Featured
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Article
| Open AccessA candidate sex determination locus in amphibians which evolved by structural variation between X- and Y-chromosomes
Genetic mechanisms of sex determination are still unknown in most amphibians. This study elucidates a mechanism behind amphibian sex determination by uncovering a sex-determining locus (bod1l gene and a Y-specific non-coding RNA, ncRNA-Y) in European green toads (Bufo(tes) viridis) which initiates male development.
- Heiner Kuhl
- , Wen Hui Tan
- & Matthias Stöck
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Article
| Open AccessPulmonary maternal immune activation does not cross the placenta but leads to fetal metabolic adaptation
Maternal immune activation during pregnancy can negatively impact the developing fetus. Here, applying multi-omics (RNA-seq, phosphoproteomics and lipidomics) and imaging, the authors show that while maternal immune activation induces strong innate response in maternal organs it does not extend through the placenta but leads to fetal metabolic changes.
- Signe Schmidt Kjølner Hansen
- , Robert Krautz
- & Albin Sandelin
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Article
| Open AccessA persistent variant telomere sequence in a human pedigree
A variant telomerase template demonstrates that human telomeres can tolerate significant degeneracy and remain functional. Once incorporated by telomerase, variant sequences can influence telomere length dynamics.
- Angela M. Hinchie
- , Samantha L. Sanford
- & Jonathan K. Alder
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Article
| Open AccessHaplotype-resolved gapless genome and chromosome segment substitution lines facilitate gene identification in wild rice
Genetic variation present in wild rice is a reservoir of useful genes for rice breeding. Here, the authors report the haplotype-resolved gapless genome assembly of wild rice, the development of two sets of chromosome segment substitution lines, and the cloning of a blast resistance gene originated from wild rice.
- Jingfen Huang
- , Yilin Zhang
- & Weihua Qiao
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Article
| Open AccessA polygenic score method boosted by non-additive models
Polygenic scores aggregate the effects of multiple genetic variants and can be used to predict disease risk. Here, the authors present a polygenic score method that incorporates non-additive inheritance modes (recessive, dominant, over-recessive, and over-dominant) and show that this can improve risk prediction for certain polygenic diseases.
- Rikifumi Ohta
- , Yosuke Tanigawa
- & Shinichi Morishita
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Article
| Open AccessAcute depletion of BRG1 reveals its primary function as an activator of transcription
Here, the authors generate a mouse line by knocking in the auxin-inducible degron tag to the SMARCA4 gene, which encodes BRG1. They suggest that BRG1 primarily contributes positively to chromatin accessibility, RNAP binding, and nascent RNA production.
- Gang Ren
- , Wai Lim Ku
- & Keji Zhao
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Article
| Open AccessGermline Cas9 promoters with improved performance for homing gene drive
High-performance promoters are needed for gene drives; these are currently lacking in Drosophila melanogaster. Here the authors tested eleven Drosophila melanogaster germline promoters in several configurations and show higher drive conversion efficiency with minimal embryo resistance.
- Jie Du
- , Weizhe Chen
- & Jackson Champer
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Article
| Open AccessMulti-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations
Here, the authors suggest that molecular dysregulation on three axes may play a critical role in asthma within the African Diaspora. RNASeq and DNA methylation data are generated from nasal epithelium including cases and controls from seven different geographic sites.
- Brooke Szczesny
- , Meher Preethi Boorgula
- & Rasika A. Mathias
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Article
| Open AccessLong-read sequencing for 29 immune cell subsets reveals disease-linked isoforms
This paper unveils the complexity of human immune cell splicing, highlighting cell-specific isoforms and establishing connections between alternative splicing and complex traits. These findings have implications for understanding diseases and the evolution of the genome.
- Jun Inamo
- , Akari Suzuki
- & Yuta Kochi
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Article
| Open AccessTAD border deletion at the Kit locus causes tissue-specific ectopic activation of a neighboring gene
Research on the Kit locus shows TAD boundary deletion may or may not trigger ectopic gene activation in different cell types, influenced by active enhancers’ position relative gene promoters.
