Biology subjects

Gupta, S. K.

Publications and source records attributed to Gupta, S. K..

35 records · Page 2Linked to original sources

bioRxiv2022

MicroRNA397 regulates tolerance to drought and fungal infection by regulating lignin deposition in chickpea root

Plants deposit lignin in the secondary cell wall as a common response to drought and pathogen attacks. Cell wall localized multicopper oxidase family enzymes LACCASES (LACs) catalyze the formation of monolignol radicals and facilitate lignin formation. We show an upregulation of the expression of several LAC genes and a downregulation of microRNA397 (CamiR397) in response to natural drought in chickpea roots. CamiR397 was found to target LAC4 and LAC17L out of twenty annotated LACs in chickpea. CamiR397 and its target genes are expressed in root. Overexpression of CamiR397 reduced expression of LAC4 and LAC17L and lignin deposition in chickpea root xylem causing reduction in xylem diameter. Downregulation of CamiR397 activity by expressing a short tandem target mimic (STTM397) construct increased root lignin deposition in chickpea. CamiR397-overexpressing (miR397OX) and STTM397 chickpea lines showed sensitivity and tolerance, respectively, to drought. Infection with a fungal pathogen Macrophomina phaseolina, responsible for dry root rot disease in chickpea, induced local lignin deposition and LAC gene expression. CamiR397-overexpressing and STTM397 chickpea lines showed more sensitivity and tolerance, respectively, to dry root rot. Our results demonstrated the regulatory role of CamiR397 in root lignification during drought and dry root rot in an agriculturally important crop chickpea.

plant biology↗

bioRxiv2022

Biochemical analysis of anthocyanin and proanthocyanidin and their regulation in determining chickpea flower and seed coat colours

Flower and seed coat colour are important agronomic traits in chickpea (Cicer arietinum L.). Cultivated chickpeas are of two types namely, desi (dark seeded, purple flower) and kabuli (light colour seeded, white flower). There has been limited information about the molecular mechanism underlying the colour variation of flower and seed coats in desi and kabuli chickpea. We profiled the anthocyanin and proanthocyanidin (PA) contents in chickpea flowers and seed coats. Tissue-specific silencing of two genes encoding a basic helix-loop-helix (CabHLH) protein and a tonoplast-localized multidrug and toxic compound extrusion (CaMATE1) transporter in a desi genotype resulted in the reduction in expressions of anthocyanin and PA biosynthetic genes and anthocyanin and PA contents in the flower and seed coat and produced flowers and seeds with kabuli characteristics. Transcriptional regulation of a subset of anthocyanin and PA biosynthetic genes by a natural CabHLH variant and transport assay of a natural CaMATE1 variant explained the association of these alleles with the kabuli phenotype. We carried out a detailed molecular characterization of these genes, and provided evidences that kabuli chickpea flower and seed colour phenotype can be derived by manipulation of single genes in a desi chickpea background. HighlightIn this study, we have defined the molecular link between flower and seed color in chickpea and identified CaMATE1 and CabHLH as the regulators of both the traits.

plant biology↗

bioRxiv2022

Innate immune response and distinct metabolomic signatures together drive and shape the SARS-CoV-2-specific T cell response during COVID-19

The underlying factors contributing to the evolution of SARS-CoV-2-specific T cell responses during COVID-19 infection remain unidentified. To address this, we characterized innate and adaptive immune responses with metabolomic profiling longitudinally at three different time points (0-3, 7-9, and 14-16 days post-COVID-19 positivity) from young mildly symptomatic active COVID-19 patients infected during the first wave in mid-2020. We observed that anti-RBD IgG and viral neutralization are significantly reduced against the Delta variant compared to the ancestral strain. In contrast, compared to the ancestral strain, T cell responses remain preserved against the delta and omicron variants. We determined innate immune responses during the early stage of active infection in response to TLR 3/7/8 mediated activation in PBMCs and serum metabolomic profiling. Correlation analysis indicated PBMCs-derived proinflammatory cytokines, IL-18, IL-1{beta}, and IL-23, and the abundance of plasma metabolites involved in arginine biosynthesis were predictive of a robust SARS-CoV-2-specific Th1 response at a later stage (two weeks after PCR positivity). These observations may contribute to designing effective vaccines and adjuvants that promote innate immune responses and metabolites to induce long-lasting anti-SARS-CoV-2 specific T cells response.

