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1. Identifying Protein Features and Pathways Responsible for Toxicity Using Machine Learning and Tox21: Implications for Predictive Toxicology

   https://doi.org/10.3390/molecules27093021  

   Moukheiber, Lama; Mangione, William; Moukheiber, Mira; Maleki, Saeed; Falls, Zackary; Gao, Mingchen; Samudrala, Ram (May 2022, Molecules)

   Humans are exposed to numerous compounds daily, some of which have adverse effects on health. Computational approaches for modeling toxicological data in conjunction with machine learning algorithms have gained popularity over the last few years. Machine learning approaches have been used to predict toxicity-related biological activities using chemical structure descriptors. However, toxicity-related proteomic features have not been fully investigated. In this study, we construct a computational pipeline using machine learning models for predicting the most important protein features responsible for the toxicity of compounds taken from the Tox21 dataset that is implemented within the multiscale Computational Analysis of Novel Drug Opportunities (CANDO) therapeutic discovery platform. Tox21 is a highly imbalanced dataset consisting of twelve in vitro assays, seven from the nuclear receptor (NR) signaling pathway and five from the stress response (SR) pathway, for more than 10,000 compounds. For the machine learning model, we employed a random forest with the combination of Synthetic Minority Oversampling Technique (SMOTE) and the Edited Nearest Neighbor (ENN) method (SMOTE+ENN), which is a resampling method to balance the activity class distribution. Within the NR and SR pathways, the activity of the aryl hydrocarbon receptor (NR-AhR) and the mitochondrial membrane potential (SR-MMP) were two of the top-performing twelve toxicity endpoints with AUCROCs of 0.90 and 0.92, respectively. The top extracted features for evaluating compound toxicity were analyzed for enrichment to highlight the implicated biological pathways and proteins. We validated our enrichment results for the activity of the AhR using a thorough literature search. Our case study showed that the selected enriched pathways and proteins from our computational pipeline are not only correlated with AhR toxicity but also form a cascading upstream/downstream arrangement. Our work elucidates significant relationships between protein and compound interactions computed using CANDO and the associated biological pathways to which the proteins belong for twelve toxicity endpoints. This novel study uses machine learning not only to predict and understand toxicity but also elucidates therapeutic mechanisms at a proteomic level for a variety of toxicity endpoints. 

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2. Formation of insoluble brown carbon through iron-catalyzed reaction of biomass burning organics

   https://doi.org/10.1039/d2ea00141a  

   Hopstock, Katherine S.; Carpenter, Brooke P.; Patterson, Joseph P.; Al-Abadleh, Hind A.; Nizkorodov, Sergey A. (January 2023, Environmental Science: Atmospheres)

   Biomass burning organic aerosol (BBOA) is one of the largest sources of organics in the atmosphere. Mineral dust and biomass burning smoke frequently co-exist in the same atmospheric environment. Common biomass burning compounds, such as dihydroxybenzenes and their derivatives, are known to produce light-absorbing, water-insoluble polymeric particles upon reaction with soluble Fe( iii ) under conditions characteristic of aerosol liquid water. However, such reactions have not been tested in realistic mixtures of BBOA compounds. In this study, model organic aerosol (OA), meant to replicate BBOA from smoldering fires, was generated through the pyrolysis of Canary Island pine needles in a tube furnace at 300, 400, 500, 600, 700, and 800 °C in nitrogen gas, and the water-soluble fractions were reacted with iron chloride under dark, acidic conditions. We utilized spectrophotometry to monitor the reaction progress. For OA samples produced at lower temperatures (300 and 400 °C), particles (P300 and P400) formed in solution, were syringe filtered, and extracted in organic solvents. Analysis was conducted with ultrahigh pressure liquid chromatography coupled to a photodiode array spectrophotometer and a high-resolution mass spectrometer (UHPLC-PDA-HRMS). For OA samples formed at higher pyrolysis temperatures (500–800 °C), water-insoluble, black particles (P500–800) formed in solution. In contrast to P300 and P400, P500–800 were not soluble in common solvents. Scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS) and transmission electron microscopy (TEM) were used to image P600 and determine bulk elemental composition. Electron microscopy revealed that P600 had fractal morphology, reminiscent of soot particles, and contained no detectable iron. These results suggest that light-absorbing aerosol particles can be produced from Fe( iii )-catalyzed reactions in aging BBOA plumes produced from smoldering combustion in the absence of any photochemistry. This result has important implications for understanding the direct and indirect effects of aged BBOA on climate. 

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3. Laboratory studies of fresh and aged biomass burning aerosol emitted from east African biomass fuels – Part 2: Chemical properties and characterization

   https://doi.org/10.5194/acp-20-10169-2020  

   Smith, Damon M.; Cui, Tianqu; Fiddler, Marc N.; Pokhrel, Rudra P.; Surratt, Jason D.; Bililign, Solomon (January 2020, Atmospheric Chemistry and Physics)

   null (Ed.)

