bluuebunny/crossref_metadata_2025 huggingface dataset:
Practical and veritable threshold multi-factor authentication for mobile devices
Authors: Qin Shihan , Xiao Yuting , Xin Yansen , Gao Birou , Zhang Rui
Published: January 2025

Multi-factor authentication (MFA) is extensively employed in mobile applications to enhance security, including Internet of Vehicles, healthcare systems, smart homes, etc. Traditional MFA requires users to present specific factors, which can be inconvenient if certain factors are unavailable. To address this, $ (t, n) $-threshold MFA (T-MFA) allows users to select any $ t $ out of $ n $ registered factors for authentication. However, existing T-MFA solutions face four key issues: (i) reliance on $ n-1 $ devices, which may be impractical; (ii) susceptibility to denial of service when the mandatory factor fails; (iii) limited factor types, reducing user flexibility; and (iv) increasing client-side computational costs with higher $ t $. In this work, we propose a veritable $ (t, n) $-threshold multi-factor authenticated key exchange protocol that addresses these challenges. Utilizing oblivious programmable pseudorandom functions (OPPRF) as main tools, we eliminate dependence on multiple devices, mandatory factors, and restricted factor types, achieving what we called veritable. We present a new construction of batched OPPRF to reduce client-side costs from $ O(t) $ to $ O(1) $, with 2 exponentiations cost by the client and $ t+1 $ by the server. We implement it with JavaScript to validate its flexibility and efficiency, making it highly suitable for mobile device applications.
Patient and Healthcare Professional Perspectives on Crohn’s Perianal Fistula Treatment: Results From a Discrete Choice Experiment
Authors: Jiang Jeanne , Goodwin Bridgett , Athavale Amod , Cazzetta Susan E , Chen Lily , Edelblut Josiah , Fan Tao , Hadker Nandini , Nazarey Pradeep P
Published: January 2025

Background

Crohn’s perianal fistulas (CPF) are difficult to manage and often require multiple interventions. This study aimed to assess the preferences of patients and healthcare professionals (HCPs) for attributes of CPF-related procedures/surgeries to better inform CPF management.

Methods

This US cross-sectional, observational study was conducted via a web-enabled questionnaire (October 2021-January 2022) among patients aged 21-89 years with a self-reported physician diagnosis of CPF (with or without CPF-related surgery experience) and HCPs (gastroenterologists and colorectal surgeons who managed ≥3 patients with CPF in the past 12 months). Patient and HCP preferences for CPF-related procedure/surgery attributes were assessed using a discrete choice experiment and stated preference methodology.

Results

In total, 100 patients and 137 HCPs were recruited. Benefits of therapy (symptom control and/or fistula closure) were rated as the most important CPF treatment attribute by both patients and HCPs influencing treatment decisions (mean relative importance 23.9 and 36.3, respectively). The mean relative importance of procedure invasiveness and postoperative discomfort was higher for patients (19.3 and 20.2, respectively) than for HCPs (14.3 and 11.0, respectively), whereas the mean relative importance of fecal incontinence was greater for HCPs than patients (25.0 vs. 19.3, respectively).

Conclusions

Patients and HCPs have different perspectives on the importance of specific CPF-related procedure/surgery attributes. The attributes identified as important to patients and HCPs in this study should be considered when managing patients with CPF and making treatment decisions.
Machine learning-based scoring system to predict cardiogenic shock in acute coronary syndrome
Authors: Böhm Allan , Segev Amitai , Jajcay Nikola , Krychtiuk Konstantin A , Tavazzi Guido , Spartalis Michael , Kollarova Marta , Berta Imrich , Jankova Jana , Guerra Frederico , Pogran Edita , Remak Andrej , Jarakovic Milana , Sebenova Jerigova Viera , Petrikova Katarina , Matetzky Shlomi , Skurk Carsten , Huber Kurt , Bezak Branislav
Published: January 2025

Aims

Cardiogenic shock (CS) is a severe complication of acute coronary syndrome (ACS) with mortality rates approaching 50%. The ability to identify high-risk patients prior to the development of CS may allow for pre-emptive measures to prevent the development of CS. The objective was to derive and externally validate a simple, machine learning (ML)-based scoring system using variables readily available at first medical contact to predict the risk of developing CS during hospitalization in patients with ACS.

Methods and results

Observational multicentre study on ACS patients hospitalized at intensive care units. Derivation cohort included over 40 000 patients from Beth Israel Deaconess Medical Center, Boston, USA. Validation cohort included 5123 patients from the Sheba Medical Center, Ramat Gan, Israel. The final derivation cohort consisted of 3228 and the final validation cohort of 4904 ACS patients without CS at hospital admission. Development of CS was adjudicated manually based on the patients’ reports. From nine ML models based on 13 variables (heart rate, respiratory rate, oxygen saturation, blood glucose level, systolic blood pressure, age, sex, shock index, heart rhythm, type of ACS, history of hypertension, congestive heart failure, and hypercholesterolaemia), logistic regression with elastic net regularization had the highest externally validated predictive performance (c-statistics: 0.844, 95% CI, 0.841–0.847).

