@article{cero_house_verdi_ferguson_jima_selmek_patania_dwyer_wei_lloyd_et al._2024, title={Profiling the cancer-prone microenvironment in a zebrafish model for MPNST}, volume={11}, ISSN={["1476-5594"]}, url={https://doi.org/10.1038/s41388-024-03210-1}, DOI={10.1038/s41388-024-03210-1}, abstractNote={Microenvironmental contributions to soft tissue sarcoma progression are relatively undefined, particularly during sarcoma onset. Use of animal models to reveal these contributions is impeded by difficulties in discriminating between microenvironmental, precancerous, and cancer cells, and challenges in defining a precancerous microenvironment. We developed a zebrafish model that allows segregation of microenvironmental, precancerous, and cancerous cell populations by fluorescence-activated cell sorting. This model has high predilection for malignant peripheral nerve sheath tumor (MPNST), a type of soft tissue sarcoma that exhibits rapid, aggressive growth. Using RNA-seq, we profiled the transcriptomes of microenvironmental, precancerous, and cancer cells from our zebrafish MPNST model. We show broad activation of inflammation/immune-associated signaling networks, describe gene expression patterns that uniquely characterize the transition from precancerous to cancer ME, and identify macrophages as potential contributors to microenvironmental phenotypes. We identify conserved gene expression changes and candidate genes of interest by comparative genomics analysis of MPNST versus benign lesions in both humans and zebrafish. Finally, we functionally validate a candidate extracellular matrix protein, periostin (POSTN), in human MPNST. This work provides insight into how the microenvironment may regulate MPNST initiation and progression.}, journal={ONCOGENE}, author={Cero, Cheryl and House, John S. and Verdi, Vincenzo and Ferguson, Jordan L. and Jima, Dereje D. and Selmek, Aubrie A. and Patania, Olivia M. and Dwyer, Jennifer E. and Wei, Bih-Rong and Lloyd, Dillon T. and et al.}, year={2024}, month={Nov} }
 @article{wang_lloyd_zhao_motsinger-reif_2024, title={Taxanorm: a novel taxa-specific normalization approach for microbiome data}, volume={25}, ISSN={["1471-2105"]}, DOI={10.1186/s12859-024-05918-z}, abstractNote={In high-throughput sequencing studies, sequencing depth, which quantifies the total number of reads, varies across samples. Unequal sequencing depth can obscure true biological signals of interest and prevent direct comparisons between samples. To remove variability due to differential sequencing depth, taxa counts are usually normalized before downstream analysis. However, most existing normalization methods scale counts using size factors that are sample specific but not taxa specific, which can result in over- or under-correction for some taxa.}, number={1}, journal={BMC BIOINFORMATICS}, author={Wang, Ziyue and Lloyd, Dillon and Zhao, Shanshan and Motsinger-Reif, Alison}, year={2024}, month={Sep} }
 @article{cordova_dodds_tsai_lloyd_roman-hubers_wright_chiu_mcdonald_zhu_newman_et al._2023, title={Application of Ion Mobility Spectrometry-Mass Spectrometry for Compositional Characterization and Fingerprinting of a Library of Diverse Crude Oil Samples}, ISSN={["1552-8618"]}, DOI={10.1002/etc.5727}, abstractNote={Exposure characterization of crude oils, especially in time-sensitive circumstances such as spills and disasters, is a well-known analytical chemistry challenge. Gas chromatography-mass spectrometry is commonly used for "fingerprinting" and origin tracing in oil spills; however, this method is both time-consuming and lacks the resolving power to separate co-eluting compounds. Recent advances in methodologies to analyze petroleum substances using high-resolution analytical techniques have demonstrated both improved resolving power and higher throughput. One such method, ion mobility spectrometry-mass spectrometry (IMS-MS), is especially promising because it is both rapid and high-throughput, with the ability to discern among highly homologous hydrocarbon molecules. Previous applications of IMS-MS to crude oil analyses included a limited number of samples and did not provide detailed characterization of chemical constituents. We analyzed a diverse library of 195 