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An actionable annotation scoring framework for gas chromatography-high-resolution mass spectrometry

Koelmel, Jeremy P.; Xie, Hongyu; Price, Elliott J.; Lin, Elizabeth; Manz, Katherine E.; Stelben, Paul J.; Paige, Matthew K.; Papazian, Stefano; Okeme, Joseph; Rostkowski, Pawel Marian; Nikiforov, Vladimir; Wang, Thanh; Hu, Xin; Lai, Yunjia; Miller, Gary W.; Walker, Douglas; Martin, Jonathan W.; Pollitt, Krystal J. Godri

Omics-based technologies have enabled comprehensive characterization of our exposure to environmental chemicals (chemical exposome) as well as assessment of the corresponding biological responses at the molecular level (eg, metabolome, lipidome, proteome, and genome). By systematically measuring personal exposures and linking these stimuli to biological perturbations, researchers can determine specific chemical exposures of concern, identify mechanisms and biomarkers of toxicity, and design interventions to reduce exposures. However, further advancement of metabolomics and exposomics approaches is limited by a lack of standardization and approaches for assigning confidence to chemical annotations. While a wealth of chemical data is generated by gas chromatography high-resolution mass spectrometry (GC-HRMS), incorporating GC-HRMS data into an annotation framework and communicating confidence in these assignments is challenging. It is essential to be able to compare chemical data for exposomics studies across platforms to build upon prior knowledge and advance the technology. Here, we discuss the major pieces of evidence provided by common GC-HRMS workflows, including retention time and retention index, electron ionization, positive chemical ionization, electron capture negative ionization, and atmospheric pressure chemical ionization spectral matching, molecular ion, accurate mass, isotopic patterns, database occurrence, and occurrence in blanks. We then provide a qualitative framework for incorporating these various lines of evidence for communicating confidence in GC-HRMS data by adapting the Schymanski scoring schema developed for reporting confidence levels by liquid chromatography HRMS (LC-HRMS). Validation of our framework is presented using standards spiked in plasma, and confident annotations in outdoor and indoor air samples, showing a false-positive rate of 12% for suspect screening for chemical identifications assigned as Level 2 (when structurally similar isomers are not considered false positives). This framework is easily adaptable to various workflows and provides a concise means to communicate confidence in annotations. Further validation, refinements, and adoption of this framework will ideally lead to harmonization across the field, helping to improve the quality and interpretability of compound annotations obtained in GC-HRMS.

2022

The miniaturized enzyme-modified comet assay for genotoxicity testing of nanomaterials

El Yamani, Naouale; Rundén-Pran, Elise; Collins, Andrew Richard; Longhin, Eleonora Marta; Elje, Elisabeth; Hoet, Peter; Vrček, Ivana Vinković; Doak, Shareen H.; Fessard, Valérie; Dusinska, Maria

The in vitro comet assay is a widely applied method for investigating genotoxicity of chemicals including engineered nanomaterials (NMs). A big challenge in hazard assessment of NMs is possible interference between the NMs and reagents or read-out of the test assay, leading to a risk of biased results. Here, we describe both the standard alkaline version of the in vitro comet assay with 12 mini-gels per slide for detection of DNA strand breaks and the enzyme-modified version that allows detection of oxidized DNA bases by applying lesion-specific endonucleases (e.g., formamidopyrimidine DNA glycosylase or endonuclease III). We highlight critical points that need to be taken into consideration when assessing the genotoxicity of NMs, as well as basic methodological considerations, such as the importance of carrying out physicochemical characterization of the NMs and investigating uptake and cytotoxicity. Also, experimental design—including treatment conditions, cell number, cell culture, format and volume of medium on the plate—is crucial and can have an impact on the results, especially when testing NMs. Toxicity of NMs depends upon physicochemical properties that change depending on the environment. To facilitate testing of numerous NMs with distinct modifications, the higher throughput miniaturized version of the comet assay is essential.

Frontiers Media S.A.

