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| Open AccessPD-L1- and IL-4-expressing basophils promote pathogenic accumulation of T follicular helper cells in lupus
Basophils have been implicated in systemic lupus erythematosus (SLE), as evidenced by the fact that basophil-deficient mice do not develop the disease. Here, the authors demonstrate that PD-L1 and IL-4 expression in basophils promotes the pathogenic accumulation of follicular helper T cells in patients with SLE and murine models.
- John TCHEN
- , Quentin SIMON
- & Nicolas CHARLES
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Article
| Open AccessThe IL-33/ST2 axis is protective against acute inflammation during the course of periodontitis
Current animal models of periodontitis are biased towards sample collection from gingival tissue, while other periodontal structures may play similarly important role in the initiation and maintenance of inflammation. Here authors present a model that enables a more comprehensive and longitudinal assessment of periodontal tissues, which points to a pivotal role for the peri-root tissues and an IL-33/ST2 axis in the pathogenesis.
- Anhao Liu
- , Mikihito Hayashi
- & Tomoki Nakashima
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Article
| Open AccessFibrinolytic-deficiencies predispose hosts to septicemia from a catheter-associated UTI
Catheter-associated urinary tract infections can often lead to secondary bloodstream infections, and catheter-induced bladder inflammation. In this work, authors utilise murine models to probe defective fibrinolysis drives extravascular fibrin formation, potentially predisposing hosts to severe CAUTI.
- Jonathan J. Molina
- , Kurt N. Kohler
- & Ana L. Flores-Mireles
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Article
| Open AccessExpression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease
IgG4-related disease is a fibro-inflammatory disorder, characterized by infiltration of IgG4 producing plasma cells in the target organs. Here authors show that the affected B cells express less ubiquitin-specific protease 25 (USP25), and this results in activation of multiple pathways involved in cytoskeleton reorganization, inflammation and energy metabolism, which might govern disease pathogenesis.
- Panpan Jiang
- , Yukai Jing
- & Chaohong Liu
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Article
| Open AccessMutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance
Mutations in mexZ, encoding a negative regulator of efflux pump genes, are frequently acquired by Pseudomonas aeruginosa during early lung infection, but do not confer high antibiotic resistance as measured in lab tests. Here, Laborda et al. show that mexZ mutations affect quorum sensing pathways, thus promoting tissue invasiveness and protecting bacteria from the action of antibiotics within tissues.
- Pablo Laborda
- , Signe Lolle
- & Helle Krogh Johansen
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Article
| Open AccessParechovirus infection in human brain organoids: host innate inflammatory response and not neuro-infectivity correlates to neurologic disease
In comparison to PeV-A1, infection with PeV-A3 is associated with neurological illness in infants. Here, using brain organoids, the authors suggest that the innate inflammatory response as the underlying reason, and not replication kinetics.
- Pamela E. Capendale
- , Inés García-Rodríguez
- & Katja C. Wolthers
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Article
| Open AccessRapid evolution of an adaptive multicellular morphology of Candida auris during systemic infection
Bing et al. report that Candida auris undergoes rapid evolution via de novo genetic mutations and forms multicellular aggregates that exhibit a survival advantage over the single-celled yeast-form phenotype during host infection.
- Jian Bing
- , Zhangyue Guan
- & Guanghua Huang
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Article
| Open AccessTargeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis
P2Y14R regulates necroptosis of intestinal epithelial cells though PKA/CREB/RIPK1 axis in the pathogenesis of ulcerative colitis (UC). Targeting P2Y14R with a small molecule inhibitor improves dextran sulfate sodium-induced UC in mice, suggesting P2Y14R as a promising target for treatment of UC.
- Chunxiao Liu
- , Hui Wang
- & Qinghua Hu
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Article
| Open AccessBTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion
Acute-on-chronic liver failure (ACLF) is characterized by rapid deterioration of liver function in patients with chronic liver disease. Here, the authors show that BTLA expression in CD4+ T cells is associated with disease severity and inflammation in hepatitis B virus-related ACLF.