crude oil samples using IMS-MS and applied a computational workflow to assign molecular formulas to individual features. The oils were from 12 groups based on geographical and geological origins: non-US (1 group), US onshore (3), and US Gulf of Mexico offshore (8). We hypothesized that information acquired through IMS-MS data would provide a more confident grouping and yield additional fingerprint information. Chemical composition data from IMS-MS was used for unsupervised hierarchical clustering, as well as machine learning-based supervised analysis to predict geographic and source rock categories for each sample; the latter also yielded several novel prospective biomarkers for fingerprinting of crude oils. We found that IMS-MS data have complementary advantages for fingerprinting and characterization of diverse crude oils and that proposed polycyclic aromatic hydrocarbon biomarkers can be used for rapid exposure characterization. Environ Toxicol Chem 2023;42:2336-2349. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.}, journal={ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY}, author={Cordova, Alexandra C. and Dodds, James N. and Tsai, Han-Hsuan D. and Lloyd, Dillon T. and Roman-Hubers, Alina T. and Wright, Fred A. and Chiu, Weihsueh A. and McDonald, Thomas J. and Zhu, Rui and Newman, Galen and et al.}, year={2023}, month={Aug} }
 @article{lloyd_skinner_maguire_murphy_motsinger-reif_hoyo_house_2022, title={Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions}, volume={23}, ISSN={["1422-0067"]}, url={https://doi.org/10.3390/ijms231810450}, DOI={10.3390/ijms231810450}, abstractNote={Children conceived with assisted reproductive technology (ART) have an increased risk of adverse outcomes, including congenital malformations and imprinted gene disorders. In a retrospective North Carolina-based-birth-cohort, we examined the effect of ovulation drugs and ART on CpG methylation in differentially methylated CpGs in known imprint control regions (ICRs). Nine ICRs containing 48 CpGs were assessed for methylation status by pyrosequencing in mixed leukocytes from cord blood. After restricting to non-smoking, college-educated participants who agreed to follow-up, ART-exposed (n = 27), clomifene-only-exposed (n = 22), and non-exposed (n = 516) groups were defined. Associations of clomifene and ART with ICR CpG methylation were assessed with linear regression and stratifying by offspring sex. In males, ART was associated with hypomethylation of the PEG3 ICR [β(95% CI) = −1.46 (−2.81, −0.12)] and hypermethylation of the MEG3 ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the NNAT ICR [−5.25 (−10.12, −0.38)]. In female offspring, ART was associated with hypomethylation of the IGF2 ICR [−3.67 (−6.79, −0.55)]. Aberrant methylation of these ICRs has been associated with cardiovascular disease and metabolic and behavioral outcomes in children. The results suggest that the increased risk of adverse outcomes in offspring conceived through ART may be due in part to altered methylation of ICRs. Larger studies utilizing epigenome-wide interrogation are warranted.}, number={18}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Lloyd, Dillon T. and Skinner, Harlyn G. and Maguire, Rachel and Murphy, Susan K. and Motsinger-Reif, Alison A. and Hoyo, Cathrine and House, John S.}, year={2022}, month={Sep} }
 @article{king_sparling_lloyd_satusky_martinez_grenier_bergemann_maguire_hoyo_meyer_et al._2022, title={Sex-specific DNA methylation and associations with in utero tobacco smoke exposure at nuclear-encoded mitochondrial genes}, volume={3}, ISSN={["1559-2308"]}, url={https://doi.org/10.1080/15592294.2022.2043591}, DOI={10.1080/15592294.2022.2043591}, abstractNote={Sex-linked differences in mitochondrial ATP production, enzyme activities, and reactive oxygen species generation have been reported in multiple tissue and cell types. While the effects of reproductive hormones underlie many of these differences, regulation of sexually dimorphic mitochondrial function has not been fully characterized. We hypothesized that sex-specific DNA methylation contributes to sex-specific expression of nuclear genes that influence mitochondrial function. Herein, we analysed DNA methylation