2022

The NORMAN Suspect List Exchange (NORMAN-SLE): facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry

Mohammed Taha, Hiba; Aalizadeh, Reza; Alygizakis, Nikiforos; Antignac, Jean-Philippe; Arp, Hans Peter; Bade, Richard; Baker, Nancy; Belova, Lidia; Bijlsma, Lubertus; Bolton, Evan E.; Brack, Werner; Celma, Alberto; Chen, Wen-Ling; Cheng, Tiejun; Chirsir, Parviel; Čirka, Ľuboš; D’Agostino, Lisa A.; Djoumbou Feunang, Yannick; Dulio, Valeria; Fischer, Stellan; Gago-Ferrero, Pablo; Galani, Aikaterini; Geueke, Birgit; Głowacka, Natalia; Glüge, Juliane; Groh, Ksenia; Grosse, Sylvia; Haglund, Peter; Hakkinen, Pertti J.; Hale, Sarah; Hernandez, Felix; Janssen, Elisabeth M.-L.; Jonkers, Tim; Kiefer, Karin; Kirchner, Michal; Koschorreck, Jan; Krauss, Martin; Krier, Jessy; Lamoree, Marja H.; Letzel, Marion; Letzel, Thomas; Li, Qingliang; Little, James; Liu, Yanna; Lunderberg, David M.; Martin, Jonathan W.; McEachran, Andrew D.; McLean, John A.; Meier, Christiane; Meijer, Jeroen; Menger, Frank; Merino, Carla; Muncke, Jane; Muschket, Matthias; Neumann, Michael; Neveu, Vanessa; Ng, Kelsey; Oberacher, Herbert; O’Brien, Jake; Oswald, Peter; Oswaldova, Martina; Picache, Jaqueline A.; Postigo, Cristina; Ramirez, Noelia; Reemtsma, Thorsten; Renaud, Justin; Rostkowski, Pawel; Rüdel, Heinz; Salek, Reza M.; Samanipour, Saer; Scheringer, Martin; Schliebner, Ivo; Schulz, Wolfgang; Schulze, Tobias; Sengl, Manfred; Shoemaker, Benjamin A.; Sims, Kerry; Singer, Heinz; Singh, Randolph R.; Sumarah, Mark; Thiessen, Paul A.; Thomas, Kevin V; Torres, Sonia; Trier, Xenia; van Wezel, Annemarie P.; Vermeulen, Roel C. H.; Vlaanderen, Jelle J.; von der Ohe, Peter C.; Wang, Zhanyun; Williams, Antony J.; Willighagen, Egon L.; Wishart, David S.; Zhang, Jian; Thomaidis, Nikolaos S.; Hollender, Juliane; Slobodnik, Jaroslav; Schymanski, Emma L.

Background

The NORMAN Association (https://www.norman-network.com/) initiated the NORMAN Suspect List Exchange (NORMAN-SLE; https://www.norman-network.com/nds/SLE/) in 2015, following the NORMAN collaborative trial on non-target screening of environmental water samples by mass spectrometry. Since then, this exchange of information on chemicals that are expected to occur in the environment, along with the accompanying expert knowledge and references, has become a valuable knowledge base for “suspect screening” lists. The NORMAN-SLE now serves as a FAIR (Findable, Accessible, Interoperable, Reusable) chemical information resource worldwide.

Results

The NORMAN-SLE contains 99 separate suspect list collections (as of May 2022) from over 70 contributors around the world, totalling over 100,000 unique substances. The substance classes include per- and polyfluoroalkyl substances (PFAS), pharmaceuticals, pesticides, natural toxins, high production volume substances covered under the European REACH regulation (EC: 1272/2008), priority contaminants of emerging concern (CECs) and regulatory lists from NORMAN partners. Several lists focus on transformation products (TPs) and complex features detected in the environment with various levels of provenance and structural information. Each list is available for separate download. The merged, curated collection is also available as the NORMAN Substance Database (NORMAN SusDat). Both the NORMAN-SLE and NORMAN SusDat are integrated within the NORMAN Database System (NDS). The individual NORMAN-SLE lists receive digital object identifiers (DOIs) and traceable versioning via a Zenodo community (https://zenodo.org/communities/norman-sle), with a total of > 40,000 unique views, > 50,000 unique downloads and 40 citations (May 2022). NORMAN-SLE content is progressively integrated into large open chemical databases such as PubChem (https://pubchem.ncbi.nlm.nih.gov/) and the US EPA’s CompTox Chemicals Dashboard (https://comptox.epa.gov/dashboard/), enabling further access to these lists, along with the additional functionality and calculated properties these resources offer. PubChem has also integrated significant annotation content from the NORMAN-SLE, including a classification browser (https://pubchem.ncbi.nlm.nih.gov/classification/#hid=101).