immunology↗

bioRxiv2021

Horn trophy seized in illegal wildlife trade assigned to swamp buffalo using a combined morphometric and DNA based approach in wildlife forensics in India

The illegal wildlife trade has threatened the existence of many extant wild animal species throughout the world. While dealing with the illegal wildlife trade of horns, we face problems of not having a proper protocol and lack of reference database to assign the species for proper implementation of wildlife laws. In one such condition, a horn trophy suspected to be of a wild buffalo was seized by authorities and sent to us for species identification. We used a combined approach of morphological and DNA analysis to ascertain the seized horns species. The two measurements, circumference at the base (CAB) and length on the front curve (LOFC) were measured for the seized and other horns of different bovid species, showing morphological resemblance with the seized horn. The 3-D scatter plot, generated by the values of CAB, LOFC and CAB/ LOFC, differentiated the different bovid species into distinct clusters and placed the seized horn in the proximity of domestic buffaloes. The Bayesian evolutionary analysis of the partial D-loop gene (521bp) placed the seized horn in a clade with swamp buffaloes. Since swamp buffaloes are domestic buffaloes, both these approaches concluded the same results. Hence, the current protocol developed may also be used to differentiate among wild buffalo, domestic buffalo, Cattle, Wild yak, Gaur and Takin using a combined approach of morphometric and DNA-based analysis, which may be used to deal with illegal wildlife trade of different bovid species at the world level.

zoology↗

bioRxiv2021

Fast and cost-effective age estimation in Bengal tiger and Asiatic lion: applicability of cementum analysis method

Age estimation methods, through cementum analysis, for wild animals are rarely developed in Southeast Asian Countries. In the present study, we describe the applicability of the cementum analysis technique for developing a fast ({+/-}19 hours) and cost-effective age estimation method for Bengal tiger (Panthera tigris tigris) and Asiatic lion (Panthera leo persica) using incisor tooth. The I2 and I3 incisor teeth from the right mandible of a tiger and I2 and I3 from the left maxilla of a lion were used in the study. The longitudinal sections of the tooth were made using a low cost hand grinding technique on sand papers followed by decalcification and staining with hematoxylin. The cementum layers were counted under the microscope at 100X or 200X magnifications. Two cementum layers were observed in each of the I2 and I3 incisor tooth of tiger and six cementum layers were observed in each of the I2 and I3 incisor teeth of lion. The permanent incisors in tiger and lion erupt between 12-14 months; hence, we added 1 year to the counted number of cementum layers to estimate the final age of tiger and lion incisors. The absolute age of tiger and lion incisors was estimated to be of 2+1 years and 6+1 years, respectively. The same number of cementum layers in both incisors respective to the tiger and lion were observed. Therefore, we suggest (i) undertake the blind test and (ii) collect incisor teeth from naturally died or killed individuals for strengthening the database on the age of the wild population. This optimized method may be suitable for many carnivore species, applicable in wildlife forensic studies and can be used by researchers with minimum expertise, time, and funds requirements throughout the world.

zoology↗

bioRxiv2021

Ecological memory of prior nutrient exposure in the human gut microbiome

Many ecosystems retain an ecological memory of past conditions that affects responses to future stimuli. However, it remains unknown what mechanisms and dynamics may govern such a memory in microbial communities. Here, in both a human dietary intervention cohort and an artificial gut, we show that the human gut microbiome encodes a memory of past carbohydrate exposures. Changes in the relative abundance of primary degraders were sufficient to enhance metabolism, and these changes were mediated by transcriptional changes within hours of initial exposure. We further found that ecological memory of one carbohydrate species impacted metabolism of others. These findings demonstrate that the human gut microbiomes metabolic potential reflects dietary exposures over preceding days and changes within hours of exposure to a novel nutrient. One Sentence SummaryRecent nutrient exposures are encoded into the structure and activity of human gut microbial communities, which enables more efficient future metabolic responses.

ecology↗

bioRxiv2021

Immunological and cardio-vascular pathologies associated with SARS-CoV-2 infection in golden syrian hamster

