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| Open AccessDeterminants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.
- Julia K. Goodrich
- , Moriel Singer-Berk
- & Miriam S. Udler
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Article
| Open AccessAltered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders
Lysosomal storage disorders, characterized by altered metabolism of heparan sulfate, cause autistic symptoms followed by dementia in children. Here, the authors show that embryonic dopaminergic neurodevelopmental defects due to altered function of heparan sulfate cause autistic behaviours in mice.
- Maria De Risi
- , Michele Tufano
- & Elvira De Leonibus
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Article
| Open AccessDeep learning boosts sensitivity of mass spectrometry-based immunopeptidomics
The identification of HLA peptides by mass spectrometry is non-trivial. Here, the authors extended and used the wealth of data from the ProteomeTools project to improve the prediction of non-tryptic peptides using deep learning, and show their approach enables a variety of immunological discoveries.
- Mathias Wilhelm
- , Daniel P. Zolg
- & Bernhard Kuster
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Article
| Open AccessMitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo
Heteroplasmic mitochondrial DNA mutations lack effective treatments. Here the authors adapt I-CreI meganuclease to target the mitochondria and specifically-eliminate mtDNA with a m.5024C>T mutation in the mttRNA Ala gene.
- Ugne Zekonyte
- , Sandra R. Bacman
- & Carlos T. Moraes
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Article
| Open AccessIdentifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism
Age at onset of X-linked dystonia-parkinsonism is 50% explained by the length of a repeat in an SVA insert. The authors perform a GWAS for genetic modifiers and discover three more loci, accounting for another 13% of variability in age at onset with the protective alleles delaying onset by seven years.
- Björn-Hergen Laabs
- , Christine Klein
- & Ana Westenberger
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| Open AccessThe VRNetzer platform enables interactive network analysis in Virtual Reality
Data-rich networks can be difficult to interpret beyond a certain size. Here, the authors introduce a platform that uses virtual reality to allow the visual exploration of large networks, while interfacing with data repositories and other analytical methods to improve the interpretation of big data.
- Sebastian Pirch
- , Felix Müller
- & Jörg Menche
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Article
| Open AccessLoss of endothelial glucocorticoid receptor accelerates diabetic nephropathy
The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.
- Swayam Prakash Srivastava
- , Han Zhou
- & Julie Goodwin
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| Open AccessSingle-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes
The molecular identity of renal glomerular cells is poorly characterized and rodent glomerulopathy models translate poorly to humans. Here, the authors show molecular signatures of glomerulus-associated cells using single cell RNA sequencing and highlight differences between mouse and human cells.
- Bing He
- , Ping Chen
- & Jaakko Patrakka
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Article
| Open AccessLead compounds for the development of SARS-CoV-2 3CL protease inhibitors
The essential SARS-CoV-2 3CL protease is of interest as a drug target. Here, the authors identify three 3CL inhibitors and characterize them both in vitro and with a cell-based assay, and they also present the inhibitor-bound 3CL crystal structures, which may allow for the design of improved compounds.
- Sho Iketani
- , Farhad Forouhar
- & David D. Ho
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Article
| Open AccessAn endothelial activin A-bone morphogenetic protein receptor type 2 link is overdriven in pulmonary hypertension
Pulmonary arterial hypertension is a progressive fatal disease characterized by pathological pulmonary artery remodeling. Here the authors show that the dysregulation of the activin A-bone morphogenetic protein receptor type 2 link in the endothelium is involved in the progression of pulmonary hypertension.
- Gusty R. T. Ryanto
- , Koji Ikeda
- & Noriaki Emoto
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Article
| Open AccessPOLRMT mutations impair mitochondrial transcription causing neurological disease
POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.
- Monika Oláhová
- , Bradley Peter
- & Robert W. Taylor
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Article
| Open AccessPharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise
The physiological role of GDF15 remains poorly defined. Here, the authors show that circulating GDF15 increases in response to prolonged exercise, but that this exercise-induced GDF15, unlike pharmacological GDF15, does not affect post-exercise food intake or exercise motivation.
- Anders B. Klein
- , Trine S. Nicolaisen
- & Christoffer Clemmensen
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Article
| Open AccessIndividualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes
Understanding patient-specific pathobiological pathways is a critical step for advancing precision medicine. Here the authors show that individualized protein-protein interaction networks provide key insight on patient-level pathobiology and clinically relevant pathophenotypic characteristics in a complex disease.
- Bradley A. Maron
- , Rui-Sheng Wang
- & Joseph Loscalzo
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Article
| Open AccessThe molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma
Progression from asymptomatic smoldering multiple myeloma (SMM) to symptomatic Multiple Myeloma occurs at different rates in different patients. Here, the authors report fewer NRAS and FAM46C mutations and adverse translocations in SMM compared to MM, while KRAS mutations are associated with a shorter time to progression.