Conclusions

The NORMAN-SLE offers a specialized service for hosting suspect screening lists of relevance for the environmental community in an open, FAIR manner that allows integration with other major chemical resources. These efforts foster the exchange of information between scientists and regulators, supporting the paradigm shift to the “one substance, one assessment” approach. New submissions are welcome via the contacts provided on the NORMAN-SLE website (https://www.norman-network.com/nds/SLE/).

Springer

2022

State of the Climate in 2021: 5. The Arctic

Thoman, Richard L.; Druckenmiller, Matthew L.; Moon, Twila A.; Andreassen, LM.; Baker, E.; Ballinger, Thomas J.; Berner, L.T.; Bernhard, Germar H.; Bhatt, U.S.; Bjerke, Jarle W.; Boisvert, Linette N.; Box, Jason E.; Brettschneider, B.; Burgess, D.; Butler, Amy H.; Cappelen, John; Christiansen, Hanne H.; Decharme, Bertrand; Derksen, C.; Divine, Dmitry V; Drozdov, D. S.; Elias, Chereque A.; Epstein, Howard E.; Farrell, Sinead L.; Fausto, Robert S.; Fettweis, Xavier; Fioletov, Vitali E.; Forbes, Bruce C.; Frost, Gerald V.; Gerland, Sebastian; Goetz, Scott J.; Grooß, Jens-Uwe; Haas, Christian; Hanna, Edward; Hanssen-Bauer, Inger; Heijmans, M. M. P. D.; Hendricks, Stefan; Ialongo, Iolanda; Isaksen, Ketil; Jensen, C.D.; Johnsen, Bjørn; Kaleschke, L.; Kholodov, A. L.; Kim, Seong-Joong; Kohler, Jack; Korsgaard, Niels J.; Labe, Zachary; Lakkala, Kaisa; Lara, Mark J.; Lee, Simon H.; Loomis, Bryant; Luks, B.; Luojus, K; Macander, Matthew J.; Magnússon, R. Í.; Malkova, GV; Mankoff, Kenneth D.; Manney, Gloria L.; Meier, Walter N.; Mote, Thomas; Mudryk, Lawrence; Müller, Rolf; Nyland, K. E.; Overland, James E.; Pálsson, Finnur; Park, T.; Parker, C.L.; Perovich, Don; Petty, Alek; Phoenix, Gareth K.; Pinzon, J. E.; Ricker, Robert; Romanovsky, Vladimir E.; Serbin, S. P.; Sheffield, G.; Shiklomanov, Nikolai I; Smith, Sharon L.; Stafford, K.M.; Steer, Adam; Streletskiy, Dmitry A.; Svendby, Tove Marit; Tedesco, Marco; Thomson, L.; Thorsteinsson, T; Tian-Kunze, X.; Timmermans, Mary-Louise; Tømmervik, Hans; Tschudi, Mark; Tucker, C.J.; Walker, Donald A.; Walsh, John E.; Wang, Muyin; Webster, Melinda; Wehrlé, Adrien; Winton, Øyvind; Wolken, G; Wood, K.; Wouters, B.; Yang, D.

American Meteorological Society

2022

In vivo Mammalian Alkaline Comet Assay: Method Adapted for Genotoxicity Assessment of Nanomaterials

Cardoso, Renato; Dusinska, Maria; Collins, Andrew Richard; Manjanatha, Mugamane; Pfuhler, Stefan; Registre, Marilyn; Elespuru, Rosalie K.

The in vivo Comet assay measures the generation of DNA strand breaks under conditions in which the DNA will unwind and migrate to the anode in an electrophoresis assay, producing comet-like figures. Measurements are on single cells, which allows the sampling of a diversity of cells and tissues for DNA damaging effects. The Comet assay is the most common in vivo method for genotoxicity assessment of nanomaterials (NM). The Method outlined here includes a recommended step-by-step approach, consistent with OECD 489, taking into consideration the issues impacting assessment of NM, including choice of cells or systems, handling of NM test articles, dose determination, assay methods and data assessment. This method is designed to be used along with the accompanying “Common Considerations” paper, which discusses issues common to any genotoxicity assay using NM as a test article.

Frontiers Media S.A.