data specifically focused on nuclear-encoded mitochondrial genes in 191 males and 190 females. We found 596 differentially methylated sites (DMSs) (FDR p < 0.05), corresponding to 324 genes, with at least a 1% difference in methylation between sexes. To investigate the potential functional significance, we utilized gene expression microarray data. Of the 324 genes containing DMSs, 17 showed differences in gene expression by sex. Particularly striking was that ATP5G2, encoding subunit C of ATP synthase, contains seven DMSs and exhibits a sex difference in expression (p = 0.04). Finally, we also found that alterations in DNA methylation associated with in utero tobacco smoke exposure were sex-specific in these nuclear-encoded mitochondrial genes. Interestingly, the level of sex differences in DNA methylation at nuclear-encoded mitochondrial genes and the level of methylation changes associated with smoke exposure were less prominent than that of other genes. This suggests more conservative regulation of DNA methylation at these nuclear-encoded mitochondrial genes as compared to others. Overall, our findings suggest that sex-specific DNA methylation may help establish sex differences in expression and function and that sex-specific alterations in DNA methylation in response to exposures could contribute to sex-variable toxicological responses.}, journal={EPIGENETICS}, author={King, Dillon E. and Sparling, Anna Clare and Lloyd, Dillon and Satusky, Matthew Joseph and Martinez, Mackenzie and Grenier, Carole and Bergemann, Christina Michelle and Maguire, Rachel and Hoyo, Cathrine and Meyer, Joel Newman and et al.}, year={2022}, month={Mar} }
 @article{maguire_house_lloyd_skinner_allen_raffi_skaar_park_mccullough_kollins_et al._2021, title={Associations between maternal obesity, gestational cytokine levels and child obesity in the NEST cohort}, volume={16}, ISSN={["2047-6302"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85098446153&partnerID=MN8TOARS}, DOI={10.1111/ijpo.12763}, abstractNote={Although maternal systemic inflammation is hypothesized to link maternal pre-pregnancy obesity to offspring metabolic dysfunction, patient empirical data are limited.}, number={7}, journal={PEDIATRIC OBESITY}, author={Maguire, Rachel L. and House, John S. and Lloyd, Dillon T. and Skinner, Harlyn G. and Allen, Terrence K. and Raffi, Asifa Mohamed and Skaar, David A. and Park, Sarah S. and McCullough, Lauren E. and Kollins, Scott H. and et al.}, year={2021}, month={Jul} }
 @article{roman-hubers_cordova_aly_mcdonald_lloyd_wright_baker_chiu_rusyn_2021, title={Data Processing Workflow to Identify Structurally Related Compounds in Petroleum Substances Using Ion Mobility Spectrometry-Mass Spectrometry}, volume={35}, ISSN={["1520-5029"]}, DOI={10.1021/acs.energyfuels.1c00892}, abstractNote={Ion mobility spectrometry coupled with mass spectrometry (IMS-MS) is a post-ionization separation technique that can be used for rapid multidimensional analyses of complex samples. IMS-MS offers untargeted analysis, including ion-specific conformational data derived as collisional cross section (CCS) values. Here, we combine nitrogen gas drift tube CCS (DTCCSN2) and Kendrick mass defect (KMD) analyses based on CH2 and H functional units to enable compositional analyses of petroleum substances. First, polycyclic aromatic compound standards were analyzed by IMS-MS to demonstrate how CCS assists the identification of isomeric species in homologous series. Next, we used case studies of a gasoline standard previously characterized for paraffin, isoparaffin, aromatic, naphthene, and olefinic (PIANO) compounds, and a crude oil sample to demonstrate the application of the KMD analyses and CCS filtering. Finally, we propose a workflow that enables confident molecular formula assignment to the IMS-MS-derived features in petroleum samples. Collectively, this work demonstrates how rapid untargeted IMS-MS analysis and the proposed data processing workflow can be used to provide confident compositional characterization of hydrocarbon-containing substances.}, number={13}, journal={ENERGY & FUELS}, author={Roman-Hubers, Alina T. and Cordova, Alexandra C. and Aly, Noor A. and McDonald, Thomas J. and Lloyd, Dillon T. and Wright, Fred A. and Baker, Erin S. and Chiu, Weihsueh A. and Rusyn, Ivan}, year={2021}, month={Jul}, pages={10529–10539} }