- Xueping Yu
- , Feifei Yang
- & Jiming Zhang
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Article
| Open AccessSNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation
SNURPORTIN-1, encoded by the SNUPN gene, plays a key role in the nuclear import of spliceosomal small nuclear ribonucleoproteins, however its physiological function remains unclear. Here the authors report that recessive SNUPN mutations cause a distinct subtype of childhood muscular dystrophy and reveal SNURPORTIN-1’s role in muscle homeostasis, offering insights for new therapeutic strategies.
- Marwan Nashabat
- , Nasrinsadat Nabavizadeh
- & Nathalie Escande-Beillard
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Article
| Open AccessGlobal fungal-host interactome mapping identifies host targets of candidalysin
Candidalysin is a toxin secreted by Candida albicans. Although critical for pathogenesis, its intracellular targets are not well mapped. Here, Zhang et al screen for interacting proteins and identify that candidalysin can modulate the DNA damage repair pathway to promote fungal infection.
- Tian-Yi Zhang
- , Yao-Qi Chen
- & Ning-Ning Liu
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Article
| Open AccessCOVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase
Less is known about SARS-CoV-2 infection in unstudied geographical areas such as sub-Saharan Africa. Here the authors use multi-omics to characterize the immune response to SARS-CoV-2 in Uganda and consider how people living with HIV immunologically differentially respond to the virus.
- Matthew J. Cummings
- , Barnabas Bakamutumaho
- & Max R. O’Donnell
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Article
| Open AccessHijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus
The oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) is known to reprogram cellular metabolism. Here, Wan et al show that viral Cyclin exploits host nucleotide synthesis and glycolysis to support KSHV pathogenesis.
- Quanyuan Wan
- , Leah Tavakoli
- & Jun Zhao
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Article
| Open AccessEFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death
Physiologically, the host suppresses intestinal epithelial cell death to prevent intestinal inflammation. Here, the authors show that EF-hand domain-containing protein D2 (EFHD2) endogenously suppresses intestinal epithelial cell death by blocking TNFR1 internalization and protects the intestine from excessive inflammation.
- Jiacheng Wu
- , Xiaoqing Xu
- & Xuetao Cao
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Article
| Open AccessThe role of extracellular vesicle fusion with target cells in triggering systemic inflammation
Extracellular vesicles (EVs) play a crucial role in intercellular communication by transferring bioactive molecules from donor to recipient cells. Here, the authors show that EVs play a crucial role in activating immune responses through cell fusion, shedding light on their impact on inflammation.
- Praveen Papareddy
- , Ines Tapken
- & Heiko Herwald
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Article
| Open AccessEosinophils preserve bone homeostasis by inhibiting excessive osteoclast formation and activity via eosinophil peroxidase
Eosinophils are traditional immune effectors involved in tissue homeostasis. In this study, eosinophils emerge as key regulators of bone homeostasis by interacting with osteoclasts, inhibiting their differentiation and pathological bone loss.
- Darja Andreev
- , Katerina Kachler
- & Aline Bozec
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Article
| Open AccessVEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation
Acquired mutations of the gene UBA1 occurring in myeloid cells that result in the expression of impaired isoforms of the enzyme E1 have been described in patients with a severe adult onset auto-inflammatory syndrome called VEXAS. Here the authors profile patients with UBA1 mutations presenting with or without VEXAS disease and show VEXAS disease is characterized by inflammasome activation and monocyte dysregulation.
- Olivier Kosmider
- , Céline Possémé
- & Benjamin Terrier
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Article
| Open AccessPRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury
Excessive inflammatory responses contribute to severe malaria. Here, Du et al, show that the protein tyrosine phosphatase PRL2 contributes to neutrophil activation and extracellular trap release in an experimental model of severe malaria.
