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| Open AccessSpatial transcriptomics analysis of esophageal squamous precancerous lesions and their progression to esophageal cancer
Understanding the molecular changes in the transition from esophageal squamous precancerous lesions (ESPL) to esophageal squamous cell carcinoma (ESCC) remains essential. Here, the authors analyze ESPL samples using spatial transcriptomics and reveal expression changes in TAGLN2 and CRNN during progression to ESCC.
- Xuejiao Liu
- , Simin Zhao
- & Zigang Dong
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Article
| Open AccessNeuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants
Here, Dias de Melo et al. assess the clinical, olfactory, and neuroinflammatory conditions of golden hamsters infected with SARS-CoV-2 wt and VOCs and report that viruses can infect neurons, travel inside axons, and invade the central nervous system.
- Guilherme Dias de Melo
- , Victoire Perraud
- & Hervé Bourhy
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Article
| Open AccessLILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis
Inhibition of immunocyte infiltration and activation has been suggested to ameliorate hepatic inflammation and fibrosis in nonalcoholic steatohepatitis. Here, the authors show PirB/LILRB2 regulates the migration of macrophages during NASH by binding with ANGPTL8, which is involved in the regulation of NASH development.
- Dan-Pei Li
- , Li Huang
- & Xue-Feng Yu
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Article
| Open AccessIKK2/NFkB signaling controls lung resident CD8+ T cell memory during influenza infection
CD8+ T resident memory (TRM) cells are important in protection against virus infection and NFκB signalling may function in this process. Here the authors use an inducible transgenic mouse models where T cell intrinsic NFκB levels can be increased or decreased which affects how CD8+ TRM cells seed into the lungs after influenza infection.
- Curtis J. Pritzl
- , Dezzarae Luera
- & Emma Teixeiro
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Article
| Open AccesspH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle
PfCRT is a chloroquine resistance transporter from malaria parasite Plasmodium falciparum, which is sensitive to acidic pH. Here, the authors show that residue E207 is critical for pH sensing by PfCRT, using alanine-scanning mutagenesis, MD simulations and drug uptake assays.
- Fiona Berger
- , Guillermo M. Gomez
- & Michael Lanzer
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Article
| Open AccessInterplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability
The combination of host and pathogen diversity can result in variability in disease severity between individuals. Here the authors utilise a model of Streptococcus pyogenes infection and show the impact of human STING genotype and bacterial NADase activity on pathology.
- Elin Movert
- , Jaume Salgado Bolarin
- & Fredric Carlsson
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Article
| Open AccessWhole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
Rosacea is a common, multi-factorial chronic inflammatory skin disorder. Here authors provide evidence of genetic predisposition by whole genome sequencing and whole exome sequencing of samples from familial cases, and by recapitulating a recurrent mutation in the LRRC4 gene in a mouse model, they find that neuron-derived vasoactive intestinal peptide is an important pathogenic factor for neurogenic inflammation in rosacea.’
- Zhili Deng
- , Mengting Chen
- & Ji Li
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Article
| Open AccessDifferentiation of IL-26+ TH17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis
Interleukin 26 (IL-26) has been shown to have antimicrobial and pro-inflammatory effects. Here the authors establish a role for IL-26 in the generation of IL-17A producing Th17 CD4+ T cells and suggest it involves epithelial cross talk in skin lesions of psoriasis patients.
- Anissa Fries
- , Fanny Saidoune
- & Michel Gilliet
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Article
| Open AccessDeficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. Here, using genetic data for 1.52 million individuals, the authors identify 25 genes with protein-altering variants exhibiting a strong deficit of homozygosity, suggesting they are essential for successful early development.
- Asmundur Oddsson
- , Patrick Sulem
- & Daniel F. Gudbjartsson
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Article
| Open AccessHamster model for post-COVID-19 alveolar regeneration offers an opportunity to understand post-acute sequelae of SARS-CoV-2
Heydemann et al. investigate alveolar regeneration mechanisms after SARS-CoV-2 infection in the hamster model, offering insight into the pathomechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC).