 @article{aly_casillas_luo_mcdonald_wade_zhu_newman_lloyd_wright_chiu_et al._2021, title={Environmental impacts of Hurricane Florence flooding in eastern North Carolina: temporal analysis of contaminant distribution and potential human health risks}, volume={31}, ISSN={["1559-064X"]}, DOI={10.1038/s41370-021-00325-5}, abstractNote={Hurricane Florence made landfall in North Carolina in September 2018 causing extensive flooding. Several potential point sources of hazardous substances and Superfund sites sustained water damage and contaminants may have been released into the environment.This study conducted temporal analysis of contaminant distribution and potential human health risks from Hurricane Florence-associated flooding.Soil samples were collected from 12 sites across four counties in North Carolina in September 2018, January and May 2019. Chemical analyses were performed for organics by gas chromatography-mass spectrometry. Metals were analyzed using inductively coupled plasma mass spectrometry. Hazard index and cancer risk were calculated using EPA Regional Screening Level Soil Screening Levels for residential soils.PAH and metals detected downstream from the coal ash storage pond that leaked were detected and were indicative of a pyrogenic source of contamination. PAH at these sites were of human health concern because cancer risk values exceeded 1 × 10-6 threshold. Other contaminants measured across sampling sites, or corresponding hazard index and cancer risk, did not exhibit spatial or temporal differences or were of concern.This work shows the importance of rapid exposure assessment following natural disasters. It also establishes baseline levels of contaminants for future comparisons.}, number={5}, journal={JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY}, author={Aly, Noor A. and Casillas, Gaston and Luo, Yu-Syuan and McDonald, Thomas J. and Wade, Terry L. and Zhu, Rui and Newman, Galen and Lloyd, Dillon and Wright, Fred A. and Chiu, Weihsueh A. and et al.}, year={2021}, month={Sep}, pages={810–822} }
 @article{chen_lloyd_zhou_chiu_wright_rusyn_2021, title={Risk Characterization of Environmental Samples Using In Vitro Bioactivity and Polycyclic Aromatic Hydrocarbon Concentrations Data}, volume={179}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfaa166}, abstractNote={Abstract Methods to assess environmental exposure to hazardous chemicals have primarily focused on quantification of individual chemicals, although chemicals often occur in mixtures, presenting challenges to the traditional risk characterization framework. Sampling sites in a defined geographic region provide an opportunity to characterize chemical contaminants, with spatial interpolation as a tool to provide estimates for non-sampled sites. At the same time, the use of in vitro bioactivity measurements has been shown to be informative for rapid risk-based decisions. In this study, we measured in vitro bioactivity in 39 surface soil samples collected immediately after flooding associated with Hurricane Harvey in Texas in a residential area known to be inundated with polycyclic aromatic hydrocarbon (PAH) contaminants. Bioactivity data were from a number of functional and toxicity assays in 5 human cell types, such as induced pluripotent stem cell-derived hepatocytes, cardiomyocytes, neurons, and endothelial cells, as well as human umbilical vein endothelial cells. Data on concentrations of PAH in these samples were also available and the combination of data sources offered a unique opportunity to assess the joint spatial variation of PAH components and bioactivity. We found significant evidence of spatial correlation of a subset of PAH contaminants and of cell-based phenotypes. In addition, we show that the cell-based bioactivity data can be used to predict environmental concentrations for several PAH contaminants, as well as overall PAH summaries and cancer risk. This study’s impact lies in its demonstration that cell-based profiling can be used for rapid hazard screening of environmental samples by anchoring the bioassays to concentrations of PAH. This work sets the stage for identification of the areas of concern and direct quantitative risk characterization based on bioactivity data, thereby providing an important supplement to traditional individual chemical analyses by shedding light on constituents that may be missed from targeted chemical monitoring.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Chen, Zunwei and Lloyd, Dillon and Zhou, Yi-Hui and Chiu, Weihsueh A. and Wright, Fred A. and Rusyn, Ivan}, year={2021}, month={Jan}, pages={108–120} }
