Publications by authors named "Michael Skinner"

285 Publications

Predicting environmentally responsive transgenerational differential DNA methylated regions (epimutations) in the genome using a hybrid deep-machine learning approach.

BMC Bioinformatics 2021 Nov 30;22(1):575. Epub 2021 Nov 30.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA.

Background: Deep learning is an active bioinformatics artificial intelligence field that is useful in solving many biological problems, including predicting altered epigenetics such as DNA methylation regions. Deep learning (DL) can learn an informative representation that addresses the need for defining relevant features. However, deep learning models are computationally expensive, and they require large training datasets to achieve good classification performance.

Results: One approach to addressing these challenges is to use a less complex deep learning network for feature selection and Machine Learning (ML) for classification. In the current study, we introduce a hybrid DL-ML approach that uses a deep neural network for extracting molecular features and a non-DL classifier to predict environmentally responsive transgenerational differential DNA methylated regions (DMRs), termed epimutations, based on the extracted DL-based features. Various environmental toxicant induced epigenetic transgenerational inheritance sperm epimutations were used to train the model on the rat genome DNA sequence and use the model to predict transgenerational DMRs (epimutations) across the entire genome.

Conclusion: The approach was also used to predict potential DMRs in the human genome. Experimental results show that the hybrid DL-ML approach outperforms deep learning and traditional machine learning methods.
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http://dx.doi.org/10.1186/s12859-021-04491-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630850PMC
November 2021

Role of environmentally induced epigenetic transgenerational inheritance in evolutionary biology: Unified Evolution Theory.

Environ Epigenet 2021 30;7(1):dvab012. Epub 2021 Oct 30.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA.

The current evolutionary biology theory primarily involves genetic alterations and random DNA sequence mutations to generate the phenotypic variation required for Darwinian natural selection to act. This neo-Darwinian evolution is termed the Modern Evolution Synthesis and has been the primary paradigm for nearly 100 years. Although environmental factors have a role in neo-Darwinian natural selection, Modern Evolution Synthesis does not consider environment to impact the basic molecular processes involved in evolution. An Extended Evolutionary Synthesis has recently developed that extends the modern synthesis to consider non-genetic processes. Over the past few decades, environmental epigenetics research has been demonstrated to regulate genetic processes and directly generate phenotypic variation independent of genetic sequence alterations. Therefore, the environment can on a molecular level through non-genetic (i.e. epigenetic) mechanisms directly influence phenotypic variation, genetic variation, inheritance and adaptation. This direct action of the environment to alter phenotype that is heritable is a neo-Lamarckian concept that can facilitate neo-Darwinian (i.e. Modern Synthesis) evolution. The integration of genetics, epigenetics, Darwinian theory, Lamarckian concepts, environment, and epigenetic inheritance provides a paradigm shift in evolution theory. The role of environmental-induced epigenetic transgenerational inheritance in evolution is presented to describe a more unified theory of evolutionary biology.
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http://dx.doi.org/10.1093/eep/dvab012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557805PMC
October 2021

The Impact of Transparency and Decision Risk on Human-Automation Teaming Outcomes.

Hum Factors 2021 Aug 2:187208211033445. Epub 2021 Aug 2.

2720 The University of Western Australia, Perth.

Objective: Examine the effects of decision risk and automation transparency on the accuracy and timeliness of operator decisions, automation verification rates, and subjective workload.

Background: Decision aids typically benefit performance, but can provide incorrect advice due to contextual factors, creating the potential for automation disuse or misuse. Decision aids can reduce an operator's manual problem evaluation, and it can also be strategic for operators to minimize verifying automated advice in order to manage workload.

Method: Participants assigned the optimal unmanned vehicle to complete missions. A decision aid provided advice but was not always reliable. Two levels of decision aid transparency were manipulated between participants. The risk associated with each decision was manipulated using a financial incentive scheme. Participants could use a calculator to verify automated advice; however, this resulted in a financial penalty.

Results: For high- compared with low-risk decisions, participants were more likely to reject incorrect automated advice and were more likely to verify automation and reported higher workload. Increased transparency did not lead to more accurate decisions and did not impact workload but decreased automation verification and eliminated the increased decision time associated with high decision risk.

Conclusion: Increased automation transparency was beneficial in that it decreased automation verification and decreased decision time. The increased workload and automation verification for high-risk missions is not necessarily problematic given the improved automation correct rejection rate.

Application: The findings have potential application to the design of interfaces to improve human-automation teaming, and for anticipating the impact of decision risk on operator behavior.
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http://dx.doi.org/10.1177/00187208211033445DOI Listing
August 2021

Epigenetic inheritance of DNA methylation changes in fish living in hydrogen sulfide-rich springs.

