Featured
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Article
| Open AccessStructural and functional insights into esterase-mediated macrolide resistance
Erythromycin esterases (Eres) cleave the macrolactone ring of macrolides, a class of widely used antibiotics. Structures of EreC, in silico flexible docking studies and previous mutagenesis data lead to the proposal of a detailed catalytic mechanism for the Ere family of enzymes.
- Michał Zieliński
- , Jaeok Park
- & Albert M. Berghuis
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Article
| Open AccessA human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes
Vaccines that interrupt malaria transmission will be important tools for malaria elimination. Here the authors identify a human monoclonal antibody from Pfs230 vaccinated individuals that blocks transmission of Plasmodium falciparum to mosquitoes in a complement-dependent manner and reacts with gamete surface.
- Camila H. Coelho
- , Wai Kwan Tang
- & Patrick E. Duffy
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Article
| Open AccessMechanisms and targets of Fcγ-receptor mediated immunity to malaria sporozoites
Antibodies plays critical roles in the adaptive immune response to infectious agents including malaria. Here the authors defined antibody interactions with -Fcγ-receptors expressed on immune cells with sporozoites of Plasmodium falciparum, and identified specific target epitopes of antibodies.
- Gaoqian Feng
- , Bruce D. Wines
- & James G. Beeson
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Article
| Open AccessExposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection
T cells compose a critical component of the immune response to coronavirus infection with SARS-CoV-2. Here the authors characterise the T cell response to SARS CoV-2 in patients and their close contacts, and show the presence of SARS-CoV-2 specific T cells in the absence of detectable virus infection.
- Zhongfang Wang
- , Xiaoyun Yang
- & Pixin Ran
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Article
| Open AccessAlpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection
Here, via screening of a polypeptide library from bronchoalveolar lavage, the authors identify and characterize α1-antitrypsin (α1AT) as SARS-CoV-2 inhibitor and show that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion.
- Lukas Wettstein
- , Tatjana Weil
- & Jan Münch
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Article
| Open AccessA computational workflow for the expansion of heterologous biosynthetic pathways to natural product derivatives
The top down cheminformatics method is usually used for the reconstitution of heterologous pathway to produce plant natural products. Here, the authors report a bottom up computational workflow for the identification of potential products and the enzymes required to make them in a noscapine pathway in yeast.
- Jasmin Hafner
- , James Payne
- & Christina Smolke
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Article
| Open AccessAn engineered CRISPR-Cas12a variant and DNA-RNA hybrid guides enable robust and rapid COVID-19 testing
As the COVID-19 pandemic continues, variants of the virus are emerging. Here the authors present a diagnostic assay that can detect wildtype and known variants using engineered Cas12a.
- Kean Hean Ooi
- , Mengying Mandy Liu
- & Meng How Tan
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Article
| Open AccessLong-distance electron transfer in a filamentous Gram-positive bacterium
Long-distance extracellular electron transfer has been observed in Gram-negative bacteria. Here, Yang et al. show that a filamentous, unicellular Gram-positive bacterium is capable of bidirectional extracellular electron transfer, and forms centimetre-range conductive networks consisting of 1mm-long cells and conductive appendages.
- Yonggang Yang
- , Zegao Wang
- & Mingdong Dong
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Article
| Open AccessControl of a programmed cell death pathway in Pseudomonas aeruginosa by an antiterminator
In Pseudomonas aeruginosa, the protein AlpA activates the expression of the alp locus in response to DNA damage, leading to lysis in a subset of cells and enhancing virulence of other, surviving cells. Here, the authors show that AlpA acts as an antiterminator rather than a transcriptional activator.
- Jennifer M. Peña
- , Samantha M. Prezioso
- & Simon L. Dove
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Article
| Open AccessActivation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice
GPR37 is expressed in macrophages, and has been implicated in resolution of inflammatory pain. Here the authors show that GPR37 can modulate sepsis in several animal models.
- Sangsu Bang
- , Christopher R. Donnelly
- & Ru-Rong Ji
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Article
| Open AccessA conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies
Here, the authors report the isolation and characterization of two human monoclonal antibodies (mAbs) from immunized mice with trimeric spike ectodomains of three human betacoronaviruses HCoV-OC43, SARS-CoV and MERSCoV, and show that while exhibiting cross-reactivity, the mAbs only neutralize MERS-CoV but not SARS-CoV nor SARS-CoV-2, likely due to the subtle epitope differences in the spike S2 fusion subunit.