- Evelyn Kabirova
- , Anastasiya Ryzhkova
- & Nariman Battulin
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Article
| Open AccessAn isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity
Genetic variants in the SBNO2 locus are associated with Crohns’s disease. Here the authors show that those variants cause a cell type and isoform specific effect were transcription of SBNO2 isoform 2 impacts on antimicrobial activity in macrophages providing a plausible gene-mechanism-phenotype model.
- Dominik Aschenbrenner
- , Isar Nassiri
- & Holm H. Uhlig
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Article
| Open AccessValidation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes
Here the authors conduct a multi-ancestry meta-analysis of telomere length, used diverse approaches to identify genes underlying association signals, and experimentally validated POP5 and KBTBD6 as regulators of telomere length in human cells.
- Rebecca Keener
- , Surya B. Chhetri
- & Alexis Battle
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Article
| Open AccessHDAC activity is dispensable for repression of cell-cycle genes by DREAM and E2F:RB complexes
Here, the authors investigate the interplay among DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression, suggesting that E2F:RB and DREAM complexes can repress cell-cycle genes without relying on HDAC activity.
- Alison K. Barrett
- , Manisha R. Shingare
- & Gerd A. Müller
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Article
| Open AccessIlluminating the function of the orphan transporter, SLC22A10, in humans and other primates
Orphan transporters can be found in over 20 families in the SLC superfamily. Here, the authors show that human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220; while in great apes, its orthologs transport sex steroid conjugates.
- Sook Wah Yee
- , Luis Ferrández-Peral
- & Kathleen M. Giacomini
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Article
| Open AccessAn integrated spatio-temporal view of riverine biodiversity using environmental DNA metabarcoding
Using intensive eDNA sampling in space and time across five rivers in Europe and North America, this study shows that eDNA gives relevant information on freshwater diversity and ecology across broad taxonomic groups, and with limited downstream transport. The findings demonstrate that eDNA is vital for freshwater biodiversity monitoring in a time of anthropogenic change.
- William Bernard Perry
- , Mathew Seymour
- & Simon Creer
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Article
| Open AccessA comprehensive benchmarking with interpretation and operational guidance for the hierarchy of topologically associating domains
TAD hierarchy demonstrates cell-to-cell variability, leading to the development of numerous callers. Here, authors present a comprehensive benchmark of TAD hierarchy callers and introduce the ‘air conditioner’ model to illustrate TAD hierarchy’s role in transcription.
- Jingxuan Xu
- , Xiang Xu
- & Hebing Chen
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Article
| Open AccessIntegrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions
Duarte et al. report that common genetic variants linked to psychiatric disorders influence the regulation of ancient retroviruses integrated into the genome. This suggests ancient viruses acquired millions of years ago may have shaped modern human brain function.
- Rodrigo R. R. Duarte
- , Oliver Pain
- & Timothy R. Powell
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Article
| Open AccessFar-East Asian Toxoplasma isolates share ancestry with North and South/Central American recombinant lineages
The population genome structure of Asian Toxoplasma remains incompletely understood. This study analyzes intercontinental genomic admixture in 17 isolates from Japan and China, providing insights into the evolution of parasites and their impact on public health.
- Fumiaki Ihara
- , Hisako Kyan
- & Masahiro Yamamoto
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Article
| Open AccessDNA methylation-based high-resolution mapping of long-distance chromosomal interactions in nucleosome-depleted regions
Here, the authors present MTAC, a method to map chromosomal interactions in budding yeast. By applying MTAC to various viewpoints, they find that most of the long-distance chromosomal interactions detected by MTAC reflect tethering by the nuclear pore complexes.
- Yi Li
- , James Lee
- & Lu Bai
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Article
| Open AccessCiliary tip actin dynamics regulate photoreceptor outer segment integrity
Photoreceptor outer segment abnormalities cause retinitis pigmentosa, a form of blindness. Here, authors show that the disease-associated gene RPGR regulates actin-mediated outer segment turnover through its interaction with the actin severer, cofilin.
