bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract

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.
Effects of density dependence in growth and natural mortality on FMSY and maximum sustainable yield
Authors: Horbowy Jan , Sparholt Henrik , Cordier Axelle 
Published: January 2025

Abstract
In fisheries management, it is generally assumed that density-dependent processes are confined to the pre-recruit stage of a fish. Consequently, current calculations of fishing mortality reference points include density dependence (DD) solely in recruitment dynamics. However, several studies have reported the importance of DD in growth and natural mortality (M). In this study, we tested the effect of DD on estimates of fishing mortality producing maximum sustainable yields (FMSY), comparing these estimates to those resulting from constant growth and M. We simulated fish populations with a wide range of life-history traits (LHTs), applying either constant or density-dependent growth and M and derived FMSY for each stock. Results showed that including DD in growth and M led to higher FMSY and often also higher yield estimates (MSY). The effect of DD was found to be greater in growth than in M. Additionally, FMSY estimates derived from surplus production models fitted to generated stocks with density-dependent growth and/or M were generally closer to true FMSY, compared to those from age-based long-term predictions assuming constant growth and M. However, due to the inherent uncertainties in estimates of stock dynamics and biological reference points (BRPs), caution is suggested before implementing DD in FMSY calculations. Equilibrium yield curves relating production to stock size were right-skewed, shape parameters from production models were slightly below 1 for scenarios assuming constant growth and M, but declined to 0.5 with increasing DD.
Therapeutic potential of D-amino acid oxidase inhibitors for cognitive impairment associated with schizophrenia: learnings from luvadaxistat
Authors: Terry-Lorenzo Ryan T , Fan Reuben H , Khin Ni A , Singh Jaskaran B 
Published: January 2025

Abstract
Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been proposed to underlie the pathophysiology of schizophrenia, suggesting that promoting NMDAR activity may alleviate the negative or cognitive symptoms associated with schizophrenia. To circumvent excitotoxicity that may accompany direct agonism of the glutamate binding site on the NMDAR, therapeutic trials have focused on targeting the glycine binding site on the NMDAR. Direct administration of either glycine or D-serine, both of which are endogenous coagonists at the NMDAR glycine site, has yielded mixed outcomes across an array of clinical trials investigating different doses or patient populations. Furthermore, directly administering D-serine and glycine is challenging, and thus attention has turned to alternative, indirect methods that increase endogenous D-serine and glycine levels in the brain, such as D-amino acid oxidase (DAAO) inhibitors and glycine transporter 1 inhibitors, respectively. In this review, we provide an overview of the evidence supporting the potential of NMDAR modulators in general, and DAAO inhibitors in particular, as potential adjunctive treatments for schizophrenia. We also discuss the preclinical and clinical data related to luvadaxistat, an investigational highly selective and potent DAAO inhibitor that was under development for the treatment of the cognitive impairment associated with schizophrenia.
Environmental fate and aquatic risk assessment of oxyfluorfen in California rice fields
Authors: Bonnar David J , Tjeerdema Ronald S 
Published: January 2025