Conclusion

STOP SHOCK score is a simple ML-based tool available at first medical contact showing high performance for prediction of developing CS during hospitalization in ACS patients. The web application is available at https://stopshock.org/#calculator.
The determination of wide-range pharmaceuticals class in Erzurum biological wastewater treatment plant using liquid chromatography coupled to tandem mass spectrometry: occurrence, treatment efficiency, and environmental risk assessment
Authors: Eren Zeynep
Published: January 2025

Pharmaceuticals as an important group of contaminants of emerging concern (CECs) are unintentionally discharged into the aquatic environment due to lack of advanced treatment of classical wastewater treatment plants (WWTPs). Therefore, the detection and monitoring studies of pharmaceuticals and personal care products (PPCPs) in an aquatic environment are getting more important as well as the definition of their ecological risks to the aquatic ecosystem. To conduct these studies successfully, it is necessary to develop sensitive, robust, selective, and reliable methods to be able to analyze PPCPs. This study was carried out in the biological WWTP (BWWTP) of Erzurum City, Türkiye, to investigate the treatment efficiency of pharmaceuticals in the plant and to assess the ecological risks for the Karasu River where treated wastewater is discharged into it. For this purpose, a wide range of pharmaceutical classes in influent wastewater (IWW) and effluent wastewater samples taken from Erzurum BBWWTP, Türkiye was simultaneously identified and quantified with liquid chromatography coupled with tandem mass spectrometry following liquid phase extraction for sample preparation. A total of 55 active pharmaceutical groups in 25 general drug groups (29 subgroups) were detected, with the highest average ratios being 82.459%, 7.306%, 4.949%, and 2.145% for analgesic-anti-inflammatory, antiepileptic, diabetic, and antipyretic pharmaceuticals groups, respectively, in IWW. Although flurbiprofen from the analgesic-anti-inflammatory pharmaceuticals group was treated with the average efficiency of 66.13% during the 12-month treatment period, it had a high risk quotient due to the very high initial concentration in WWT in the range of 809.01–22,901.10 µg/L.
Enhanced tolerance to narcosis in starved Daphnia magna neonates
Authors: Steigerwald Sophie , Saladin Yves , Alurralde Gastón , Abel Sebastian , Sobek Anna , Eriksson Wiklund Ann-Kristin , Gorokhova Elena
Published: January 2025

Guidelines for ecotoxicity testing with Daphnia magna specify particular feeding protocols during the exposure, yet standardization for preexposure feeding remains ambiguous despite its recognized significance in affecting organismal metabolic capacity and tolerance. This ambiguity may contribute to disparate responses and heightened uncertainty in determining the effect concentrations of test chemicals, particularly those inducing metabolic effects through narcosis. Here, we address this gap through a three-step dose-response experiment with neonates of D. magna subjected to two alternative feeding regimes in the preexposure phase: starved and moderately fed during the first 24 hr after birth. Following this treatment, the daphnids were exposed to narcosis-inducing substances (polycyclic aromatic hydrocarbons; PAHs) for 72 hr before being transferred to clean media with algal food ad libitum for a 48 hr recovery phase. Daphnid survivorship, individual protein content, and body size at the end of each experiment phase—pre-exposure, postexposure and postrecovery—were compared between the treatments. Significant treatment effects were observed, including lower and less variable protein content in the starved daphnids entering the PAH exposure phase, yet higher survivorship and greater recovery potential in these daphnids compared with the fed individuals. Our findings underscore the importance of early-life food access and advocate for mandatory reporting of pre-exposure feeding regimes, particularly when testing substances acting via nonpolar narcosis.
Assessing perfluoroalkyl substance pollution in Central Mediterranean breeding shearwaters
Authors: Michel Lucie , Zhang Junjie , Asimakopoulos Alexandros , Austad Martin , Bustamante Paco , Cecere Jacopo G , Cianchetti-Benedetti Marco , Colominas-Ciuró Roger , Dell’Omo Giacomo , De Pascalis Federico , Jaspers Veerle L B , Quillfeldt Petra
Published: January 2025

Per- and polyfluoroalkyl substances (PFAS) are synthetic organofluorine compounds used in various products, which are highly durable in the environment and may pose risks to wildlife health. We investigated the blood cell concentrations of PFAS in breeding Scopoli's shearwaters (Calonectris diomedea) from three different colonies in the central and southern Mediterranean (Linosa, Malta, and La Maddalena). Shearwaters are flexible, high trophic level foragers, and foraging areas may differ according to sex and breeding stage. We examined inter- and intracolony differences in PFAS blood concentrations and compared them with exploited foraging areas and dietary tracers. Per- and polyfluoroalkyl substances were detected in all samples, with the major congeners detected in descending order being perfluoroctanesulfonic acid (PFOS), perfluoroundecanoic acid (PFuNA), perfluorododecanoic acid (PFDoDA), and perfluorotridecanoic acid (PFTriDA). The mean sum of PFAS during the chick-rearing phase was highest in the birds from Malta (145.1 ng/g dry wt, 95% confidence interval [CI] of the mean 106.8, 183.5) compared with Linosa (91.5 ng/g dry wt, 95% CI 72.9, 110.1) and La Maddalena (84.5 ng/g dry wt, 95% CI 61.7, 107.3), and the PFAS blood composition of shearwaters from La Maddalena and Malta differed. The PFAS concentrations in shearwaters from Linosa were higher during incubation than during chick-rearing, and males had higher PFAS concentrations than females during incubation. Some PFAS were associated with carbon and nitrogen stable isotope values. After baseline adjustment of stable isotope values, no differences were observed for adjusted δ15N and δ13C between the three colonies, suggesting that differences in PFAS levels attributed to diet were minor compared with regional differences. Our study highlights that shearwaters are useful biomonitors of PFAS exposure in remote marine areas.
Predicting the toxicity of physically and chemically dispersed oil: a modelling case study with American lobster larvae (Homarus americanus)
Authors: de Jourdan Benjamin , Philibert Danielle , McGrath Joy
Published: January 2025