- Eileen M. Boyle
- , Shayu Deshpande
- & Brian A. Walker
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Article
| Open AccessCapsid-like particles decorated with the SARS-CoV-2 receptor-binding domain elicit strong virus neutralization activity
Here the authors generate a capsid-like particle based vaccine candidate displaying the receptor-binding domain of the SARS-CoV-2 spike protein and show induction of neutralizing antibodies after intramuscular prime-boost immunization in mice.
- Cyrielle Fougeroux
- , Louise Goksøyr
- & Adam F. Sander
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Article
| Open AccessHigh-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance
High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells.
- Anil Kumar
- , Kumaran Sundaram
- & Huang-Ge Zhang
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Article
| Open AccessHigh-resolution ex vivo NMR spectroscopy of human Z α1-antitrypsin
α1-Antitrypsin (AAT) is a 52 kDa serum glycoprotein, the misfolding and polymerisation of which is associated with COPD and liver disease. Here the authors demonstrate the use of high-resolution multidimensional solution-state NMR spectroscopy to characterise the structure and dynamics in solution of Z AAT purified directly from clinical patients.
- Alistair M. Jagger
- , Christopher A. Waudby
- & David A. Lomas
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Article
| Open AccessReduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase
Here the authors combine next generation sequencing on plasma from participants of the ADVANCE clinical trial with virological and follow-up data to investigate the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second-generation integrase inhibitors and find an association between NNRTI resistance prior to treatment and long-term treatment.
- Mark J. Siedner
- , Michelle A. Moorhouse
- & Ravindra K. Gupta
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Article
| Open AccessUAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression
NLRP3 inflammasome activation is regulated by various signaling pathways to ensure inflammation does not go unchecked. Here the authors show how deubiquitination avoids this regulation to activate the NLRP3 inflammasome through the function of UAF1/USP deubiquitinase complexes.
- Hui Song
- , Chunyuan Zhao
- & Wei Zhao
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Article
| Open AccessETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine
ETNK1 mutations are recurrent in leukemia but how they contribute to oncogenesis is still unclear. Here, the authors show that ETNK1 mutations increase mitochondrial activity, ROS and H2AX levels and that these effects can be rescued upon phosphoethanolamine supplementation.
- Diletta Fontana
- , Mario Mauri
- & Rocco Piazza
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Article
| Open AccessST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL
Understanding the molecular events controlling melanoma progression are necessary to find improved therapeutics. Here, the authors report oncogenic SOX2-GLI1 transcriptional complex to drive melanoma invasion through the induction of the sialyltransferase ST3GAL1, and report ST3GAL1-AXL axis as driver of melanoma metastasis.
- Silvia Pietrobono
- , Giulia Anichini
- & Barbara Stecca
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| Open AccessUpper airway gene expression reveals suppressed immune responses to SARS-CoV-2 compared with other respiratory viruses
Here, the authors provide upper airway gene expression data from patients with COVID-19 and other viral and non-viral acute respiratory illnesses. They find attenuated activation of innate immune and pro-inflammatory pathways in COVID-19 as compared to other viral infections, which may contribute to its propensity for pre-symptomatic transmission.
- Eran Mick
- , Jack Kamm
- & Charles Langelier
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Article
| Open AccessGermline AGO2 mutations impair RNA interference and human neurological development
AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference.
- Davor Lessel
- , Daniela M. Zeitler
- & Hans-Jürgen Kreienkamp
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Article
| Open AccessInhibition of aquaporin-3 in macrophages by a monoclonal antibody as potential therapy for liver injury
Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide, and hydrogen peroxide mediated oxidative stress has been implicated in liver injury. Here, the authors report the development of an anti-AQP3 monoclonal antibody, which alleviates liver injury in multiple mouse models.
- Mariko Hara-Chikuma
- , Manami Tanaka
- & Masato Yasui
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Article
| Open AccessSpatially and cell-type resolved quantitative proteomic atlas of healthy human skin
The human skin is a highly complex organ comprising multiple tissue layers and diverse cell types. Here, the authors present a spatially-resolved quantitative proteomic atlas of the healthy human skin, characterizing the protein profiles of four skin layers and nine cell types.
- Beatrice Dyring-Andersen
- , Marianne Bengtson Løvendorf
- & Matthias Mann
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Article
| Open AccessSelection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2
Here, the authors isolate several nanobodies from a synthetic library that bind the receptor-binding domain (RBD) of SARS-CoV-2 spike protein (S) and neutralize S pseudotyped viruses. Cryo-EM structure of Spike with one nanobody and further biophysical analysis shows competition with ACE2 binding.