Abstract
The herbicide oxyfluorfen [OXY; 2-chloro-1-(3-ethoxy-4-nitrophenoxy)-4-(trifluoromethyl)benzene] recently emerged as a potential solution to combat herbicide resistance in California rice. Proposed as a preemergent applied preflood to soil, products are in development for use with OXY-tolerant rice strains. Currently, OXY is not registered for use with rice and its use in or near aquatic resources is restricted due to its high aquatic toxicity. Before OXY may be registered for use in California rice fields, its potential fate and aquatic risk must be evaluated. Particularly important is the identification of the minimum period water must be held on the field (water holding period) necessary for OXY to dissipate below levels of concern. In this assessment, the environmental fate of OXY and its risk to aquatic organisms under simulated California rice field conditions are characterized. The Pesticides in Flooded Applications Model (PFAM) was used to estimate environmental concentrations based on anticipated use patterns and water management practices in California (e.g., winter flooding, turnover, water holding, etc.). Two California rice field soil conditions were simulated in addition to standard soil conditions used in ecological risk assessment for rice. Results suggest OXY is likely to concentrate in sediment, dissipate slowly, and persist. Water holding period had little effect on paddy and release water concentrations. Risks from water column exposure were generally below levels of concern (LOC) for aquatic animals, whereas risks to aquatic plants, algae, and benthic invertebrates exceeded LOCs under all conditions evaluated. California rice field soil conditions were also associated with less risk compared with standard conditions. Reduced application rates were sufficient to reduce risk to acceptable levels in some situations. However, holding times up to 30 days had no effect on risk outcomes, suggesting water management needs of growers should be strongly considered when stipulating water holding periods for OXY.
Evaluation of interspecies correlation estimation models to increase taxonomic diversity while reducing reliance on animal testing for chemicals evaluated under the Toxic Substances Control Act
Authors: Raimondo Sandy , Lilavois Crystal R , Nelson S Lexi , Koehrn Kara , Fay Kellie , Eisenreich Karen , Nolan Emily Vebrosky , Green Chris , Bressette James 
Published: January 2025

Abstract
The U.S. Environmental Protection Agency is committed to the implementation of new approach methodologies (NAMs) to enhance the scientific basis for chemical hazard assessments. Chemical evaluations under the Toxic Substance Control Act (TSCA) are often conducted with limited test data and are well suited for NAMs applications. Interspecies correlation estimation (ICE) models are log-linear least squares regressions of the sensitivity between two species that estimate the acute toxicity of an untested species from the sensitivity of a surrogate. Interspecies correlation estimation models have been developed from and validated for diverse chemical modes of action, but their application in TSCA chemical assessments has not been previously evaluated. We use ICE models and a dataset of measured acute values for five chemicals, increasing the taxonomic diversity from which concentrations of concern (CoCs) are derived. Concentrations of concern were developed using approaches typically applied in TSCA risk evaluations, including application of assessment factors to the most sensitive species and the development of species sensitivity distributions where a minimum of eight species are represented by measured data. These CoCs were compared with those derived from datasets supplemented with ICE-predicted values, as well as comparing ICE predicted species mean acute values (SMAVs) to their respective measured values. Interspecies correlation estimation models predicted SMAVs within a factor of 5 and 10 for 87% and 92% of measured values, respectively. The CoCs developed from measured data only and data supplemented with ICE predicted toxicity were generally within five-fold, showing comparable protection. The taxonomic diversity in the ICE supplemented dataset was substantially higher than the measured data for species sensitivity distributions, providing a data-driven way of reducing uncertainty and potentially reducing the need for assessment factors. Interspecies correlation estimation models show promise as a NAM to improve the taxonomic representation included in chemical evaluations under TSCA.
REACH assessment of humans exposed to chemicals indirectly via the environment: screening modeling in EUSES versus state of the science
Authors: Verdonck Frederik , Jansen Leen , Csiszar Susan A , Davis Craig , Di Paolo Carolina , Gouin Todd , Jensen Elke , Schowanek Diederik , Wormuth Matthias , Tolls Johannes 
Published: January 2025