Determining the impact of an oil spill on aquatic ecosystems is a challenge. Because of the chemical complexity of crude oil, risk assessments rely on quantitative structure associated relationships to group chemical classes of compounds based on similar modes of toxicity. Quantitative structure associated relationships like the target lipid model can be used to determine species sensitivity by determining the critical target lipid body burden (CTLBB) and can be used to calculate the toxic units (TU) of a mixture. In this study we used the CTLBB generated from single polycyclic aromatic compound toxicity data and the analytical chemistry of whole oil to predicted and validate toxicity of both water-accommodated fraction (WAF) of crude oil and chemically dispersed WAF (CEWAF) to American lobster (Homarus americanus) larvae. A two-step procedure for modelling whole oil partitioning was utilized to compute the dissolved components in each of the WAF and CEWAF dilutions. Then, a species and life stage specific CTLBB derived for lobster larvae was applied in PetroTox to compute the TUs of exposure solution. The approach used in this study was able to effectively predict the effects observed in the exposures and can be integrated into oil spill fate and effects models to improve the oil spill assessment and response.
Comparison of visual assessment and quantitative goodness-of-fit metrics on GUTS model fits
Authors: Bauer Barbara , Singer Alexander , Jakoby Oliver , Nickisch Dirk , Preuss Thomas , Witt Johannes , Wittwer Torben , Gergs André
Published: January 2025

For the application of toxicokinetic-toxicodynamic (TKTD) models in the European environmental risk assessment (ERA) of plant protection products, it is recommended to evaluate model predictions of the calibration as well as the independent validation data set based on qualitative criteria (visual assessment) and quantitative goodness-of-fit (GoF) metrics. The aims of this study were to identify whether quantitative criteria coincide with human visual perception of model performance and which evaluator characteristics influence their perception. In an anonymous online survey, > 70 calibration and validation general unified threshold models of survival (GUTS) fits were ranked by 64 volunteers with a professional interest in ecotoxicology and TKTD modeling. Participants were asked to score model fits to the time resolved survival data from toxicity experiments and to an aggregated dose-response curve representation. Dose-response curve plots tended to be scored better than time series, although both representations were based on the same toxicity test data and model results. For the time series, quantitative indices and visual assessments generally agreed on model performance. However, rankings varied with individual perceptions of the participants. Visual assessment scores were best predicted using a combination of GoF metrics. From the survey participants’ majority agreement on fit acceptance, GoF cut-off criteria could be derived that indicated sufficient fit performance. The most conservative GoF criterion well resembled current suggestions by the European Food Safety Authority. Hence, the survey results provide evidence that current quantitative GUTS assessment practice in ERA is consistent with perceptions of fit quality based on visual judgements of the dynamic model behavior by a large number of practitioners. Thus, our study fosters trust in model performance assessment.
Buff-tailed bumblebee, an underrated indicator of air pollution: a comparison of particulate matter accumulation by Bombus terrestris L. and Apis mellifera L.
Authors: Moniuszko Hanna , Przybysz Arkadiusz , Borański Mikołaj , Splitt Aleksandra , Jachuła Jacek , Popek Robert
Published: January 2025

Anthropogenic and natural particulate matter (PM) affects urban and agricultural areas and contaminates the bodies of Apis mellifera (honeybee) and Bombus terrestris (buff-tailed bumblebee). Although both species accumulate PM, scientific interest has primarily focused on A. mellifera as a pollution indicator. This study directly compared the efficacy of honeybees and bumblebees as indicators of PM and its associated trace elements (TEs). Insects were collected from ecological and conventional apple orchards and underwent quantitative analysis of total PM, PM size fractions, and TEs. To establish an environmental context, plant samples and bee products were obtained from both plantations, and screened for PM and/or TEs. Bombus terrestris accumulated 191.3 μg total PM per individual, whereas A. mellifera accumulated 64 μg. Particular PM size fractions were also significantly more abundant on bumblebees. Accumulation patterns of total and large PM on bumblebees differed between the ecological and conventional orchards. Total PM accumulated by both species combined correlated strongly with the total PM covering apple tree foliage in the ecological orchard (r = 0.836) and with grass in the conventional orchard (r = 0.851). The amount of total PM accumulated by B. terrestris strongly correlated with the concentrations of Fe (r = 0.927) and Mn (r = 0.91) in this species. Accumulation of Fe by A. mellifera correlated with the content of this metal in pollen (r = 0.912) and bee bread (r = 0.91), whereas the reverse trend was found for Mo in bee bread (r = –0.912). The results indicate that B. terrestris is a more accurate pollution indicator, with potentially greater efficacy in more polluted areas. The observed differences are most likely attributed to the distinct morphology and behavior of the species.
Individual and combined toxicity of polystyrene nanoplastics and clothianidin toward Daphnia magna, Lemna minor, Chlamydomonas reinhardtii, and Microcystis aeruginosa
Authors: Bandeira Felipe Ogliari , Alves Paulo Roger Lopes , Hennig Thuanne Braúlio , Vaz Vitor Pereira , Vicentini Denice Schulz , Juneau Philippe , Dewez David , Matias William Gerson
Published: January 2025