2022

The alamar blue assay in the context of safety testing of nanomaterials

Longhin, Eleonora Marta; El Yamani, Naouale; Rundén-Pran, Elise; Dusinska, Maria

The Alamar Blue (AB) assay is widely used to investigate cytotoxicity, cell proliferation and cellular metabolic activity within different fields of toxicology. The use of the assay with nanomaterials (NMs) entails specific aspects including the potential interference of NMs with the test. The procedure of the AB assay applied for testing NMs is described in detail and step-by-step, from NM preparation, cell exposure, inclusion of interference controls, to the analysis and interpretation of the results. Provided that the proper procedure is followed, and relevant controls are included, the AB assay is a reliable and high throughput test to evaluate the cytotoxicity/proliferation/metabolic response of cells exposed to NMs.

Frontiers Media S.A.

2022

Occurrence of emerging brominated flame retardants and organophosphate esters in marine wildlife from the Norwegian Arctic

Lippold, Anna; Harju, Mikael; Aars, Jon; Blévin, Pierre; Bytingsvik, Jenny; Gabrielsen, Geir W.; Kovacs, Kit M.; Lyche, Jan Ludvig; Lydersen, Christian; Rikardsen, Audun H.; Routti, Heli Anna Irmeli

To understand the exposure and potential sources of emerging brominated flame retardants (EBFR) and organophosphate esters (OPEs) in marine wildlife from the Norwegian Arctic, we investigated concentrations of EBFRs in 157 tissue samples from nine species of marine vertebrates and OPEs in 34 samples from three whale species. The samples, collected from a wide range of species with contrasting areal use and diets, included blubber of blue whales, fin whales, humpback whales, white whales, killer whales, walruses and ringed seals and adipose tissue and plasma from polar bears, as well as adipose tissue from glaucous gulls. Tris(2-ethylhexyl) phosphate (TEHP) and tris(2-chloroisopropyl) phosphate (TCIPP) ranged from

Elsevier

2022

Abrupt Change in the Lower Thermospheric Mean Meridional Circulation During Sudden Stratospheric Warmings and Its Impact on Trace Species

Orsolini, Yvan J.; Zhang, Jiarong; Limpasuvan, Varavut

Based on the hourly output from the 2000–2014 simulations of the National Center for Atmospheric Research's vertically extended version of the Whole Atmosphere Community Climate Model in specified dynamics configuration, we examine the roles of planetary waves (PWs), gravity waves, and atmospheric tides in driving the mean meridional circulation (MMC) in the lower thermosphere (LT) and its response to the sudden stratospheric warming phenomenon with an elevated stratopause in the northern hemisphere. Sandwiched between the two summer-to-winter overturning circulations in the mesosphere and the upper thermosphere, the climatological LT MMC is a narrow gyre that is characterized by upwelling in the middle winter latitudes, equatorward flow near 120 km, and downwelling in the middle and high summer latitudes. Following the onset of the sudden stratospheric warmings, this gyre reverses its climatological direction, resulting in a “chimney-like” feature of un-interrupted polar descent from the altitude of 150 km down to the upper mesosphere. This reversal is driven by the westward-propagating PWs, which exert a brief but significant westward forcing between 70 and 125 km, exceeding gravity wave and tidal forcings in that altitude range. The attendant polar descent potentially leads to a short-lived enhanced transport of nitric oxide into the mesosphere (with excess in the order of 1 parts per million), while carbon dioxide is decreased.

American Geophysical Union (AGU)

2022

A Portal and IT infrastructure supporting Risk Governance of nano- and advanced materials and nano-enabled products

Bouman, Evert Alwin; Isigonis, Panagiotis; Afantitis, Antreas; Jensen, K. A.; Fransman, W.; Porcari, A.; Drobne, D.; Suarez-Merino, B.; Hristozov, D.; Pozuelo Rollón, B.; Ballesteros, A.; Rodriguez-Llopis, I.; Säämänen, A.; Bakker, M.

2022

Disentangling Aerosol and Cloud effects on Dimming and Brightening in Observations and CMIP6

Julsrud, Ingeborg Rian; Storelvmo, Trude; Schulz, Michael; Moseid, Kine Onsum; Wild, Martin

