Biology subjects

Anderson, K.

Publications and source records attributed to Anderson, K..

34 records · Page 2Linked to original sources

bioRxiv2022

Exogenous Nav1.1 activity in excitatory and inhibitory neurons reverts Dravet syndrome comorbidities when delivered post-symptom onset in mice with Dravet

Dravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector-mediated delivery of a codon-modified SCN1A cDNA improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus or thalamus of DS mice improved the survival of the mice, reduced the occurrence of epileptic spikes, provided protection from thermally-induced seizures, and corrected background electrocorticography activity. Together, our results provide a proof-of-concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.

neuroscience↗

bioRxiv2022

Proportional intracranial volume correction differentially biases behavioral predictions across neuroanatomical features and populations

Individual differences in brain anatomy can be used to predict variability in cognitive function. Most studies to date have focused on broad population-level trends, but the extent to which the observed predictive features are shared across sexes and age groups remains to be established. While it is standard practice to account for intracranial volume (ICV) using proportion correction in both regional and whole-brain morphometric analyses, in the context of brain-behavior predictions the possible differential impact of ICV correction on anatomical features and subgroups within the population has yet to be systematically investigated. In this work, we evaluate the effect of proportional ICV correction on sex-independent and sex-specific predictive models of individual cognitive abilities across multiple anatomical properties (surface area, gray matter volume, and cortical thickness) in healthy young adults (Human Connectome Project; n=1013, 548 females) and typically developing children (Adolescent Brain Cognitive Development study; n=1823, 979 females). We demonstrate that ICV correction generally reduces predictive accuracies derived from surface area and gray matter volume, while increasing predictive accuracies based on cortical thickness in both adults and children. Furthermore, the extent to which predictive models generalize across sexes and age groups depends on ICV correction: models based on surface area and gray matter volume are more generalizable without ICV correction, while models based on cortical thickness are more generalizable with ICV correction. Finally, the observed neuroanatomical features predictive of cognitive abilities are unique across age groups regardless of ICV correction, but whether they are shared or unique across sexes (within age groups) depends on ICV correction. These findings highlight the importance of considering individual differences in ICV, and show that proportional ICV correction does not remove the effects of cranium volumes from anatomical measurements and can introduce ICV bias where previously there was none. ICV correction choices affect not just the strength of the relationships captured, but also the conclusions drawn regarding the neuroanatomical features that underlie those relationships.

neuroscience↗

bioRxiv2022

Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2

Wiedemann-Steiner syndrome (WSS) is a neurodevelopmental disorder caused by de novo variants in KMT2A, which encodes a multi-domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WSS, we examined the spatial distribution of likely WSS-causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WSS variants exhibit a 64.1-fold overrepresentation within the CXXC domain - which mediates binding to unmethylated CpGs - suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from Kmt2a-deficient mice demonstrate disrupted H3K4me1 preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 96.0% positive and 92.3% negative predictive value on a hold-out test set. This classification performance enabled us to subsequently perform an in silico saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WSS and provide an example of how AlphaFold2 can contribute to the in silico characterization of variant effects with very high accuracy, establishing a paradigm potentially applicable to many other Mendelian disorders.

genetics↗

bioRxiv2021

A reference induced pluripotent stem cell line for large-scale collaborative studies

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate iPSC lines and deeply characterised their genetic properties using whole genome sequencing, their genomic stability upon CRISPR/Cas9-based gene editing, and their phenotypic properties including differentiation to commonly-used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and hundreds of its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field. SummaryThe authors of this collaborative study deeply characterized human induced pluripotent stem cell (iPSC) lines to rationally select a clonally-derived cell line that performs well across multiple modalities. KOLF2.1J was identified as a candidate reference cell line based on single-cell analysis of its gene expression in the pluripotent state, whole genome sequencing, genomic stability after highly efficient CRISPR-mediated gene editing, integrity of the p53 pathway, and the efficiency with which it differentiated into multiple target cell populations. Since it is deeply characterized and can be readily acquired, KOLF2.1J is an attractive reference cell line for groups working with iPSCs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/472643v6_ufig1.gif" ALT="Figure 1"> View larger version (84K): org.highwire.dtl.DTLVardef@cef106org.highwire.dtl.DTLVardef@31d5d8org.highwire.dtl.DTLVardef@1ce6d8corg.highwire.dtl.DTLVardef@17a19d2_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