Nanoplastics (NPs) and neonicotinoids are common pollutants in aquatic ecosystems. Although their co-occurrence is expected in multiple environments, studies assessing their combined effects are still limited. This toxicological assessment investigated the potential effects of polystyrene NPs (PSNPs), clothianidin (CLO), and their mixtures on four aquatic species: the freshwater cladoceran Daphnia magna, the duckweed Lemna minor, the green algae Chlamydomonas reinhardtii, and the cyanobacteria Microcystis aeruginosa. Toxicological tests were performed following International Organization for Standardization and Organisation for Economic Co-operation and Development protocols. Acute, chronic (multigenerational) and swimming behavior tests were performed with D. magna, and growth inhibition tests were run with L. minor, C. reinhardtii, and M. aeruginosa. Abbott's model was used to predict the toxicological interactions of the mixtures for each one of the tested species. The D. magna immobility and swimming behavior tests revealed that the combined toxicities of PSNPs and CLO are decreased when the compounds are present as a mixture. Antagonistic interactions were also observed for C. reinhardtii growth, whereas for L. minor and M. aeruginosa, interactions ranged from antagonism to additivity. Chronic multigenerational tests with D. magna revealed that neonates obtained from the exposed parental generation showed a delay in the first brood during the recovery (nonexposure) phase, but this effect disappeared at the next generation, which indicates that microcrustaceans will probably be able to recover on a long-term scale if contamination is stopped. Our results provide new insights into the combined toxicity and ecological risk of NPs and neonicotinoids toward aquatic organisms.
Polyurethane microplastics and associated tris(chloropropyl)phosphate additives both affect development in larval fathead minnow Pimephales promelas
Authors: Hamilton Bonnie M , Jantunen Liisa M , Rochman Chelsea M
Published: January 2025

Microplastics (< 5 mm) are a diverse class of contaminants ranging in morphology, polymer type, and chemical cocktail. Microplastic toxicity can be driven by one or a combination of these characteristics. Most studies, however, evaluate the physical effect of the most commercially available polymers. By disregarding other polymers with high consumption and/or production rates, and the chemical constituents of plastics, we fail to have a holistic understanding of the mechanisms of toxicity. Polyurethane is understudied in terms of effects testing yet considered one of the most hazardous polymers due to its chemical composition. Polyurethane is a high production polymer and is found in common consumer products ranging from packaging to spray foam insulation. To better understand the physico-chemical effects of polyurethane and a common additive in polyurethane products, we exposed larval fathead minnows for 28 days to polyurethane without chemical additives (i.e., plastic treatment), chemical leachate from polyurethane containing chemical additives (i.e., tris(chloropropyl)phosphate [TCPP]; i.e., chemical treatment) and polyurethane with chemical additives (i.e., plastic with chemical treatment) in a fully factorial experiment. We observed significant decreases in growth at 12 days posthatch (dph) in the plastic, chemical, and plastic with chemical treatments, suggesting a physical and chemical driver of toxicity. At 28 dph, we did not observe significant differences in growth, suggesting individuals can recover. We also observed concentrations of ΣTCPPs in fathead minnow exposed to the plastic with chemical treatment and the chemical only treatment, demonstrating TCPP uptake in exposed individuals. Combined, our data suggests the importance of both the physical and chemical components of microplastics when assessing effects, and thus emphasizing the need to evaluate the effects of microplastics in a multidimensional way.
The influence of tissue morphometry on tissue mercury concentration in male and female virile crayfish (Faxonius virilis)
Authors: Libunao Tate E , Kolok Alan S
Published: January 2025

The objective of this study was to determine the influence of tissue morphometry on tissue total mercury concentration (THg) in male and female virile crayfish (Faxonius virilis). In 2023, 10 embryonized and nine stage IV female crayfish and 29 male virile crayfish were captured from Lake Roosevelt and the Spokane River Arm, in Washington, USA. Total mercury was analyzed in the adductor muscle, gills, and hepatopancreas for all individuals and the ovaries and eggs for females with developed ovaries and embryonized females, respectively. Tissue morphometrics and tissue THg were allometrically correlated to the clawless body mass of male virile crayfish. Furthermore, it was determined that in male size-adjusted virile crayfish, gill THg was significantly associated with hepatopancreas THg but not adductor muscle THg. In embryonized and reproductive developing female virile crayfish, there was evidence of considerable adductor muscle and hepatopancreas tissue atrophy; however, no significant differences in THg occurred. In both the adductor muscle and the hepatopancreas, THg was not bioamplified despite tissue atrophy, suggesting a net loss of mercury from the tissues into the hemolymph. Although the most plausible redistribution of mercury in females with developed ovaries would be from the hepatopancreas to the developing ovary, this redistribution does not completely explain the level of maternal transfer observed. Clearly, dietary mercury contributed to the body burden of mercury within the ovaries of the females in reproductive development.
Effect-based analysis of endocrine effects in surface and ground water with focus on progestagenicity using Arxula yeast-based reporter gene assays
Authors: Klein Michelle , Reibold Melissa , Reinders Petra , Itzel Fabian , Jaehne Martin , Gehrmann Linda , Klaßen Martin Daniel , Schmidt Torsten Claus , Türk Jochen
Published: January 2025