- Chunyan Wang
- , Rien van Haperen
- & Berend-Jan Bosch
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Article
| Open AccessIn situ structure and organization of the influenza C virus surface glycoprotein
Influenza C virus contains a single surface glycoprotein, the haemagglutinin-esterase-fusion (HEF) protein, that mediates receptor binding, receptor destruction, and membrane fusion activities. Here, the authors apply electron cryotomography of whole virus together with subtomogram averaging to determine the HEF structure and lattice organisation on the viral membrane and they discuss mechanistic implications for virus budding and membrane fusion.
- Steinar Halldorsson
- , Kasim Sader
- & Peter B. Rosenthal
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Article
| Open AccessIn vivo and in vitro reconstitution of unique key steps in cystobactamid antibiotic biosynthesis
The biosynthetic pathway leading to the production of cystobactamids, a group of myxobacteria-derived topoisomerase inhibitors with potent anti-Gram-negative activity, remains unclear. Here, the authors report in vivo and in vitro evidence for unique steps in cystobactamid biosynthesis.
- Sebastian Groß
- , Bastien Schnell
- & Rolf Müller
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Article
| Open AccessSARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication
Viruses rely on host metabolism for replication. Here, the authors perform transcriptional and metabolomic analyses at 8 hours after SARS-CoV-2 infection and find that the virus alters host folate and one-carbon metabolism at a post-transcriptional level.
- Yuchen Zhang
- , Rui Guo
- & Benjamin E. Gewurz
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Article
| Open AccessInteractions between timing and transmissibility explain diverse flavivirus dynamics in Fiji
Dengue and Zika virus are closely related flaviviruses but can have contrasting transmission dynamics in the same populations. Here, the authors use a model combining serological, surveillance and viral sequence data to explain differences in transmission dynamics in Fiji.
- Alasdair D. Henderson
- , Mike Kama
- & Adam J. Kucharski
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Article
| Open AccessDynamic relocalization of cytosolic type III secretion system components prevents premature protein secretion at low external pH
Many bacterial pathogens use a type III secretion system (T3SS) to inject effector proteins into host cells. Here, Wimmi et al. show that the external pH regulates the assembly of T3SS cytosolic components in intestinal pathogens, thus preventing T3SS activity in the stomach and allowing T3SS reactivation in the intestine.
- Stephan Wimmi
- , Alexander Balinovic
- & Andreas Diepold
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Article
| Open AccessDiscovery of fungal surface NADases predominantly present in pathogenic species
Some bacterial pathogens release NADase enzymes into the host cell that deplete the host’s NAD+ pool, thereby causing rapid cell death. Here, Strømland et al. identify NADases on the surface of fungal spores, and show that the enzymes display unique biochemical and structural properties.
- Øyvind Strømland
- , Juha P. Kallio
- & Mathias Ziegler
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Article
| Open AccessCircadian control of hepatitis B virus replication
The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the human liver transcriptome but their role in hepatitis B virus infection is largely unknown. Here, Zhuang et al. show that REV-ERB regulates hepatitis B virus entry and BMAL1 directly binds HBV DNA and activates viral genome transcription.
- Xiaodong Zhuang
- , Donall Forde
- & Jane A. McKeating
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Article
| Open AccessSARS-CoV and SARS-CoV-2 are transmitted through the air between ferrets over more than one meter distance
Some epidemiological data suggests that SARS-CoV-2 can be transmitted through the air over longer distances. Here, Kutter et al. show in the ferret model that SARS-CoV-2 and SARS-CoV can be transmitted through the air over more than a meter distance, however, data should be interpreted with care, as ferrets are likely more susceptible to coronavirus infections.
- Jasmin S. Kutter
- , Dennis de Meulder
- & Sander Herfst
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Article
| Open AccessPlasmodium vivax infection compromises reticulocyte stability
During Plasmodium intra-erythrocytic developmental, parasites compromise the structural integrity of host red-blood cells. Here, Clark et al. develop a flow cytometric osmotic stability assay to show that P. vivax infection destabilizes host reticulocytes, which are less stable than P. falciparum-infected normocytes.
- Martha A. Clark
- , Usheer Kanjee
- & Manoj T. Duraisingh
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Article
| Open AccessIntegrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications
Metabolism changes can modulate immune responses in many contexts, and vice versa. Here the authors associate metabolomic, as well as cytokine and chemokine, data from stratified COVID-19 patients to find that arginine, tryptophan and purine metabolic pathways correlate with hyperproliferation, thus hinting at potential therapeutic targets for severe COVID-19 patients.
- Nan Xiao
- , Meng Nie
- & Zeping Hu
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Article
| Open AccessEvaluating the impact of curfews and other measures on SARS-CoV-2 transmission in French Guiana
Identifying effective combinations of control measures in different populations is important for SARS-CoV-2 control. Here, the authors show that in French Guiana, which has a relatively young population, curfews and localised lockdowns appeared to contribute to reducing transmission.