A novel and highly divergent Canine Distemper Virus lineage causing distemper in ferrets in Australia

Canine distemper virus (CDV) is a highly contagious systemic viral disease of dogs, that regularly spills-over into other animal species. Despite widespread vaccination, CDV remains endemic in many parts of the world. In this study we report an outbreak of distemper in ferrets in two independent research facilities in Australia. We found that disease severity varied, although most animals had mild to moderate disease signs. Histopathology results of animals with severe disease presented the typical profile of distemper pathology with multi-system virus replication. Through the development of a discriminatory PCR paired with full genome sequencing we revealed that the outbreak at both facilities was caused by a single, novel lineage of CDV. This lineage was highly divergent across the H gene, F signal peptide and full genome and had less than 93% similarity across the H gene to other described lineages, including the vaccine strain. Molecular analysis indicates that this strain belongs to a distinct lineage that diverged from other clades approximately 140 to 400 years ago, and appears to be unique to Australia. Given the differences in key viral proteins of this novel CDV strain, a review of the efficacy of the CDV vaccines currently in use in Australia is warranted to ensure maximum protection of dogs and other vulnerable species. In addition, enhanced surveillance to determine the prevalence of CDV in ferrets, dogs and other at-risk species in Australia would be useful to better understand the diversity of CDV in Australia. ImportanceCanine distemper virus (CDV) is highly contagious and while dogs are the main reservoir, it may spill over into a number of other animal species. In this study we report an outbreak of distemper in ferrets in two research facilities in Australia. Outcomes of pathology and histopathology suggest ferrets have widespread multi-systemic infection, consistent with previously reported distemper infections in ferrets and dogs. Critically, through sequencing and phylogenetic analysis, we revealed that the outbreak at both facilities was caused by a single, novel and highly divergent lineage of CDV. This virus had less than 93% nucleotide similarity to other described lineages and the vaccine strain. This manuscript adds considerably to the epidemiology, ecology and evolution of this virus, and is one of few reports of distemper in Australia in the literature.

microbiology↗

bioRxiv2021

Enzyme engineering and in vivo testing of a formate-reduction pathway

Formate is an attractive feedstock for sustainable microbial production of fuels and chemicals, but its potential is limited by the lack of efficient assimilation pathways. The reduction of formate to formaldehyde would allow efficient downstream assimilation, but no efficient enzymes are known for this transformation. To develop a 2-step formate-reduction pathway, we screened natural variants of acyl-CoA synthetase (ACS) and acylating aldehyde dehydrogenase (ACDH) for activity on one-carbon substrates and identified active and highly expressed homologs of both enzymes. We then performed directed evolution, increasing ACDH specific activity by 2.5-fold and ACS lysate activity by 5-fold. To test for in vivo activity of our pathway, we expressed it in a methylotroph which can natively assimilate formaldehyde. Although the enzymes were active in cell extracts, we could not detect formate assimilation into biomass, indicating that further improvement will be required for formatotrophy. Our work provides a foundation for further development of a versatile pathway for formate assimilation.

bioengineering↗

bioRxiv2020

Quantitative trait locus mapping reveals an independent genetic basis for joint divergence in leaf function, life-history, and floral traits between scarlet monkeyflower (Mimulus cardinalis) populations

