bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multi-scenario risk assessment strategy applied to mixtures of chemicals of emerging concern in the River Aconcagua basin in Central Chile
Authors: Inostroza Pedro A. , Elgueta Sebastian , Krauss Martin , Brack Werner , Backhaus Thomas 
Published: August 2023

AbstractStreams and rivers are characterised by the presence of various chemicals of emerging concern (CECs), including pesticides, pharmaceuticals, personal care products, and industrial chemicals. While these chemicals are found usually only in low (ng/L) concentrations, they might still harm aquatic life and disrupt the ecological balance of aquatic ecosystems due to their high ecotoxicological potency. Environmental risk assessments that account for the complexity of exposures are needed in order to evaluate the toxic pressure of these chemicals, which also provide suggestions for risk mitigation and management, if necessary. Currently, most studies on the co-occurrence and environmental impacts of CECs are conducted in countries of the Global North, leaving massive knowledge gaps in countries of the Global South.In this study, we implement a multi-scenario risk assessment strategy to improve the assessment of both the exposure and hazard components in the chemical risk assessment process. Our strategy incorporates a systematic consideration and weighting of CECs that were not detected, as well as an evaluation of the uncertainties associated with Quantitative Structure-Activity Relationships (QSARs) predictions for chronic ecotoxicity. Furthermore, we present a novel approach to identifying mixture risk drivers. To expand our knowledge beyond well-studied aquatic ecosystems, we applied this multi-scenario strategy to the River Aconcagua basin of Central Chile. The analysis revealed that the concentrations of CECs exceeded acceptable risk thresholds for selected organism groups and the most vulnerable taxonomic groups. Streams flowing through agricultural areas and sites near the river mouth exhibited the highest risks. Notably, the eight risk drivers among the 153 co-occurring chemicals accounted for 66-92% of the observed risks in the river basin. Six of them are pesticides and pharmaceuticals, chemical classes known for their high biological activity in specific target organisms.Graphical abstractHighlights153 chemicals of emerging concern detected in complex multi-component mixtures.108 possible mixture risk assessment scenarios were investigated.Non-detects, QSARs, and experimental ecotoxicological data were integrated for risk assessment.8 chemicals of emerging concern were responsible for driving chronic environmental risks.
Machine learning identifies phenotypic profile alterations of human dopaminergic neurons exposed to bisphenols and perfluoroalkyls
Authors: Di Credico Andrea , Weiss Amélie , Corsini Massimo , Gaggi Giulia , Ghinassi Barbara , Wilbertz Johannes H. , Di Baldassarre Angela 
Published: August 2023

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of midbrain dopaminergic neurons. Endocrine disruptors (EDs) are active substances that interfere with hormonal signaling. Among EDs, bisphenols (BPs) and perfluoroalkyls (PFs) are chemicals leached from plastics and other household products, and humans are unavoidably exposed to these xenobiotics. Data from animal studies suggest that ED exposure may play a role in PD, but data about the effect of BPs and PFs on human models of the nervous system are lacking. Previous studies demonstrated that machine learning (ML) applied to microscopy data can classify different cell phenotypes based on image features. In this study, the effect of BPs and PFs at different concentrations within the real-life exposure range (0.01, 0.1, 1, and 2 μM) on the phenotypic profile of human stem cell-derived midbrain dopaminergic neurons (mDANs) was analyzed. Cells exposed for 72 hours to the xenobiotics were stained with neuronal markers and evaluated using high content microscopy yielding 126 different phenotypic features. Two different ML models (XGBoost and LightGBM) were trained to classify ED-treated versus control mDANs. ED-treated mDANs were identified with high accuracy (0.92). Assessment of the phenotypic feature contribution to the classification showed that EDs induced a significant increase of alpha-synuclein (αSyn) and tyrosine hydroxylase (TH) staining intensity within the neurons. Moreover, microtubule-associated protein 2 (MAP2) neurite length and branching were significantly diminished in treated neurons. Our study shows that human mDANs are adversely impacted by exposure to EDs, causing their phenotype to shift and exhibit more characteristics of PD. Importantly, ML-supported high-content imaging can identify concrete but subtle subcellular phenotypic changes that can be easily overlooked by visual inspection alone and that define EDs effects in mDANs, thus enabling further pathological characterization in the future.
Information propagation through enzyme-free catalytic templating of DNA dimerization with weak product inhibition
Authors: Cabello Garcia Javier , Mukherjee Rakesh , Bae Wooli , Stan Guy-Bart V. , Ouldridge Thomas E. 
Published: August 2023