- Alessio Andronico
- , Cécile Tran Kiem
- & Simon Cauchemez
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Article
| Open AccessBiofilm formation in the lung contributes to virulence and drug tolerance of Mycobacterium tuberculosis
Mycobacterium tuberculosis forms biofilms in vitro, but it is unclear whether biofilms are also formed during infection in vivo. Here, Chakraborty et al. demonstrate the formation of biofilms in animal models of infection and in patients with tuberculosis, and that biofilm formation can contribute to drug tolerance.
- Poushali Chakraborty
- , Sapna Bajeli
- & Ashwani Kumar
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Article
| Open AccessHepatitis B virus cccDNA is formed through distinct repair processes of each strand
HBV covalently closed circular DNA (cccDNA) enables and persists in chronic infection, but the molecular mechanism of its formation is unclear. Here, Wei and Ploss elucidate the detailed kinetics and biochemical steps by which the relaxed circular DNA is converted into cccDNA.
- Lei Wei
- & Alexander Ploss
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Article
| Open AccessBat and pangolin coronavirus spike glycoprotein structures provide insights into SARS-CoV-2 evolution
The spike glycoprotein in coronaviruses is a key viral protein for cross-species transmission and infection. Here, the authors present the cryo-EM structures of the spike ectodomains from bat and pangolin coronaviruses, compare them with the available SARS-CoV-2 spike structures and discuss implications for the evolution and cross-species transmission of SARS-CoV-2.
- Shuyuan Zhang
- , Shuyuan Qiao
- & Xinquan Wang
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Article
| Open AccessA randomised controlled trial to reduce highest priority critically important antimicrobial prescription in companion animals
Effective use of antimicrobials in both humans and animals is essential to help slow the emergence of antimicrobial resistance. Here, Singleton et al. present a randomised controlled trial demonstrating the efficacy of social norm messaging to reduce antibiotic prescription frequency in veterinary surgeries.
- David A. Singleton
- , Angela Rayner
- & Gina L. Pinchbeck
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Article
| Open AccessInfectivity, susceptibility, and risk factors associated with SARS-CoV-2 transmission under intensive contact tracing in Hunan, China
Detailed knowledge of COVID-19 epidemiology is needed to inform public health responses. Here, the authors use large-scale contact tracing data to provide empirical estimates of key parameters, and show that susceptibility increases with age but transmissibility does not vary significantly.
- Shixiong Hu
- , Wei Wang
- & Hongjie Yu
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Article
| Open AccessSubstrate-engaged type III secretion system structures reveal gating mechanism for unfolded protein translocation
Virulent type III secretion systems (T3SSs) or injectisomes enable pathogenic bacteria to inject effector proteins directly into the host cell cytoplasm. Structures of a needle complex engaged with the effector protein reveal the complete secretion channel and provide insights into the mechanism of substrate translocation through T3SSs.
- Sean Miletic
- , Dirk Fahrenkamp
- & Thomas C. Marlovits
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Article
| Open AccessApparent nosocomial adaptation of Enterococcus faecalis predates the modern hospital era
Enterococcus faecalis is a commensal microorganism of animals, insects and humans, but also a nosocomial pathogen. Here, the authors analyse genomic sequences from E. faecalis isolates from animals and humans, and find that the last common ancestors of multiple hospital-associated lineages date to the pre-antibiotic era.
- Anna K. Pöntinen
- , Janetta Top
- & Jukka Corander
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Article
| Open AccessCross-linking peptide and repurposed drugs inhibit both entry pathways of SARS-CoV-2
Until today effective antivirals for COVID-19 treatment are not widely available. Here, Zhao et al. characterize a dual-functional cross-linking peptide, 8P9R, that can inhibit SARS-CoV-2 virus entry in vitro and suppresses viral replication in vivo in golden Syrian hamster.
- Hanjun Zhao
- , Kelvin K. W. To
- & Kwok-Yung Yuen
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Article
| Open AccessNaturally acquired blocking human monoclonal antibodies to Plasmodium vivax reticulocyte binding protein 2b
Plasmodium vivax reticulocyte binding protein 2b (PvRBP2b) is important for invasion of reticulocytes and PvRBP2b antibodies correlate with protection. Here, Chan et al. isolate and characterize anti-PvRBP2b human monoclonal antibodies and describe mechanisms by which these antibodies inhibit invasion.
- Li-Jin Chan
- , Anugraha Gandhirajan
- & Wai-Hong Tham
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Article
| Open AccessSpatiotemporal persistence of multiple, diverse clades and toxins of Corynebacterium diphtheriae
Cases of diphtheria have increased in recent years. Here, the authors analyse the genomes of 502 Corynebacterium diphtheriae isolates across 16 countries and territories over 122 years, describing an increase in antimicrobial resistance genes and identifying toxin variants.
