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| Open AccessDistinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection
Although type-1 diabetes has a clear genetic component, not all children who are at risk eventually develop autoimmunity, suggesting the existence of environmental triggers. In this longitudinal transcriptomic study, the authors find that children who later develop autoimmunity have a distinct profile before the appearance of autoantibodies and may have impaired responses to enterovirus infection.
- Jake Lin
- , Elaheh Moradi
- & Matti Nykter
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Article
| Open AccessExperimental mining plumes and ocean warming trigger stress in a deep pelagic jellyfish
The deep ocean is increasingly subjected to human-induced environmental change, but little is known about species-specific responses to stressors, including those from deep sea mining. This study shows that elevated temperatures and simulated sediment plumes cause physiological stress in a cosmopolitan deep-sea jellyfish, confirming the detrimental impact of seabed mining.
- Vanessa I. Stenvers
- , Helena Hauss
- & Henk-Jan T. Hoving
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| Open AccessThe transcriptional and phenotypic characteristics that define alveolar macrophage subsets in acute hypoxemic respiratory failure
Acute hypoxemic respiratory failure (AHRF) and the associated lung immune cell features are not well understood. Here the authors use CITE-Seq to analyse the transcriptomic and phenotypic profile of lung and blood cells from a longitudinal cohort of patients with AHRF to identify gene signatures and cell surface proteins associated with disease severity.
- Eric D. Morrell
- , Sarah E. Holton
- & Carmen Mikacenic
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| Open AccessHigh-sensitive spatially resolved T cell receptor sequencing with SPTCR-seq
Understanding T cell behaviour in cancers is vital for improving immunotherapies. Here, the authors present spatially resolved T cell receptor sequencing (SPTCR-seq), a technology that annotates T cell receptors within the tumour ecosystem.
- Jasim Kada Benotmane
- , Jan Kueckelhaus
- & Dieter Henrik Heiland
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| Open AccessA statistical framework for differential pseudotime analysis with multiple single-cell RNA-seq samples
Pseudotime analysis is prevalent in single-cell RNA-seq, but it remains challenging to perform it across multiple samples and experimental conditions. Here, the authors develop Lamian, a computational framework for multi-sample pseudotime analysis that adjusts for biological and technical variation to detect gene program changes along cell trajectories and across conditions.
- Wenpin Hou
- , Zhicheng Ji
- & Hongkai Ji
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Article
| Open AccessEASTR: Identifying and eliminating systematic alignment errors in multi-exon genes
The study reveals limitations in widely used RNA-seq aligners, which create 'phantom' introns in reference databases. The authors introduce EASTR, a computational tool that not only enhances alignment accuracy but also uncovers existing annotation errors. This improvement bolsters the dependability of subsequent RNA-seq analyses.
- Ida Shinder
- , Richard Hu
- & Mihaela Pertea
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Article
| Open AccessSpatial transcriptomics uncover sucrose post-phloem transport during maize kernel development
Maize kernels have long intrigued researchers due to their complex structure. Through microscopic sectioning and spatial transcriptomics, the authors observed the spatial distribution of RNA through electronic RNA in situ hybridization maps and discovered how storage accumulation occurs.
- Yuxin Fu
- , Wenxin Xiao
- & Wenqin Wang
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| Open AccessDissecting the human leptomeninges at single-cell resolution
The meninges protect the central nervous system at the brain border, and its dysfunction can lead to neural inflammation and cell damage. Here, the authors uncover the gene signatures of diverse cell types in the aged human leptomeninges and highlight their changes in Alzheimer’s Disease.
- Nicola A. Kearns
- , Artemis Iatrou
- & Yanling Wang
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Article
| Open AccessIsoform-resolved transcriptome of the human preimplantation embryo
Human embryo development involves extensive transcriptional remodeling. In this study, the authors apply long- and short-read RNA-Seq to profile the transcriptomes of 73 human preimplantation embryos spanning zygotic to blastocyst stages, identifying tens of thousands of additional isoforms transcribed from both known and unannotated gene loci.