Proc Natl Acad Sci U S A 2021 06;118(26)

School of Biological Sciences, Washington State University, Pullman, WA 99163;

Environmental factors can promote phenotypic variation through alterations in the epigenome and facilitate adaptation of an organism to the environment. Although hydrogen sulfide is toxic to most organisms, the fish has adapted to survive in environments with high levels that exceed toxicity thresholds by orders of magnitude. Epigenetic changes in response to this environmental stressor were examined by assessing DNA methylation alterations in red blood cells, which are nucleated in fish. Males and females were sampled from sulfidic and nonsulfidic natural environments; individuals were also propagated for two generations in a nonsulfidic laboratory environment. We compared epimutations between the sexes as well as field and laboratory populations. For both the wild-caught (F0) and the laboratory-reared (F2) fish, comparing the sulfidic and nonsulfidic populations revealed evidence for significant differential DNA methylation regions (DMRs). More importantly, there was over 80% overlap in DMRs across generations, suggesting that the DMRs have stable generational inheritance in the absence of the sulfidic environment. This is an example of epigenetic generational stability after the removal of an environmental stressor. The DMR-associated genes were related to sulfur toxicity and metabolic processes. These findings suggest that adaptation of to sulfidic environments in southern Mexico may, in part, be promoted through epigenetic DNA methylation alterations that become stable and are inherited by subsequent generations independent of the environment.
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http://dx.doi.org/10.1073/pnas.2014929118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255783PMC
June 2021

Transcriptomic Analysis of Inbred Chicken Lines Reveals Infectious Bursal Disease Severity Is Associated with Greater Bursal Inflammation In Vivo and More Rapid Induction of Pro-Inflammatory Responses in Primary Bursal Cells Stimulated Ex Vivo.

Viruses 2021 05 18;13(5). Epub 2021 May 18.

Birnaviruses Group, The Pirbright Institute, Ash Road, Pirbright, Woking GU24 0NF, UK.

In order to better understand differences in the outcome of infectious bursal disease virus (IBDV) infection, we inoculated a very virulent (vv) strain into White Leghorn chickens of inbred line W that was previously reported to experience over 24% flock mortality, and three inbred lines (15I, C.B4 and 0) that were previously reported to display no mortality. Within each experimental group, some individuals experienced more severe disease than others but line 15I birds experienced milder disease based on average clinical scores, percentage of birds with gross pathology, average bursal lesion scores and average peak bursal virus titre. RNA-Seq analysis revealed that more severe disease in line W was associated with significant up-regulation of pathways involved in inflammation, cytoskeletal regulation by Rho GTPases, nicotinic acetylcholine receptor signaling, and Wnt signaling in the bursa compared to line 15I. Primary bursal cell populations isolated from uninfected line W birds contained a significantly greater percentage of KUL01+ macrophages than cells isolated from line 15I birds ( < 0.01) and, when stimulated ex vivo with LPS, showed more rapid up-regulation of pro-inflammatory gene expression than those from line 15I birds. We hypothesize that a more rapid induction of pro-inflammatory cytokine responses in bursal cells following IBDV infection leads to more severe disease in line W birds than in line 15I.
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http://dx.doi.org/10.3390/v13050933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157851PMC
May 2021

Differential DNA methylation in somatic and sperm cells of hatchery vs wild (natural-origin) steelhead trout populations.

Environ Epigenet 2021 19;7(1):dvab002. Epub 2021 May 19.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA.

Environmental factors such as nutrition, stress, and toxicants can influence epigenetic programming and phenotypes of a wide variety of species from plants to humans. The current study was designed to investigate the impacts of hatchery spawning and rearing on steelhead trout () vs the wild fish on a molecular level. Additionally, epigenetic differences between feeding practices that allow slow growth (2 years) and fast growth (1 year) hatchery trout were investigated. The sperm and red blood cells (RBC) from adult male slow growth/maturation hatchery steelhead, fast growth/maturation hatchery steelhead, and wild (natural-origin) steelhead were collected for DNA preparation to investigate potential alterations in differential DNA methylation regions (DMRs) and genetic mutations, involving copy number variations (CNVs). The sperm and RBC DNA both had a large number of DMRs when comparing the hatchery vs wild steelhead trout populations. The DMRs were cell type specific with negligible overlap. Slow growth/maturation compared to fast growth/maturation steelhead also had a larger number of DMRs in the RBC samples. A number of the DMRs had associated genes that were correlated to various biological processes and pathologies. Observations demonstrate a major epigenetic programming difference between the hatchery and wild natural-origin fish populations, but negligible genetic differences. Therefore, hatchery conditions and growth/maturation rate can alter the epigenetic developmental programming of the steelhead trout. Interestingly, epigenetic alterations in the sperm allow for potential epigenetic transgenerational inheritance of phenotypic variation to future generations. The impacts of hatchery exposures are not only important to consider on the fish exposed, but also on future generations and evolutionary trajectory of fish in the river populations.
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http://dx.doi.org/10.1093/eep/dvab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132314PMC
May 2021

Genome-wide CpG density and DNA methylation analysis method (MeDIP, RRBS, and WGBS) comparisons.

Epigenetics 2021 May 11:1-13. Epub 2021 May 11.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, USA.

Genome-wide DNA methylation analysis is one of the most common epigenetic processes analysed for genome characterization and differential DNA methylation assessment. Previous genome-wide analysis has suggested an important variable in DNA methylation methods involves CpG density. The current study was designed to investigate the CpG density in a variety of different species genomes and correlate this to various DNA methylation analysis data sets. The majority of all genomes had >90% of the genome in the low density 1-3 CpG/100 bp category, while <10% of the genome was in the higher density >5 CpG/100 bp category. Similar observations with human, rat, bird, and fish genomes were observed. The methylated DNA immunoprecipitation (MeDIP) procedure uses the anti-5-methylcytosine antibody immunoprecipitation followed by next-generation sequencing (MeDIP-Seq). The MeDIP procedure is biased to lower CpG density of <5 CpG/100 bp, which corresponds to >95% of the genome. The reduced representation bisulphite (RRBS) protocol generally identifies DMRs in higher CpG density regions of ≥3 CpG/100 bp which corresponds to approximately 20% of the genome. The whole-genome bisulphite (WGBS) analyses resulted in higher CpG densities, often greater than 10 CpG/100bp. WGBS generally identifies ≥2 CpG/100bp, which corresponds to approximately 50% of the genome. Limitations and potential optimization approaches for each method are discussed. None of the procedures can provide complete genome-wide assessment of the genome, but MeDIP-Seq provides coverage of the highest percentage. Observations demonstrate that CpG density is a critical variable in DNA methylation analysis, and different molecular techniques focus on distinct genomic regions.
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http://dx.doi.org/10.1080/15592294.2021.1924970DOI Listing
May 2021

Epigenetic transgenerational inheritance, gametogenesis and germline development†.

