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Waterways that drain the Great Barrier Reef catchment area (GBRCA) transport pollutants to marine habitats, provide a critical corridor between freshwater and marine habitats for migratory fish species, and are of high socioecological value. Some of these waterways contain concentrations of pesticide active ingredients (PAIs) that exceed Australian ecotoxicity threshold values (ETVs) for ecosystem protection. In this article, we use a "pathway to harm" model with five key criteria to assess whether the available information supports the hypothesis that PAIs are or could have harmful effects on fish and arthropod populations. Strong evidence of the first three criteria and circumstantial weaker evidence of the fourth and fifth criteria are presented. Specifically, we demonstrate that exceedances of Australian and New Zealand ETVs for ecosystem protection are widespread in the GBRCA, that the PAI contaminated water occurs (spatially and temporally) in important habitats for fisheries, and that there are clear direct and indirect mechanisms by which PAIs could cause harmful effects. The evidence of individuals and populations of fish and arthropods being adversely affected species is more circumstantial but consistent with PAIs causing harmful effects in the freshwater ecosystems of Great Barrier Reef waterways. We advocate strengthening the links between PAI concentrations and fish health because of the cultural values placed on the freshwater ecosystems by relevant stakeholders and Traditional Owners, with the aim that stronger links between elevated PAI concentrations and changes in recreationally and culturally important fish species will inspire improvements in water quality. Integr Environ Assess Manag 2024;20:1256-1279. © 2023 Commonwealth of Australia and The Commonwealth Scientific and Industrial Research Organisation. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2023 Commonwealth of Australia and The Commonwealth Scientific and Industrial Research Organisation. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

Suppressor of Mek1 (Smek1) is a regulatory subunit of protein phosphatase 4. Genome-wide association studies have shown the protective effect of SMEK1 in Alzheimer's disease (AD). However, the physiological and pathological roles of Smek1 in AD and other tauopathies are largely unclear. Here, the role of Smek1 in preventing neurodegeneration is investigated in tauopathy. Smek1 is downregulated in the aged human brain. Through single-cell sequencing, a novel neuronal cluster is identified that possesses neurodegenerative characteristics in Smek1 -/- mice. Smek1 deficiency caused markedly more severe motor and cognitive impairments in mice, as well as neuronal loss, gliosis, and tau hyperphosphorylation at major glycogen synthase kinase 3β (Gsk3β) sites. Protein-protein interaction analysis revealed that the Ran-binding domain (RanBD) in the N-terminus of Smek1 facilitated binding with kinesin family member 2A (Kif2a). Depletion of Smek1 resulted in cytoplasmic aggregation of Kif2a, axon outgrowth defects, and impaired mitochondrial axonal trafficking. Downregulation of Kif2a markedly attenuated tau hyperphosphorylation and axon outgrowth defects in shSmek1 cells. For the first time, this study demonstrates that Smek1 deficiency progressively induces neurodegeneration by exacerbating tau pathology and mitochondrial dysfunction in an age-dependent manner., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Therapeutic oligonucleotides, such as antisense DNA, show promise in treating previously untreatable diseases. However, their applications are still hindered by the poor membrane permeability of naked oligonucleotides. Therefore, it is necessary to develop efficient methods for intracellular oligonucleotide delivery. Previously, our group successfully developed disulfide-based Membrane Permeable Oligonucleotides (MPON), which achieved enhanced cellular uptake and gene silencing effects through an endocytosis-free uptake mechanism. Herein, we report a new molecular design for the next generation of MPON, called trimer MPON. The trimer MPON consists of a tri-branched backbone, three α-lipoic acid units, and a spacer linker between the oligonucleotides and tri-branched cyclic disulfide unit. We describe the design, synthesis, and functional evaluation of the trimer MPON, offering new insights into the molecular design for efficient oligonucleotide delivery., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Neurodegenerative diseases (NDDs) refer to a complex heterogeneous group of diseases which are associated with the accumulation of amyloid fibrils or plaques in the brain leading to progressive loss of neuronal functions. Alzheimer's disease is one of the major NDD responsible for 60-80 % of all dementia cases. Currently, there are no curative or disease-reversing/modifying molecules for many of the NDDs except a few such as donepezil, rivastigmine, galantamine, carbidopa and levodopa which treat the disease-associated symptoms. Similarly, there are very few FDA-approved tracers such as flortaucipir (Tauvid) for tau fibril imaging and florbetaben (Neuraceq), flutemetamol (Vizamyl), and florbetapir (Amyvid) for amyloid imaging available for diagnosis. Recent advances in the cryogenic electron microscopy reported distinctly different microstructures for tau fibrils associated with different tauopathies highlighting the possibility to develop tauopathy-specific imaging agents and therapeutics. In addition, it is important to identify the proteins that are associated with disease development and progression to know about their 3D structure to develop various diagnostics, therapeutics and theranostic agents. The current article discusses in detail the disease-associated amyloid and non-amyloid proteins along with their structural insights. We comprehensively discussed various novel proteins associated with NDDs and their implications in disease pathology. In addition, we document various emerging chemical compounds developed for diagnosis and therapy of different NDDs with special emphasis on theranostic agents for better management of NDDs., (© 2024 Wiley-VCH GmbH.)