PREMISEAcross taxa, vegetative and floral traits that vary along a fast-slow life-history axis are often correlated with leaf functional traits arrayed along the leaf economics spectrum, suggesting a constrained set of adaptive trait combinations. Such broad-scale convergence may arise from genetic constraints imposed by pleiotropy (or tight linkage) within species, or from natural selection alone. Understanding the genetic basis of trait syndromes and their components is key to distinguishing these alternatives and predicting evolution in novel environments. METHODSWe used a line-cross approach and quantitative trait locus (QTL) mapping to characterize the genetic basis of twenty leaf functional/physiological, life history, and floral traits in hybrids between annualized and perennial populations of scarlet monkeyflower (Mimulus cardinalis). RESULTSWe mapped both single and multi-trait QTLs for life history, leaf function and reproductive traits, but found no evidence of genetic co-ordination across categories. A major QTL for three leaf functional traits (thickness, photosynthetic rate, and stomatal resistance) suggests that a simple shift in leaf anatomy may be key to adaptation to seasonally dry habitats. CONCLUSIONSOur results suggest that the co-ordination of resource-acquisitive leaf physiological traits with a fast life history and more selfing mating system results from environmental selection rather than functional or genetic constraint. Independent assortment of distinct trait modules, as well as a simple genetic basis to leaf physiological traits associated with drought escape, may facilitate adaptation to changing climates.

plant biology↗

bioRxiv2020

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease

A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), which is the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illuminas Infinium MethylationEPIC BeadChip arrays (n=862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p[≤]x10-8 and fold change {+/-}2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Top-ranked genes within which several dmCpGs were located and supported by in silico functional data, and replication where possible, include; AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9, and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-{beta} signalling and Th17 cell differentiation. Epigenetic alterations provide a dynamic link between an individuals genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals, has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

molecular biology↗

bioRxiv2020

Drone-derived canopy height predicts biomass across non-forest ecosystems globally

Non-forest ecosystems, dominated by shrubs, grasses and herbaceous plants, provide ecosystem services including carbon sequestration and forage for grazing, yet are highly sensitive to climatic changes. Yet these ecosystems are poorly represented in remotely-sensed biomass products and are undersampled by in-situ monitoring. Current global change threats emphasise the need for new tools to capture biomass change in non-forest ecosystems at appropriate scales. Here we assess whether canopy height inferred from drone photogrammetry allows the estimation of aboveground biomass (AGB) across low-stature plant species sampled through a global site network. We found mean canopy height is strongly predictive of AGB across species, demonstrating standardised photogrammetric approaches are generalisable across growth forms and environmental settings. Biomass per-unit-of-height was similar within, but different among, plant functional types. We find drone-based photogrammetry allows for monitoring of AGB across large spatial extents and can advance understanding of understudied and vulnerable non-forested ecosystems across the globe.

ecology↗

bioRxiv2019

Species and habitat mapping in two dimensions and beyond. Structure-from-Motion Multi-View Stereo photogrammetry for the conservation community.

Structure-from-Motion Multi View Stereo (SfM-MVS) photogrammetry is a technique by which volumetric data can be derived from overlapping image sets, using changes of an objects position between images to determine its height and spatial structure. Whilst SfM-MVS has fast become a powerful tool for scientific research, its potential lies beyond the scientific setting, since it can aid in delivering information about habitat structure, biomass, landscape topography, spatial distribution of species in both two and three dimensions, and aid in mapping change over time - both actual and predicted. All of which are of strong relevance for the conservation community, whether from a practical management perspective or understanding and presenting data in new and novel ways from a policy perspective. For practitioners outside of academia wanting to use SfM-MVS there are technical barriers to its application. For example, there are many SfM-MVS software options, but knowing which to choose, or how to get the best results from the software can be difficult for the uninitiated. There are also free and open source software options (FOSS) for processing data through a SfM-MVS pipeline that could benefit those in conservation management and policy, especially in instances where there is limited funding (i.e. commonly within grassroots or community-based projects). This paper signposts the way for the conservation community to understand the choices and options for SfM-MVS implementation, its limitations, current best practice guidelines and introduces applicable FOSS options such as OpenDroneMap, MicMac, CloudCompare, QGIS and speciesgeocodeR. It will also highlight why and where this technology has the potential to become an asset for spatial, temporal and volumetric studies of landscape and conservation ecology.