- Denis Torre
- , Nancy J. Francoeur
- & Robert Sebra
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Article
| Open AccesseQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk
Fetal development plays an important role in defining adult diabetes risk. Here, authors identified a genetic link between fetal pancreatic gene expression, obesity, and diabetes risk through eQTL mapping of iPSC-derived pancreatic progenitor cells.
- Jennifer P. Nguyen
- , Timothy D. Arthur
- & Kelly A. Frazer
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Article
| Open AccessProfiling of the Helicobacter pylori redox switch HP1021 regulon using a multi-omics approach
Helicobacter pylori adapted to the harsh conditions of the human stomach using a handful of regulatory proteins. Here, the authors identify H. pylori processes controlled by the HP1021 response regulator under optimal growth and oxidative stress.
- Mateusz Noszka
- , Agnieszka Strzałka
- & Anna Zawilak-Pawlik
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Article
| Open AccessDNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts
Epigenetic therapies are known to synergize with immunotherapies through the de-repression of endogenous retroviral element (ERV)-encoded promoters. Here the authors identify treatment-induced neoantigens and validate their ability to induce T cell response and anti-tumor effects in vitro and in patient samples.
- Ashish Goyal
- , Jens Bauer
- & Christoph Plass
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Article
| Open AccessPhagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination
The CD47/SIRPα axis is well known to mediate immune escape by promoting cancer resistance to phagocytosis. Here the authors show that low CD47-expressing prostate cancer cells still allow phagocytosis but the process is incomplete leading to the formation of macrophage:tumor hybrid cells with immune evasive and pro-metastatic properties.
- Chih-Wei Chou
- , Chia-Nung Hung
- & Tim Hui-Ming Huang
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| Open AccessMiniature spatial transcriptomics for studying parasite-endosymbiont relationships at the micro scale
The filarial worm Brugia malayi has evolved a mutualistic association with the endosymbiotic bacteria Wolbachia. Here, Sounart et al describe a spatial transcriptomic technique that can spatially resolve these miniature specimens.
- Hailey Sounart
- , Denis Voronin
- & Stefania Giacomello
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| Open AccessSpecies-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction
The innate immune cells undergo metabolic reprogramming upon inflammation. Here, the authors report that both mouse and human microglia display a metabolic reprogramming in the presence of a TLR4 activation, however species-specific enzymes are responsible for this process.
- Angélica María Sabogal-Guáqueta
- , Alejandro Marmolejo-Garza
- & Amalia Dolga
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| Open AccessUnaltered hepatic wound healing response in male rats with ancestral liver injury
How much the environment influences inherited adaptive traits is debated and challenging to demonstrate in mammals. Here the authors performed a multigeneration study that failed to morphologically replicate enhanced wound healing response following ancestral liver injury in rats. However, heritable transcriptional effects suggest transmission at the molecular level, albeit of unclear functional relevance.
- Johanna Beil
- , Juliane Perner
- & Rémi Terranova
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Article
| Open AccessPositive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice
Metabolic reprogramming is a hallmark of tumorigenesis. Here, the authors show that nuclear myosin 1 regulates mitochondrial oxidative phosphorylation via the TFAM and PGC1α transcription factors and suggest its depletion contributes to the Warburg effect during tumorigenesis.
- Tomas Venit
- , Oscar Sapkota
- & Piergiorgio Percipalle
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Article
| Open AccessA molecular staging model for accurately dating the endometrial biopsy
Natural variability in menstrual cycle length with rapid changes in gene expression makes it difficult to accurately compare different stages of the endometrial cycle. Here, the authors show a method for precisely determining endometrial cycle stage based on global gene expression that reveals remarkably synchronised daily changes for over 3,400 endometrial genes.
- W. T. Teh
- , J. Chung
- & P. A. W. Rogers
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| Open AccessTargetable NOTCH1 rearrangements in reninoma
Reninomas are very rare kidney tumours of juxtaglomerular cells. Here, the authors analyse reninomas using whole-genome and transcriptome sequencing, and reveal the presence and functional effects of NOTCH1 rearrangements.