Biol Reprod 2021 09;105(3):570-592

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, USA.

One of the most important developing cell types in any biological system is the gamete (sperm and egg). The transmission of phenotypes and optimally adapted physiology to subsequent generations is in large part controlled by gametogenesis. In contrast to genetics, the environment actively regulates epigenetics to impact the physiology and phenotype of cellular and biological systems. The integration of epigenetics and genetics is critical for all developmental biology systems at the cellular and organism level. The current review is focused on the role of epigenetics during gametogenesis for both the spermatogenesis system in the male and oogenesis system in the female. The developmental stages from the initial primordial germ cell through gametogenesis to the mature sperm and egg are presented. How environmental factors can influence the epigenetics of gametogenesis to impact the epigenetic transgenerational inheritance of phenotypic and physiological change in subsequent generations is reviewed.
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http://dx.doi.org/10.1093/biolre/ioab085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444706PMC
September 2021

update.

Environ Epigenet 2021 8;7(1):dvab001. Epub 2021 Apr 8.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA.

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http://dx.doi.org/10.1093/eep/dvab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032962PMC
April 2021

Ancestral plastics exposure induces transgenerational disease-specific sperm epigenome-wide association biomarkers.

Environ Epigenet 2021 20;7(1):dvaa023. Epub 2021 Mar 20.

School of Biological Sciences, Center for Reproductive Biology, Washington State University, Pullman, WA, USA.

Plastic-derived compounds are one of the most frequent daily worldwide exposures. Previously a mixture of plastic-derived toxicants composed of bisphenol A, bis(2-ethylhexyl) phthalate, and dibutyl phthalate at low-dose exposures of a gestating female rats was found to promote the epigenetic transgenerational inheritance of disease to the offspring (F1 generation), grand-offspring (F2 generation), and great-grand-offspring (F3 generation). Epigenetic analysis of the male sperm was found to result in differential DNA methylation regions (DMRs) in the transgenerational F3 generation male sperm. The current study is distinct and was designed to use an epigenome-wide association study to identify potential sperm DNA methylation biomarkers for specific transgenerational diseases. Observations indicate disease-specific DMRs called epimutations in the transgenerational F3 generation great-grand-offspring of rats ancestrally exposed to plastics. The epigenetic DMR biomarkers were identified for testis disease, kidney disease, and multiple (≥2) diseases. These disease sperm epimutation biomarkers were found to be predominantly disease-specific. The genomic locations and features of these DMRs were identified. Interestingly, the disease-specific DMR-associated genes were previously shown to be linked with each of the specific diseases. Therefore, the germline has ancestrally derived epimutations that potentially transmit transgenerational disease susceptibilities. Epigenetic biomarkers for specific diseases could be used as diagnostics to facilitate clinical management of disease and preventative medicine.
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http://dx.doi.org/10.1093/eep/dvaa023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022921PMC
March 2021

Real-time prediction of short-timescale fluctuations in cognitive workload.

Cogn Res Princ Implic 2021 04 9;6(1):30. Epub 2021 Apr 9.

Department of Psychology, University of Tasmania, Sandy Bay, Australia.

Human operators often experience large fluctuations in cognitive workload over seconds timescales that can lead to sub-optimal performance, ranging from overload to neglect. Adaptive automation could potentially address this issue, but to do so it needs to be aware of real-time changes in operators' spare cognitive capacity, so it can provide help in times of peak demand and take advantage of troughs to elicit operator engagement. However, it is unclear whether rapid changes in task demands are reflected in similarly rapid fluctuations in spare capacity, and if so what aspects of responses to those demands are predictive of the current level of spare capacity. We used the ISO standard detection response task (DRT) to measure cognitive workload approximately every 4 s in a demanding task requiring monitoring and refueling of a fleet of simulated unmanned aerial vehicles (UAVs). We showed that the DRT provided a valid measure that can detect differences in workload due to changes in the number of UAVs. We used cross-validation to assess whether measures related to task performance immediately preceding the DRT could predict detection performance as a proxy for cognitive workload. Although the simple occurrence of task events had weak predictive ability, composite measures that tapped operators' situational awareness with respect to fuel levels were much more effective. We conclude that cognitive workload does vary rapidly as a function of recent task events, and that real-time predictive models of operators' cognitive workload provide a potential avenue for automation to adapt without an ongoing need for intrusive workload measurements.
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http://dx.doi.org/10.1186/s41235-021-00289-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035388PMC
April 2021

Chicken cGAS Senses Fowlpox Virus Infection and Regulates Macrophage Effector Functions.

Front Immunol 2020 1;11:613079. Epub 2021 Feb 1.

Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

The anti-viral immune response is dependent on the ability of infected cells to sense foreign nucleic acids. In multiple species, the pattern recognition receptor (PRR) cyclic GMP-AMP synthase (cGAS) senses viral DNA as an essential component of the innate response. cGAS initiates a range of signaling outputs that are dependent on generation of the second messenger cGAMP that binds to the adaptor protein stimulator of interferon genes (STING). Here we show that in chicken macrophages, the cGAS/STING pathway is essential not only for the production of type-I interferons in response to intracellular DNA stimulation, but also for regulation of macrophage effector functions including the expression of MHC-II and co-stimulatory molecules. In the context of fowlpox, an avian DNA virus infection, the cGAS/STING pathway was found to be responsible for type-I interferon production and MHC-II transcription. The sensing of fowlpox virus DNA is therefore essential for mounting an anti-viral response in chicken cells and for regulation of a specific set of macrophage effector functions.
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http://dx.doi.org/10.3389/fimmu.2020.613079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901977PMC
June 2021

Integration of sperm ncRNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance.

Epigenetics Chromatin 2021 Jan 12;14(1). Epub 2021 Jan 12.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA.

Background: Environmentally induced epigenetic transgenerational inheritance of pathology and phenotypic variation has been demonstrated in all organisms investigated from plants to humans. This non-genetic form of inheritance is mediated through epigenetic alterations in the sperm and/or egg to subsequent generations. Although the combined regulation of differential DNA methylated regions (DMR), non-coding RNA (ncRNA), and differential histone retention (DHR) have been shown to occur, the integration of these different epigenetic processes remains to be elucidated. The current study was designed to examine the integration of the different epigenetic processes.

Results: A rat model of transiently exposed F0 generation gestating females to the agricultural fungicide vinclozolin or pesticide DDT (dichloro-diphenyl-trichloroethane) was used to acquire the sperm from adult males in the subsequent F1 generation offspring, F2 generation grand offspring, and F3 generation great-grand offspring. The F1 generation sperm ncRNA had substantial overlap with the F1, F2 and F3 generation DMRs, suggesting a potential role for RNA-directed DNA methylation. The DMRs also had significant overlap with the DHRs, suggesting potential DNA methylation-directed histone retention. In addition, a high percentage of DMRs induced in the F1 generation sperm were maintained in subsequent generations.

Conclusions: Many of the DMRs, ncRNA, and DHRs were colocalized to the same chromosomal location regions. Observations suggest an integration of DMRs, ncRNA, and DHRs in part involve RNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance.
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http://dx.doi.org/10.1186/s13072-020-00378-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802319PMC
January 2021

Sperm DNA methylation epimutation biomarker for paternal offspring autism susceptibility.

Clin Epigenetics 2021 01 7;13(1). Epub 2021 Jan 7.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA.

Background: Autism spectrum disorder (ASD) has increased over tenfold over the past several decades and appears predominantly associated with paternal transmission. Although genetics is anticipated to be a component of ASD etiology, environmental epigenetics is now also thought to be an important factor. Epigenetic alterations, such as DNA methylation, have been correlated with ASD. The current study was designed to identify a DNA methylation signature in sperm as a potential biomarker to identify paternal offspring autism susceptibility.

Methods And Results: Sperm samples were obtained from fathers that have children with or without autism, and the sperm then assessed for alterations in DNA methylation. A genome-wide analysis (> 90%) for differential DNA methylation regions (DMRs) was used to identify DMRs in the sperm of fathers (n = 13) with autistic children in comparison with those (n = 13) without ASD children. The 805 DMR genomic features such as chromosomal location, CpG density and length of the DMRs were characterized. Genes associated with the DMRs were identified and found to be linked to previously known ASD genes, as well as other neurobiology-related genes. The potential sperm DMR biomarkers/diagnostic was validated with blinded test sets (n = 8-10) of individuals with an approximately 90% accuracy.

Conclusions: Observations demonstrate a highly significant set of 805 DMRs in sperm that can potentially act as a biomarker for paternal offspring autism susceptibility. Ancestral or early-life paternal exposures that alter germline epigenetics are anticipated to be a molecular component of ASD etiology.
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http://dx.doi.org/10.1186/s13148-020-00995-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789568PMC
January 2021

Epigenome-wide association study (EWAS) for potential transgenerational disease epigenetic biomarkers in sperm following ancestral exposure to the pesticide methoxychlor.

Environ Epigenet 2020 22;6(1):dvaa020. Epub 2020 Dec 22.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA.

Environmental exposures such as chemical toxicants can alter gene expression and disease susceptibility through epigenetic processes. Epigenetic changes can be passed to future generations through germ cells through epigenetic transgenerational inheritance of increased disease susceptibility. The current study used an epigenome-wide association study (EWAS) to investigate whether specific transgenerational epigenetic signatures of differential DNA methylation regions (DMRs) exist that are associated with particular disease states in the F3 generation great-grand offspring of F0 generation rats exposed during gestation to the agricultural pesticide methoxychlor. The transgenerational epigenetic profiles of sperm from F3 generation methoxychlor lineage rats that have only one disease state were compared to those that have no disease. Observations identify disease specific patterns of DMRs for these transgenerational rats that can potentially serve as epigenetic biomarkers for prostate disease, kidney disease, obesity, and the presence of multiple diseases. The chromosomal locations, genomic features, and gene associations of the DMRs are characterized. Disease specific DMR sets contained DMR-associated genes that have previously been shown to be associated with that specific disease. Future epigenetic biomarkers could potentially be developed and validated for humans as a disease susceptibility diagnostic tool to facilitate preventative medicine and management of disease.
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http://dx.doi.org/10.1093/eep/dvaa020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757123PMC
December 2020

Modulation of Early Host Innate Immune Response by an Avipox Vaccine Virus' Lateral Body Protein.