The use of effect-based methods in water monitoring for identifying risks to aquatic organisms and human health is important for aiding regulatory decisions. In the past decades, the database on monitoring, especially in surface waters, has grown as this aquatic environment is openly exposed to various contamination sources. With regard to endocrine disruption, estrogenic and androgenic effects have been primarily investigated. Here, yeast-based bioassays emerged as potent tools, offering sensitivity to environmentally relevant concentrations and high robustness. The objectives of this study were to investigate further endocrine endpoints and extend the monitoring to ground waters. The inclusion of progestagenic effects is crucial due to their multifaceted roles in various functions of organisms. Hence, three different Arxula-yeast hormone screens (estrogen, androgen, and progesterone receptors) were applied, revealing simultaneous exposure to diverse endocrine effects in surface and ground water matrices. Although effect profiles in surface waters showed mainly activation of hormone receptors, in-ground water samples inhibitory effects clearly predominate. Although toxicological thresholds are not yet legally binding, they are essential for effective regulatory measures and risk management to ensure the good ecological status of aquatic ecosystems. The results were compared with effect-based trigger values for ecological as well as human risk assessment depending on the sample matrix, none of which were exceeded.
Impacts of seasonality on mercury concentrations, polyunsaturated fatty acids, and stable isotopes: implications for the use of tetragnathid spiders as sentinels
Authors: Landaverde Jessica , Olson Connor , Montesdeoca Mario , Hannappel Madeline , Otter Ryan R
Published: January 2025

Riparian spiders are used in ecotoxicology as sentinels of bioavailable contaminants that are transferred from aquatic to terrestrial habitats via emergent aquatic insects. Spiders in the family Tetragnathidae are particularly of interest because a high proportion of their diet consists of emergent aquatic insects and their contaminant loads reflect the amount transferred through the food web to riparian predators. The transfer of contaminants can be determined through food web tracers such as stable isotopes and polyunsaturated fatty acids; however, it is unclear how contaminants and tracers vary over the course of a year. The objective of this study was to determine whether seasonality affected size, carbon and nitrogen stable isotopes, polyunsaturated fatty acid biomarkers, mercury, and other trace metal concentrations in tetragnathid spiders. Spiders were sampled fortnightly from a single site on the Stones River in Tennessee, USA, for an entire active season (April through October). Spider mass and length steadily increased from April to September to a maximum average value of 0.078 ± 0.03 g, then decreased in October. Seasonal trends were observed for carbon and nitrogen stable isotopes, with significantly decreased signatures occurring late in the active season. Overall, methyl mercury concentrations (range: 12.1–134.4 ng/g) and the methyl-total mercury ratio (range: 49%–98%) increased throughout the active season, with higher variability observed at the end of the active season. Collectively, our results indicate that seasonality affected several important endpoints and that spiders collected during the end of the active season may not be representative of spiders during the entire active season.
Study on the developmental, behavioral toxicity, and toxicological mechanism of the antidepressant drug venlafaxine and its active metabolites in zebrafish
Authors: Chen Qian , Gu Siying , Lan Yufen , Xu Jiaming , Lin Wenting , Qin Yingjun , Ren Yuan
Published: January 2025

As a representative agent of bicyclic antidepressants, venlafaxine (VEN) has become widely used worldwide and is frequently detected in surface waters with concentrations ranging from ng/L to µg/L. To evaluate the toxicological effects of such medications on aquatic species, studies on environmentally relevant concentrations are essential. Zebrafish were used as a model organism to assess growth and development in larvae and examine tissue accumulation, oxidative stress, and DNA methylation in adults. The results showed adverse effects, including an 18.5% decrease in embryo hatching rate and an increase in mortality by 18.5%. There was also a reduction in body length (4.5%) and eye area (12.2%) in the larvae, along with abnormal developmental issues, such as pericardial edema, yolk sac edema, and spinal curvature. Venlafaxine and its metabolites induced oxidative stress, leading to observable toxic effects. In adult zebrafish, VEN and O-desmethylvenlafaxine (ODV) accumulated primarily in the liver, followed by the brain and intestines, and caused a reduction in DNA methyltransferase activity, leading to DNA hypomethylation. VEN had the most significant impact on DNA methyltransferase 1 and altered its conformation more than ODV. Overall, venlafaxine was found to be more toxic than its metabolites, providing a scientific basis for evaluating the toxic effects and ecological risks of antidepressant residues on aquatic organisms.
Computational new approach methods guide focused testing and enhance understanding of chlorantraniliprole toxicity across species
Authors: Jensen-Brickley Marissa A , Glimsdal Leah , Johnson Abigail , Stacy Emma , Santana-Rodriguez Kelvin , Mattingly Kali , Villeneuve Daniel L , Hockett Russ , Blackwell Brett , Cavallin Jenna , LaLone Carlie A
Published: January 2025