 @article{mukherjee_beykal_szafran_onel_stossi_mancini_lloyd_wright_zhou_mancini_et al._2020, title={Classification of estrogenic compounds by coupling high content analysis and machine learning algorithms}, volume={16}, ISSN={["1553-7358"]}, DOI={10.1371/journal.pcbi.1008191}, abstractNote={Environmental toxicants affect human health in various ways. Of the thousands of chemicals present in the environment, those with adverse effects on the endocrine system are referred to as endocrine-disrupting chemicals (EDCs). Here, we focused on a subclass of EDCs that impacts the estrogen receptor (ER), a pivotal transcriptional regulator in health and disease. Estrogenic activity of compounds can be measured by many in vitro or cell-based high throughput assays that record various endpoints from large pools of cells, and increasingly at the single-cell level. To simultaneously capture multiple mechanistic ER endpoints in individual cells that are affected by EDCs, we previously developed a sensitive high throughput/high content imaging assay that is based upon a stable cell line harboring a visible multicopy ER responsive transcription unit and expressing a green fluorescent protein (GFP) fusion of ER. High content analysis generates voluminous multiplex data comprised of minable features that describe numerous mechanistic endpoints. In this study, we present a machine learning pipeline for rapid, accurate, and sensitive assessment of the endocrine-disrupting potential of benchmark chemicals based on data generated from high content analysis. The multidimensional imaging data was used to train a classification model to ultimately predict the impact of unknown compounds on the ER, either as agonists or antagonists. To this end, both linear logistic regression and nonlinear Random Forest classifiers were benchmarked and evaluated for predicting the estrogenic activity of unknown compounds. Furthermore, through feature selection, data visualization, and model discrimination, the most informative features were identified for the classification of ER agonists/antagonists. The results of this data-driven study showed that highly accurate and generalized classification models with a minimum number of features can be constructed without loss of generality, where these machine learning models serve as a means for rapid mechanistic/phenotypic evaluation of the estrogenic potential of many chemicals.}, number={9}, journal={PLOS COMPUTATIONAL BIOLOGY}, author={Mukherjee, Rajib and Beykal, Burcu and Szafran, Adam T. and Onel, Melis and Stossi, Fabio and Mancini, Maureen G. and Lloyd, Dillon and Wright, Fred A. and Zhou, Lan and Mancini, Michael A. and et al.}, year={2020}, month={Sep} }
 @article{house_bouzos_fahy_francisco_lloyd_wright_motsinger-reif_asuri_wheeler_2020, title={Low-Dose Silver Nanoparticle Surface Chemistry and Temporal Effects on Gene Expression in Human Liver Cells}, volume={16}, ISSN={["1613-6829"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85082473420&partnerID=MN8TOARS}, DOI={10.1002/smll.202000299}, abstractNote={Silver nanoparticles (AgNPs) are widely incorporated into consumer and biomedical products for their antimicrobial and plasmonic properties with limited risk assessment of low-dose cumulative exposure in humans. To evaluate cellular responses to low-dose AgNP exposures across time, human liver cells (HepG2) are exposed to AgNPs with three different surface charges (1.2 µg mL}, number={21}, journal={SMALL}, author={House, John S. and Bouzos, Evangelia and Fahy, Kira M. and Francisco, Victorino Miguel and Lloyd, Dillon T. and Wright, Fred A. and Motsinger-Reif, Alison A. and Asuri, Prashanth and Wheeler, Korin E.}, year={2020}, month={May} }