Biomedicines 2020 Dec 19;8(12). Epub 2020 Dec 19.

Section of Virology, School of Medicine, St Mary's Campus, Imperial College, London W2 1PG, UK.

The avian pathogen fowlpox virus (FWPV) has been successfully used as a vaccine vector in poultry and humans, but relatively little is known about its ability to modulate host antiviral immune responses in these hosts, which are replication-permissive and nonpermissive, respectively. FWPV is highly resistant to avian type I interferon (IFN) and able to completely block the host IFN-response. Microarray screening of host IFN-regulated gene expression in cells infected with 59 different, nonessential FWPV gene knockout mutants revealed that FPV184 confers immunomodulatory capacity. We report that the -knockout virus (FWPVΔ184) induces the cellular IFN response as early as 2 h postinfection. The wild-type, uninduced phenotype can be rescued by transient expression of in FWPVΔ184-infected cells. Ectopic expression of inhibited polyI:C activation of the chicken IFN-β promoter and IFN-α activation of the chicken Mx1 promoter. Confocal and correlative super-resolution light and electron microscopy demonstrated that FPV184 has a functional nuclear localisation signal domain and is packaged in the lateral bodies of the virions. Taken together, these results provide a paradigm for a late poxvirus structural protein packaged in the lateral bodies, capable of suppressing IFN induction early during the next round of infection.
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http://dx.doi.org/10.3390/biomedicines8120634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766033PMC
December 2020

Epigenome-wide association study for atrazine induced transgenerational DNA methylation and histone retention sperm epigenetic biomarkers for disease.

PLoS One 2020 16;15(12):e0239380. Epub 2020 Dec 16.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America.

Atrazine is a common agricultural herbicide previously shown to promote epigenetic transgenerational inheritance of disease to subsequent generations. The current study was designed as an epigenome-wide association study (EWAS) to identify transgenerational sperm disease associated differential DNA methylation regions (DMRs) and differential histone retention regions (DHRs). Gestating female F0 generation rats were transiently exposed to atrazine during the period of embryonic gonadal sex determination, and then subsequent F1, F2, and F3 generations obtained in the absence of any continued exposure. The transgenerational F3 generation males were assessed for disease and sperm collected for epigenetic analysis. Pathology was observed in pubertal onset and for testis disease, prostate disease, kidney disease, lean pathology, and multiple disease. For these pathologies, sufficient numbers of individual males with only a single specific disease were identified. The sperm DNA and chromatin were isolated from adult one-year animals with the specific diseases and analyzed for DMRs with methylated DNA immunoprecipitation (MeDIP) sequencing and DHRs with histone chromatin immunoprecipitation (ChIP) sequencing. Transgenerational F3 generation males with or without disease were compared to identify the disease specific epimutation biomarkers. All pathologies were found to have disease specific DMRs and DHRs which were found to predominantly be distinct for each disease. No common DMRs or DHRs were found among all the pathologies. Epimutation gene associations were identified and found to correlate to previously known disease linked genes. This is one of the first observations of potential sperm disease biomarkers for histone retention sites. Although further studies with expanded animal numbers are required, the current study provides evidence the EWAS analysis is effective for the identification of potential pathology epimutation biomarkers for disease susceptibility.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239380PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743986PMC
January 2021

Epigenome-wide association study for glyphosate induced transgenerational sperm DNA methylation and histone retention epigenetic biomarkers for disease.

Epigenetics 2021 Oct 9;16(10):1150-1167. Epub 2020 Dec 9.

Center for Reproductive Biology School of Biological Sciences, Washington State University, Pullman, WA, USA.

The herbicide glyphosate has been shown to promote the epigenetic transgenerational inheritance of pathology and disease in subsequent great-grand offspring (F3 generation). This generational toxicology suggests the impacts of environmental exposures need to assess subsequent generations. The current study was designed to identify epigenetic biomarkers for glyphosate-induced transgenerational diseases using an epigenome-wide association study (EWAS). Following transient glyphosate exposure of gestating female rats (F0 generation), during the developmental period of gonadal sex determination, the subsequent transgenerational F3 generation, with no direct exposure, were aged to 1 year and animals with specific pathologies identified. The pathologies investigated included prostate disease, kidney disease, obesity, and presence of multiple disease. The sperm were collected from the glyphosate lineage males with only an individual disease and used to identify specific differential DNA methylation regions (DMRs) and the differential histone retention sites (DHRs) associated with that pathology. Unique signatures of DMRs and DHRs for each pathology were identified for the specific diseases. Interestingly, at a lower statistical threshold overlapping sets of DMRs and DHRs were identified that were common for all the pathologies. This is one of the first observations that sperm histone retention can potentially act as a biomarker for specific diseases. The DMR and DHR associated genes were identified and correlated with known pathology specific-associated genes. Observations indicate transgenerational epigenetic biomarkers of disease pathology can be identified in the sperm that appear to assess disease susceptibility. These biomarkers suggest epigenetic diagnostics could potentially be used to facilitate preventative medicine.
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http://dx.doi.org/10.1080/15592294.2020.1853319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510602PMC
October 2021

Environmentally Induced Epigenetic Transgenerational Inheritance and the Weismann Barrier: The Dawn of Neo-Lamarckian Theory.

J Dev Biol 2020 Dec 4;8(4). Epub 2020 Dec 4.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA.