- Roly Megaw
- , Abigail Moye
- & Pleasantine Mill
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Article
| Open AccessDeep learning of left atrial structure and function provides link to atrial fibrillation risk
In this study, a deep learning-based model of left atrial size in UK Biobank enabled genome-wide association studies in 35,049 healthy participants. Several lines of evidence, including the PITX2 locus, linked left atrial dysfunction to atrial fibrillation risk.
- James P. Pirruccello
- , Paolo Di Achille
- & Patrick T. Ellinor
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Article
| Open AccessParental experiences orchestrate locust egg hatching synchrony by regulating nuclear export of precursor miRNA
The parental experience exerts a profound impact on offspring phenotypes. Zhu et al. find that in locusts the population density of parents regulates the hatching synchrony of progeny eggs via the FOXN1-PTBP1/XPO5 pathway, facilitating the nuclear export of precursor miRNA in the oocytes.
- Ya′nan Zhu
- , Jing He
- & Le Kang
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Article
| Open AccessThe SUN-family protein Sad1 mediates heterochromatin spatial organization through interaction with histone H2A-H2B
Here authors identify the interaction between the SUN-family protein Sad1 and histone H2A-H2B in S. pombe, and reveal the roles of the Sad1-histone interaction in the association of heterochromatin with the nuclear envelope and heterochromatin silencing.
- Wenqi Sun
- , Qianhua Dong
- & Yong Chen
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Article
| Open AccessOsMAPK6 phosphorylation and CLG1 ubiquitylation of GW6a non-additively enhance rice grain size through stabilization of the substrate
OsMAPK6 and CLG1, respectively, target GW6a for phosphorylation and ubiquitylation to favor the substrate stabilization using a different mechanism from prior reports, and the corresponding genetic axes operate non-additively to regulate seed size.
- Chen Bai
- , Gao-Jie Wang
- & Xian-Jun Song
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Article
| Open AccessCell of origin epigenetic priming determines susceptibility to Tet2 mutation
HSC mutations lead to diverse clonal hematopoiesis outcomes. This study shows how epigenetic traits can predispose clones for dominance. Sox4 increases sensitivity to Tet2 KO, offering insights into variable phenotypes despite identical mutations.
- Giulia Schiroli
- , Vinay Kartha
- & David T. Scadden
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Article
| Open AccessIntegrating single cell expression quantitative trait loci summary statistics to understand complex trait risk genes
The authors describe a new transcriptome-wide association study (TWAS) method that integrates single cell eQTL summary statistics with GWAS data to identify cell type-specific risk genes, together with a cell type-aware drug repurposing pipeline.
- Lida Wang
- , Chachrit Khunsriraksakul
- & Bibo Jiang
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Article
| Open AccessTwo telomere-to-telomere gapless genomes reveal insights into Capsicum evolution and capsaicinoid biosynthesis
Chili pepper (Capsicum) is an important vegetables known for fruit pungency given by capsaicinoids. Here, the authors assemble the telomere-to-telomere genomes of a pungent pepper C. annuum and its non-pungent wild relative C. rhomboideum and reveal insights into Capsicum evolution and capsaicinoid biosynthesis.
- Weikai Chen
- , Xiangfeng Wang
- & Li Guo
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Article
| Open AccessSex-specific developmental gene expression atlas unveils dimorphic gene networks in C. elegans
Genetic sex introduces variation in phenotypic traits in sexually reproducing organisms. Here, the authors report a developmental gene expression atlas for C. elegans males and hermaphrodites, highlighting the key role of the insulin-like peptide INS-39 in male development and suggesting genetic underpinnings of sexual dimorphism.
- Rizwanul Haque
- , Sonu Peedikayil Kurien
- & Meital Oren-Suissa
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Article
| Open AccessGenome-scale analysis of interactions between genetic perturbations and natural variation
Here the authors investigate the interactions between genetic perturbations and segregating loci on a genome scale in yeast using barcoded CRISPRi. Strains’ responses to perturbations are shaped by perturbation-locus interactions that cannot be measured by examining perturbations or natural variation alone.