- Tânia F. Custódio
- , Hrishikesh Das
- & Christian Löw
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Perspective
| Open AccessA high-stringency blueprint of the human proteome
The Human Proteome Project (HPP) was launched in 2010 to enhance accurate annotation of the genome-encoded proteome. Ten years later, the HPP releases its first blueprint of the human proteome, annotating 90% of all known proteins at high-stringency and discussing the implications of proteomics for precision medicine.
- Subash Adhikari
- , Edouard C. Nice
- & Mark S. Baker
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Article
| Open AccessThe ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress
The bacterial pathogen Helicobacter pylori is known for its ability to induce DNA double-strand breaks in the genome of its target cells. Here, we show that H. pylori-induced DNA damage and replication stress occurs in S-phase cells as a result of R-loop-mediated transcription/replication conflicts that are triggered by activation of the ALPK1/TIFA/NF-κB signaling axis.
- Michael Bauer
- , Zuzana Nascakova
- & Anne Müller
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Article
| Open AccessHIF-2α is indispensable for regulatory T cell function
HIF-1α is known to repress regulatory T (Treg) cell function, but less is known about the effect of HIF-2α on these cells. Here, the authors use three different mouse models of inflammatory diseases to show that HIF-2α limits HIF-1α expression and is critical for Treg cell function.
- Tzu-Sheng Hsu
- , Yen-Lin Lin
- & Ming-Zong Lai
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Article
| Open AccessMolecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis
There are currently only a few biomarkers to predict the response of muscle invasive bladder cancer to therapy. Here, the authors analyse 300 tumors using exome and RNA sequencing and find that tumors with a high degree of genomic instability and a non-basal/squamous gene expression subtype are most likely to respond to treatment.
- Ann Taber
- , Emil Christensen
- & Lars Dyrskjøt
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Article
| Open AccessDeregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing
Diabetic foot ulcers (DFU) represent a complex disease with limited treatment options. Here, the authors compare human RNASeq patient data from DFU, oral mucosa and skin acute wounds, identifying FOXM1 as a mediator of macrophage and neutrophil recruitment, which contributes to disease pathogenesis and is dysregulated in patients.
- Andrew P. Sawaya
- , Rivka C. Stone
- & Marjana Tomic-Canic
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Article
| Open AccessIntegration of molecular profiles in a longitudinal wellness profiling cohort
An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, the authors sample a longitudinal wellness cohort and analyse blood molecular profiles as well as gut microbiota composition.
- Abdellah Tebani
- , Anders Gummesson
- & Linn Fagerberg
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Article
| Open AccessTargeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome
In recent years, hematopoietic stem cells gene editing has emerged as a promising tool to treat blood disorders. Here the authors develop a CRISPR/Cas9-based genome editing strategy that allows the precise correction of Wiskott-Aldrich Syndrome in vitro and in vivo with high efficiency.
- Rajeev Rai
- , Marianna Romito
- & Alessia Cavazza
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Article
| Open AccessMolecular engineering of safe and efficacious oral basal insulin
Recently, the first orally-administered ultra-long acting insulin was shown to have clinical efficacy. Here, the authors report the molecular engineering, as well as the biological and pharmacological properties of these insulin analogues.
- Frantisek Hubálek
- , Hanne H. F. Refsgaard
- & Thomas Kjeldsen
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Article
| Open AccessCoordinate β-adrenergic inhibition of mitochondrial activity and angiogenesis arrest tumor growth
Targeting mitochondrial metabolism in cancer cells has shown promising therapeutic potential. Here, the authors screen FDA-approved compound library and show that the β1-blocker nebivolol inhibits oxidative phosphorylation and angiogenesis in cancer cells and can be re-purposed for cancer therapy.
- Cristina Nuevo-Tapioles
- , Fulvio Santacatterina
- & José M. Cuezva
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Article
| Open AccessSelf-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice
Here, the authors develop a self-amplifying RNA encoding the SARS-CoV-2 spike protein encapsulated within a lipid nanoparticle as a vaccine candidate and show induction of neutralization antibody titers in mice that are comparable to titers in convalescent sera of patients.
- Paul F. McKay
- , Kai Hu
- & Robin J. Shattock
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Article
| Open AccessA nanotrap improves survival in severe sepsis by attenuating hyperinflammation
Sepsis is a difficult to treat condition. Here, the authors present a telodendrimer nanotrap that captures inflammator mediators to improve survival in combination with antibiotic treatment.