- Robert C. Will
- , Thandavarayan Ramamurthy
- & Ankur Mutreja
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Article
| Open AccessHyperproduction of 3-hydroxypropionate by Halomonas bluephagenesis
3-Hydroxypropionic acid (3HP) is an important platform chemical. Here, the authors engineer Halomonas bluephagenesis by deleting newly identified degradation pathway and balancing redox state to achieve high level production of 3HP and its copolymer under open and unsterile conditions.
- Xiao-Ran Jiang
- , Xu Yan
- & Guo-Qiang Chen
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Article
| Open AccessComplex yeast–bacteria interactions affect the yield of industrial ethanol fermentation
Industrial sugarcane ethanol fermentations are accomplished by a microbial community dominated by S. cerevisiae and co-occurring bacteria. Here, the authors investigate how microbial community composition contributes to community function and reveal the role of acetaldehyde in improving yeast growth rate and ethanol production.
- Felipe Senne de Oliveira Lino
- , Djordje Bajic
- & Morten Otto Alexander Sommer
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Article
| Open AccessReal-time tracking and prediction of COVID-19 infection using digital proxies of population mobility and mixing
Digital proxies of human mobility can be used to monitor social distancing, and therefore have potential to infer COVID-19 dynamics. Here, the authors integrate travel card data from Hong Kong into a transmission model and show that it can be used to track transmissibility in near real-time.
- Kathy Leung
- , Joseph T. Wu
- & Gabriel M. Leung
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Article
| Open AccessDeciphering the state of immune silence in fatal COVID-19 patients
Integrated studies of matched tissue sites and cell types in COVID-19 patients are important to define the immune mechanisms of pathology. Here, the authors describe an immune signature in fatal COVID-19 patients harmonizing single-cell RNA sequencing of blood and matched BAL cells with deep clinical, immunological and functional data.
- Pierre Bost
- , Francesco De Sanctis
- & Vincenzo Bronte
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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 AccessEngineered yeast genomes accurately assembled from pure and mixed samples
The cost and complexity of whole genome sequencing limits its use in identifying and validating sequences used for genetic engineering and synthetic biology. Here the authors present Prymetime, an integrated workflow to sequence engineered strains and identify engineering in metagenomes.
- Joseph H. Collins
- , Kevin W. Keating
- & Eric M. Young
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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 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 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 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 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 AccessImmunogenicity and protective efficacy of inactivated SARS-CoV-2 vaccine candidate, BBV152 in rhesus macaques
SARS-CoV-2 vaccines are needed to fight the pandemic. Here, authors show protective efficacy and immunogenicity of the inactivated SARS-CoV-2 vaccine BBV152 in rhesus macaques. This vaccine is currently in clinical development.
- Pragya D. Yadav
- , Raches Ella
- & Balram Bhargava
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Article
| Open AccessThe prevalence of antibodies to SARS-CoV-2 among blood donors in China
Here, the authors determine seroprevalence of antibodies to SARS-CoV-2 in healthy blood donors in the cities of Wuhan, Shenzhen, and Shijiazhuang in China between January and April 2020. The age- and sex-standardized SARS-CoV-2 seroprevalence among 18–60 year-old adults is, with 2.66%, the highest in Wuhan.
- Le Chang
- , Wangheng Hou
- & Lunan Wang
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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 AccessS-Trimer, a COVID-19 subunit vaccine candidate, induces protective immunity in nonhuman primates
Vaccines for SARS-CoV-2 are needed to fight the pandemic. Here the authors show immunogenicity of an adjuvanted subunit vaccine, SARS-CoV-2 spike protein trimerized with trimer-tag technology, in small animal models and protection from SARS-CoV-2 challenge in non-human primates.
- Joshua G. Liang
- , Danmei Su
- & Peng Liang
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Article
| Open AccessStructural characterization of the microbial enzyme urocanate reductase mediating imidazole propionate production
Imidazole propionate (ImP) produced by gut microbiota has been associated with type 2 diabetes. Here, the authors present crystal structures of the ImP biosynthesis enzyme urocanate reductase in four different states, providing molecular insights into its catalytic mechanism.
- Raminta Venskutonytė
- , Ara Koh
- & Karin Lindkvist-Petersson
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Article
| Open AccessChemogenetic ON and OFF switches for RNA virus replication
Therapeutic application of RNA viruses requires tight control over viral activity. Here the authors design a regulatory switch that enables control over activity with clinically approved HIV protease inhibitors.
- E. Heilmann
- , J. Kimpel
- & D. von Laer
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