Technical complexity associated with biodegradation testing, particularly for substances of unknown or variable composition, complex reaction products, or biological materials (UVCB), necessitates the advancement of non-testing methods such as quantitative structure-property relationships (QSPRs). Models for describing the biodegradation of petroleum hydrocarbons (HCs) have been previously developed. A critical limitation of available models is their inability to capture the variability in biodegradation rates associated with variable test systems and environmental conditions. Recently, the Hydrocarbon Biodegradation System Integrated Model (HC-BioSIM) was developed to characterize the biodegradation of HCs in aquatic systems with the inclusion of key test system variables. The present study further expands the HC-BioSIM methodology to soil and sediment systems using a database of 2195 half-life (i.e., degradation time [DT]50) entries for HCs in soil and sediment. Relevance and reliability criteria were defined based on similarity to standard testing guidelines for biodegradation testing and applied to all entries in the database. The HC-BioSIM soil and sediment models significantly outperformed the existing biodegradation HC half-life (BioHCWin) and virtual evaluation of chemical properties and toxicities (VEGA) quantitative Mario Negri Institute for Pharmacological Research (IRFMN) models in soil and sediment. Average errors in predicted DT50s were reduced by up to 6.3- and 8.7-fold for soil and sediment, respectively. No significant bias as a function of HC class, carbon number, or test system parameters was observed. Model diagnostics demonstrated low variability in performance and high consistency of parameter usage/importance and rule structure, supporting the generalizability and stability of the models for application to external data sets. The HC-BioSIM provides improved accuracy of Persistence categorization, with correct classification rates of 83.9%, and 90.6% for soil and sediment, respectively, demonstrating a significant improvement over the existing BioHCWin (70.7% and 58.6%) and VEGA (59.5% and 18.5%) models. Environ Toxicol Chem 2024;43:1352-1363. © 2024 Concawe. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2024 Concawe. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Aim: This study analyzed psychiatric-mental health nurse practitioner (PMHNP) students' reflections following a virtual simulated encounter with a patient who identified as transgender or gender expansive (TGE)., Background: To reduce mental health disparities, PMHNP students must be prepared to deliver affirming care. Engaging in and reflecting on simulated encounters with standardized patients can improve PMHNP students' affirming care competency., Method: A thematic analysis process was used to analyze student reflections during simulation debriefings., Results: Five themes emerged: application of affirming care principles, recognizing minority stressors, treating all patients the same, desire to learn more, and valuing authentic practice., Conclusion: PMHNP students' reflections on the experience of providing care to a standardized patient who identified as TGE support the use of virtual simulations to prepare future providers to deliver affirming, person-centered care., Competing Interests: The authors have declared no conflict of interest., (Copyright © 2023 National League for Nursing.)