- Changying Shi
- , Xiaojing Wang
- & Juntao Luo
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Article
| Open AccessStructural characterization of a novel human adeno-associated virus capsid with neurotropic properties
Adeno-associated viruses (AAVs) are vehicles for gene therapy in humans, but currently only a limited amount of AAV serotypes is available. Here, the authors identify a novel AAV, AAVv66, and demonstrate enhanced production yields, virion stability, and CNS transduction compared to the clinically approved serotype AAV2.
- Hung-Lun Hsu
- , Alexander Brown
- & Guangping Gao
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Article
| Open AccessHepatic HuR modulates lipid homeostasis in response to high-fat diet
Human antigen R (HuR) is a RNA binding protein involved in the regulation of many cellular functions. Here the authors show that, hepatocyte specific deletion of HuR exacerbates high-fat diet-induced NAFLD in mice by regulating transcripts involved in lipid transport and ATP synthesis.
- Zhuojun Zhang
- , Chen Zong
- & Wengong Wang
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Article
| Open AccessCharacterization of a pluripotent stem cell-derived matrix with powerful osteoregenerative capabilities
Production of a safe and manufacturable material to mimic anabolic bone for tissue engineering has been hard to achieve to date. Here the authors use a mesenchymal stem cell line generated from induced pluripotent stem cells to produce osteogenic cell-matrix, displaying significant healing properties in mice.
- Eoin P. McNeill
- , Suzanne Zeitouni
- & Carl A. Gregory
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Article
| Open AccessNuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia
Loss of function mutations of NSD1 occur in blood cancers. Here, the authors report that NSD1 loss blocks erythroid differentiation which leads to an erythroleukemia-like disease in mice by impairing GATA1-induced target gene activation.
- Katharina Leonards
- , Marwa Almosailleakh
- & Juerg Schwaller
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Article
| Open AccessCellular census of human fibrosis defines functionally distinct stromal cell types and states
New anti-fibrotics aided by a better understanding of fibrotic cell subsets and their functions are needed. Here the authors perform single-cell RNA-seq and CyTOF on nodules from patients with Dupuytren’s disease to map subsets and the state of mesenchymal cells during pathogenic fibrogenesis.
- Thomas B. Layton
- , Lynn Williams
- & Jagdeep Nanchahal
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Article
| Open AccessUltrasensitive digital quantification of cytokines and bacteria predicts septic shock outcomes
Ultrasensitive methods for detection of biomarkers for infectious disease are needed for diagnosing, monitoring and targeting treatment. Here the authors develop a digital assay for inflammatory markers, bacterial DNA and antibotic-resistance genes and apply it to characterise asthma patients and predict mortality from septic shock.
- M. Fatih Abasıyanık
- , Krysta Wolfe
- & Savaş Tay
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Article
| Open AccessExploiting evolutionary steering to induce collateral drug sensitivity in cancer
Evolutionary steering uses therapies to control tumour evolution by exploiting trade-offs. Here, using a barcoding approach applied to large cell populations, the authors explore evolutionary steering in lung cancer cells treated with EGFR inhibitors.
- Ahmet Acar
- , Daniel Nichol
- & Andrea Sottoriva
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Perspective
| Open AccessDeveloping a new class of engineered live bacterial therapeutics to treat human diseases
The role microbes play in human health and the ability of synthetic biology to engineer microbial properties opens up new ways of treating disease. In this perspective, the authors describe the design and development of these living therapeutics.
- Mark R. Charbonneau
- , Vincent M. Isabella
- & Caroline B. Kurtz
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Article
| Open AccessWireless optogenetics protects against obesity via stimulation of non-canonical fat thermogenesis
Cardiovascular risks of cold exposure and the subsequent activation of the β3-AR pathway limit the application of beige fat thermogenesis for the treatment of obesity. Here, the authors show that optogenetics light-activated Ca2+ cycling in adipocytes triggers a fat-specific “cold-mimetic” thermogenesis response protecting mice against diet-induced obesity.
- Kazuki Tajima
- , Kenji Ikeda
- & Shingo Kajimura
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Article
| Open AccessInterference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects
Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.
- Angela Tomasovic
- , Theresa Brand
- & Kristina Lorenz
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Article
| Open Access2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations
Nonsense mutations can be corrected by several molecules that activate readthrough of premature termination codon. Here, the authors report that 2,6-diaminopurine efficiently corrects UGA nonsense mutations with no significant toxicity.
- Carole Trzaska
- , Séverine Amand
- & Fabrice Lejeune
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Article
| Open AccessHyperoxia induces glutamine-fuelled anaplerosis in retinal Müller cells
Prematurely born babies need extra oxygen to survive, but this can cause damage to the eyes and lead to infant blindness. Here the authors show that this hyperoxia changes the metabolism of Müller cells in the retina such that they use up, rather than produce, glutamine and secrete excess ammonium.
- Charandeep Singh
- , Vincent Tran
- & Jonathan E. Sears