ecology↗

bioRxiv2019

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

Dravet syndrome (Dravet) epilepsy begins with febrile seizures followed by worsening to refractory seizures, with some improvement and stabilization toward adolescence. The neuronal basis of Dravet is debatable, with evidence favoring reduced inhibition or enhanced excitation. Focusing on the firing properties of hippocampal CA1 pyramidal neurons and oriens-lacunosum moleculare (O-LM) interneurons, we provide a comprehensive analysis of the activity of both cell types through the febrile, worsening and stabilization stages. Our data indicate a temporary increase in the excitability of CA1 pyramidal neurons during the febrile stage, which is fully reversed by the onset of spontaneous seizures. In contrast, reduced function of O-LM interneurons persisted from the febrile through the stabilization stages, with the greatest impairment of excitability occurring during the worsening stage. Thus, both excitatory and inhibitory neurons contribute to Dravet, indicating complex and reciprocal pathophysiological neuronal changes during the different stages of the disease.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC=\"FIGDIR/small/790170v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (15K):\norg.highwire.dtl.DTLVardef@220862org.highwire.dtl.DTLVardef@54840eorg.highwire.dtl.DTLVardef@a9d006org.highwire.dtl.DTLVardef@9854ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

Gene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-{beta}-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encoding KRAS, MYC and FAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosis in vitro and in vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/{beta}-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.\n\nGraphical Summary\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC=\"FIGDIR/small/594184_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (52K):\norg.highwire.dtl.DTLVardef@20c737org.highwire.dtl.DTLVardef@1f714faorg.highwire.dtl.DTLVardef@823560org.highwire.dtl.DTLVardef@7e6219_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIHigh grade serous ovarian carcinoma tumors contain PTK2 (FAK) 8q24.3 gains associated with prognostic differences.\nC_LIO_LIKMF, a new murine ovarian cancer model with K-Ras, Myc, and FAK gene gains and intrinsic platinum resistance.\nC_LIO_LIFAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.\nC_LIO_LIFAK facilitates a {beta}-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.\nC_LIO_LIFAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance.\nC_LI

cancer biology↗

bioRxiv2019

The Gag Protein PEG10 Binds to RNA and Regulates Trophoblast Stem Cell Lineage Specification.

Peg10 (paternally expressed gene 10) is an imprinted gene that is essential for placental development. It is thought to derive from a Ty3-gyspy LTR (long terminal repeat) retrotransposon and retains Gag and Pol-like domains. Here we show that the Gag domain of PEG10 can promote vesicle budding similar to the HIV p24 Gag protein. Expressed in a subset of mouse endocrine organs in addition to the placenta, PEG10 was identified as a substrate of the deubiquitinating enzyme USP9X. Consistent with PEG10 having a critical role in placental development, PEG10-deficient trophoblast stem cells (TSCs) exhibited impaired differentiation into placental lineages. PEG10 expressed in wild-type, differentiating TSCs was bound to many cellular RNAs including Hbegf (Heparin-binding EGF-like growth factor), which is known to play an important role in placentation. Expression of Hbegf was reduced in PEG10-deficient TSCs suggesting that PEG10 might bind to and stabilize RNAs that are critical for normal placental development.

molecular biology↗

bioRxiv2018

Extreme copy number variation at a tRNA ligase affecting phenology and fitness in yellow monkeyflowers

Copy number variation (CNV) is a major part of the genetic diversity segregating within populations, but remains poorly understood relative to single nucleotide variation. Here, we report on a tRNA ligase gene (Migut.N02091; RLG1a) exhibiting unprecedented, and fitness-relevant, CNV within an annual population of the yellow monkeyflower Mimulus guttatus. RLG1a variation was associated with multiple traits in pooled population sequencing (PoolSeq) scans of phenotypic and phenological cohorts. Resequencing of inbred lines revealed intermediate frequency three-copy variants of RLG1a (trip+; 5/35 = 14%), and trip+ lines exhibited elevated RLG1a expression under multiple conditions. trip+ carriers, in addition to being over-represented in late-flowering and large-flowered PoolSeq populations, flowered later under stressful conditions in a greenhouse experiment (P < 0.05). In wild population samples, we discovered an additional rare RLG1a variant (high+) that carries 250-300 copies of RLG1a totaling [~]5.7Mb (20-40% of a chromosome). In the progeny of a high+ carrier, Mendelian segregation of diagnostic alleles and qPCR-based copy counts indicate that high+ is a single tandem array unlinked from the single copy RLG1a locus. In the wild, high+ carriers had highest fitness in two particularly dry and/or hot years (2015 and 2017; both p < 0.01), while single copy individuals were twice as fecund as either CNV type in a lush year (2016: p < 0.005). Our results demonstrate fluctuating selection on CNVs affecting phenological traits in a wild population, suggest that plant tRNA ligases mediate stress-responsive life-history traits, and introduce a novel system for investigating the molecular mechanisms of gene amplification.