- Laura Heydemann
- , Małgorzata Ciurkiewicz
- & Federico Armando
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Article
| Open AccessIntrinsic TGF-β signaling attenuates proximal tubule mitochondrial injury and inflammation in chronic kidney disease
Chronic kidney disease (CKD) is a disease that irreversibly leads to loss of renal function. Here, the authors demonstrate the beneficial effect of intrinsic TGF-b signaling on mitochondrial function and inflammation in the proximal tubule epithelium in response to kidney injury.
- Merve Kayhan
- , Judith Vouillamoz
- & Stellor Nlandu Khodo
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Article
| Open AccessSequential intrahost evolution and onward transmission of SARS-CoV-2 variants
There is limited understanding of SARS-CoV-2 intra-host evolution and subsequent transmission and adaptations in the context of persistent infection. Here, the authors describe sequential persistent SARS-CoV-2 infections that led to the emergence, transmission and further evolution of a novel Omicron BA.1.23 lineage.
- Ana S. Gonzalez-Reiche
- , Hala Alshammary
- & Harm van Bakel
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Article
| Open AccessFibroblasts are a site of murine cytomegalovirus lytic replication and Stat1-dependent latent persistence in vivo
Fibroblasts are an established cell type permissive for cytomegalovirus infection. Here the authors identify a population of fibroblast cells that can support murine cytomegalovirus lytic and latent virus infection in vivo and propose STAT1 as critically involved in murine cytomegalovirus latency.
- Katarzyna M. Sitnik
- , Fran Krstanović
- & Luka Čičin-Šain
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Article
| Open AccessViral subversion of selective autophagy is critical for biogenesis of virus replication organelles
Virus triggered lipophagy is important for flaviviral assembly and coordinated by Aup1 and the ubiquitin conjugating enzyme E2. Here, Lan et al further characterise the interplay between these proteins and how they function to modulate selective autophagy and viral replication.
- Yun Lan
- , Sophie Wilhelmina van Leur
- & Sumana Sanyal
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Article
| Open AccessPPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis
IL-9-producing helper T (TH9) cells contribute to allergic inflammation. In this study, the authors demonstrate that the transcription factor PPAR-γ regulates TH9 effector function by promoting glucose metabolism and mTOR signaling in human allergic contact dermatitis.
- Nicole L. Bertschi
- , Oliver Steck
- & Christoph Schlapbach
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Article
| Open AccessSample-to-answer platform for the clinical evaluation of COVID-19 using a deep learning-assisted smartphone-based assay
The lateral flow assay (LFA) has been considered a rapid test tool but with low sensitivity hampering the precise diagnosis. Here, the authors report bioengineered enrichment tools for LFAs with enhanced sensitivity and specificity that can reinforce LFA’s clinical performance.
- Seungmin Lee
- , Sunmok Kim
- & Jeong Hoon Lee
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Article
| Open AccessAGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling
Thoracic aortic aneurysm (TAA) causes many sudden deaths each year, however, no effective drug treatment is available. Here, the authors show that AGGF1 protein therapy attenuates TAA in three different mouse models through integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signalling.
- Xingwen Da
- , Ziyan Li
- & Qing K. Wang
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Article
| Open AccessMultiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19
In this work, authors take a multiomics and microfluidics-based approach to elucidate the mechanism of endothelial damage in critical illness associated with SARS-CoV-2.
- Samuel Druzak
- , Elizabeth Iffrig
- & Cheryl L. Maier
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Article
| Open AccessA DNA tumor virus globally reprograms host 3D genome architecture to achieve immortal growth
The dynamic and temporal changes of host genome architecture during Epstein-Barr virus (EBV) transformation are not well known. Here the authors transform human primary B lymphocyte into lymphoblastoid cell lines (LCLs) with EBV and show that the host 3D genome is rewired to facilitate expression of key oncogenes.