- Taryn D. Treger
- , John E. G. Lawrence
- & Tanzina Chowdhury
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| Open AccessA CCL2+DPP4+ subset of mesenchymal stem cells expedites aberrant formation of creeping fat in humans
Extra-intestinal “creeping fat” is a hallmark of Crohn’s disease. Here, using single-cell transcriptomics and lipid metabolomics, the authors identify a subset of mesenchymal stem cells that promote adipogenesis in creeping fat formation.
- Fengfei Wu
- , Fangting Wu
- & Lan Bai
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| Open AccessCircular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease
Dopamine neurons control movements while pyramidal neurons regulate memory and language. Here the authors show that circular RNAs production in these neurons appears tailored to neuron identity and genetically linked to neuropsychiatric disease such as Parkinson’s and Alzheimer’s disease.
- Xianjun Dong
- , Yunfei Bai
- & Clemens R. Scherzer
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| Open AccessDivergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation
Non-coding repeat expansion in the C9ORF72 gene is the most frequent cause of ALS and frontotemporal dementia. Here, the authors performed single cell analyses of gene expression and epigenetic regulation in these patients’ brains and emphasized the role of astrocytes and neurons in neurodegeneration.
- Junhao Li
- , Manoj K. Jaiswal
- & Stella Dracheva
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| Open AccessSingle nucleus transcriptomics of ventral midbrain identifies glial activation associated with chronic opioid use disorder
The cellular signatures of the opioid exposed human midbrain remain unexplored. Here, authors show by single nuclei transcriptomics activation of the glial immune response and dysregulation of synaptic signaling in opioid exposed individuals
- Julong Wei
- , Tova Y. Lambert
- & Schahram Akbarian
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Article
| Open AccessCell diversity and plasticity during atrioventricular heart valve EMTs
Lotto et al. delineate cell diversity and mechanisms during heart valve development using scRNA-seq. They identify distinct cell types and states, the emergence of epithelial-mesenchymal plasticity, and cell interactions that may govern this process.
- Jeremy Lotto
- , Rebecca Cullum
- & Pamela A. Hoodless
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| Open AccessCoordination of alternative splicing and alternative polyadenylation revealed by targeted long read sequencing
In this study using a targeted long read RNA sequencing approach called PL-Seq, the authors uncover coordination of alternative splicing and alternative polyadenylation within individual genes in Drosophila melanogaster.
- Zhiping Zhang
- , Bongmin Bae
- & Pedro Miura
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| Open AccessSingle cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A
The mechanism and disease-relevance of pancreatic b-cell heterogeneity remains elusive. Here the authors show that variable HNF1A-FXYD2 activity drives single b-cell heterogeneity at transcriptomic, epigenomic, and electro-physiological levels, which strongly mark the progression of type 2 diabetes.
- Chen Weng
- , Anniya Gu
- & Yan Li
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Article
| Open AccessFunctionally distinct cancer-associated fibroblast subpopulations establish a tumor promoting environment in squamous cell carcinoma
During the progression of cutaneous squamous cell carcinoma (cSCC), dermal fibroblasts become activated into cancer-associated fibroblasts (CAFs) which are pro-tumorigenic. Here, using single-cell RNA sequencing of patients’ samples at different stages of cSCC progression, the authors identify two main CAF subsets and deduce their potential functions using bioinformatics.
- Sabrina Schütz
- , Llorenç Solé-Boldo
- & Frank Lyko
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Article
| Open AccessNotch and retinoic acid signals regulate macrophage formation from endocardium downstream of Nkx2-5
A subset of endocardial cells gives rise to hematopoietic cells which are important for the formation of cardiac valves. In this follow up study, authors report the molecular regulatory mechanisms behind the formation of macrophages in the heart.
- Norika Liu
- , Naofumi Kawahira
- & Atsushi Nakano
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| Open AccessA nuclear receptor HR96-related gene underlies large trans-driven differences in detoxification gene expression in a generalist herbivore
Adaptation to toxins in agricultural pests is often caused by increased expression of detoxification genes. Here, the authors reveal that variation in a family of transcriptional regulators facilitates rapid evolution to diverse pesticides and host plants.
