An in vitro and machine learning framework for quantifying serum albumin binding of per- and polyfluoroalkyl substances.

Per- and polyfluoroalkyl substances (PFAS) are a diverse class of anthropogenic chemicals; many are persistent, bioaccumulative, and mobile in the environment. Worldwide, PFAS bioaccumulation causes serious adverse health impacts, yet the physiochemical determinants of bioaccumulation and toxicity for most PFAS are not well understood, largely due to experimental data deficiencies. As most PFAS are proteinophilic, protein binding is a critical parameter for predicting PFAS bioaccumulation and toxicity.

Deep autoencoder-based behavioral pattern recognition outperforms standard statistical methods in high-dimensional zebrafish studies.

Zebrafish have become an essential model organism in screening for developmental neurotoxic chemicals and their molecular targets. The success of zebrafish as a screening model is partially due to their physical characteristics including their relatively simple nervous system, rapid development, experimental tractability, and genetic diversity combined with technical advantages that allow for the generation of large amounts of high-dimensional behavioral data. These data are complex and require advanced machine learning and statistical techniques to comprehensively analyze and capture spatiotemporal responses.

Deep autoencoder-based behavioral pattern recognition outperforms standard statistical methods in high-dimensional zebrafish studies.

Zebrafish have become an essential tool in screening for developmental neurotoxic chemicals and their molecular targets. The success of zebrafish as a screening model is partially due to their physical characteristics including their relatively simple nervous system, rapid development, experimental tractability, and genetic diversity combined with technical advantages that allow for the generation of large amounts of high-dimensional behavioral data. These data are complex and require advanced machine learning and statistical techniques to comprehensively analyze and capture spatiotemporal responses.

The Effects of Long-term, Low-dose β-N-methylamino-L-alanine (BMAA) Exposures in Adult SOD Transgenic Zebrafish.

β-N-Methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid produced by cyanobacteria, which has been implicated in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). It is postulated that chronic exposure to BMAA can lead to formation of protein aggregates, oxidative stress, and/or excitotoxicity, which are mechanisms involved in the etiology of ALS. While specific genetic mutations are identified in some instances of ALS, it is likely that a combination of genetic and environmental factors, such as exposure to the neurotoxin BMAA, contributes to disease.

Pharmacogenomic Analyses Implicate B Cell Developmental Status and as Determinants of Sensitivity toward Anti-CD20 Monoclonal Antibody Therapy.

Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment.

Gene Expression Associated with Variation in Drug Response to Oxaliplatin and Clinical Outcomes in Colorectal Cancer Patients.

Oxaliplatin (OXAL) is a commonly used chemotherapy for treating colorectal cancer (CRC). A recent genome wide association study (GWAS) showed that a genetic variant (rs11006706) in the lncRNA gene and partnered sense gene could impact the response of genetically varied cell lines to OXAL treatment. This study found that the expression levels of and in lymphocytes (LCLs) and CRC cell lines differed between the rs11006706 genotypes, indicating that this gene pair could play a role in OXAL response.

Gene Expression Associated with Drug Response Variation of Temozolomide and Clinical Outcomes in Glioma Patients.

Temozolomide (TMZ) chemotherapy is an important tool in the treatment of glioma brain tumors. However, variable patient response and chemo-resistance remain exceptionally challenging. Our previous genome-wide association study (GWAS) identified a suggestively significant association of SNP rs4470517 in the (receptor-like kinase) gene with TMZ drug response.

Developmental cadmium exposure disrupts zebrafish vestibular calcium channels interfering with otolith formation and inner ear function.

Dizziness or balance problems are estimated to affect approximately 3.3 million children aged three to 17 years. These disorders develop from a breakdown in the balance control system and can be caused by anything that affects the inner ear or the brain, including exposure to environmental toxicants.

LGR5 is a conserved marker of hair follicle stem cells in multiple species and is present early and throughout follicle morphogenesis.

Hair follicle stem cells are key for driving growth and homeostasis of the hair follicle niche, have remarkable regenerative capacity throughout hair cycling, and display fate plasticity during cutaneous wound healing. Due to the need for a transgenic reporter, essentially all observations related to LGR5-expressing hair follicle stem cells have been generated using transgenic mice, which have significant differences in anatomy and physiology from the human. Using a transgenic pig model, a widely accepted model for human skin and human skin repair, we demonstrate that LGR5 is a marker of hair follicle stem cells across species in homeostasis and development.

Development of a Pandemic Awareness STEM Outreach Curriculum: Utilizing a Computational Thinking Taxonomy Framework.

Computational thinking is an essential skill in the modern global workforce. The current public health crisis has highlighted the need for students and educators to have a deeper understanding of epidemiology. While existing STEM curricula has addressed these topics in the past, current events present an opportunity for new curricula that can be designed to present epidemiology, the science of public health, as a modern topic for students that embeds the problem-solving and mathematics skills of computational thinking practices authentically.

High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs.

Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients.

Leveraging high-throughput screening data, deep neural networks, and conditional generative adversarial networks to advance predictive toxicology.

There are currently 85,000 chemicals registered with the Environmental Protection Agency (EPA) under the Toxic Substances Control Act, but only a small fraction have measured toxicological data. To address this gap, high-throughput screening (HTS) and computational methods are vital. As part of one such HTS effort, embryonic zebrafish were used to examine a suite of morphological and mortality endpoints at six concentrations from over 1,000 unique chemicals found in the ToxCast library (phase 1 and 2).

Extending the lymphoblastoid cell line model for drug combination pharmacogenomics.

Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalable and low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research.

Cadmium exposure increases the risk of juvenile obesity: a human and zebrafish comparative study.

Objective: Human obesity is a complex metabolic disorder disproportionately affecting people of lower socioeconomic strata, and ethnic minorities, especially African Americans and Hispanics. Although genetic predisposition and a positive energy balance are implicated in obesity, these factors alone do not account for the excess prevalence of obesity in lower socioeconomic populations. Therefore, environmental factors, including exposure to pesticides, heavy metals, and other contaminants, are agents widely suspected to have obesogenic activity, and they also are spatially correlated with lower socioeconomic status.

The neurological toxicity of heavy metals: A fish perspective.

The causes of neurodegenerative diseases are complex with likely contributions from genetic susceptibility and environmental exposures over an organism's lifetime. In this review, we examine the role that aquatic models, especially zebrafish, have played in the elucidation of mechanisms of heavy metal toxicity and nervous system function over the last decade. Focus is applied to cadmium, lead, and mercury as significant contributors to central nervous system morbidity, and the application of numerous transgenic zebrafish expressing fluorescent reporters in specific neuronal populations or brain regions enabling high-resolution neurodevelopmental and neurotoxicology research.

Perinatal triphenyl phosphate exposure accelerates type 2 diabetes onset and increases adipose accumulation in UCD-type 2 diabetes mellitus rats.

Triphenyl phosphate (TPhP) is a flame retardant additive frequently found in consumer products and household dust. We administered 170μg of TPhP in maternal food from gestational day 8.5 to weaning and evaluated metabolic phenotypes of 3.