Aim: The aim of this study was to examine the impact of reverse-role simulation on nursing students' empathy levels toward ethnoculturally diverse patients., Background: Empathy is an essential component of culturally competent care; however, it is often left out of cultural competence education. Enhancing nursing students' cultural empathy may benefit students and patients., Method: The study used a quasi-experimental one-group pretest-posttest design in a private nursing school in the Northeast. The sample consisted of 37 undergraduate nursing students., Results: Pretest and posttest scores were statistically different, indicating a significant increase in the students' ethnocultural empathy, t (36) = -3.20, p = .003., Conclusion: This study supports using reverse-role simulation as an effective teaching strategy to enhance nursing students' empathy toward ethnocultural diverse patients. Placing students in the "shoes" of an ethnoculturally diverse patient can increase their empathy levels and enhance cultural competence education., Competing Interests: The author has declared no conflict of interest., (Copyright © 2024 National League for Nursing.)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance of plasma low-density lipoprotein cholesterol (LDL-C). PCSK9 inhibitors are developed to primarily reduce the cardiovascular risk by lowering LDL-C level. Recently, a number of pleiotropic extrahepatic functions of PCSK9 beyond the regulation of cholesterol metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence have revealed that PCSK9 may play a significant role in neurocognition, depression, Alzheimer's disease, and stroke. The focus of this review is to elucidate the functions of PCSK9 and highlight the effects of PCSK9 in CNS diseases, with the aim of identifying the potential risks that may arise from low PCSK9 level (variant or inhibitor) in the clinical practice., (© 2023 Wiley Periodicals LLC.)

Abstract: Advanced practice registered nurse (APRN) students face challenges transitioning to practice. They benefit greatly from simulated learning experiences that build confidence and increase competence in the skills needed to perform in an APRN role. The purpose of this quality improvement project was to evaluate the effectiveness of a simulated adolescent well visit in an advanced health assessment course. Using a pretest/posttest design, qualitative and quantitative data were collected from participants. Results included high learner satisfaction, an increase in both self-reported competence and confidence, and an appreciation for the "safe space" of learning., Competing Interests: The authors have declared no conflict of interest., (Copyright © 2024 National League for Nursing.)

Bayesian network (BN) models are increasingly used as tools to support probabilistic environmental risk assessments (ERAs), because they can better account for uncertainty compared with the simpler approaches commonly used in traditional ERA. We used BNs as metamodels to link various sources of information in a probabilistic framework, to predict the risk of pesticides to aquatic communities under given scenarios. The research focused on rice fields surrounding the Albufera Natural Park (Valencia, Spain), and considered three selected pesticides: acetamiprid (an insecticide), 2-methyl-4-chlorophenoxyacetic acid (MCPA; a herbicide), and azoxystrobin (a fungicide). The developed BN linked the inputs and outputs of two pesticide models: a process-based exposure model (Rice Water Quality [RICEWQ]), and a probabilistic effects model (Predicts the Ecological Risk of Pesticides [PERPEST]) using case-based reasoning with data from microcosm and mesocosm experiments. The model characterized risk at three levels in a hierarchy: biological endpoints (e.g., molluscs, zooplankton, insects, etc.), endpoint groups (plants, invertebrates, vertebrates, and community processes), and community. The pesticide risk to a biological endpoint was characterized as the probability of an effect for a given pesticide concentration interval. The risk to an endpoint group was calculated as the joint probability of effect on any of the endpoints in the group. Likewise, community-level risk was calculated as the joint probability of any of the endpoint groups being affected. This approach enabled comparison of risk to endpoint groups across different pesticide types. For example, in a scenario for the year 2050, the predicted risk of the insecticide to the community (40% probability of effect) was dominated by the risk to invertebrates (36% risk). In contrast, herbicide-related risk to the community (63%) resulted from risk to both plants (35%) and invertebrates (38%); the latter might represent (in the present study) indirect effects of toxicity through the food chain. This novel approach combines the quantification of spatial variability of exposure with probabilistic risk prediction for different components of aquatic ecosystems. Environ Toxicol Chem 2024;43:182-196. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Kraft lignin, a by-product from the production of pulp, is currently incinerated in the recovery boiler during the chemical recovery cycle, generating valuable bioenergy and recycling inorganic chemicals to the pulping process operation. Removing lignin from the black liquor or its gasification lowers the recovery boiler load enabling increased pulp production. During the past ten years, lignin separation technologies have emerged and the interest of the research community to valorize this underutilized resource has been invigorated. The aim of this Review is to give (1) a dedicated overview of the kraft process with a focus on the lignin, (2) an overview of applications that are being developed, and (3) a techno-economic and life cycle asseeements of value chains from black liquor to different products. Overall, it is anticipated that this effort will inspire further work for developing and using kraft lignin as a commodity raw material for new applications undeniably promoting pivotal global sustainability concerns., (© 2023 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