AbstractInformation propagation by sequence-specific, template-catalyzed molecular assembly is the source of the biochemical complexity of living systems. Templating allows the production of thousands of sequence-defined proteins from only 20 distinct building blocks. By contrast, exploitation of this powerful chemical motif is rare in non-biological contexts, particularly in enzyme-free environments, where even the template-catalyzed formation of dimers is a significant challenge. The main obstacle is product inhibition: the tendency of products to bind to their templates more strongly than individual monomers, preventing the effective catalytic templating of longer polymers. Here we present a rationally designed enzyme-free system in which a DNA template catalyzes, with weak competitive product inhibition, the production of sequence-specific DNA dimers. We demonstrate the selective templating of 9 different dimers with high specificity and catalytic turnover. Most importantly, our mechanism demonstrates a rational design principle for engineering information propagation by molecular templating of longer polymers.
Effects of biological and environmental factors on filovirus serology in bats in Guinea
Authors: Champagne Maëliss , Cappelle Julien , Caron Alexandre , Pouliquen Thibault , Samoura Aboubacar , Doumbouya Mohamed Idriss , Thaurignac Guillaume , Ayouba Ahidjo , Keita Alpha Kabinet , Peeters Martine , Bourgarel Mathieu , De Nys Hélène M. 
Published: August 2023

AbstractWe investigated factors which might influence the circulation of ebolaviruses in fruit bats in Guinea in order to better understand their role in the ecology of ebolaviruses and evaluate risks of spill-over to other animals or humans. We performed serological tests on populations of 4 bat species (Eidolon helvum,Hypsignathus monstrosus,Lissonycteris angolensisandRousettus aegyptiacus) sampled longitudinally for 18 months (2018-2020). The analysis of 1,427 bat samples for antibodies directed against different ebolavirus species allowed to test the influence of biological and environmental variables on seropositivity. Results showed that species (Eidolon helvum and Rousettus aegyptiacus), sex (males), age (sexually immature adults, and thus reproductive life-cycle), as well as season (dry) have a significant positive effect on the presence of antibodies against ebolaviruses in bats. These factors may play an important role in the circulation of filoviruses. Search for viral evidence and surveillance strategies should take these into consideration.
Voxel-wise regression without intensity normalization provides better sensitivity when identifying injury regions after stroke in FDG-PET images
Authors: He Wuxian , Tang Hongtu , Li Jia , Shen Xiaoyan , Zhang Xuechen , Li Chenrui , Liu Huafeng , Yu Weichuan 
Published: August 2023