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in golden Syrian hamster (GSH) causes lung pathology and resembles human coronavirus disease (Covid-19). However, extra-pulmonary pathologies of SARS-CoV-2 infection that result in long Covid remains undefined in GSH. Here, using in silico modelling we show that hamster angiotensin-converting enzyme-2 (ACE-2) and neuropilin-1 (NRP-1) interaction with SARS-CoV-2 is similar to human. Intranasal SARS-CoV-2 infection in GSH resulted in early onset of lung pathologies marked by aggressive inflammatory response. Remarkably, late phase of SARS-CoV2 infection in GSH showed cardiovascular complications (CVC) characterized by ventricular hypertrophy, ventricular wall thickening, interstitial coronary fibrosis and altered lipidomics with elevated cholesterol, low-density lipoprotein and long chain fatty acid triglycerides. Moreover, serum metabolomics profile of infected GSH correlated with Covid19 patients. Together, we propose GSH as a suitable animal model to study immediate and long Covid19 pathologies that could be extended to therapeutics against Covid19 related CVC.

microbiology↗

bioRxiv2020

Aspergillus fumigatus versus Genus Aspergillus: Conservation, adaptive evolution and specific virulence genes

Aspergillus is an important fungal genus containing economically important species, as well as pathogenic species of animals and plants. Using eighteen fungal species of the genus Aspergillus, we conducted a comprehensive investigation of conserved genes and their evolution. This also allows to investigate the selection pressure driving the adaptive evolution in the pathogenic species A. fumigatus. Among single-copy orthologs (SCOs) for A. fumigatus and the closely related species A. fischeri, we identified 122 versus 50 positively selected genes (PSGs), respectively. Moreover, twenty conserved genes of unknown function were established to be clearly positively selected and thus important for adaption. A. fumigatus PSGs interacting with human host proteins show over-representation of adaptive, symbiosis-related, immunomodulatory, and virulence related pathways such as the TGF-{beta} pathway, insulin receptor signaling, IL1 pathway and interfering with phagosomal of GTPase signaling. Additionally, among the virulence factor coding genes, secretory and membrane protein coding genes in multi-copy gene families, 212 genes underwent positive selection and also suggest increased adaptation such as fungal immune evasion mechanisms (aspf2), siderophore biosynthesis (sidD), fumarylalanine production (sidE), stress tolerance (atfA) and thermotolerance (sodA). These genes presumably contribute to host adaptation strategies. Genes for the biosynthesis of gliotoxin are shared among all the close relatives of A. fumigatus as ancient defense mechanism. Positive selection plays a crucial role in the adaptive evolution of A. fumigatus. The genome-wide profile of PSGs provides valuable targets for further research on the mechanisms of immune evasion, for antimycotic targeting and understanding fundamental processes of virulence.

bioinformatics↗

bioRxiv2020

COVID-19 Disease Map, a computational knowledge repository of SARS-CoV-2 virus-host interaction mechanisms

We describe a large-scale community effort to build an open-access, interoperable, and computable repository of COVID-19 molecular mechanisms - the COVID-19 Disease Map. We discuss the tools, platforms, and guidelines necessary for the distributed development of its contents by a multi-faceted community of biocurators, domain experts, bioinformaticians, and computational biologists. We highlight the role of relevant databases and text mining approaches in enrichment and validation of the curated mechanisms. We describe the contents of the Map and their relevance to the molecular pathophysiology of COVID-19 and the analytical and computational modelling approaches that can be applied for mechanistic data interpretation and predictions. We conclude by demonstrating concrete applications of our work through several use cases and highlight new testable hypotheses.

systems biology↗

bioRxiv2020

Disulfiram inhibits M. tuberculosis growth by altering methionine pool, redox status and host-immune response

