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Albumin orchestrates a natural host defence mechanism against mucormycosis
Albumin selectively inhibits Mucorales growth through the release of bound free fatty acids.
- Antonis Pikoulas
- , Ioannis Morianos
- & Georgios Chamilos
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Article
| Open Access
Spatial fibroblast niches define Crohn’s fistulae
Spatial transcriptomic analysis of cells in intestinal fistulae of patients with Crohn’s disease reveals the existence of specialized fistula-associated cell states with distinct signalling profiles and extracellular matrix architecture.
- Colleen McGregor
- , Xiao Qin
- & Alison Simmons
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Article
| Open Access
Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus
PLD4 loss-of-function mutations in patients with systemic lupus erythematosus leads to excessive activation of TLR7 and TLR9.
- Qintao Wang
- , Honghao Zhu
- & Zhihong Liu
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Article
| Open Access
A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia
In mammals, the enzyme TGDS produces UDP-4-keto-6-deoxyglucose, which binds to the catalytic pocket of UDP-xylose synthase, thereby regenerating the essential NAD+ cofactor of UDP-xylose synthase in conditions of low NAD+.
- Jean Jacobs
- , Hristiana Lyubenova
- & Guido T. Bommer
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Epithelial cell membrane perforation induces allergic airway inflammation
The ability to form pores in the plasma membrane of host airway epithelial cells is a common feature of many structurally diverse allergens that induce type 2 immune responses by stimulating IL-33 release and causing Ca2+ influx.
- Kejian Shi
- , Yao Lv
- & Mo Xu
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Article |
Identification of medication–microbiome interactions that affect gut infection
An analysis of prescription medications shows that several non-antibiotic drugs, such as the heart medication digoxin, can reduce the immune response to pathogens and increase the risk of gastrointestinal infections by altering the composition of the microbiome.
- Aman Kumar
- , Ruizheng Sun
- & Andrew L. Goodman
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Article
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R9AP is a common receptor for EBV infection in epithelial cells and B cells
R9AP is a key receptor for entry of Epstein–Barr virus into human epithelial and B cells, and interacts directly with the viral glycoprotein gH/gL complex to mediate virus–host membrane fusion.
- Yan Li
- , Hua Zhang
- & Mu-Sheng Zeng
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Article |
RELMβ sets the threshold for microbiome-dependent oral tolerance
RELMβ mediates a gut immune–epithelial circuit regulating tolerance to food antigens, offering targetable candidates for the prevention and treatment of food allergies.
- Emmanuel Stephen-Victor
- , Gavin A. Kuziel
- & Talal A. Chatila
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Article
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Prolonged persistence of mutagenic DNA lesions in somatic cells
Persistent DNA lesions can occur throughout the human lifespan and can remain in the genome of affected cells for several years and generate a substantial proportion of the mutational burden.
- Michael Spencer Chapman
- , Emily Mitchell
- & Peter J. Campbell
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Article
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GZMK-expressing CD8+ T cells promote recurrent airway inflammatory diseases
Comparing T cells in nasal polyps from repeated surgeries shows that effector memory-like persistent clones colonize the mucosal tissue during disease recurrence and promote inflammation by producing Granzyme K, a complement-activating tryptase, which is a potential therapeutic target.
- Feng Lan
- , Jizhou Li
- & Hai Qi
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Article
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Site-saturation mutagenesis of 500 human protein domains
Large-scale experimental analysis of Human Domainome 1, a library containing more than 500,000 missense mutation variants across more than 500 human protein domains, reveals that 60% of pathogenic missense variants reduce stability of protein domains.
- Antoni Beltran
- , Xiang’er Jiang
- & Ben Lehner
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Article |
Immune responses in checkpoint myocarditis across heart, blood and tumour
The molecular characteristics of myocarditis associated with immune checkpoint inhibitors are described and potential biomarkers of onset and severity are identified.