Diamide insecticides, specifically chlorantraniliprole (CHL), have been rising in popularity over the past decade, becoming one of the most widely used insecticide classes globally. These insecticides target the ryanodine receptor (RyR), primarily for control of lepidopteran agricultural pests. Field studies have revealed that some lepidopteran species have developed mutations where a methionine in a particular position (e.g., I4790M) increases resistance to CHL. The toxicity data for CHL across species is limited, as is the case for many chemicals, which creates an opportunity to apply both traditional toxicity test methods and new approach methods (NAMs) to address data gaps. Here, the U.S. Environmental Protection Agency’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool was used to query the RyR to generate susceptibility predictions for species exposed to CHL to fill those data gaps. These SeqAPASS results generated testable hypotheses that were used to guide focused acute aquatic toxicity studies using Daphnia magna, Daphnia pulex, Pimephales promelas, and Danio rerio. The fish species were not sensitive to CHL, whereas D. magna and D. pulex were found to be sensitive to CHL at environmentally relevant concentrations, despite having the methionine residue in the position of the I4790M resistance mutation. Additional SeqAPASS results showed that many other species, including beneficial pollinators and Lepidoptera, are predicted as likely susceptible to CHL. This study provided multiple lines of evidence toward the unlikelihood for the I4790M mutation to be the primary cause of resistance across species, filled knowledge gaps concerning CHL toxicity across species, and generated predictions of susceptibility for nontarget species that are not generally amenable to toxicity testing. This work presents a case example that demonstrates how NAMs can be used in combination with other types of data to direct targeted testing and build confidence in predictive approaches for their use in risk assessment.
Waterborne toxicity of several dichlorodiphenyltrichloroethane congeners to Hyalella azteca and its implications for contaminated sediment assessment
Authors: Mount David R , Burkhard Lawrence P , Hockett J Russell , Holloway Chloe J , Howe Sarah E , Jenson James J , Kadlec Sarah M , Kasparek Alex J , Lahren Tylor J , Lott Kevin G , Piasecki Edward F , Swanson John J , Votava Lauren K
Published: January 2025

Although banned long ago in many countries and jurisdictions, the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) and compounds related to it remain in the aquatic environment, particularly in sediments, and can pose risks to aquatic life. To inform ecological risk assessment of these compounds, we tested the toxicity of six DDT congeners, specifically the p, p’ (4,4’) forms of DDT, dichlorodiphenyldichloroethylene (DDE), dichlorodiphenyldichloroethane (DDD), and dichlorodiphenylchloroethylene (DDMU), as well as the o, p’ (2,4’) isomers of DDT and DDD. The epibenthic amphipod, Hyalella azteca, was exposed for 7 days to waterborne chemical and assessed for changes in survival and growth. Median effect concentrations for biomass gain (aggregating effects on growth and survival) ranged from 0.14 µg/L (p, p’DDT) to 5.8 µg/L (o, p’DDD). Among p, p’ congeners, relative toxicity was DDT ≫ DDD > DDE ≈ DDMU. Ortho-para’ isomers were approximately five-fold less toxic than their p, p’ analogs. Much of the observed effect was expressed as lethality, as half maximal effect concentrations based on biomass were on average only 25% lower than the corresponding median lethal concentration. Effects in parallel 7-day and 10-day exposures indicated close comparability between the two durations for o, p’-DDT. Application of these waterborne exposure endpoints in ecological risk assessment of contaminated sediments is discussed.
High-performance thin-layer chromatography–umu combined with nontarget analysis—a sensitive genotoxicity screening tool applicable for potable water analysis
Authors: Flörs Markus , Schertzinger Gerhard , Pannekens Helena , Seitz Wolfram , Zwiener Christian , Winzenbacher Rudi
Published: January 2025

Monitoring of genotoxic chemicals released into the water cycle or formed through transformation processes is critical to prevent harm to human health. The development of the high-performance thin-layer chromatography (HPTLC)–umu bioassay combines sample separation and detection of genotoxic substances in the low ng/L concentration range. In this study, raw, process, and drinking water samples from 11 different waterworks in Germany were analyzed using the HPTLC-umu. A genotoxic response was detected in three out of 42 samples (one raw water sample and two drinking water samples). Genotoxicity testing using the micronucleus and p53-CALUX (chemical activated luciferase gene expression) assays revealed genotoxic effects for the raw water sample and one of the drinking water samples. Fortunately, only minor genotoxic effects could be detected in the two drinking water samples, with estimated 4-nitroquinoline-N-oxide equivalency concentrations of 0.12 ng/L and 0.17 ng/L, respectively. After extraction of the genotoxic zones from HPTLC plates, identification attempts were conducted with nontarget analysis (NTA). A prioritization approach based on chlorine and bromine isotope pattern revealed several halogenated features for both drinking water samples. These tentatively identified substances were previously reported in the literature as possible carcinogens. Although the detected features could not be conclusively identified, the presence of halogenated features in the genotoxic effective zone of the HPTLC-umu assay strongly suggests that the chlorine disinfection process in both waterworks was responsible for the formation of the genotoxic substances in the drinking water samples. These findings emphasize that the HPTLC-umu in combination with additional genotoxicity assays and NTA can be used to evaluate even relatively clean samples, such as drinking water.
Mycoremediation of Louisiana sweet crude oil with Pleurotus ostreatus and nutrient amendments
Authors: Crescent Summer S , Pisarski Emily C , Wirth Ed F , Long Richard A
Published: January 2025