- Xinyue Du
- , Baiyang Ren
- & Zhaojun Wang
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Article
| Open AccessLOX-1 acts as an N6-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase
N6-methyladenosine (m6A) modification of mRNA regulates gene expression in eukaryotes. Here, Zeng et al. show that m6A modification of mRNAs contributes to protection against the pathogen Helicobacter pylori by downregulating a host protein that acts as receptor for the pathogen.
- Judeng Zeng
- , Chuan Xie
- & William K. K. Wu
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Article
| Open AccessCompartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage
The mechanisms regulating the balance between proliferation and differentiation in medulloblastomas with extensive nodularity (MBEN) remain poorly understood. Here, single cell multi-omics and spatial analysis characterises the spatial tissue organisation of MBEN in the context of the developmental trajectory.
- David R. Ghasemi
- , Konstantin Okonechnikov
- & Kristian W. Pajtler
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Article
| Open AccessMulti-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions
The molecular characteristics and therapeutic vulnerabilities of TFCP2-rearranged rhabdomyosarcomas (RMS) require further exploration. Here, the authors use multi-omics analyses and functional and mechanistic investigations to characterize TFCP2-rearranged RMS – including cases with FUS/EWSR1-TFCP2 fusions – across two precision oncology programs.
- Julia Schöpf
- , Sebastian Uhrig
- & Claudia Scholl
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Article
| Open AccessThe Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival
Singh et al. show how the M. tuberculosis methyltransferase Rv2067c outsmarts host epigenetic machinery by methylating histone H3 prior to its assembly into nucleosomes, thereby ensuring the pathogen’s intracellular survival/success.
- Prakruti R. Singh
- , Venkatareddy Dadireddy
- & Valakunja Nagaraja
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Article
| Open AccessNuclear RPSA senses viral nucleic acids to promote the innate inflammatory response
Innate immune responses are the first line of defence against viral pathogens. Here, Jiang et al show that the nuclear located 40S ribosomal protein SA senses viral nucleic acids to selectively enhance proinflammatory cytokine gene expression through epigenetic modification.
- Yan Jiang
- , Siqi Sun
- & Xuetao Cao
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Article
| Open AccessMaternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling
Treatment of pregnant animals with antibiotics can have unexpected effects on offspring. Here the authors use mouse models to show that antibiotic treatment of mothers leads to changes in ILC2 phenotype in neonatal lungs accompanied by changes in the microbiota and microbiota derived butyrate.
- Haixu Xu
- , Xianfu Yi
- & Jie Zhou
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Article
| Open AccessInterleukin 31 receptor α promotes smooth muscle cell contraction and airway hyperresponsiveness in asthma
Although IL-31 has been implicated in asthma, the exact contribution of the IL-31 receptor (IL-31RA) signalling to airway hyperresponsiveness remains unexplored. Here, the authors demonstrate that IL31RA promotes muscarinic acetylcholine receptor 3 expression and calcium signalling, as well as smooth muscle cell contraction.
- Santhoshi V. Akkenepally
- , Dan J. K. Yombo
- & Satish K. Madala
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Article
| Open AccessInhibition of host PARP1 contributes to the anti-inflammatory and antitubercular activity of pyrazinamide
The mode of action of the tuberculosis antibiotic pyrazinamide is poorly understood. Here, Krug et al show that pyrazinamide inhibits the immune regulator PARP1 and demonstrate PARP1 inhibition as a host-directed therapy.
- Stefanie Krug
- , Manish Gupta
- & William R. Bishai
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Article
| Open AccessGeometric constraint-triggered collagen expression mediates bacterial-host adhesion
Cells in the body live in geometrically constrained microenvironments. Here, Feng at al report that these constraints induce collagen IV expression which is responsible for location dependent bacterial adhesion.