Methionine biosynthetic pathway, essential for the growth of Mycobacterium tuberculosis (Mtb) in the host, represents an attractive target for the development of novel anti-tuberculars. Here, we have biochemically characterized homoserine acetyl transferase (HSAT viz. MetA) of Mtb, which catalyses the first committed step of methionine and S-adenosylmethionine (SAM) biosynthesis. High-throughput screening of a 2300 compound library resulted in identification of thiram, an anti-fungal organosulfur compound, as the most potent MetA inhibitor. Further analysis of thiram analogs led to the identification of orally bioavailable disulfiram (DIS, an anti-alcoholism FDA approved drug) as a novel inhibitor of MetA. Both thiram and DIS restricted the growth of drug-sensitive and drug-resistant Mtb strains in a bactericidal manner. ThermoFlour assay demonstrated direct binding of DIS with MetA. Metabolomic and transcriptomic studies showed DIS mediated perturbation of methionine and redox homeostasis, respectively, in Mtb. In concordance, the effect of DIS on Mtb growth was partially rescued by supplementation with either L-methionine as well as N-acetyl cysteine, suggesting a multi-target killing mechanism. In Mtb-infected mice, DIS administration restricted bacterial growth, increased efficacy of isoniazid, ameliorated lung pathology, modulated lung immune cell landscape and protective immune response. Taken together, our results demonstrate that DIS can be repurposed for designing an effective anti-tubercular therapy.

microbiology↗

bioRxiv2019

Proteome-wide characterization and biomarker identification of intracranial aneurysm

The scientific basis of intracranial aneurysm (IA) formation, its rupture and further development of cerebral vasospasm remains incompletely understood. Deciphering the molecular mechanisms underlying these events will lead to identification of early detection biomarkers and in turn, improved treatment outcomes. Aberrant protein expression may drive structural alterations of vasculature found in IA. To unravel these aberrations, we performed untargeted, global, quantitative proteomic analysis of aneurysm tissue and serum from patients with IA. Samples were derived from patients of three clinical sub groups- 1) unruptured aneurysm 2) ruptured aneurysm without vasospasm 3) ruptured aneurysm who developed vasospasm. A total of 937 and 294 proteins were identified in aneurysm tissue and serum samples respectively. Several proteins that are known to maintain the structural integrity of vasculature were found to be dysregulated. ORM1, a glycoprotein, was significantly upregulated in both the aneurysm tissue and serum samples of unruptured IA patients. We employed a larger cohort of patients and validated ORM1 as a potential biomarker for screening of unruptured aneurysm using ELISA. Samples from ruptured aneurysm with vasospasm showed significant upregulation of MMP9 as compared to ruptured aneurysm without vasospasm. Using a cohort of ruptured aneurysm patients with and without vasospasm, we validated MMP9 as a potential biomarker for vasospasm. This study reveals pathophysiology underlying different clinical sub groups of IA and also suggests potential biomarkers.

neuroscience↗

bioRxiv2019

Genome-wide, integrative analysis implicates circular RNA dysregulation in autism and the corresponding circular RNA-microRNA-mRNA regulatory axes

Circular RNAs (circRNAs), a class of long non-coding RNAs, are known to be enriched in mammalian brain and neural tissues. While the effects of regulatory genetic variants on gene expression in autism spectrum disorder (ASD) have been widely reported, the role of circRNAs in ASD remains largely unknown. Here, we performed genome-wide circRNA expression profiling in post-mortem brains from individuals with ASD and controls and identified 60 circRNAs and three co-regulated modules that were perturbed in ASD. By integrating circRNA, microRNA, and mRNA dysregulation data derived from the same cortex samples, we identified 8,170 ASD-associated circRNA-microRNA-mRNA interactions. Putative targets of the axes were enriched for ASD risk genes and genes encoding inhibitory postsynaptic density (PSD) proteins, but not for genes implicated in monogenetic forms of other brain disorders or genes encoding excitatory PSD proteins. This result reflects the previous observation that ASD-derived organoids exhibit overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were indeed regulated by an upregulated circRNA (circARID1A) via sponging a downregulated microRNA (miR-204-3p) in human neuronal cells. We provided a systems-level view of landscape of circRNA regulatory networks in ASD cortex samples. We also provided multiple lines of evidence for the functional role of ASD for circRNA dysregulation and a rich set of ASD-associated circRNA candidates and the corresponding circRNA-miRNA-mRNA axes, particularly those involving ASD risk genes. Our findings thus support a role for circRNA dysregulation and the corresponding circRNA-microRNA-mRNA axes in ASD pathophysiology.

bioinformatics↗

bioRxiv2019

Genetic diversity of clinical Bordetella pertussis ST2 strains in comparison with vaccine reference strains of India