- Chong Wang
- , Xiang Liu
- & Bo Zhao
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Article
| Open AccessCryptosporidium uses CSpV1 to activate host type I interferon and attenuate antiparasitic defenses
Cryptosporidium parvum virus 1 is a virus harbored by the pathogenic protozoan Cryptosporidium parvum, and whose role in parasite biology and host interactions remains unclear. Here, Deng et al. demonstrate the impact this virus has on host response and infection outcome.
- Silu Deng
- , Wei He
- & Xian-Ming Chen
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Article
| Open AccessSerum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model
The immune response has been suggested to be involved in the pathology of Ménière’s disease. Here the authors implicate serum glucocorticoid-inducible kinase 1 as a regulator of the NLRP3 inflammasome and link to macrophage function in a model of Ménière’s disease pathology.
- Dao-Gong Zhang
- , Wen-Qian Yu
- & Hai-Bo Wang
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Article
| Open AccessZika virus RNA structure controls its unique neurotropism by bipartite binding to Musashi-1
Human RNA binding protein Musashi-1 binds various host transcripts as well as Zika virus RNA in neural progenitor cells. Here, Chen et al. characterise the interactions between Musashi-1 and its binding site using a combination of molecular and biophysical methods to shed light on its role in viral neurotropism.
- Xiang Chen
- , Yan Wang
- & Cheng-Feng Qin
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Article
| Open AccessTEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
Van Haute et al describe autosomal recessive TEFM variants that impair mitochondrial transcription elongation and reduce the levels of promoter distal mitochondrial RNA transcripts, leading to heterogeneous mitochondrial diseases with a treatable neuromuscular transmission defect.
- Lindsey Van Haute
- , Emily O’Connor
- & Rita Horvath
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Article
| Open AccessThe cytomegalovirus gB/MF59 vaccine candidate induces antibodies against an antigenic domain controlling cell-to-cell spread
A gB/MF59 vaccine candidate for human cytomegalovirus (HCMV) provided partial protection in organ transplant patients. Here, the authors identify antibody responses in trial participants that target virally infected cells to control cell-to-cell spread of HCMV, providing a potential mechanism for the observed protection.
- A. C. Gomes
- , I. A. Baraniak
- & M. B. Reeves
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Article
| Open AccessReciprocal modulation of ammonia and melanin production has implications for cryptococcal virulence
Cryptococcus neoformans has numerous described virulence mechanisms including urease secretion and melanization. Here, Baker and Casadevall, describe the reciprocal relationship between these two factors and their contribution to infection.
- Rosanna P. Baker
- & Arturo Casadevall
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Article
| Open AccessPersonalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation
PREGCARE is a new strategy for families who had a child with a pathogenic de novo mutation, that efficiently identifies couples at higher recurrence risk due to parental mosaicism, while reassuring many others that their recurrence risk is negligible.
- Marie Bernkopf
- , Ummi B. Abdullah
- & Anne Goriely
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Article
| Open AccessRepair of airway epithelia requires metabolic rewiring towards fatty acid oxidation
Airway epithelial repair, a key process in the recovery from lung injury, requires a metabolic shift from glycolysis to fatty acid oxidation (FAO). Pharmacological FAO promotion enhances epithelial differentiation, suggesting new therapeutic options.
- Stefania Crotta
- , Matteo Villa
- & Andreas Wack
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Article
| Open AccessDistinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19
Infection with SARS-CoV-2 has been linked with substantive inflammation, lung pathology and development of COVID-19. Here the authors spatially associate CCL18 and CCL21 in distinct tissue niches with lung pathology of severe COVID-19.
- Ronja Mothes
- , Anna Pascual-Reguant
- & Anja E. Hauser
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Article
| Open AccessA subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis
Although anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis and generally considered pathogenic, their functional relevance is incompletely understood. In this study, the authors describe an ACPA with a protective effect against antibody-induced arthritis in mice.
- Yibo He
- , Changrong Ge
- & Rikard Holmdahl
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Article
| Open AccessHigh-depth sequencing characterization of viral dynamics across tissues in fatal COVID-19 reveals compartmentalized infection
Here, by high-resolution SARS-CoV-2 sequencing, genomic and transcriptomic analyses from tissue samples, Normandin et al. investigate viral dynamics in fatal cases of COVID-19, revealing persistent infection in distinct anatomical sites, including the heart and testis.