In the North Sea and North Atlantic coastal areas, fish experience relatively high background levels of persistent organic pollutants. This study aimed to compare the mode of action of environmentally relevant concentrations of mixtures of halogenated compounds in Atlantic cod. Juvenile male cod with mean weight of 840 g were exposed by gavage to dietary mixtures of chlorinated (PCBs, DDT analogs, chlordane, lindane, and toxaphene), brominated (PBDEs), and fluorinated (PFOS) compounds for 4 weeks. One group received a combined mixture of all three compound groups. The results showed that the accumulated levels of chemicals in cod liver after 4 weeks of exposure reflected concentrations found in wild fish in this region. Pathway analysis revealed that the treatment effects by each of the three groups of chemicals (chlorinated, brominated, and fluorinated) converged on activation of the unfolded protein response (UPR). Upstream regulator analysis predicted that almost all the key transcription factors (XBP1, ERN1, ATF4, EIF2AK3, and NFE2L2) regulating the UPR were significantly activated. No additive effect was observed in cod co-treated with all three compound groups. In conclusion, the genome-wide transcriptomic study suggests that the UPR pathway is a sensitive common target of halogenated organic environmental pollutants in fish., (© 2023 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.)

Based on surface air temperature and precipitation, the current study examines the climate fluctuations over Sistan-and-Baluchestan Province, Iran's second-largest province. This area suffers from insufficient direct observations and a lack of climatic investigation. Three datasets were utilized including in situ data, gridded data (1984-2013), outputs of historical runs (during 1984-2013), and projections under the SSP5-8.5, SSP3-7.0, and SSP1-2.6 scenarios (in 2020-2049) of twenty-six Global Climate Models (GCMs) from the latest Coupled Model Intercomparison Project (CMIP6). The models' performance has been evaluated and ranked using the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) in Multi-Criteria Decision Making (MCDM) technique including eight metrics in both seasonal and annual scales. The surface air temperature showed an increasing trend in seasonal and annual scales during 1984-2013, while the monthly precipitation trend increased for September-October-November and decreased for the other seasons and annual scale during 1984-2013. The top-ranked models for simulating surface air temperature (precipitation) were CESM2 (GFDL-ESM4), IPSL-CM6A-LR (UKESM1-0-LL), ACCESS-CM2 (GFDL-ESM4), and MIROC-ES2L (MPI-ESM1-2-LR) models in DJF, MAM, JJA, and SON seasons, respectively, while ACCESS-CM2 (CNRM-CM6-1-HR) model outperformed others in annual scale. Bias-corrected outputs of the top-ranked CMIP6 GCMs showed an increasing trend for surface air temperature in all seasons (from a 0.7 K increase in December-January-February season under SSP3-7.0 scenario to a 2.5 K increase in June-July-August season under SSP5-8.5 scenario) for period 2020-2049, comparing with that in 1984-2013 period. Bias-corrected monthly precipitation projected by top-ranked CMIP6 GCMs indicated both increasing and decreasing trends depending on selected season and scenario. This varied from a 5 mm/month decrease within December-January-February season under SSP5-8.5 scenario to a 13 mm/month increase during the March-April-May season under SSP1-2.6 scenario in 2020-2050, comparing with that from previous years., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The Japanese medaka (Oryzias latipes) extended one-generation reproduction test (MEOGRT) (Test Guideline 890.2200) is a Tier 2 test within the Endocrine Disruptor Screening Program of the US Environmental Protection Agency (US EPA). A modified MEOGRT was used to evaluate multigenerational effects of 2-ethylhexyl 4-hydroxybenzoate (2-EHHB) under flow-through conditions starting with adults (parent generation, F0) through a 3-week reproductive phase of the second generation (F2). Fish were exposed to one of five 2-EHHB test concentrations or a dechlorinated tap water control. Fecundity was affected at the lowest exposure (5.32 μg/L) and greater sensitivity occurred in the F1 and F2 generations. Percent fertility was also diminished from no effect level observed in the F0 generation to 101 and 48.8 μg/L in the F1 and F2 generations, respectively. Growth indices were decreased for F0 adult females and F1 subadults and adults at 48.8 μg/L 2-EHHB. Histopathologic examination of gonads, liver, kidney, and thyroid yielded possible delayed reproductive tract development in F1 subadult males, masculinization of the renal phenotype in F1 adult females (renal tubular eosinophilia) and reduced hepatic energy storage (liver glycogen vacuoles) in F1 (11.3 and 48.8 μg/L) and F2 (48.8 and 101 μg/L) males and females, respectively. Endocrine-related findings included a decrease in anal fin papillae in F2 adult males at 101 μg/L. Results of this study demonstrate effects on growth, development, and reproduction that may be mediated by endocrine (weak estrogenic) and nonendocrine mechanisms. Duration of the MEOGRT should not be routinely extended beyond the OCSPP 890 guideline study design., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Per- and polyfluoroalkyl substances (PFAS) are an emerging class of compounds that cause health and environmental problems worldwide. In aquatic environments, PFAS may bioaccumulate in sediment organisms, which can affect the health of organisms and ecosystems. As such, it is important to develop tools to understand their bioaccumulation potential. In the present study, the uptake of perfluorooctanoic acid (PFOA) and perfluorobutane sulfonic acid (PFBS) from sediments and water was assessed using a modified polar organic chemical integrative sampler (POCIS) as a passive sampler. While POCIS has previously been used to measure time-weighted concentrations of PFAS and other compounds in water, in our study, the design was adapted for analyzing contaminant uptake and porewater concentrations in sediments. The samplers were deployed into seven different tanks containing PFAS-spiked conditions and monitored over 28 days. One tank contained only water with PFOA and PFBS, three tanks contained soil with 4% organic matter, and three tanks contained soil combusted at 550 °C to minimize the influence of labile organic carbon. The uptake of PFAS from the water was consistent with previous research using a sampling rate model or simple linear uptake. For the samplers placed in the sediment, the uptake process was explained well using a mass transport based on the external resistance from the sediment layer. Uptake of PFOS in the samplers occurred faster than that of PFOA and was more rapid in the tanks containing the combusted soil. A small degree of competition was observed between the two compounds for the resin, although these effects are unlikely to be significant at environmentally relevant concentrations. The external mass transport model provides a mechanism to extend the POCIS design for measuring porewater concentrations and sampling releases from sediments. This approach may be useful for environmental regulators and stakeholders involved in PFAS remediation. Environ Toxicol Chem 2023;42:2171-2183. © 2023 SETAC., (© 2023 SETAC.)