- Steven M. Blum
- , Daniel A. Zlotoff
- & Alexandra-Chloé Villani
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Article |
AARS1 and AARS2 sense l-lactate to regulate cGAS as global lysine lactyltransferases
The tRNA synthases AARS1 and AARS2 are identified as evolutionarily conserved sensors of intracellular l-lactate to mediate the global lysine lactylome.
- Heyu Li
- , Chao Liu
- & Long Zhang
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Article |
A human autoimmune organoid model reveals IL-7 function in coeliac disease
A human in vitro model of coeliac disease comprising duodenal organoids that maintain both epithelium and an immune microenvironment finds a previously unsuspected role for IL-7 in gluten-induced epithelial destruction.
- António J. M. Santos
- , Vincent van Unen
- & Calvin J. Kuo
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Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis
In mouse and human, lung-specialized alveolar fibroblasts adopt multiple molecular states that are induced by pro-inflammatory and fibrotic signals and have diverse protective roles against lung injury.
- Tatsuya Tsukui
- , Paul J. Wolters
- & Dean Sheppard
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Article
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Multimodal decoding of human liver regeneration
Harnessing single-nucleus RNA sequencing and spatial profiling, this work dissects unanticipated aspects of human liver regeneration to uncover a novel migratory hepatocyte subpopulation mediating wound closure following acute liver injury.
- K. P. Matchett
- , J. R. Wilson-Kanamori
- & N. C. Henderson
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Article
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Ancestral allele of DNA polymerase gamma modifies antiviral tolerance
The POLG1 mutation p.W748S, which is associated with mitochondrial recessive ataxia syndrome, dampens innate immune responses by compromising mtDNA replisome stability, and this explains why a viral infection can trigger the development of the disease and contribute to its variable clinical manifestation.
- Yilin Kang
- , Jussi Hepojoki
- & Anu Suomalainen
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C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation
The molecular mechanism underlying the severe neurogenic inflammation induced by Clostridioides difficile is presented, providing a therapeutic target for treating this infection.
- John Manion
- , Melissa A. Musser
- & Min Dong
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Matters Arising
| Open Access
Common orthopaedic trauma may explain 31,000-year-old remains
- Nicholas J. Murphy
- , Joshua S. Davis
- & Zsolt J. Balogh
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SARS-CoV-2 infection and persistence in the human body and brain at autopsy
A study reports the distribution, replication and persistence of SARS-CoV-2 throughout the human body including in the brain at autopsy from acute infection to more than seven months following symptom onset.
- Sydney R. Stein
- , Sabrina C. Ramelli
- & Daniel S. Chertow
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Article
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Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes
A study examining DNA transfer from mitochondria to the nucleus using whole-genome sequences from 66,083 people shows that this is an ongoing dynamic process in normal cells with distinct roles in different types of cancer.
- Wei Wei
- , Katherine R. Schon
- & Patrick F. Chinnery
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Enteric viruses replicate in salivary glands and infect through saliva
Enteric viruses replicate in salivary glands, can be propagated in salivary gland-derived spheroids and cell lines, and are released into saliva, which is a new transmission route having implications for therapeutics, diagnostics and sanitation measures.
- S. Ghosh
- , M. Kumar
- & N. Altan-Bonnet
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Article
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TLR7 gain-of-function genetic variation causes human lupus
The missense TLR7Y264H gain-of-function genetic variation causes systemic lupus erythematosus in humans and mice.
- Grant J. Brown
- , Pablo F. Cañete
- & Carola G. Vinuesa
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Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells
Single-cell RNA sequencing and imaging of macrophages in human non-small cell lung cancer and in a mouse model of lung adenocarcinoma show that tissue-resident macrophages have a key role in early tumour progression.
- María Casanova-Acebes
- , Erica Dalla
- & Miriam Merad
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Review Article |
Unconventional viral gene expression mechanisms as therapeutic targets
This Review outlines the gene and protein expression strategies used by viruses to expand the efficiency of their coding and regulatory sequences, and the implications of these mechanisms for developing antiviral agents.