- Erica Normandin
- , Melissa Rudy
- & Isaac H. Solomon
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Article
| Open AccessMechanism of regulation of the Helicobacter pylori Cagβ ATPase by CagZ
Cagβ is an ATPase in the H. pylori CagType4 secretion system essential for delivering the CagA effector to host cells. Here, authors present crystal structures of hexameric apo-Cagβ and Cagβ trapped in the monomeric state by its regulator CagZ, uncovering the regulatory mechanisms of Cagβ.
- Xiuling Wu
- , Yanhe Zhao
- & Yunkun Wu
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Article
| Open AccessQuantitative dose-response analysis untangles host bottlenecks to enteric infection
Here, using Citrobacter rodentium colonization of mice as a model, the authors characterize the impact of pathogen dose on the number of bacteria that initiate infection in the mouse gut, providing a framework for quantifying the host bottlenecks that eliminate pathogens to protect from infection.
- Ian W. Campbell
- , Karthik Hullahalli
- & Matthew K. Waldor
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Article
| Open AccessKaposi’s sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs
Viruses rely on the translational machinery of the host cell to synthesis viral proteins. We show that KSHV manipulates the composition of host cell ribosomes creating a specialised ribosome to specifically translate viral mRNAs.
- James C. Murphy
- , Elena M. Harrington
- & Adrian Whitehouse
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Article
| Open AccessGenome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure
Otosclerosis is a common form of hearing loss, with an unclear genetic etiology. Here, the authors perform a genome-wide association study meta-analysis of otosclerosis identifying 27 genetic loci, pointing to genes involved in bone remodeling, skeletal disorders and transforming growth factor β signaling.
- Joel T. Rämö
- , Tuomo Kiiskinen
- & Aarno Palotie
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| Open AccessA gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation
TPC2 is an important organellar Na+/Ca2+ release channel which regulates function of lysosomes and lysosome-related organelles. Here, Wang et al. demonstrate that a gain-of-function mutation (R210C) in TPC2 leads to hypopigmentaion, enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification.
- Qiaochu Wang
- , Zengge Wang
- & Wei Li
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Article
| Open AccessEffects of tuberculosis and/or HIV-1 infection on COVID-19 presentation and immune response in Africa
Here the authors describe outcomes of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence. They find that tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19 and that the immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis.
- Elsa du Bruyn
- , Cari Stek
- & Robert J. Wilkinson
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Article
| Open AccessMicrobiome-mediated fructose depletion restricts murine gut colonization by vancomycin-resistant Enterococcus
Vancomycin-resistant Enterococcus (VRE) represents a major threat for patients’ health. Here, using a mouse model, the authors show that specific commensals restrict VRE gut colonization through depletion of fructose, a nutrient source that boosts VRE growth in vivo.
- Sandrine Isaac
- , Alejandra Flor-Duro
- & Carles Ubeda
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Article
| Open AccessAutomated high-throughput genome editing platform with an AI learning in situ prediction model
A large number of cell disease models with pathogenic SNVs are needed. Here the authors report an automated high-throughput platform to perform the genome editing process from gRNA design to the analysis of the editing results; they characterise in situ base editing outcomes.
- Siwei Li
- , Jingjing An
- & Meng Wang
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Article
| Open AccessmTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome
Still’s disease is an inflammatory syndrome linked to the development of further immune dysregulation and hypercytokinaemia termed macrophage activation syndrome. Here the authors implicate the mechanistic target of rapamycin complex 1 in murine models of Still’s disease and macrophage activation syndrome, and provide associations with clinical cases in patients
- Zhengping Huang
- , Xiaomeng You
- & Pui Y. Lee
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Article
| Open AccessCXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease
Idiopathic multicentric Castleman disease (iMCD) is a life-threatening inflammatory disease requiring immediate intervention, for which the recommended first-line therapy is the Interleukin-6 pathway inhibitor siltuximab. Authors here show that the change in levels of the chemokine CXCL13 shortly following the start of siltuximab treatment is predictive of response.