Abstract
The assessment of humans indirectly exposed to chemicals via the environment (HvE) is an assessment element of the Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) regulation. The European Union System for the Evaluation of Substances (EUSES) is the default screening tool, aimed at prioritizing chemicals for further refinement/higher tier assessment. This review summarizes the approach used in EUSES, evaluates the state of the science in human exposure modeling via the environment, and identifies areas for further research to strengthen the confidence and applicability of EUSES for assessing HvE. It confirms that EUSES v2.2 does serve as a conservative screening tool for identifying potential human risk due to HvE (via consumption of crops, meat and milk, fish, drinking water, and inhalation). However, certain submodels within EUSES have not been updated for at least two decades. For example, for highly soluble or highly hydrophobic or ionized organic substances, substance parameters are estimated based on outdated predictive models. We recommend to also update the REACH Technical Guidance to highlight possible refinements in HvE assessments as well as the integration of measured and (bio)monitoring data. Addressing limitations in the EUSES applicability domain, particularly for highly soluble and highly hydrophobic organic substances and ionized organics, would improve its applicability. We identified that some HvE submodels in EUSES could be readily updated to improve screening-level assessment in EUSES. In addition, updating the EUSES “food basket” using recent European Union food consumption data is crucial to accurately reflect recent dietary trends. Further research is required for prediction of leaf crop and drinking water exposure to better reflect the fate of chemicals in the environment. In particular for ionizable substances, research focused on QSAR (Quantitative Structure Acitivity Relationship) development and experimental measurement of fate properties is necessary to enhance the confidence of EUSES assessments.
Trends, challenges, and research pathways in emerging contaminants: a comprehensive bibliometric analysis
Authors: Alam Md Shahin , Tahriri Farzaneh , Chen Gang 
Published: January 2025

Abstract
The growing concern over environmental pollution has spurred extensive research into various contaminants impacting ecosystems and human health. Emerging contaminants (ECs), including pharmaceuticals, personal care products, endocrine-disrupting chemicals, nanomaterials, and microplastics, have garnered significant attention due to their persistence, bioaccumulation, and toxicity. This study presents a comprehensive bibliometric analysis of EC research, aiming to detail the research landscape, highlight significant contributions, and identify influential researchers and pivotal studies. Data were sourced from the Web of Science, encompassing 62,670 documents from January 2000 to May 2024. Advanced bibliometric tools, including Bibliometrix, VOSviewer, and CiteSpace, were employed to analyze publication outputs, citation metrics, and collaboration patterns. The analysis revealed an exponential increase in EC research, with annual publications growing from fewer than 1,000 before 2006 to nearly 7,000 by 2022. Environmental Science & Technology emerged as the most influential journal. Based on the number of publications and citations as a country, China and the United States led in research outputs. Co-authorship and collaboration networks highlighted key hubs and prominent researchers, with significant contributions from environmental sciences, chemical engineering, and toxicology. Keyword co-occurrence analysis identified core themes, such as degradation, removal, and the impacts of ECs, reflecting evolving research interests and emerging topics. This bibliometric analysis provides valuable insights into the development and current state of EC research, serving as a resource for guiding future research efforts and fostering collaborations. The study indicates the critical need for continued research to address the challenges posed by ECs and develop effective regulatory policies and remediation strategies.
Identifying priority areas for conservation based on the evaluation of ecological network resilience in the Hyrcanian Forest ecosystem
Authors: Karimi Sepideh , Amiri Mohammad Javad , Yavari Ahmad Reza 
Published: January 2025

Abstract
Habitat loss and fragmentation in forest ecosystems are serious threats that lead to reduced resilience. The integrity and stability of the ecosystem are fostered by recognizing and protecting areas that are essential to maintaining the resilience of the ecological network. Research in the field of ecological network resilience has garnered attention in recent years, although the necessity of developing various assessment methods for network resilience is evident. Taking the Hyrcanian Forest ecosystem as a case study, this research aimed to identify the most important areas of the ecological network in maintaining and enhancing the resilience. To achieve this goal, first, a combination of the morphological spatial pattern analysis method and the assessment of the significance of ecosystem services was used to extract ecological source areas. Next, utilizing circuit theory and the least-cost path method, a network connecting sources was constructed, and pinch points were identified. After that, high-risk areas in ecological sources were found using the habitat risk assessment method. Using this integrated approach leads to the identification of valuable areas that are vulnerable to human threats and disturbances. Finally, the node removal method coupled with the calculation of network resilience indices, connectivity, and efficiency was employed to prioritize conservation areas. The results of the study indicated that the most important nodes were located in the northern edges of the forest, which have been under threat in recent years. Additionally, the region ranked moderately in terms of connectivity, indicating the importance of focusing on the conservation of forest patches before the complete fragmentation of the area. Furthermore, our findings underscore the importance of considering landscape connectivity and ecological network resilience in conservation planning for policymakers and managers aiming to protect biodiversity in the Hyrcanian Forest ecosystem.
Socio-hydrological analysis: a new approach in water resources management in western Iran
Authors: Javanbakht Sheikhahmad Fatemeh , Rostami Farahnaz , Azadi Hossein , Veisi Hadi , Amiri Farzad , Witlox Frank 
Published: January 2025