- Jessica Sook Yuin Ho
- , Zeyu Zhu
- & Ivan Marazzi
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A molecular single-cell lung atlas of lethal COVID-19
Lung samples collected soon after death from COVID-19 are used to provide a single-cell atlas of SARS-CoV-2 infection and the ensuing molecular changes.
- Johannes C. Melms
- , Jana Biermann
- & Benjamin Izar
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Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia
Lungs from patients who died from COVID-19 show atypical fused cells, the formation of which is mediated by the SARS-CoV-2 spike protein, and drugs that inhibit TMEM16F can prevent spike-induced syncytia formation.
- Luca Braga
- , Hashim Ali
- & Mauro Giacca
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The spatial landscape of lung pathology during COVID-19 progression
Imaging mass cytometry of the human lung reveals the cellular composition and spatial architecture during COVID-19 and other acute injuries, enabling the characterization of lung pathophysiology from structural, immunological and clinical perspectives.
- André F. Rendeiro
- , Hiranmayi Ravichandran
- & Robert E. Schwartz
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The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis
Accelerated atherosclerosis in a mouse model of clonal haematopoiesis is prevented by genetic interruption of AIM2 inflammasome activation or by inhibition of interleukin-1β.
- Trevor P. Fidler
- , Chenyi Xue
- & Alan R. Tall
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Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator
The long non-coding RNA locus Maenli controls mouse limb development by regulating En1 activity, and the absence of the homolgous MAENLI locus is associated with severe congenital limb defects in humans.
- Lila Allou
- , Sara Balzano
- & Andrea Superti-Furga
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Local immune response to food antigens drives meal-induced abdominal pain
In mice, oral tolerance to food antigens can break down after enteric infection, and this leads to food-induced pain resembling irritable bowel syndrome in humans.
- Javier Aguilera-Lizarraga
- , Morgane V. Florens
- & Guy E. Boeckxstaens
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Article |
Pervasive chromosomal instability and karyotype order in tumour evolution
Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.
- Thomas B. K. Watkins
- , Emilia L. Lim
- & Charles Swanton
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Article |
The National Lung Matrix Trial of personalized therapy in lung cancer
Current outcomes are reported from the ongoing National Lung Matrix Trial, an umbrella trial for the treatment of non-small-cell lung cancer in which patients are triaged according to their tumour genotype and matched with targeted therapeutic agents.
- Gary Middleton
- , Peter Fletcher
- & Lucinda Billingham
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Article |
IGF1R is an entry receptor for respiratory syncytial virus
Respiratory syncytial virus enters cells by binding to cell-surface IGFR1, which activates PKCζ and induces trafficking of the NCL coreceptor to the RSV particles at the cell surface.
- Cameron D. Griffiths
- , Leanne M. Bilawchuk
- & David J. Marchant
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Article |
Respiratory disease in rhesus macaques inoculated with SARS-CoV-2
Infection with SARS-CoV-2 in rhesus macaques causes a respiratory disease that recapitulates aspects of COVID-19 in humans, establishing this species as an animal model for investigating the pathogenesis of SARS-CoV-2.
- Vincent J. Munster
- , Friederike Feldmann
- & Emmie de Wit
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Article |
The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice
Infection with SARS-CoV-2 causes interstitial pneumonia and viral replication in the lungs of transgenic mice that express a human version of ACE2, confirming the pathogenicity of the virus in this model.
- Linlin Bao
- , Wei Deng
- & Chuan Qin
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Article |
The molecular basis for sugar import in malaria parasites
Crystal structure of the Plasmodium falciparum hexose transporter PfHT1 reveals the molecular basis of its ability to transport multiple types of sugar as efficiently as the dedicated mammalian glucose and fructose transporters.