- Joseph J. Hale
- , Takeshi Matsui
- & Ian M. Ehrenreich
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Article
| Open AccessAI-enhanced integration of genetic and medical imaging data for risk assessment of Type 2 diabetes
Type 2 diabetes is a global health threat demanding precise healthcare methods. Here, the authors show that their AI-driven risk assessment models, integrating genetic, imaging, and demographic data, achieve high accuracy in identifying high-risk groups, promising advancements in prevention strategies.
- Yi-Jia Huang
- , Chun-houh Chen
- & Hsin-Chou Yang
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Article
| Open AccessAn improved epigenetic counter to track mitotic age in normal and precancerous tissues
DNA methylation (DNAm) clocks can track mitotic age, but their potential use for cancer risk prediction remains less explored. Here, the authors develop a DNAm counter of total mitotic age (stemTOC) that shows an increase of mitotic age in normal tissues and precancerous lesions.
- Tianyu Zhu
- , Huige Tong
- & Andrew E. Teschendorff
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Article
| Open AccessWhole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers
Efforts to allow routine whole genome and transcriptome analysis (WGTA) for pediatric cancers in the clinic remain critical. Here, the authors present results of a unified genomics and bioinformatics pipeline for WGTA in paediatric cancers, the Personalized OncoGenomics (POG) program, with a focus on potential therapeutic targets.
- Rebecca J. Deyell
- , Yaoqing Shen
- & Shahrad R. Rassekh
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Article
| Open AccessCEBPA restricts alveolar type 2 cell plasticity during development and injury-repair
Cell plasticity underlies development and regeneration. Here, the authors show that mouse lung alveolar type 2 cells undergo maturation postnatally and their plasticity is restricted by CEBPA and increases upon viral infection.
- Dalia Hassan
- & Jichao Chen
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Article
| Open AccessBenchmarking of methods for DNA methylome deconvolution
Determining the different cell types that contribute to a mixture of DNA is key for research and diagnostic applications. Here, authors comprehensively benchmark DNA methylation-based deconvolution methods, evaluating their performance and robustness to technical bias.
- Kobe De Ridder
- , Huiwen Che
- & Bernard Thienpont
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Article
| Open AccessMycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin
Lipid biosynthesis in the pathogen M. tuberculosis depends on biotin for posttranslational modification of key enzymes. Here, Qu et al. identify an auxiliary protein that is required by M. tuberculosis to synthesize biotin.
- Di Qu
- , Peng Ge
- & Dirk Schnappinger
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Article
| Open AccessCorrelative single molecule lattice light sheet imaging reveals the dynamic relationship between nucleosomes and the local chromatin environment
This study combines lattice light sheet microscopy and single molecule imaging to study protein dynamics and chromatin structure in live cells. The authors describe how nucleosomes and proteins move and are organised in relation to chromatin density.
- Timothy A. Daugird
- , Yu Shi
- & Wesley R. Legant
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Article
| Open AccessEndocardial HDAC3 is required for myocardial trabeculation
Lack of trabeculation compromises heart structure and function. How myocardial trabeculation is regulated by nonmyocytes is poorly understood. Researchers found that histone deacetylase 3 in the developing endocardial cells guides myocardial trabeculation by inducing growth signals.
- Jihyun Jang
- , Mette Bentsen
- & Deqiang Li
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Article
| Open AccessStructure and genome editing of type I-B CRISPR-Cas
Here the authors present two cryo-EM structures of the Synechocystis sp. PCC 6714 (Syn) type I-B Cascade, revealing the molecular mechanisms that underlie RNA-directed Cascade assembly, target DNA recognition and local conformational changes of the effector complex upon R-loop formation.
- Meiling Lu
- , Chenlin Yu
- & Yibei Xiao
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Article
| Open AccessTransfer learning enables identification of multiple types of RNA modifications using nanopore direct RNA sequencing
Simultaneous profiling of multiple RNA modifications is a promising yet understudied field of research. Here, authors develop a transferable deep learning framework capable of detecting multiple types of RNA modifications in single nanopore sequencing sample.
- You Wu
- , Wenna Shao
- & Xiang Yu
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Article
| Open AccessDeep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants
The details of how the protein folding and degradation systems collaborate to combat potentially toxic non-native proteins are unknown. Here the authors perform systematic studies of missense and nonsense variants of the cytosolic aspartoacylase, ASPA, where loss-of-function variants are linked to Canavan disease.
