CR1+CD8+ T cells in preclinical tumor models and in a cohort of patients with non-small cell lung cancer treated with anti-PD-1.
- Takayoshi Yamauchi
- , Toshifumi Hoki
- & Fumito Ito
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Article
| Open AccessGlycan chip based on structure-switchable DNA linker for on-chip biosynthesis of cancer-associated complex glycans
Current methods for on-chip glycan biosynthesis suffer from analysing products, often resulting in poor purity and yield. Here the authors report a glycan chip developed by introducing a pH-responsive i-motif DNA linker to control the immobilization and isolation of glycans on chips.
- Hye Ryoung Heo
- , Kye Il Joo
- & Hyung Joon Cha
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Article
| Open AccessProgrammable C:G to G:C genome editing with CRISPR-Cas9-directed base excision repair proteins
Many diseases are caused by single-nucleotide polymorphisms. Here, the authors present CRISPR base editors that use the base excision machinery for single-base transversions.
- Liwei Chen
- , Jung Eun Park
- & Wei Leong Chew
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Article
| Open AccessLarge-scale discovery of protein interactions at residue resolution using co-evolution calculated from genomic sequences
Our understanding of the residue-level details of protein interactions remains incomplete. Here, the authors show sequence coevolution can be used to infer interacting proteins with residue-level details, including predicting 467 interactions de novo in the Escherichia coli cell envelope proteome.
- Anna G. Green
- , Hadeer Elhabashy
- & Debora S. Marks
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Article
| Open AccessStructures of mouse and human GITR–GITRL complexes reveal unique TNF superfamily interactions
Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and GITR ligand (GITRL) regulate immune cell activities, including anti-tumor immune responses. Structures and visualization of human and mouse GITR–GITRL complexes offer insight into the architecture of higher-order membrane assemblies, and their signaling.
- Feng Wang
- , Bryant Chau
- & Pavel Strop
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Article
| Open AccessStructure–function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting
An EGFR mutant with kinase domain duplication (EGFR-KDD) was previously identified in an index patient, but the functional and therapeutic implications remain unclear. Here, the authors show that KDD occurs in other ErbB receptors in multiple cancers, and characterize the mechanism and inhibition of EGFR-KDD.
- Zhenfang Du
- , Benjamin P. Brown
- & Christine M. Lovly
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Article
| Open AccessMulti-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response
The response to hypoxia can significantly impact oncogenic processes. Here, the authors define the early transcriptional response to acute hypoxia and identify HIF1A target genes as part of this acute response, providing a resource for investigating context-dependent roles of HIF1A in the biology of cancer.
- Zdenek Andrysik
- , Heather Bender
- & Joaquin M. Espinosa
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Perspective
| Open AccessApplications, challenges, and needs for employing synthetic biology beyond the lab
Current developments in synthetic biology are not immediately applicable outside of the controlled laboratory environment. In this Perspective, the authors outline the advances and challenges the field faces in operating in resource limited and off-the-grid scenarios.
- Sierra M. Brooks
- & Hal S. Alper
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Article
| Open AccessN4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization
NF-κB signalling is critical to TLR mediated cytokine release in various immune responses. Here the authors show how N4BP1 inhibits NEMO signalling and subsequent NF-κB activation and how this pathway is negatively regulated by caspase-8 cleavage of N4BP1.
- Hexin Shi
- , Lei Sun
- & Bruce Beutler
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Article
| Open AccessComplete biosynthesis of a sulfated chondroitin in Escherichia coli
Chondroitin sulfate (CS) is a type of sulfated glycosaminoglycan that is manufactured by extraction from animal tissues for the treatment of osteoarthritis and in drug delivery applications. Here, the authors report the development of single microbial cell factories capable of compete, one-step biosynthesis of animal-free CS production in E. coli.
- Abinaya Badri
- , Asher Williams
- & Mattheos A. G. Koffas
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Article
| Open AccessMeta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data
The neural mechanisms of placebo analgesia are not fully understood. Here the authors conducted a large scale meta-analysis of individual data from fMRI studies of pain and placebo conditions.
- Matthias Zunhammer
- , Tamás Spisák
- & Fadel Zeidan
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