Quantifying causal exposure-response relationships for polychlorinated biphenyl (PCB) toxicity to benthic invertebrates can be an important component of contaminated sediment assessments, informing cleanup decisions and natural resource injury determinations. Building on prior analyses, we demonstrate that the target lipid model accurately predicts aquatic toxicity of PCBs to invertebrates, providing a means to account for effects of PCB mixture composition on the toxicity of bioavailable PCBs. We also incorporate updated data on PCB partitioning between particles and interstitial water in field-collected sediments, to better account for effects of PCB mixture composition on PCB bioavailability. To validate the resulting model, we compare its predictions with sediment toxicity data from spiked sediment toxicity tests and a variety of recent case studies from sites where PCBs are the primary sediment contaminant. The updated model should provide a useful tool for both screening-level and in-depth risk analyses for PCBs in sediment, and it should aid in diagnosing potential contributing factors at sites where sediment toxicity and benthic community impairment are observed. Environ Toxicol Chem 2023;42:1134-1151. © 2023 SETAC., (© 2023 SETAC.)

Background: Atrazine simazine and propazine, widely used triazine herbicides on food crops and in residential areas, disrupt the neuroendocrine system raising human health concerns. USEPA developed a PBPK model based on triazine common Mode of Action (MOA)-suppression of luteinizing hormone surge in female rats-to generate human regulatory points of departure (POD: mg/kg/day). We compared triazine Human Administered Equivalent Dose (AED Human mg/kg/day) predictions from open access computational tools to the PBPK PODs to assess concordance., Methods: Computational tools were the following: ToxCast/Tox21 in vitro assays; Toxicogenomic databases to assess concordance with ToxCast/Tox21 targets; integrated chemical environment (ICE) models with ToxCast/Tox21 inputs to predict AED Human PODs and population-based age-refined high throughput toxicokinetics (HTTK-Pop) to compare to age-related PBPK PODs., Results: ToxCast/Tox21 assays identified critical targets in the triazine common MOA and gene databases; ICE AED Human predictions were mainly concordant with the USEPA PBPK PODs quantitatively. Low fold-differences between PBPK POD and ICE AED Human predictions indicated that the ICE models are health-protective. HTTK-Pop age-refinements were within 10-fold of the USEPA PBPK PODs., Conclusions: CompTox tools were used to identify assay targets in the MOA and identify potential molecular initiating targets in the adverse outcome pathway for potential use in risk assessment., (© 2022 Wiley Periodicals LLC.)