Pertussis is a highly contagious disease of the respiratory tract caused by Bordetella pertussis, a bacteria that lives in the mouth, nose, and throat. Current study reports the highly accurate complete genomes of two clinical B. pertussis strains from India for the first time. The analysis revealed insertional elements flanked by IS481, which has been previously regarded as the important component for bacterial evolution. The two B. pertussis clinical strains exhibited diversity through genome degradation when compared to whole-cell pertussis vaccine reference strains of India. These isolates harboured multiple genetic virulence traits and toxin subunits, which belonged to sequence type ST2. The genome information of Indian clinical B. pertussis strains will serve as a baseline data to decipher more information on the genome evolution, virulence factors and their role in pathogenesis for effective vaccine strategies.

microbiology↗

bioRxiv2018

Increasing Rates of Diagnosis, Substantial Co-occurrence, and Variable Treatment Patterns of Eosinophilic Gastritis, Gastroenteritis and Colitis Based on 10 Year Data Across a Multi-Center Consortium

Financial Support and AcknowledgementsSupport for this project was provided through a research training grant as part of the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) (U54 AI117804). CEGIR is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. CEGIR is also supported by patient advocacy groups including APFED CURED and EFC. This project also received support from NIH T32 DK007634 (CCR).\n\nAuthor DisclosersPatricia Fulkerson: Grant funding from the NIH; Consultant for Genentech, Inc; Research support from Knopp Biosciences, LLC.\n\nGary Falk: Research support from Shire, Celgene, Adare, Regeneron. Consulting for Shire\n\nJonathan M. Spergel: Consultant for Regeneron, DBV Technology, Kaleo; Grant funding from DBV Technology, Aimmune Therapeutics, Food Allergy Research Education; Royalties from UpToDate\n\nNirmala Gonsalves: Royalties from UpToDate; Advisory board for Allakos\n\nSandeep K Gupta: Consultant for Alkalos, Abbott, QOL, Receptos; research support from Shire\n\nGlenn Furuta: Founder of EnteroTrack; Consultant for Shire; Royalties from UpToDate\n\nMarc E. Rothenberg: Consultant for Pulm One, Spoon Guru, ClostraBio, Celgene, Shire, Astra Zeneca, GlaxoSmithKline, Allakos, Adare, Regeneron and Novartis and has an equity interest in the first four listed and Immune Pharmaceuticals, and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust) and UpToDate. M.E.R. is an inventor of patents owned by Cincinnati Childrens.\n\nEvan Dellon: Consultant for Adare, Allakos, Alivio, Banner, Celgen/Receptos, Enumeral, GSK, Regeneron, Shire; Research funding from Adare, Celegene/Receptos, Miraca, Meritage, Nutricia, Regeneron, Shire, Educational grant from Banner, Holoclara\n\nStudy HighlightsO_ST_ABSWhat is current knowledge?C_ST_ABSO_LIEosinophilic gastrointestinal disorders (EGIDs) include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), gastroenteritis (EGE), and colitis (EC).\nC_LIO_LINon-EoE EGIDs are rare with most studies limited to case reports or review of single center experiences.\nC_LIO_LIThere are no widely established guidelines for the diagnosis of EG, EGE, or EC.\nC_LI\n\nWhat is new here?O_LIIn this multicenter study, EG, EGE, and EC were all diagnosed with increasing frequency over the past decade.\nC_LIO_LIPresenting symptoms are non-specific and do not reliably distinguish between disorders.\nC_LIO_LIThere was no male predominance and the majority of subjects had atopy.\nC_LIO_LICo-occurrence of EG, EGE, and EC diagnoses is common, seen in 41% of patients.\nC_LIO_LIThere is substantial variability between centers in initial treatment approaches.\nC_LI

epidemiology↗

bioRxiv2018

sFlt-1 commutes unfolded protein response into endoplasmic reticulum stress in trophoblast cells in preeclamptic pregnancies