For the past 120 years, the Weismann barrier and associated germ plasm theory of heredity have been a doctrine that has impacted evolutionary biology and our concepts of inheritance through the germline. Although August Weismann in his 1872 book was correct that the sperm and egg were the only cells to transmit molecular information to the subsequent generation, the concept that somatic cells do not impact the germline (i.e., the Weismann barrier) is incorrect. However, the doctrine or dogma of the Weismann barrier still influences many scientific fields and topics. The discovery of epigenetics, and more recently environmentally induced epigenetic transgenerational inheritance of phenotypic variation and pathology, have had significant impacts on evolution theory and medicine today. Environmental epigenetics and the concept of epigenetic transgenerational inheritance refute aspects of the Weismann barrier and require a re-evaluation of both inheritance theory and evolution theory.
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http://dx.doi.org/10.3390/jdb8040028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768451PMC
December 2020

Bulky granulomatous disease resulting in constrictive tuberculous pericarditis requiring pericardiectomy: a case report.

Eur Heart J Case Rep 2020 Oct 27;4(5):1-6. Epub 2020 Sep 27.

Department of Cardiology, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145, Australia.

Background : We present a 23-year-old Nepalese migrant with mycobacterial tuberculosis (TB) pericarditis manifesting as effusive constrictive disease and subsequent rapid progression to constrictive pericarditis resulting from bulky granulomatous disease.

Case Summary : Following initial presumptive diagnosis of TB pericarditis based on presence of moderate pericardial effusion and positive polymerase chain reaction on concurrent pleural aspirate, the patient was managed with standard empiric therapy. Despite treatment, he developed progressive heart failure with New York Heart Association (NYHA) class III symptoms and had confirmation of constrictive physiology on simultaneous left and right heart catheterization. He underwent pericardiectomy 4 months after his initial diagnosis, with debridement of large necrotizing granulomas and an associated immediate improvement clinical improvement. He remains well at 6-month follow-up with no residual heart failure symptoms off diuretic therapy.

Discussion : Tuberculous pericarditis accounts for 1-2% of presentations with TB infection, with progression to constrictive pericarditis in between 17 and 40% of cases. To date, pericardiectomy remains mainstay of treatment for constriction, albeit with high perioperative risk. In combination with anti-tuberculous therapy, prednisone and pericardiocentesis may reduce risk of progression to constriction, however, neither have shown mortality benefit. Our patient continued to progress, despite medical therapy and proceeded to pericardiectomy only 4 months after his initial diagnosis, with rapid improvement in symptoms, demonstrating the importance of close monitoring and revision of management strategy in these patients.
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http://dx.doi.org/10.1093/ehjcr/ytaa208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649499PMC
October 2020

Epigenome-wide association study for pesticide (Permethrin and DEET) induced DNA methylation epimutation biomarkers for specific transgenerational disease.

Environ Health 2020 11 4;19(1):109. Epub 2020 Nov 4.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA.

Background: Permethrin and N,N-diethyl-meta-toluamide (DEET) are the pesticides and insect repellent most commonly used by humans. These pesticides have been shown to promote the epigenetic transgenerational inheritance of disease in rats. The current study was designed as an epigenome-wide association study (EWAS) to identify potential sperm DNA methylation epimutation biomarkers for specific transgenerational disease.

Methods: Outbred Sprague Dawley gestating female rats (F0) were transiently exposed during fetal gonadal sex determination to the pesticide combination including Permethrin and DEET. The F3 generation great-grand offspring within the pesticide lineage were aged to 1 year. The transgenerational adult male rat sperm were collected from individuals with single and multiple diseases and compared to non-diseased animals to identify differential DNA methylation regions (DMRs) as biomarkers for specific transgenerational disease.

Results: The exposure of gestating female rats to a permethrin and DEET pesticide combination promoted transgenerational testis disease, prostate disease, kidney disease, and the presence of multiple disease in the subsequent F3 generation great-grand offspring. The disease DMRs were found to be disease specific with negligible overlap between different diseases. The genomic features of CpG density, DMR length, and chromosomal locations of the disease specific DMRs were investigated. Interestingly, the majority of the disease specific sperm DMR associated genes have been previously found to be linked to relevant disease specific genes.

Conclusions: Observations demonstrate the EWAS approach identified disease specific biomarkers that can be potentially used to assess transgenerational disease susceptibility and facilitate the clinical management of environmentally induced pathology.
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http://dx.doi.org/10.1186/s12940-020-00666-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643320PMC
November 2020

Transgenerational disease specific epigenetic sperm biomarkers after ancestral exposure to dioxin.

Environ Res 2021 01 8;192:110279. Epub 2020 Oct 8.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA. Electronic address:

Dioxin was historically one of the most common industrial contaminants with several major industry accidents, as well as governmental actions involving military service, having exposed large numbers of the worldwide population over the past century. Previous rat studies have demonstrated the ability of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)) exposure to promote the epigenetic transgenerational inheritance of disease susceptibility in subsequent generations. The types of disease previously observed include puberty abnormalities, testis, ovary, kidney, prostate and obesity pathologies. The current study was designed to use an epigenome-wide association study (EWAS) to identify potential sperm DNA methylation biomarkers for specific transgenerational diseases. Therefore, the transgenerational F3 generation dioxin lineage male rats with and without a specific disease were compared to identify differential DNA methylation regions (DMRs) as biomarkers for disease. The genomic features of the disease-specific DMRs were characterized. Observations demonstrate that disease-specific epimutation DMRs exist for the transgenerational dioxin lineage rats that can potentially be used as epigenetic biomarkers for testis, kidney, prostate and obesity diseases. These disease-specific DMRs were associated with genes that have previously been shown to be linked with the specific diseases. This EWAS for transgenerational disease identified potential epigenetic biomarkers and provides the proof of concept of the potential to develop similar biomarkers for humans to diagnose disease susceptibilities and facilitate preventative medicine.
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http://dx.doi.org/10.1016/j.envres.2020.110279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130889PMC
January 2021

Effect of automation transparency in the management of multiple unmanned vehicles.