AbstractBackgroundIn the analysis of brain fluorodeoxyglucose positron emission tomography (FDG-PET), intensity normalization is a necessary step to reduce inter-subject variability. However, the choice of an appropriate normalization method in stroke studies remains unclear, leading to inconsistent findings in the literature.Materials and methodsHere, we propose a regression-based and single-subject-based model for analyzing FDG-PET images without intensity normalization. Two independent data sets were collected before and after middle cerebral artery occlusion (MCAO), with one comprising 120 rats and the other comprising 96 rats. After data preprocessing, voxel intensities in the same region and hemisphere were paired before and after the MCAO scan. A linear regression model was applied to the paired data, and the coefficient of determination was calculated to measure the linearity. The results between the ipsilateral and contralateral hemispheres were compared, and significant regions were defined as those having reduced linearity. Our method was compared with existing intensity normalization methods and validated using the triphenyl tetrazolium chloride (TTC) staining data.ResultsThe proposed method detected more injury areas compared to existing approaches, as confirmed by the ground truth provided by TTC. The area under the curve (AUC) of the average receiver operating characteristic (ROC) curves using our method reached 0.84, whereas the AUCs using existing methods ranged from 0.77 ∼ 0.79. The average false positive rate (FPR) and true positive rate (TPR) of the individual analysis results using our method (FPR = 0.06, TPR = 0.56) were better than the group-wise analysis results usingt-tests (FPR = 0.10, TPR = 0.51). The identified injury regions were consistent in the two independent data sets. Some of them were confirmed by other publications.ConclusionsThe proposed method offers a new quantitative approach to analyzing FDG-PET images. The calculation does not involve intensity normalization and can be applied to a single subject. The method yields more sensitive results than existing intensity normalization methods.
The pharynx of the iconic stem-group chondrichthyanAcanthodes(Agassiz, 1833) revisited with micro computed tomography
Authors: Dearden Richard P. , Herrel Anthony , Pradel Alan 
Published: August 2023

AbstractAcanthodeshas long been the primary source of information on the pharyngeal skeleton of ‘acanthodians’, a stem-group chondrichthyan grade. Because of this its anatomy has played an outsized role in attempts to understand the evolution of the jawed vertebrate pharynx and the clade as a whole. However, the anatomy of the pharynx ofAcanthodesremains poorly understood and subject to several competing interpretations. We use computed tomography (CT) to image the articulated pharyngeal skeletons of three specimens ofAcanthodes confususfrom Lebach, Germany.Acanthodeshad amélangeof osteichthyan-like and chondrichthyan-like morphologies in its pharyngeal skeleton. Like other stem-chondrichthyans,Acanthodeshad a basihyal with no hypohyals, and four pairs of posteriorly oriented pharyngobranchials. Like osteichthyans,Acanthodespossessed an interhyal, but lacked the separate infra- and supra-pharyngobranchial elements present in osteichthyans and the crown-chondrichthyanOzarcus. Using this new data we build and animated a digital 3D model of the pharyngeal endoskeleton inAcanthodes, showing that the jaws would have swung outwards during the opening cycle, increasing the anteriorly facing area of the gape for suspension feeding. These new data provide a more definitive picture of the anatomy of a taxon that has long been of great significance in early vertebrate palaeontology.
Age-dependent extinction and the neutral theory of biodiversity
Authors: Saulsbury James G. , Parins-Fukuchi C. Tomomi , Wilson Connor J. , Reitan Trond , Liow Lee Hsiang 
Published: August 2023

AbstractRed Queen (RQ) theory states that adaptation does not protect species from extinction because their competitors are continually adapting alongside them. RQ was founded on the apparent independence of extinction risk and fossil taxon age, but analytical developments have since demonstrated that age-dependent extinction is widespread, usually most intense among young species. Here we develop ecological neutral theory as a general framework for modeling fossil species survivorship under incomplete sampling. We show that it provides excellent fit to a high-resolution dataset of species durations for Paleozoic zooplankton, and more broadly can account for age-dependent extinction seen throughout the fossil record. Unlike widely used alternative models, the neutral model has parameters with biological meaning, thereby generating testable hypotheses on changes in ancient ecosystems. The success of this approach suggests novel interpretations of mass extinctions and of scaling in eco-evolutionary systems. Intense extinction among young species does not necessarily refute RQ or require a special explanation, but can instead be parsimoniously explained by neutral dynamics operating across species regardless of age.Significance StatementRed Queen theory predicts that competition among species should cause extinction risk to be independent of species age, but recent analyses have refuted this central prediction. To fill the resulting theoretical vacuum, we used ecological neutral theory to build a model of the lifespans of incompletely sampled species evolving under zero-sum competition. This model predicts survivorship among fossil zooplankton with surprising accuracy and accounts for empirical deviations from the predictions of Red Queen more generally. A neutral model of background extinction allows for interpreting survivorship curves in terms of biological process, suggests a novel understanding of mass extinctions, and supports a role for competition in extinction.
Defining unique structural features in the MAFA and MAFB transcription factors that controlInsulingene activity
Authors: Cha Jeeyeon , Tong Xin , Coate Katie C. , Guo Min , Liu Jin-hua , Reynolds Garrett , Walker Emily M. , Stein Richard A. , Mchaourab Hassane , Stein Roland 
Published: August 2023