Periods of dimming and brightening have been recorded in observational datasets of surface solar radiation (SSR) between the mid-20th century and present day. Atmospheric components affect SSR, including aerosols and clouds, though studies disagree somewhat about the relative effect of each component in different regions. Current Earth system models (ESMs) are unable to simulate observed trends in SSR. This study includes an investigation into observed SSR variations between 1961 and 2014 and an evaluation of the effects of cloud cover variations and impacts of aerosol extinction, using timeseries of SSR and cloud cover from in-situ measurements. Historical simulations by 42 ESMs participating in the Coupled Model Intercomparison Project Phase 6 (CMIP6) have also been studied and compared to observations. The observational study indicates that cloud cover has had a dampening effect on the variations of SSR and that emissions of aerosol and aerosol precursors are the main cause of the general trends in observed SSR in four regions—China, Japan, Europe and the United States—during 1961-2014. The study of simulated SSR in CMIP6 yields the conclusion that current ESMs remain unable to simulate the magnitude of observed dimming and brightening in China, Japan and the United States, but that the European SSR trends between 1961 and 2014 are fairly well reproduced in the ESMs. A rough quantification of the regional surface radiation extinction efficiency of aerosol and precursor emissions in the simulations is found to agree with observed values in Europe, but not in the other three regions.

American Geophysical Union (AGU)

2022

National Mercury Assessment – An Evaluation of the Effectiveness of Norwegian Mercury Regulations and Policies

Braaten, Hans Fredrik Veiteberg; Pfaffhuber, Katrine Aspmo; Routti, Heli Anna Irmeli; Knutsen, Helle Katrine; Bank, Michael; Travnikov, Oleg; Enge, Caroline; Gundersen, Cathrine Brecke; Eckhardt, Sabine; Tørseth, Kjetil; Vejrup, Kristine; Brantsæter, Anne Lise

The National Mercury (Hg) Assessment in Norway evaluates the connections among: (a) national, regional and global Hg policies and regulations, (b) emissions, releases, uses and exposure pathways of Hg, and (c) concentrations of Hg in the environment, biota, and humans, measured during 2000-2020. Our findings suggest that the key changes of Hg in humans and the environment are highly dependent on the quality of the datasets, yet connections both to national and regional sources, as well as climate related drivers could be made for some data sets.

Norwegian Environment Agency

2022

Impact of 3D cloud structures on the atmospheric trace gas products from UV-Vis sounders - Part 2: Impact on NO2retrieval and mitigation strategies

Yu, Huan; Emde, Claudia; Kylling, Arve; Veihelmann, Ben; Mayer, Bernhard; Stebel, Kerstin; Van Roozendael, Michel

Operational retrievals of tropospheric trace gases from space-borne spectrometers are based on one-dimensional radiative transfer models. To minimize cloud effects, trace gas retrievals generally implement a simple cloud model based on radiometric cloud fraction estimates and photon path length corrections. The latter relies on measurements of the oxygen collision pair (O2–O2) absorption at 477 nm or on the oxygen A-band around 760 nm to determine an effective cloud height. In reality however, the impact of clouds is much more complex, involving unresolved sub-pixel clouds, scattering of clouds in neighbouring pixels, and cloud shadow effects, such that unresolved three-dimensional effects due to clouds may introduce significant biases in trace gas retrievals. Although clouds have significant effects on trace gas retrievals, the current cloud correction schemes are based on a simple cloud model, and the retrieved cloud parameters must be interpreted as effective values. Consequently, it is difficult to assess the accuracy of the cloud correction only based on analysis of the accuracy of the cloud retrievals, and this study focuses solely on the impact of the 3D cloud structures on the trace gas retrievals. In order to quantify this impact, we study NO2 as a trace gas example and apply standard retrieval methods including approximate cloud corrections to synthetic data generated by the state-of-the-art three-dimensional Monte Carlo radiative transfer model MYSTIC. A sensitivity study is performed for simulations including a box cloud, and the dependency on various parameters is investigated. The most significant bias is found for cloud shadow effects under polluted conditions. Biases depend strongly on cloud shadow fraction, NO2 profile, cloud optical thickness, solar zenith angle, and surface albedo. Several approaches to correct NO2 retrievals under cloud shadow conditions are explored. We find that air mass factors calculated using fitted surface albedo or corrected using the O2–O2 slant column density can partly mitigate cloud shadow effects. However, these approaches are limited to cloud-free pixels affected by surrounding clouds. A parameterization approach is presented based on relationships derived from the sensitivity study. This allows measurements to be identified for which the standard NO2 retrieval produces a significant bias and therefore provides a way to improve the current data flagging approach.