- Yuting Feng
- , Shuyi Wang
- & Jianyong Huang
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Article
| Open AccessDermis resident macrophages orchestrate localized ILC2 eosinophil circuitries to promote non-healing cutaneous leishmaniasis
Tissue resident macrophages are intricately involved in homeostatic processes but also in tissue repair. Here Lee and colleagues show dermis-resident macrophages are a source of thymic stromal lymphopoietin and CCL24, which act on type 2 innate lymphoid cells and eosinophils respectively, to maintain their M2 properties and promote non-healing cutaneous leishmaniasis.
- Sang Hun Lee
- , Byunghyun Kang
- & David L. Sacks
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Article
| Open AccessRNA is a key component of extracellular DNA networks in Pseudomonas aeruginosa biofilms
The roles of extracellular RNAs present in bacterial biofilms are poorly understood. Here, Mugunthan et al. show that specific mRNAs associate with extracellular DNA in the matrix of bacterial biofilms, facilitating the formation of viscoelastic networks.
- Sudarsan Mugunthan
- , Lan Li Wong
- & Thomas Seviour
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Article
| Open AccessThe extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome
Although B cell-targeting therapies can provide clinical benefits to children with idiopathic nephrotic syndrome (INS), B lymphocyte subsets have not been extensively studied in this disease. Here, using single-cell RNA sequencing, the authors identify an extrafollicular B cell signature in children with INS.
- Tho-Alfakar Al-Aubodah
- , Lamine Aoudjit
- & Tomoko Takano
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Article
| Open AccessMouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures
Paediatric high-grade gliomas with MYCN amplification (HGG-MYCN) are rare and highly aggressive. Here, the authors generate a mouse model for HGG-MYCN that can recapitulate the histological and molecular profiles of the human tumours, and perform high-throughput drug screening to identify potential treatment options.
- Melanie Schoof
- , Shweta Godbole
- & Ulrich Schüller
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Article
| Open AccessSLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling
White adipose tissue is closely associated with energy expenditure and obesity. Here, the authors show that SLC35D3 promotes white adipose tissue browning through the NOTCH1 signalling pathway and SLC35D3 may be a potential therapeutic target for obesity and related complications.
- Hongrui Wang
- , Liang Yu
- & Yibo Wang
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Article
| Open AccessSynthetic genetic oscillators demonstrate the functional importance of phenotypic variation in pneumococcal-host interactions
Here, Rueff et al engineered a CRISPRi-based oscillator to rewire capsule production in Streptococcus pneumoniae from its native control. They show that heterogeneity in capsule production is beneficial for fitness in several virulence associated traits.
- Anne-Stéphanie Rueff
- , Renske van Raaphorst
- & Jan-Willem Veening
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Article
| Open AccessEpidermal growth factor receptor activation is essential for kidney fibrosis development
Fibrosis is the progressive accumulation of excess extracellular matrix produced by myofibroblasts leading to organ failure. Here the authors show that expression of the Epidermal Growth Factor Receptor (EGFR) increases in interstitial myofibroblasts in human and mouse fibrotic kidneys, and selective EGFR deletion in the fibroblast/pericyte population inhibits interstitial fibrosis in response to unilateral ureteral obstruction, ischemia or nephrotoxins.
- Shirong Cao
- , Yu Pan
- & Raymond C. Harris
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Article
| Open AccessInteractome profiling of Crimean-Congo hemorrhagic fever virus glycoproteins
Here, Ning et al report the cellular interactomes of Crimean-Congo haemorrhagic fever virus glycoproteins and uncover a host restriction factor HAX1 that hijacks the viral glycoproteins to mitochondria, disabling progeny virion packaging.
- Shiyu Dai
- , Yuan-Qin Min
- & Yun-Jia Ning
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Article
| Open AccessA single amino acid substitution in the capsid protein of Zika virus contributes to a neurovirulent phenotype
The neurovirulence determinants of Zika virus remain not fully established. Song et al identified a single K101R substitution in the capsid protein that contributes to the lineage-specific virulence phenotypes.