- Meiyuan Ji
- , Marilou Vandenhole
- & Thomas Van Leeuwen
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| Open AccessHigh-sensitive nascent transcript sequencing reveals BRD4-specific control of widespread enhancer and target gene transcription
Here the authors reveal that high-sensitive nascent transcript sequencing provides an extended high-resolution view on transcription, including lowly transcribed enhancers. Widespread transcription at enhancers and their target genes depends on the BET family protein BRD4.
- Annkatrin Bressin
- , Olga Jasnovidova
- & Andreas Mayer
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Article
| Open AccessOntogenetically distinct neutrophils differ in function and transcriptional profile in zebrafish
Neutrophil ontogeny in zebrafish may be a continuum or consist of distinct lineages. Here the authors characterise neutrophils derived from rostral blood island and caudal haematopoietic tissue lineages and show differential gene expression and function in steady state and during wound healing.
- Juan P. García-López
- , Alexandre Grimaldi
- & Carmen G. Feijoo
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Article
| Open AccessREPTOR and CREBRF encode key regulators of muscle energy metabolism
Obesity and cancer-induced cachexia are linked to an impairment in the ability of muscle to use glucose or lipids interchangeably as energy substrates. Here, the authors propose that Drosophila REPTOR and its mammalian ortholog CREBRF act as key transcriptional regulators of fuel choice in muscle.
- Pedro Saavedra
- , Phillip A. Dumesic
- & Norbert Perrimon
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| Open AccessSpatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models
Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting one in 5000 male births. To enrich our understanding of the underlying pathology, the authors apply spatial transcriptomics on dystrophic skeletal muscle to unravel markers related to histopathological changes in Duchenne mouse models.
- L.G.M. Heezen
- , T. Abdelaal
- & P. Spitali
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| Open AccessTEQUILA-seq: a versatile and low-cost method for targeted long-read RNA sequencing
The authors report TEQUILA-seq, a versatile, easy-to-implement, and low-cost method for targeted long-read RNA sequencing. TEQUILA-seq uncovers transcript isoforms and RNA mechanisms associated with human health and disease.
- Feng Wang
- , Yang Xu
- & Lan Lin
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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 AccessspinDrop: a droplet microfluidic platform to maximise single-cell sequencing information content
Droplet microfluidics enables high-throughput single-cell sequencing, but often with increased noise. Here the authors report spinDrop (sorting picoinjection inDrop) to increase gene detection and reduce noise; they use this to generate a high-quality molecular atlas of mouse brain development.
- Joachim De Jonghe
- , Tomasz S. Kaminski
- & Florian Hollfelder
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| Open AccessSingle-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction
This study identified a subset of osteoclastogenic fibroblasts expressing INHBA/activin A in human cholesteatoma. It further elucidated the mechanism behind the induction of inflammatory bone destruction, suggesting a potential therapeutic target.
- Kotaro Shimizu
- , Junichi Kikuta
- & Masaru Ishii
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Article
| Open AccessIntegrative analysis of transcriptome dynamics during human craniofacial development identifies candidate disease genes
Craniofacial disorders are among the most common congenital defects. Here, the authors examined the genetic causes of non-syndromic craniofacial disorders during human development through analysis of gene expression and epigenomics.
- Tara N. Yankee
- , Sungryong Oh
- & Justin Cotney
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Article
| Open AccessThree-dimensional molecular architecture of mouse organogenesis
Qu et al. present a detailed three-dimensional spatial transcriptome atlas of all major organs in the mouse embryo at E13.5, providing a better understanding of organ development and cellular interactions during mammalian development.
- Fangfang Qu
- , Wenjia Li
- & Guangdun Peng
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Article
| Open AccessIdentification of transcriptional programs using dense vector representations defined by mutual information with GeneVector
In single-cell RNA-seq analyses, it would be critical to measure the relationships between genes. Here, the authors develop a framework for single-cell dimensionality reduction that incorporates gene-specific relationships - GeneVector -, and use it for tasks such as annotating cell types and analysing pathway variation after treatment.