Effect-based methods (EBMs) using in vitro bioassays and well plate-based in vivo assays are recommended for water quality monitoring because they can capture the mixture effects of the many chemicals present in water. Many in vitro bioassays are highly sensitive, so an effect in a bioassay does not necessarily indicate poor chemical water quality. Consequently, effect-based trigger values (EBTs) have been introduced to differentiate between acceptable and unacceptable chemical water quality and are required for the wider acceptance of EBMs by the water sector and regulatory bodies. These EBTs have been derived for both drinking water and surface water to protect human and ecological health, respectively, and are available for assays indicative of specific receptor-mediated effects, as well as assays indicative of adaptive stress responses, apical effects, and receptor-mediated effects triggered by many chemicals. An overview of currently available EBTs is provided, and a simple approach is proposed to predict interim EBTs for assays currently without an EBT based on the effect concentration of the assay reference compound. There was good agreement between EBTs predicted using this simplistic approach and EBTs from the literature derived using more robust methods. Finally, an interpretation framework that outlines the steps to take if the effect of a sample exceeds the EBT was developed to help facilitate the uptake of EBMs in routine water quality monitoring and water safety planning for drinking water production. Environ Toxicol Chem 2023;42:714-726. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Triacylglycerol (TG) metabolism is tightly regulated to maintain a pool of TG within circulating lipoproteins that can be hydrolyzed in a tissue-specific manner by lipoprotein lipase (LPL) to enable the delivery of fatty acids to adipose or oxidative tissues as needed. Elevated serum TG concentrations, which result from a deficiency of LPL activity or, more commonly, an imbalance in the regulation of tissue-specific LPL activities, have been associated with an increased risk of atherosclerotic cardiovascular disease through multiple studies. Among the most critical LPL regulators are the angiopoietin-like (ANGPTL) proteins ANGPTL3, ANGPTL4, and ANGPTL8, and a number of different apolipoproteins including apolipoprotein A5 (ApoA5), apolipoprotein C2 (ApoC2), and apolipoprotein C3 (ApoC3). These ANGPTLs and apolipoproteins work together to orchestrate LPL activity and therefore play pivotal roles in TG partitioning, hydrolysis, and utilization. This review summarizes the mechanisms of action, epidemiological findings, and genetic data most relevant to these ANGPTLs and apolipoproteins. The interplay between these important regulators of TG metabolism in both fasted and fed states is highlighted with a holistic view toward understanding key concepts and interactions. Strategies for developing safe and effective therapeutics to reduce circulating TG by selectively targeting these ANGPTLs and apolipoproteins are also discussed., (© 2022 Wiley-VCH GmbH.)

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a large class of industrial chemicals with a ubiquitous and persistent presence in the environment. Of the thousands of PFAS used by consumers and industry, very few have been thoroughly characterized for potential adverse effects. This is especially true for the novel short-chain (C < 8) alternatives that replaced legacy PFAS. Perfluoroalkyl and polyfluoroalkyl substances have revealed inconsistencies in the toxicokinetics predicted by animal models and empirical findings in humans. To adequately assess the possible health effects of short-chain PFAS, there is a need for robust aggregated data sets on the mechanistic underpinnings and physiochemical properties of these alternatives. Acquiring relevant data on the health effects of short-chain PFAS can be achieved through high-throughput methods supported by in vitro human cell-based models. This review briefly summarizes some of the toxicity data obtained using human cells in vitro, discusses the advantages and limitations of cell-based models, and provides insights on potential solutions to challenges presented with the use of these methods for use in safety assessments., (© 2021 John Wiley & Sons, Ltd.)