- Abdul Aziz Qureshi
- , Albert Suades
- & David Drew
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Article |
Host-mediated ubiquitination of a mycobacterial protein suppresses immunity
Mycobacterium tuberculosis suppresses the production of inflammatory cytokines by host cells through the host-mediated ubiquitination of a mycobacterial protein, enhancing the interaction of a host signalling inhibitor with another signalling molecule.
- Lin Wang
- , Juehui Wu
- & Baoxue Ge
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Article |
A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1
A dominantly inherited human autoinflammatory disease caused by mutations in RIPK1 is identified, and RIPK1 mutations that prevent caspase-8 cleavage sensitize cells to apoptosis, necroptosis and inflammation.
- Panfeng Tao
- , Jinqiao Sun
- & Qing Zhou
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Matters Arising |
Do not discard Staphylococcus aureus WTA as a vaccine antigen
- Rob van Dalen
- , Michèle M. Molendijk
- & Nina M. van Sorge
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Letter |
Cholera toxin promotes pathogen acquisition of host-derived nutrients
Cholera toxin selectively promotes the growth of Vibrio cholerae through the acquisition of nutrients, including haem and fatty acids, from the host gut.
- Fabian Rivera-Chávez
- & John J. Mekalanos
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Letter |
FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes
Mutations in the transcription factor FOXA1 that are common in prostate cancer result in gain-of-function effects that promote changes in the differentiation of tumour cells.
- Elizabeth J. Adams
- , Wouter R. Karthaus
- & Charles L. Sawyers
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Letter |
Distinct fibroblast subsets drive inflammation and damage in arthritis
Distinct subsets of fibroblasts, which differ in their expression of thymus cell antigen 1 (THY1), are responsible for inflammation and tissue damage in mouse models of arthritis.
- Adam P. Croft
- , Joana Campos
- & Christopher D. Buckley
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Letter |
Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death
Histone H4 is released from neutrophil extracellular traps and induces membrane lysis in vascular smooth muscle cells, leading to the destabilization of atherosclerotic plaques.
- Carlos Silvestre-Roig
- , Quinte Braster
- & Oliver Soehnlein
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Letter |
Structure of Plasmodium falciparum Rh5–CyRPA–Ripr invasion complex
A subnanometre-resolution cryo-electron microscopy structure of the Rh5–CyRPA–Ripr complex of Plasmodium falciparum provides insights into how this ligand interacts with the receptor basigin in erythrocyte hosts.
- Wilson Wong
- , Rick Huang
- & Alan F. Cowman
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Letter |
Nuclear cGAS suppresses DNA repair and promotes tumorigenesis
DNA damage induces translocation of cyclic GMP–AMP synthase to the nucleus, where it suppresses homologous recombination by interfering with the formation of the PARP1–Timeless complex.
- Haipeng Liu
- , Haiping Zhang
- & Baoxue Ge
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Brief Communications Arising |
Conflicting evidence for HIV enrichment in CD32+ CD4 T cells
- Liliana Pérez
- , Jodi Anderson
- & Eli A. Boritz
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Article |
Precancerous neoplastic cells can move through the pancreatic ductal system
Comparison of multiple lesions from individual pancreases sheds light on how ancestral clones can spread through the ductal system and give rise to precursor lesions, with acquisition of further mutations leading to pancreatic cancer.
- Alvin P. Makohon-Moore
- , Karen Matsukuma
- & Christine A. Iacobuzio-Donahue
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Letter |
Mxra8 is a receptor for multiple arthritogenic alphaviruses
The cell adhesion molecule Mxra8 is identified as a receptor for multiple arthritogenic alphaviruses such as chikungunya virus, and anti-Mxra8 monoclonal antibodies are shown to reduce rates of chikungunya virus infection in mice and a range of human cells.
- Rong Zhang
- , Arthur S. Kim
- & Michael S. Diamond
Mucosal vaccination clears Clostridioides difficile colonization