Appl Ergon 2021 Jan 9;90:103243. Epub 2020 Sep 9.

The University of Western Australia, 35 Stirling Highway, Perth WA, 6009, Australia. Electronic address:

Automated decision aids can undoubtedly benefit system performance, but have the potential to provide incorrect advice, creating the possibility for automation disuse or misuse. This paper examined the extent to which increased automation transparency could improve the accuracy of automation use in a simulation of unmanned vehicle control. Participants were required to assign the best unmanned vehicle to complete missions. An automated recommender system provided advice but was not always reliable. Three levels of automation transparency were manipulated between-participants. Providing transparency regarding the reasoning underlying automated recommendations improved the accuracy of automation use, with no cost to decision time or subjective workload. Higher transparency in the form of projected decision outcome visualizations led to faster decisions, but less accurate automation use and an automation bias. Implications for the design of transparent interfaces to improve human-autonomy teaming outcomes in time-pressured environments are discussed.
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http://dx.doi.org/10.1016/j.apergo.2020.103243DOI Listing
January 2021

Epigenome-wide association study for transgenerational disease sperm epimutation biomarkers following ancestral exposure to jet fuel hydrocarbons.

Reprod Toxicol 2020 12 6;98:61-74. Epub 2020 Sep 6.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA. Electronic address:

Jet fuel hydrocarbons is the generic name for aviation fuels used in gas-turbine engine powered aircraft. The Deepwater Horizon oil rig explosion created the largest environmental disaster in U.S. history, and the second largest oil spill in human history with over 800 million liters of hydrocarbons released into the Gulf of Mexico over a period of 3 months. Due to the widespread use of jet fuel hydrocarbons, this compound mixture has been recognized as the single largest chemical exposure for military personnel. Previous animal studies have demonstrated the ability of jet fuel (JP-8) exposure to promote the epigenetic transgenerational inheritance of disease susceptibility in subsequent generations. The diseases observed include late puberty, kidney, obesity and multiple disease pathologies. The current study is distinct and was designed to identify potential sperm DNA methylation biomarkers for specific transgenerational diseases. Observations show disease specific differential DNA methylation regions (DMRs) called epimutations in the transgenerational F3 generation great-grand-offspring male rats ancestrally exposed to jet fuel. The potential epigenetic DMR biomarkers were identified for late puberty, kidney, obesity, and multiple diseases, and found to be predominantly disease specific. These disease specific DMRs have associated genes that were previously shown to be linked with each of these specific diseases. Therefore, the germline (i.e. sperm) has environmentally induced ancestrally derived epimutations that have the potential to transgenerationally transmit disease susceptibilities to subsequent generations. Epigenetic biomarkers for specific diseases could be developed as medical diagnostics to facilitate clinical management of disease, and allow preventative medicine therapeutics.
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http://dx.doi.org/10.1016/j.reprotox.2020.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736201PMC
December 2020

Between-Generation Phenotypic and Epigenetic Stability in a Clonal Snail.

Genome Biol Evol 2020 09;12(9):1604-1615

School of Biological Sciences, Center for Reproductive Biology, Washington State University.

Epigenetic variation might play an important role in generating adaptive phenotypes by underpinning within-generation developmental plasticity, persistent parental effects of the environment (e.g., transgenerational plasticity), or heritable epigenetically based polymorphism. These adaptive mechanisms should be most critical in organisms where genetic sources of variation are limited. Using a clonally reproducing freshwater snail (Potamopyrgus antipodarum), we examined the stability of an adaptive phenotype (shell shape) and of DNA methylation between generations. First, we raised three generations of snails adapted to river currents in the lab without current. We showed that habitat-specific adaptive shell shape was relatively stable across three generations but shifted slightly over generations two and three toward a no-current lake phenotype. We also showed that DNA methylation specific to high-current environments was stable across one generation. This study provides the first evidence of stability of DNA methylation patterns across one generation in an asexual animal. Together, our observations are consistent with the hypothesis that adaptive shell shape variation is at least in part determined by transgenerational plasticity, and that DNA methylation provides a potential mechanism for stability of shell shape across one generation.
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http://dx.doi.org/10.1093/gbe/evaa181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513791PMC
September 2020

Neural Networks to Predict Radiographic Brain Injury in Pediatric Patients Treated with Extracorporeal Membrane Oxygenation.

J Clin Med 2020 Aug 22;9(9). Epub 2020 Aug 22.

Children's Health Dallas, Dallas, TX 75201, USA.