2022

Towards risk governance of nanomaterials: adaptation and validation of test methods for characterization and hazard assessment

Longhin, Eleonora Marta; Doak, Shareen H.; Lynch, Iseult; Moschini, Elisa; Rundén-Pran, Elise; El Yamani, Naouale; Bouman, Evert; Burgum, Michael J.; Reilly, Katie; Cambier, Sebastien; Gutleb, Arno C.; Cimpan, Mihaela-Roxana; Rios-Mondragon, Ivan; Xue, Ying; Cimpan, Emil; Puzyn, Tomasz; Sosnowska, Anita; Fessard, Valérie; Varet, Julie; Vinković Vrček, Ivana; Pem, Barbara; de la Fuente, Jesus Martinez; Sánchez del Castillo, Victor Manuel; Cuestas Ayllón, Carlos; Hoet, Peter; Murugadoss, Sivakumar; de Souza Nunes, Juliana; Lopez, Aitziber; Dupin, Damien; Ghahremani, MH; Gharailou, D; Badetti, Elena; Brunelli, Andrea; Isigonis, Panagiotis; Afantitis, Antreas; Melagraki, Georgia; Bohmer, Nils; Malsch, Ineke; Dusinska, Maria

2022

Genotoxicity assessment of lung cells cultured at the air-liquid interface: comparison of bronchial and alveolar mono- and cocultures

Elje, Elisabeth; McFadden, Erin; Mariussen, Espen; Dusinska, Maria; Rundén-Pran, Elise

2022

Validation of an advanced 3D respiratory tri-culture model at the air-liquid interface for hazard assessment of nanomaterials

Camassa, Laura Maria Azzurra; Elje, Elisabeth; Mariussen, Espen; Longhin, Eleonora Marta; Haugen, Kristine; Dusinska, Maria; Zienolddiny-Narui, Shan; Rundén-Pran, Elise

2022

Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression

Buociková, Verona; Tyciakova, Sylvia; Pilalis, Eleftherios; Mastrokalou, Chara; Urbanova, Maria; Matuskova, Miroslava; Demkova, Lucia; Medova, Veronika; Longhin, Eleonora Marta; Rundén-Pran, Elise; Dusinska, Maria; Rios Mondragon, Ivan; Cimpan, Mihaela-Roxana; Gábelová, Alena; Soltysova, Andrea; Smolkova, Bozena; Chatziioannou, Aristotelis

Decitabine (DAC), a DNA methyltransferase (DNMT) inhibitor, is tested in combination with conventional anticancer drugs as a treatment option for various solid tumors. Although epigenome modulation provides a promising avenue in treating resistant cancer types, more studies are required to evaluate its safety and ability to normalize the aberrant transcriptional profiles. As deoxycytidine kinase (DCK)-mediated phosphorylation is a rate-limiting step in DAC metabolic activation, we hypothesized that its intracellular overexpression could potentiate DAC’s effect on cell methylome and thus increase its therapeutic efficacy. Therefore, two breast cancer cell lines, JIMT-1 and T-47D, differing in their molecular characteristics, were transfected with a DCK expression vector and exposed to low-dose DAC (approximately IC20). Although transfection resulted in a significant DCK expression increase, further enhanced by DAC exposure, no transfection-induced changes were found at the global DNA methylation level or in cell viability. In parallel, an integrative approach was applied to decipher DAC-induced, methylation-mediated, transcriptomic reprogramming. Besides large-scale hypomethylation, accompanied by up-regulation of gene expression across the entire genome, DAC also induced hypermethylation and down-regulation of numerous genes in both cell lines. Interestingly, TET1 and TET2 expression halved in JIMT-1 cells after DAC exposure, while DNMTs’ changes were not significant. The protein digestion and absorption pathway, containing numerous collagen and solute carrier genes, ranking second among membrane transport proteins, was the top enriched pathway in both cell lines when hypomethylated and up-regulated genes were considered. Moreover, the calcium signaling pathway, playing a significant role in drug resistance, was among the top enriched in JIMT-1 cells. Although low-dose DAC demonstrated its ability to normalize the expression of tumor suppressors, several oncogenes were also up-regulated, a finding, that supports previously raised concerns regarding its broad reprogramming potential. Importantly, our research provides evidence about the involvement of active demethylation in DAC-mediated transcriptional reprogramming.

Frontiers Media S.A.

2022

Particle Precipitation Effects on the Global Secondary Ozone Distribution

Espy, Patrick Joseph; Murberg, Lise Eder; Løvset, Tiril; Orsolini, Yvan J.

2022

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