- Guang-Yuan Song
- , Xing-Yao Huang
- & Cheng-Feng Qin
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Article
| Open AccessLocalized cardiac small molecule trajectories and persistent chemical sequelae in experimental Chagas disease
The impact of antiparasitic treatment on local tissue responses in the case of chronic Chagas disease (caused by Trypanosoma cruzi infection) is not well understood. Authors provide insight into clinical treatment failure and drivers of post-infectious conditions.
- Zongyuan Liu
- , Rebecca Ulrich vonBargen
- & Laura-Isobel McCall
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Article
| Open AccessUbiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions
Vascular endothelial cadherin (VE-cadherin), endothelial cell-cell adhesive protein maintains blood vessel barrier integrity and vascular homeostasis. Here, the authors show that infectious bacterial toxin activates ubiquitin ligase CHFR which in turn degrades VEcadherin via ubiquitylation in endothelial cells to cause vascular injury.
- Chinnaswamy Tiruppathi
- , Dong-Mei Wang
- & Asrar B. Malik
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Article
| Open AccessGut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria
Specific gut microbiota constituents that affect the severity of malaria are unknown. Here, Mandal et al. identify specific Bacteroides species causing susceptibility to severe malaria in mice and correlate with the severity of malaria in Ugandan children.
- Rabindra K. Mandal
- , Anita Mandal
- & Nathan W. Schmidt
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Article
| Open AccessSARS-CoV-2 infection of human lung epithelial cells induces TMPRSS-mediated acute fibrin deposition
Severe SARS-CoV-2 infection has been associated with extensive diffuse alveolar damage and fibrin formation. Here, Erickson et al describe an infection-induced coagulation mechanism which involves activation of prothrombin by members of TMPRSS genes.
- Rachel Erickson
- , Chang Huang
- & Peter D. Sun
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Article
| Open AccessNLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity
Bacterial infection of immune cells can result in engagement of different immunological pathways. Here the authors show that a Pseudomonas aeruginosa type three secretion system exoenzyme is linked to the differential selection of inflammasome usage between macrophages and neutrophils.
- Martin S. Minns
- , Karl Liboro
- & Eric Pearlman
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Article
| Open AccessStromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent
Breast cancer patients of African ancestry face worse clinical outcomes, so understanding related cellular and molecular features remains critical. Here, the authors show that stromal cells that are particularly enriched in breast cancer patients with African ancestry can trans-differentiate into different lineages and can be transformed into metaplastic carcinoma.
- Brijesh Kumar
- , Aditi S. Khatpe
- & Harikrishna Nakshatri
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Article
| Open AccessNAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis
Mycobacterium tuberculosis disrupts glycolysis in infected myeloid cells. Here, Pacl et al. show that maximal glycolytic capacity in myeloid cells is essential for host protection from tuberculosis and that NAD(H) homeostasis underlies glycolysis-mediated protection of the host.
- Hayden T. Pacl
- , Krishna C. Chinta
- & Adrie J. C. Steyn
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Article
| Open AccessIdentification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts
Developing selective N-myristoyltransferase (NMT) inhibitors has been challenging. Here, the authors describe selective NMT inhibitors that can be used as multistage antimalarials, targeting dormant and developing forms of liver and blood stage.
- Diego Rodríguez-Hernández
- , Kamalakannan Vijayan
- & Morten Grøtli
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Article
| Open AccessAcquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype
Acquired resistance to immune checkpoint inhibitors limits therapeutic success in non-small-cell lung cancer, however, the underpinning immune parameters are largely unknown. Here authors distinguish resistance types based on immune cell infiltration, immune checkpoint molecule and cytokine expression level, using paired samples from patients in the sensitive and in the resistant disease phase.
- Stefanie Hiltbrunner
- , Lena Cords
- & Alessandra Curioni-Fontecedro
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Article
| 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