- Martin Grønbæk-Thygesen
- , Vasileios Voutsinos
- & Rasmus Hartmann-Petersen
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Article
| Open AccessCoordinated wound responses in a regenerative animal-algal holobiont
The term ‘holobiont’ refers to a multicellular organism and its microbial symbionts. Whether and how symbionts react to host injury and how cellular responses are integrated across species remain unexplored. Here, the authors report a deeply conserved animal regeneration regulatory program that links molecular networks across species in an animal-algal holobiont.
- Dania Nanes Sarfati
- , Yuan Xue
- & Bo Wang
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Article
| Open AccessMammographic density mediates the protective effect of early-life body size on breast cancer risk
Mammographic density is known to be linked to breast cancer risk. Here, the authors use Mendelian randomization to estimate the effects of childhood body size and age at menarche on density phenotypes and breast cancer risk.
- Marina Vabistsevits
- , George Davey Smith
- & Eleanor Sanderson
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Article
| Open AccessEnhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways
Precise genome editing is crucial. Here the authors demonstrate that dual inhibition of p53-mediated cell death and distinct activation of the DNA damage repair system upon DNA damage by cytosine base editor (CBE) or prime editor (PE) additively enhanced editing efficiency in hPSCs.
- Ju-Chan Park
- , Yun-Jeong Kim
- & Hyuk-Jin Cha
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Article
| Open AccessThe greenbeard gene tgrB1 regulates altruism and cheating in Dictyostelium discoideum
Greenbeards encode perceptible signals, signal recognition ability, and altruism towards others displaying the signal. This study shows that activation of the greenbeard receptor gene tgrB1 increases altruism and inactivation causes kin-specific cheating in the social amoeba Dictyostelium discoideum.
- Mariko Katoh-Kurasawa
- , Peter Lehmann
- & Gad Shaulsky
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Article
| Open AccessA time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues
The mechanisms underlying high-altitude acclimatization remain unclear. Here authors use the sheep model to reveal multi-tissue temporal dynamics of gene transcription and regulation during acclimatization, and provide resources for hypoxia-related studies.
- Ze Yan
- , Ji Yang
- & Meng-Hua Li
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Article
| Open AccessRegulation of Myc transcription by an enhancer cluster dedicated to pluripotency and early embryonic expression
MYC regulates numerous genes involved in cell growth and proliferation. Here, Li-Bao et al. study the DNA regions that regulate Myc transcription in early mouse embryos and pluripotent stem cells. They report a specific region with independent modules dedicated to discrete temporal and spatial phases of Myc expression.
- Lin Li-Bao
- , Covadonga Díaz-Díaz
- & Miguel Torres
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Article
| Open AccessUnveiling the A-to-I mRNA editing machinery and its regulation and evolution in fungi
A-to-I editing in animals is catalyzed by enzymes of the Adenosine Deaminase Acting on RNA family, orthologues of which do not exist in fungi. Here, Feng et al. characterise the enzymes involved in A-to-I mRNA editing in Fusarium graminearum.
- Chanjing Feng
- , Kaiyun Xin
- & Huiquan Liu
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Article
| Open AccessThree concurrent mechanisms generate gene copy number variation and transient antibiotic heteroresistance
Bacterial heteroresistance is a medically relevant phenotype where small antibiotic-resistant subpopulations coexist within predominantly susceptible bacterial populations. Here, Nicoloff et al. describe how three different mechanisms that increase the copy number of resistance genes can lead to unstable and transient heteroresistance.
- Hervé Nicoloff
- , Karin Hjort
- & Helen Wang
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Article
| Open AccessA common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma
Type 2 inflammation drives the formation of pathologic mucus in patients with asthma. Here, authors reveal a role for intelectin-1 in IL-13-induced mucus properties, and that an ITLN1 eQTL is associated with protection from the formation of mucus plugs in T2-high asthma.
- Jamie L. Everman
- , Satria P. Sajuthi
- & Max A. Seibold
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