   Abstract. There are many fuels used for domestic purposes in east Africa, producing a significant atmospheric burden of the resulting aerosols, which includes biomass burning particles. However, the aerosol physicochemical properties are poorly understood. Here, the combustion of eucalyptus, acacia, and olive fuels was performed at 500 and 800 ∘C in a tube furnace, followed by immediate filter collection for fresh samples or introduction into a photochemical chamber to simulate atmospheric photochemical aging under the influence of anthropogenic emissions. The aerosol generated in the latter experiment was collected onto filters after 12 h of photochemical aging. 500 and 800 ∘C were selected to simulate smoldering and flaming combustion, respectively, and to cover a range of combustion conditions. Methanol extracts from Teflon filters were analyzed by ultra-performance liquid chromatography interfaced to both a diode array detector and an electrospray ionization high-resolution quadrupole time-of-flight mass spectrometer (UPLC/DAD-ESI-HR-QTOFMS) to determine the light absorption properties of biomass burning organic aerosol constituents chemically characterized at the molecular level. Few chemical or UV–visible (UV: ultraviolet) differences were apparent between samples for the fuels when combusted at 800 ∘C. Differences in single-scattering albedo (SSA) between fresh samples at this temperature were attributed to compounds not captured in this analysis, with eucalyptol being one suspected missing component. For fresh combustion at 500 ∘C, many species were present; lignin pyrolysis and distillation products are more prevalent in eucalyptus, while pyrolysis products of cellulose and at least one nitro-aromatic species were more prevalent in acacia. SSA trends areconsistent with this, particularly if the absorption of those chromophoresextends to the 500–570 nm region. Upon aging, both show that resorcinolor catechol was removed to the highest degree, and both aerosol types weredominated by loss of pyrolysis and distillation products, though they differed in the specific compounds being consumed by the photochemical aging process. 

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4. Effect of relative humidity on the composition of secondary organic aerosol from the oxidation of toluene

   https://doi.org/10.5194/acp-18-1643-2018  

   Hinks, Mallory L.; Montoya-Aguilera, Julia; Ellison, Lucas; Lin, Peng; Laskin, Alexander; Laskin, Julia; Shiraiwa, Manabu; Dabdub, Donald; Nizkorodov, Sergey A. (January 2018, Atmospheric Chemistry and Physics)

   The effect of relative humidity (RH) on the chemical composition of secondary organic aerosol (SOA) formed from low-NO_x toluene oxidation in the absence of seed particles was investigated. SOA samples were prepared in an aerosol smog chamber at < 2 % RH and 75 % RH, collected on Teflon filters, and analyzed with nanospray desorption electrospray ionization high-resolution mass spectrometry (nano-DESI–HRMS). Measurements revealed a significant reduction in the fraction of oligomers present in the SOA generated at 75 % RH compared to SOA generated under dry conditions. In a separate set of experiments, the particle mass concentrations were measured with a scanning mobility particle sizer (SMPS) at RHs ranging from < 2 to 90 %. It was found that the particle mass loading decreased by nearly an order of magnitude when RH increased from < 2 to 75–90 % for low-NO_x toluene SOA. The volatility distributions of the SOA compounds, estimated from the distribution of molecular formulas using the molecular corridor approach, confirmed that low-NO_x toluene SOA became more volatile on average under high-RH conditions. In contrast, the effect of RH on SOA mass loading was found to be much smaller for high-NO_x toluene SOA. The observed increase in the oligomer fraction and particle mass loading under dry conditions were attributed to the enhancement of condensation reactions, which produce water and oligomers from smaller compounds in low-NO_x toluene SOA. The reduction in the fraction of oligomeric compounds under humid conditions is predicted to partly counteract the previously observed enhancement in the toluene SOA yield driven by the aerosol liquid water chemistry in deliquesced inorganic seed particles. 

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5. Biogenic Emissions and Aerosol Response on the North Slope (BEAR-oNS) datasets for Utqiagvik, Alaska in the summer of 2023

   https://doi.org/10.18739/A2BC3T01M  

   Sheesley, Rebecca; Matthews, Tate; Shrestha, Sujan (January 2025, NSF Arctic Data Center)

   Climate in the Arctic is changing at a rapid pace. When vegetation reacts to these changes, chemicals called biogenic volatile organic compounds (BVOCs) can be released into the atmosphere in new ways. This project seeks to investigate how climate change affects the quantity and type of BVOCs released into the atmosphere on the North Slope of Alaska (NSA). In addition, we are interested in the chemical reactions these BVOCs undergo in the Arctic atmosphere. Project goals will be accomplished through field work on the NSA, and collection and laboratory analysis of atmospheric samples. Specifically, the project intends to measure the concentration of BVOCs and their secondary organic aerosol products during North Slope of Alaska field campaigns. In addition to BVOCs and organic acids, the measurements include additional baseline measurements of other volatile organic compounds (VOC) and aerosol components. We are reporting inorganic ions, alkanes, and polycyclic aromatic hydrocarbons (PAHs) for aerosol composition and select aromatic and oxidized VOCs. The time period for these detailed measurements is Jun - Aug 2023 for Utqiagvik, Alaska (AK). VOC measurements were made by proton transfer reaction mass spectrometry. The proton transfer reaction mass spectrometer (PTR-MS) was operated with Hydronium (H3O+) ion at the Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) site in Utqiagvik, AK from 170623 to 130823. Total suspended particulate matter samples were collected on quartz fiber filters at a roughly weekly schedule. These filters were then used for offline analysis. Offline measurement of cations and anions was conducted using ion chromatography. Offline measurement of alkanes and PAH was conducted using thermal desorption gas chromatography - mass spectrometry. 

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