- Nicholas Ceglia
- , Zachary Sethna
- & Andrew McPherson
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Article
| Open AccessHigh throughput single cell long-read sequencing analyses of same-cell genotypes and phenotypes in human tumors
There is a need for methods that allow the analysis of single-cell long-read sequencing data without depending on known barcode lists or short-read sequencing. Here, the authors develop scNanoGPS, a tool that can independently deconvolute long reads into single cells and single molecules, and apply it on tumour and cell line data.
- Cheng-Kai Shiau
- , Lina Lu
- & Ruli Gao
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Article
| Open AccessnnSVG for the scalable identification of spatially variable genes using nearest-neighbor Gaussian processes
The identification of top spatially variable genes is a key step in the analysis of spatially-resolved transcriptomics data. Here, the authors develop a scalable method based on nearest-neighbor Gaussian processes and evaluate performance compared to existing and baseline methods.
- Lukas M. Weber
- , Arkajyoti Saha
- & Stephanie C. Hicks
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Article
| Open AccessA spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
Many key developmental transcriptional regulators are broadly expressed but perform distinct functions in specific tissues. Here they show that ubiquitously expressed PBX factors gain limb bud functionality by interaction with HAND2, uncovering fundamental principles of cooperation between promiscuous and tissue-specific regulators to instruct developmental programs.
- Marta Losa
- , Iros Barozzi
- & Licia Selleri
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Article
| Open AccessExtensive diversity in RNA termination and regulation revealed by transcriptome mapping for the Lyme pathogen Borrelia burgdorferi
Transcription termination can tune bacterial gene expression in response to diverse signals. Here, the authors use several RNA-seq approaches to map RNA ends for the transcriptome of the spirochete Borrelia burgdorferi, providing insights into various modes of transcription termination and identifying potential RNA regulators in this pathogen.
- Emily Petroni
- , Caroline Esnault
- & Philip P. Adams
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Article
| Open AccessSingle-cell profiling of lncRNA expression during Ebola virus infection in rhesus macaques
Long non-coding RNAs (lncRNAs) play key roles in the immune response but their properties at the single-cell level are less well understood. Here, the authors characterize differential features of lncRNAs and protein-coding genes upon Ebola infection in macaques at single-cell resolution.
- Luisa Santus
- , Maria Sopena-Rios
- & Marta Melé
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| Open AccessSingle-cell transcriptomics and epigenomics unravel the role of monocytes in neuroblastoma bone marrow metastasis
The bone marrow is a common site of metastasis for neuroblastoma patients. Here, the authors perform single cell RNA-seq and ATAC-seq of bone marrow aspirates from 16 subjects and show conservation of tumor cell plasticity in metastases and identify tumor-to-bone marrow cell signals that trigger tumor promoting monocytes.
- Irfete S. Fetahu
- , Wolfgang Esser-Skala
- & Sabine Taschner-Mandl
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Article
| Open AccessMycobacterium abscessus VapC5 toxin potentiates evasion of antibiotic killing by ribosome overproduction and activation of multiple resistance pathways
Mycobacterium abscessus (Mab) infections are difficult to clear with antibiotics. Here the authors show that clinical Mab strains can acquire a toxin-antitoxin system that enhances survival upon treatment with current first-line antibiotics through depletion of tRNASerCGA and subsequent ribosome overproduction.
- Eduardo A. Troian
- , Heather M. Maldonado
- & Nancy A. Woychik
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Article
| Open AccessSignaling mechanisms in renal compensatory hypertrophy revealed by multi-omics
The authors used a multi-omic approach in a mouse unilateral nephrectomy model to identify signaling processes associated with compensatory hypertrophy of the renal proximal tubule. The results indicate that PPARα is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.
- Hiroaki Kikuchi
- , Chung-Lin Chou
- & Mark A. Knepper
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| Open AccessgrandR: a comprehensive package for nucleotide conversion RNA-seq data analysis
Nucleotide conversion approaches facilitate metabolic RNA labelling experiments but complicate computational analysis. Here, the authors develop a methodology and software package to enable specific analysis methods for nucleotide conversion RNA-seq data.
- Teresa Rummel
- , Lygeri Sakellaridi
- & Florian Erhard