Brain injury is a significant source of morbidity and mortality for pediatric patients treated with Extracorporeal Membrane Oxygenation (ECMO). Our objective was to utilize neural networks to predict radiographic evidence of brain injury in pediatric ECMO-supported patients and identify specific variables that can be explored for future research. Data from 174 ECMO-supported patients were collected up to 24 h prior to, and for the duration of, the ECMO course. Thirty-five variables were collected, including physiological data, markers of end-organ perfusion, acid-base homeostasis, vasoactive infusions, markers of coagulation, and ECMO-machine factors. The primary outcome was the presence of radiologic evidence of moderate to severe brain injury as established by brain CT or MRI. This information was analyzed by a neural network, and results were compared to a logistic regression model as well as clinician judgement. The neural network model was able to predict brain injury with an Area Under the Curve (AUC) of 0.76, 73% sensitivity, and 80% specificity. Logistic regression had 62% sensitivity and 61% specificity. Clinician judgment had 39% sensitivity and 69% specificity. Sequential feature group masking demonstrated a relatively greater contribution of physiological data and minor contribution of coagulation factors to the model's performance. These findings lay the foundation for further areas of research directions.
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http://dx.doi.org/10.3390/jcm9092718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565544PMC
August 2020

Genome-Wide Mapping of DNA Methylation 5mC by Methylated DNA Immunoprecipitation (MeDIP)-Sequencing.

Methods Mol Biol 2021 ;2198:301-310

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, USA.

Methylated DNA immunoprecipitation is a large scale purification technique. It enables the isolation of methylated DNA fragments for subsequent locus-specific or genome-wide analysis. Here we describe an immunoprecipitation protocol using a monoclonal mouse anti 5-methyl-cytidine antibody followed by next-generation sequencing (MeDIP-Seq).
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http://dx.doi.org/10.1007/978-1-0716-0876-0_23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285090PMC
March 2021

Developmental origins of transgenerational sperm histone retention following ancestral exposures.

Dev Biol 2020 09 3;465(1):31-45. Epub 2020 Jul 3.

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA. Electronic address:

Numerous environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. Alterations in the germline epigenome are necessary to transmit transgenerational phenotypes. In previous studies, the pesticide DDT (dichlorodiphenyltrichloroethane) and the agricultural fungicide vinclozolin were shown to promote the transgenerational inheritance of sperm differential DNA methylation regions, non-coding RNAs and histone retention, which are termed epimutations. These epimutations are able to mediate this epigenetic inheritance of disease and phenotypic variation. The current study was designed to investigate the developmental origins of the transgenerational differential histone retention sites (called DHRs) during gametogenesis of the sperm. Vinclozolin and DDT were independently used to promote the epigenetic transgenerational inheritance of these DHRs. Male control lineage, DDT lineage and vinclozolin lineage F3 generation rats were used to isolate round spermatids, caput epididymal spermatozoa, and caudal sperm. The DHRs distinguishing the control versus DDT lineage or vinclozolin lineage samples were determined at these three developmental stages. DHRs and a reproducible core of histone H3 retention sites were observed using an H3 chromatin immunoprecipitation-sequencing (ChIP-Seq) analysis in each of the germ cell populations. The chromosomal locations and genomic features of the DHRs were analyzed. A cascade of epigenetic histone retention site alterations was found to be initiated in the round spermatids and then further modified during epididymal sperm maturation. Observations show that in addition to alterations in sperm DNA methylation and ncRNA expression previously identified, the induction of differential histone retention sites (DHRs) in the later stages of spermatogenesis also occurs. This novel component of epigenetic programming during spermatogenesis can be environmentally altered and transmitted to subsequent generations through epigenetic transgenerational inheritance.
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http://dx.doi.org/10.1016/j.ydbio.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484192PMC
September 2020

The Stronger Downregulation of and Innate Antiviral Responses by a Very Virulent Strain of Infectious Bursal Disease Virus (IBDV), Compared to a Classical Strain, Is Mediated, in Part, by the VP4 Protein.

Front Cell Infect Microbiol 2020 9;10:315. Epub 2020 Jun 9.

Birnaviruses Group, The Pirbright Institute, Woking, United Kingdom.

IBDV is economically important to the poultry industry. Very virulent (vv) strains cause higher mortality rates than other strains for reasons that remain poorly understood. In order to provide more information on IBDV disease outcome, groups of chickens ( = 18) were inoculated with the vv strain, UK661, or the classical strain, F52/70. Birds infected with UK661 had a lower survival rate (50%) compared to F52/70 (80%). There was no difference in peak viral replication in the bursa of Fabricius (BF), but the expression of chicken IFNα, IFNβ, MX1, and IL-8 was significantly lower in the BF of birds infected with UK661 compared to F52/70 ( < 0.05) as quantified by RTqPCR, and this trend was also observed in DT40 cells infected with UK661 or F52/70 ( < 0.05). The induction of expression of type I IFN in DF-1 cells stimulated with polyI:C (measured by an IFN-β luciferase reporter assay) was significantly reduced in cells expressing ectopic VP4 from UK661 ( < 0.05), but was higher in cells expressing ectopic VP4 from F52/70. Cells infected with a chimeric recombinant IBDV carrying the UK661-VP4 gene in the background of PBG98, an attenuated vaccine strain that induces high levels of innate responses (PBG98-VP4) also showed a reduced level of IFNα and IL-8 compared to cells infected with a chimeric virus carrying the F52/70-VP4 gene (PBG98-VP4) ( < 0.01), and birds infected with PBG98-VP4 also had a reduced expression of IFNα in the BF compared to birds infected with PBG98-VP4 ( < 0.05). Taken together, these data demonstrate that UK661 induced the expression of lower levels of anti-viral type I IFN and proinflammatory genes than the classical strain and and this was, in part, due to strain-dependent differences in the VP4 protein.
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http://dx.doi.org/10.3389/fcimb.2020.00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296162PMC
June 2021
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