evolutionary biology↗

bioRxiv2018

A Polygenic Score for Higher Educational Attainment is Associated with Larger Brains

People who score higher on intelligence tests tend to have larger brains. Twin studies suggest the same genetic factors influence both brain size and intelligence. This has led to the hypothesis that genetics influence intelligence partly by contributing to development of larger brains. We tested this hypothesis with molecular genetic data using discoveries from a genome-wide association study (GWAS) of educational attainment, a correlate of intelligence. We analyzed genetic, brain imaging, and cognitive test data from the UK Biobank, the Dunedin Study, the Brain Genomics Superstruct Project (GSP), and the Duke Neurogenetics Study (DNS) (combined N=8,271). We measured genetics using polygenic scores based on published GWAS. We conducted meta-analysis to test associations among participants genetics, total brain volume (i.e., brain size), and cognitive test performance. Consistent with previous findings, participants with higher polygenic scores achieved higher scores on cognitive tests, as did participants with larger brains. Participants with higher polygenic scores also had larger brains. We found some evidence that brain size partly mediated associations between participants education polygenic scores and their cognitive test performance. Effect-sizes were larger in the population-based UK Biobank and Dunedin samples than in the GSP and DNS samples. Sensitivity analysis suggested this effect-size difference partly reflected restricted range of cognitive performance in the GSP and DNS samples. Recruitment and retention of population-representative samples should be a priority for neuroscience research. Findings suggest promise for studies integrating GWAS discoveries with brain imaging data to understand neurobiology linking genetics with individual differences in cognitive performance.

neuroscience↗

bioRxiv2017

Hydrogen peroxide formation by Nox4 limits malignant transformation

Reactive oxygen species (ROS) can cause cellular damage and are thought to promote cancer-development. Nevertheless, under physiological conditions, all cells constantly produce ROS, either as chemical by-products or for signaling purpose. During differentiation cells induce the NADPH oxidase Nox4, which constitutively produces low amounts of H2O2. We infer that this constitutive H2O2 is unlikely to be carcinogenic and may rather maintain basal activity of cellular surveillance systems.\n\nUtilizing two different murine tumor models we demonstrate that Nox4 prevents malignant transformation and facilitated the recognition of DNA-damage. Upon DNA-damage repair is initiated as consequence of phosphorylation of H2AX ({gamma}H2AX). Repair only occurs if nuclear activity of the {gamma}H2AX-dephosphorylating phosphatase PP2A is kept sufficiently low, a task fulfilled by Nox4: Nox4 continuously oxidizes AKT, and once oxidized AKT captures PP2A in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of {gamma}H2AX. Simultaneously the proportion of active, phosphorylated AKT is increased. Thus, DNA-damage is not recognized and the increase in AKT activity promotes proliferation. The combination of both events resulted in genomic instability and tumor initiation.\n\nWith the identification of the first cancer-protective source of reactive oxygen species, Nox4, the paradigm of reactive-oxygen species-induced initiation of malignancies should be revised.\n\nSignificanceThe stereotype of ROS produced by NADPH oxidases as cause of malignant diseases persists generalized since decades. We demonstrate that the NADPH oxidase Nox4, as constitutive source of ROS, prevents malignant transformation and that its pharmacological inhibition as currently aspired by several companies will potentially increase the risk of malignant cell transformation and eventually tumor formation.\n\nPrecisBy oxidizing AKT and keeping PP2A in the cytosol, the NADPH oxidase Nox4 allows proper DNA damage repair and averts cancer development.

cancer biology↗