Preeclampsia (PE) and its subtypes (early and late onset) are serious concerns all across the globe affecting about 8% of total pregnancies and accounts for approximately 60,000 deaths annually with a predominance in developing under-developed and countries. The two-stage model in the progression of this disease, deficient spiral artery remodelling and an imbalance between angiogenic (VEGF) and anti-antigenic factor(s) (sFlt-1) are well established facts pertaining to this disease. The presence of increased sFlt-1, high oxidative stress and Endoplasmic reticulum stress (ER stress) have been proposed in preeclamptic pregnancies. Recently, the role of endoplasmic reticulum stress in the onset of the variant forms of PE highlighted a new window to explore further. In our previous studies, we demonstrated that sFlt-1 can induce apoptosis and oxidative stress in trophoblast cells. However the role of sFlt-1, in inducing ER stress is not known so far. In the present study, we for the first time demonstrated significant ER stress in the placental cells (BeWo Cells) (in vitro) when exposed to sera from preeclamptic pregnancies having increased concentration of sFlt-1. The expression of ER stress markers (GRP78, eIF2, XBP1, ATF6 and CHOP) at both transcript and protein levels were compared (between preeclamptic and normotensive non-proteinuric women) at three different time points (8h, 14h and 24hrs), analyzed and found to be significant (p<0.05).\n\nConclusionOur results suggested that sFlt-1, released from placental cells in preeclampsia may be one of the various factors having potential to induce endoplasmic reticulum stress in BeWo cells.

developmental biology↗

bioRxiv2017

sFlt-1 (sVEGFR1) induces placental endoplasmic reticulum stress in trophoblast cell: implications for the complications in preeclampsia - an in vitro study

BackgroundThe concentration of sFlt-1, a major anti-angiogenic protein in maternal circulation has been seen to be raised in preeclamptic pregnancies. Endoplasmic reticulum (ER) stress represents one of the three (immunological, oxidative and ER stress) major stresses which placenta undergoes during pregnancies. The present study is designed to investigate the role of sFlt-1 in induction of ER stress in trophoblast cells.\n\nMaterials and MethodsMaternal serum levels of anti-angiogenic protein sFlt-1 and central regulator of unfolded protein response GRP78 was measured using sandwich ELISA. The expression of various ER stress markers (GRP78, eIF2, XBP1, ATF6 and apoptotic protein CHOP) were analyzed depending on various treatments given to the trophoblast cells using Immunofluorescence, western blot and q-RT PCR.\n\nResultsIncreased expression of ER stress markers (GRP78, eIF2, XBP1 ATF6 and apoptotic protein CHOP) was detected in the placental trophoblast cells treated with raised concentration of sFlt-1.\n\nConclusionSignificant upregulated expression of ER stress markers in trophoblast cells exposed with increased concentration of sFlt-1 suggested that it may be one of the anti-angiogenic factors present in maternal sera which not only contributes to oxidative stress but also may cause endoplasmic reticulum stress.

developmental biology↗

bioRxiv2017

RNA-mediated Genomic Arrangements in Mammalian Cells

One of the hallmarks of cancer is the formation of oncogenic fusion genes as a result of chromosomal translocations. Fusion genes are presumed to occur prior to fusion RNA expression. However, studies have reported the presence of fusion RNAs in individuals who were negative for chromosomal translocations. These observations give rise to \"the cart before the horse\" hypothesis, in which fusion RNA precedes the fusion gene and guides the genomic rearrangements that ultimately result in gene fusions. Yet RNA-mediated genomic rearrangement in mammalian cells has never been demonstrated. Here we provide evidence that expression of a chimeric RNA drives formation of a specified gene fusion via genomic rearrangement in mammalian cells. The process is (1) specified by the sequence of chimeric RNA involved, (2) facilitated by physiological hormone levels, (3) permissible regardless of intra-chromosomal (TMPRSS2-ERG) or inter-chromosomal (TMPRSS2-ETV1) fusion, and (4) can occur in normal cells prior to malignant transformation. We demonstrate that, contrary to \"the cart before the horse\" model, it is the antisense rather than sense chimeric RNAs that effectively drive gene fusion, and that this disparity can be explained by transcriptional conflict. Furthermore, we identified an endogenous RNA AZI1 that acts as the initiator RNA to induce TMPRSS2-ERG fusion. RNA-driven gene fusion demonstrated in this report provides important insight in early disease mechanism, and could have fundamental implications in the biology of mammalian genome stability, as well as gene editing technology via mechanisms native to mammalian cells.

cancer biology↗