Oyster mushrooms (Pleurotus ostreatus) are known to metabolize polycyclic aromatic hydrocarbons in petroleum crude oil, making them candidates for oil spill remediation studies. This work aimed to assess P. ostreatus for its hydrocarbon degradation potential in estuarine conditions. In vitro experiments evaluated nutrient amendments based on P. ostreatus carbon: nitrogen: phosphorous (C: N: P) ratios to optimize mycelium growth, increase degradation efficiencies, and reduce potential nutrient runoff in broader applications. Image analysis was used to track mycelium growth response to various salinities, nutrient amendments, and oil types. Subsequent evaluation of alterations within the saturate, aromatic, resin, and asphaltene (SARA) fractions constituting Louisiana sweet crude (LSC) was conducted via SARA analysis. Results indicate that P. ostreatus mycelium tolerates estuarine salinities, with maximum growth between 5 and 15‰. Relative to 0‰, growth was reduced at salinities >25‰, but positive growth was still observed. Nutrient amendments significantly increased growth over 7 days relative to untreated samples (p < 0.0001). The combination of ammonium chloride and potassium phosphate yielded optimal mycelium growth after 7 days. Mycelium and nutrients significantly altered saturate (p = 0.0015) and asphaltene (p = 0.0124) fractions in LSC. This study suggests that mycelium growth is viable under estuarine salinities and can be enhanced with nutrient amendments. Introducing nutrient factors was shown to influence oil degradation. Results also indicate that mycelium can reduce recalcitrant oil fractions. Thus, this study highlights the adaptability of P. ostreatus to estuarine conditions and its response to nutrient amendments, all while offering a promising approach to crude oil bioremediation.
Drinking water treatment residuals reduce toxicity to fish from metal-contaminated sediments
Authors: Kurita-Oyamada Hajime G , Kroll Kevin J , Zhou Lang , Kozuch Marianne , Wallace Samuel M , Gaillard Jean-François , Bonzongo Jean-Claude J , Denslow Nancy D
Published: January 2025

Drinking water treatment residuals (DWTRs) produced as a result of the coagulation-flocculation process during water treatment are considered waste materials. Characterization of this material shows its ability to sequester metals and other anionic and cationic chemicals. Drinking water treatment residuals from two different drinking water treatment plants located in Wyoming and Oregon were evaluated for their ability to function as viable capping materials of metal-contaminated sediments. The contaminated sediments tested were either spiked with a mixture of metals, 1 mg/kg of Cu, Zn, Cd, and Pb, or coming from an intertidal sediment collected at a U.S. Naval Air Station. A Gust chamber experiment was used to determine metal fluxes from these sediments into the overlying water with applied hydrodynamic stress of 0.05 and 0.4 Pa in the absence and presence of DWTR as a capping material. The DWTR effectively reduced the amount of metal released to the overlying waters to a value below the National Recommended Aquatic Life Criteria for Cr, Cu, Pb, and Zn, but slightly above the value for Cd. The toxicity of these waters was tested with an in vivo 96 hr fathead minnow survival assay. In the absence of capping, all the fry died within 1 hr. Capping with DWTR from Wyoming effectively reduced contamination, and 95% of the fish survived. The DWTR from Oregon was less successful, but the survival of fish was equivalent to diluting the original contaminated waters by a factor of 100. Drinking water treatment residual effectively reduced metallothionein in fish, a biomarker of metal contamination, corroborating the survival experiments. These results suggest that DWTRs may be very effective for remediation of metal-contaminated sites.
Mind the gap—national pesticide monitoring data needs for invertebrate effects assessments in English rivers
Authors: Poyntz-Wright Imogen P , Tyler Charles R
Published: January 2025

Pesticides are an integral part of agriculture in arable and pastoral farming and in animal and pet care, but they have been shown to have detrimental impacts on biodiversity, including of freshwater systems. The United Kingdom (UK) has the 7th highest pesticide usage per area of arable land across 30 European and African countries assessed between the years 2000 and 2012 and thus an associated higher likelihood for impacts on riverine biodiversity. In our analysis of the UK’s 24-year national chemical monitoring program (WIMS database; years 2000 to 2023), we show that of the nine pesticides that pose the greatest likely threat to UK freshwater invertebrates based on concentrations measured in British rivers exceeding the lowest effect concentrations (ECs) in laboratory-based toxicity tests, seven pesticides have exceeded the ECs across England between the years 2000 and 2023. The Anglian and Midland regions of England that have the highest regional arable pesticide use recorded the greatest number of pesticides exceeding the ECs for aquatic invertebrates. However, this finding may also be influenced by the more limited sampling/monitoring bias across England, and greater sampling of southern and northwest rivers is needed to better establish the potential impact of pesticides on riverine invertebrate communities in those regions.
Mutation impact on mRNA versus protein expression across human cancers
Authors: Liu Yuqi , Elmas Abdulkadir , Huang Kuan-lin
Published: January 2025

Background

Cancer mutations are often assumed to alter proteins, thus promoting tumorigenesis. However, how mutations affect protein expression—in addition to gene expression—has rarely been systematically investigated. This is significant as mRNA and protein levels frequently show only moderate correlation, driven by factors such as translation efficiency and protein degradation. Proteogenomic datasets from large tumor cohorts provide an opportunity to systematically analyze the effects of somatic mutations on mRNA and protein abundance and identify mutations with distinct impacts on these molecular levels.