- Sheila K. Pierson
- , Laura Katz
- & David C. Fajgenbaum
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Article
| Open AccessGut to lung translocation and antibiotic mediated selection shape the dynamics of Pseudomonas aeruginosa in an ICU patient
In this paper the authors show that the pathogenic bacterium Pseudomonas aeruginosa migrates between the gut and lungs of an ICU patient, and that differential evolutionary responses to antibiotic treatment occur in these organs.
- Rachel M. Wheatley
- , Julio Diaz Caballero
- & R. Craig MacLean
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Article
| Open AccessOsteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection
MYD88 mediates the signal of bacterial infection. Here, in the context of periodontal infection, the authors show that the MYD88 pathway in osteocytes plays a dominant role in regulating osteolysis.
- Tetsuya Yoshimoto
- , Mizuho Kittaka
- & Yasuyoshi Ueki
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Article
| Open Accessp53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition
Ageing normal oesophagus epithelium contains p53 mutant clones. Here the authors use transgenic mice to show how these clones form and contribute to cancer development.
- Kasumi Murai
- , Stefan Dentro
- & Philip H. Jones
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Article
| Open AccessStructural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro
The authors report crystallographic and computational studies that detail how SARS-CoV-2 3CLpro cleaves the host NF-κB Essential Modulator in addition to its canonical viral substrates. The association with the high fitness of SARS-CoV-2 in humans is discussed.
- Mikhail A. Hameedi
- , Erica T. Prates
- & Daniel Jacobson
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Article
| Open AccessThe mutational signatures of formalin fixation on the human genome
Many archived tumour samples are stored as formalin-fixed and paraffin-embedded (FFPE) blocks, but this treatment can impact downstream genomics analyses. Here, the authors derive the mutational signatures of formalin on the cancer genome, and present FFPEsig, an algorithm that can distinguish and correct FFPE mutational signatures in archived cancer samples.
- Qingli Guo
- , Eszter Lakatos
- & Ville Mustonen
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Article
| Open AccessLong-term memory CD8+ T cells specific for SARS-CoV-2 in individuals who received the BNT162b2 mRNA vaccine
mRNA vaccines have been shown to prevent SARS-CoV-2 infection and reduce hospitalization and mortality rates. Here, the authors show evidence of long-term memory CD8 + T cells in individuals who received the BNT162b2 SARS-CoV-2 mRNA vaccine.
- Nozomi Kuse
- , Yu Zhang
- & Masafumi Takiguchi
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Article
| Open AccessNeutralization of hepatitis B virus with vaccine-escape mutations by hepatitis B vaccine with large-HBs antigen
The hepatitis B vaccine is recognised as the most effective approach in reducing hepatitis-B-related morbidity; vaccine-escape mutations are however capable of infecting vaccinated individuals. In this work, authors aim to establish a hepatitis B vaccine candidate, which they assess in rhesus macaques in terms of efficacy and safety.
- Ayaka Washizaki
- , Asako Murayama
- & Takanobu Kato
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Article
| Open AccessContext-dependent function of TSLP and IL-1β in skin allergic sensitization and atopic march
Allergic sensitisation in the skin can lead to allergic dermatitis and further to airway asthma in a process of atopic march. Here the authors examine the difference between superficial or deep skin sensitisation, characterise the immune cells generated and show differential TSLP and IL-1β involvement.
- Justine Segaud
- , Wenjin Yao
- & Mei Li
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Article
| Open AccessOXTRHigh stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling
Worst pattern of invasion (WPOI) is a parameter used to quantify tumor invasiveness of oral squamous cell carcinoma (OSCC). Here the authors show that a fibroblast subset characterized by the expression of the oxytocin receptor is enriched in highly invasive WPOI 4-5 OSCC tumors and can be targeted to reduce the desmoplastic stroma and tumor metastasis.
- Liang Ding
- , Yong Fu
- & Yanhong Ni