Understanding the environmental fate, transport, and occurrence of pesticides and pharmaceuticals in aquatic environments is of utmost concern to regulators. Traditionally, monitoring of environmental contaminants in surface water has consisted of liquid chromatography-tandem mass spectrometry analyses for a set of targeted compounds in discrete samples. These targeted approaches are limited by the fact that they only provide information on compounds within a target list present at the time and location of sampling. To address these limitations, there has been considerable interest in suspect screening and nontargeted analysis (NTA), which allow for the detection of all ionizable compounds in the sample with the added benefit of data archiving for retrospective mining. Even though NTA can detect a large number of contaminants, discrete samples only provide a snapshot perspective of the chemical disposition of an aquatic environment at the time of sampling, potentially missing episodic events. We evaluated two types of passive chemical samplers for nontargeted analysis in mixed-use watersheds. Nontargeted data were processed using MS-DIAL to screen against our in-house library and public databases of more than 1300 compounds. The data showed that polar organic chemicals integrative samplers (POCIS) were able to capture the largest number of analytes with better reproducibility than organic compound-diffusive gradients in thin film (o-DGT), resulting from the greater amount of binding sorbent. We also showed that NTA combined with passive sampling gives a more representative picture of the contaminants present at a given site and enhances the ability to identify the nature of point and nonpoint pollution sources and ecotoxicological impacts. Environ Toxicol Chem 2022;41:1131-1143. © 2021 Her Majesty the Queen in Right of Canada Environmental Toxicology and Chemistry © 2021 SETAC. Reproduced with the permission of the Minister of Agriculture and Agri-Food Canada., (© 2021 Her Majesty the Queen in Right of Canada Environmental Toxicology and Chemistry © 2021 SETAC. Reproduced with the permission of the Minister of Agriculture and Agri-Food Canada.)

Background: Understanding the pathophysiology of degenerative diseases pertaining to nervous system, ocular region, bone/cartilage, and muscle are still being comprehended, thus delaying the availability of targeted therapies., Purpose and Scope: Newer micro-physiological systems (organ-on-chip technology) involves development of more sophisticated devices, modelling a range of in vitro human tissues and an array of models for diseased conditions. These models expand opportunities for high throughput screening (HTS) of drugs and are likely to be rapid and cost-effective, thus reducing extensive usage of animal models., Conclusion: Through this review article, we aim to present an overview of the degenerative disease models that are presently being developed using microfluidic platforms with the aim of mimicking in vivo tissue physiology and micro-architecture. The manuscript provides an overview of the degenerative disease models and their potential for testing and screening of possible biotherapeutic molecules and drugs. It highlights the perspective of the regulatory bodies with respect to the established-on chip models and thereby enhancing its translational potential., (© 2021 Wiley-VCH GmbH.)

Worldwide demand for petroleum products has resulted in increased oil and gas activities in many countries. Conventional and unconventional oil and gas extraction, production, and transport lead to increased levels of petroleum-derived polycyclic aromatic hydrocarbons (PAHs) in the environment. PAH exposure has profound effects on reproduction by affecting pathways involved in placental trophoblast cell function and impairing normal placental development and function-key contributors to reproductive success. However, other components found in petroleum and wastewaters from oil and gas extraction, including the sulfur-containing heterocyclic aromatic compounds such as dibenzothiophene (DBT) and its alkylated derivatives, may also impact reproductive success. The goal of this study was to examine the effect of exposure to DBT, a compound commonly detected in the environment, and one of its alkylated analogues, 2,4,7-trimethyldibenzothiophene (2,4,7-DBT), on steroidogenic and angiogenic pathways critical for mammalian development in placental trophoblast cells (HTR-8/SVneo cells). 2,4,7-DBT but not DBT increased estradiol output in association with increased tube-like formation (surrogate for angiogenesis). These changes in angiogenesis did not appear to be related to altered expression of the key placental angiogenic gene targets (ANGPTL4, VEGFA, and PGF). Neither compound showed a concentration related effect on progesterone synthesis or its receptor expression. Our results suggest that 2,4,7-DBT can disrupt key pathways important for placental trophoblast function and highlight the importance of determining the impact of exposure to both parent and alkylated compounds. Further, these data suggest that exposure to sulfur-containing heterocyclic aromatic compounds may lead to placental dysfunction and impact reproductive success at environmentally relevant levels., (© 2020 John Wiley & Sons, Ltd.)