Results

We conduct a comprehensive analysis of mutation impacts on mRNA- and protein-level expressions of 953 cancer cases with paired genomics and global proteomic profiling across 6 cancer types. Protein-level impacts are validated for 47.2% of the somatic expression quantitative trait loci (seQTLs), including CDH1 and MSH3 truncations, as well as other mutations from likely “long-tail” driver genes. Devising a statistical pipeline for identifying somatic protein-specific QTLs (spsQTLs), we reveal several gene mutations, including NF1 and MAP2K4 truncations and TP53 missenses showing disproportional influence on protein abundance not readily explained by transcriptomics. Cross-validating with data from massively parallel assays of variant effects (MAVE), TP53 missenses associated with high tumor TP53 proteins are more likely to be experimentally confirmed as functional.

Conclusion

This study reveals that somatic mutations can exhibit distinct impacts on mRNA and protein levels, underscoring the necessity of integrating proteogenomic data to comprehensively identify functionally significant cancer mutations. These insights provide a framework for prioritizing mutations for further functional validation and therapeutic targeting.
Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways
Authors: Wyatt Rachael A , Jamaluddin Aqfan , Mistry Vinesh , Quinn Caitlin , Gorvin Caroline M
Published: January 2025

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed at hypothalamic neurons that has an important role in appetite suppression and food intake. Mutations in MC4R are the most common cause of monogenic obesity and can affect multiple signaling pathways including Gs-cAMP, Gq, ERK1/2, β-arrestin recruitment, internalization and cell surface expression. The melanocortin-2 receptor accessory protein 2 (MRAP2), is a single-pass transmembrane protein that interacts with and regulates signaling by MC4R. Variants in MRAP2 have also been identified in overweight and obese individuals. However, functional studies that have only measured the effect of MRAP2 variants on MC4R-mediated cAMP signaling have produced inconsistent findings and most do not reduce MC4R function. Here we investigated the effect of twelve of these previously reported MRAP2 variants and showed that all variants that have been identified in overweight or obese individuals impair MC4R function. When expressed at equal concentrations, seven MRAP2 variants impaired MC4R-mediated cAMP signaling, while nine variants impaired IP3 signaling. Four mutations in the MRAP2 C-terminus affected internalization. MRAP2 variants had no effect on total or cell surface expression of either the MRAP2 or MC4R proteins. Structural models predicted that MRAP2 interacts with MC4R transmembrane helices 5 and 6, and mutations in two MRAP2 residues in putative contact sites impaired the ability of MRAP2 to facilitate MC4R signaling. In summary, our studies demonstrate that human MRAP2 variants associated with obesity impair multiple MC4R signaling pathways and that both Gs-cAMP and Gq-IP3 pathways should be assessed to determine variant pathogenicity.
A Similar Mutation in the AAUU-Rich Elements of the Mouse TNF Gene Results in a Distinct Ileocolitic Phenotype: A New Strain of TNF-Overexpressing Mice
Authors: Chilukuri Amruth , Kim Margaret , Mitra Taniya , Gubatan John M , Urrete Josef , Saxon Leo D , Ablack Amber , Mikulski Zbigniew , Dobaczewska Katarzyna , Shen Zining , Keir Mary , Yi Tangsheng , Kaur Prabhdeep , Oliveira Patricia , Murillo-Saich Jessica , Chang Eric Y , Steiner Calen A , Jedlicka Paul , Guma Mónica , Rivera-Nieves Jesús
Published: January 2025

Background

Tumor necrosis factor (TNF) is a pleiotropic cytokine that plays a critical role in the pathogenesis of immune-mediated diseases including inflammatory bowel disease (IBD). The stability of its mRNA transcript, determined in part by destabilizing sequences in its AAUU repeats (ARE) gene region, is an important regulator of its tissue and systemic levels. A deletion in the ARE region of the gene resulted in IBD and arthritis in mice and pigs, supporting a critical role for the cytokine in human IBD and several human arthritides. A mutation in the same area of the mouse genome by Genentech scientists (T.Y., M.K.) resulted in a similar but not identical phenotype.

Methods

Here, we compare histopathological, cellular, and molecular features of the strains and propose reasons for their distinct phenotypes. First, while homozygous TNFΔARE mice develop severe arthritis and die after weaning, homozygous Genentech TNFΔARE (ΔG/ΔG) mice have normal lifespans, and males are often fertile.

Results

We found that while the ileitic phenotype had peaked at 12 weeks of age in all mice, colitis progressed mostly after 20 weeks of age in heterozygous mice. Their variably penetrant arthritic phenotype progressed mostly after 20 weeks, also in heterozygous mice from both strains. There was expansion of central memory T and B cells in lymphoid organs of TNF-overproducing strains and their transcriptional profile shared well-known pathogenetic pathways with human IBD. Finally, we found differences in the mutated sequences within the ARE regions of the TNF gene and in their microbiota composition and genetic background. These differences likely explain their phenotypic differences.

Conclusions

In summary, we describe a different strain of TNF-overproducing mice with an overlapping, yet not identical phenotype, which may have differential applications than the original strain.