Abstract
Human consumption patterns have a significant impact on the amount of available water. However, the human effect on water resources is perceived to have been poorly studied. For the effective management of water resources, social and hydrological components should be studied. To fill this gap, the aim of this study was to investigate the socio-hydrological system of the Gavshan Dam in western Iran. Therefore, the qualitative method and root cause analysis (RCA) were used to investigate the causes of the imbalance between water consumption and water resources. Root cause analysis was used to investigate the perceptions of 87 farmers and extension experts from Kermanshah province in Iran. Participants were chosen using the snowball technique and interviewed using a semistructured questionnaire. The results showed that the ineffective administrative structure was the most important and fundamental cause of water management inefficiency, accounting for 48.49% of the total inefficiency. Furthermore, the community sensitivity component (1.34%) indicated that the socio-hydrological system in the studied basin is not fully understood and that network users are not concerned about water crisis and environmental degradation. Poor yield, low income of farmers, reduction of cultivated area, social instability, and lack of secondary agricultural jobs are the main reasons for mismanagement of water resources. Conceptualizing water challenges based on the socio-hydrology revealed by this study can help designers focus on the fundamental causes, discover opportunities for policy, and implement sustainable water management strategies.
The ESG Onramp: from Organized Hypocrisy to Normative Practice
Authors: Jacobson David , Sommer Jamie M , Hargrove Andrew , Georgiev Georgi , Aquino Michele J 
Published: January 2025

Abstract
ESG can be described as the environmental, social, and governance practices institutionalized by companies over time. Much of the previous literature in this area cites these “pro-social” corporate restructuring, re-branding, or policy changes as emerging from scrutiny, or pressures from a company's stakeholders, shareholders, peers, and the public to incorporate more transparency, equity, environmental protection, and social responsibility in its management and operations. We combine theoretical frames from the sociology of organizations, specifically the theory of organized hypocrisy, the sociology of human rights, and the World Society approach. We articulate how social, political, and economic pressures, both internal and external to a company, as well as its current position in society (such as its characteristics like assets, size, stakeholders, etc.), influence its location and trajectory vis-a-vis ESG. We use two-way fixed-effects analysis of over 3,600 US-based firms from 1991 to 2016. Our research suggests that there is an ESG “onramp,” which we argue signals a shift from organized hypocrisy to a progressively expansive normative practice.
Sexual reproduction during diatom bloom
Authors: Prigent Léa , Quéré Julien , Plus Martin , Le Gac Mickael 
Published: January 2025

Abstract
Phytoplankton supports food webs in all aquatic ecosystems. Ecological studies highlighted the links between environmental variables and species successions in situ. However, the role of life cycle characteristics on phytoplankton community dynamics remains poorly characterized. In diatoms, sexual reproduction creates new genetic combinations and prevents excessive cell size miniaturization. It has been extensively studied in vitro but seldom in the natural environment. Here, analyzing metatranscriptomic data in the light of the expression patterns previously characterized in vitro, we identified a synchronized and transient sexual reproduction event during a bloom of the toxic diatom species Pseudo-nitzschia australis. Despite the complexity of environmental conditions encountered in situ, sexual reproduction appeared to be the strongest differential gene expression signal that occurred during the bloom. The potential link between environmental conditions and the initiation of sexual reproduction remain to be determined, but sexual reproduction probably had a major impact on the bloom dynamic.