ABSTRACTMAFA and MAFB are related basic-leucine-zipper domain containing transcription factors which have important overlapping and distinct regulatory roles in a variety of cellular contexts, including hormone production in pancreatic islet α and β cells. Here we first examined how mutating conserved MAF protein-DNA contacts obtained from X-ray crystal structure analysis impacted their DNA-binding andInsulinenhancer-driven activity. While most of these interactions were essential and their disruption severely compromised activity, we identified that regions outside of the contact areas also contributed to activity. AlphaFold 2, an artificial intelligence-based structural prediction program, was next used to determine if there were also differences in the three-dimensional organization of the non-DNA binding/dimerization sequences of MAFA and MAFB. This analysis was conducted on the wildtype (WT) proteins as well as the pathogenic MAFASer64Pheand MAFBSer70Alatrans-activation domain mutants, with differences revealed between MAFAWTand MAFBWTas well as between MAFASer64Pheand MAFAWT, but not between MAFBSer70Alaand MAFBWT. Moreover, dissimilarities between these proteins were also observed in their ability to cooperatively stimulateInsulinenhancer-driven activity in the presence of other islet-enriched transcription factors. Analysis of MAFA and MAFB chimeras disclosed that these properties were greatly influenced by unique C-terminal region structural differences predicted by AlphaFold 2. Importantly, these results have revealed features of these closely related proteins that are functionally significant in islet biology.
PKCδ splicing variant (PKCδIII) induces neurite outgrowth in PC12 cells in the absence of NGF
Authors: Yamasaki Hiroyuki , Nakai Tomoko , Kitatani Kanae , Kato Chikara , Takekoshi Susumu 
Published: August 2023

AbstractProtein kinase C (PKC)δ is a serine/threonine kinase involved in many cellular processes in response to diverse stimuli, including cell proliferation, differentiation, apoptosis, tumor inhibition, and cell migration. PKCδ consists of the N terminal regulatory domain and the C terminal catalytic domain, which are linked with a hinge region. An alternative splicing variant of rat PKCδ (also known as PKCδIII) has been reported, and this PKCδ splicing variant (SV) has only the regulatory domain without the catalytic domain. However, its function remains unclear. In this study, we found that PKCδ SV induced neurite outgrowth in the absence of nerve growth factor (NGF) in PC12 cells. Immunoblot analysis revealed that ERK was phosphorylated by NGF treatment, but not by PKCδ SV induction, indicating that PKCδ SV-mediated neurite outgrowth was different from NGF-mediated one. In addition, we showed that PKCδ full length and SV increased their mRNA expression after NGF treatment and that PKCδ SV was more susceptible to its proteasomal degradation. Our findings provided insights into the role of PKCδSV in neurite outgrowth.
Transient overdominance, coadaptation, and the fixability of heterosis
Authors: Schneemann Hilde , Welch John J. 
Published: August 2023

AbstractMany species pairs form F1 hybrids that are fitter than their parents. Such heterosis can arise if the parents carry recessive deleterious mutations; and in this case, the heterosis should be fixable, because selecting out the deleterious mutations yields a high-fitness homozygous hybrid. However, heterosis might not be fixable if caused by overdominance (an intrinisic advantage to heterozygosity) or if the parents contain coadapted gene complexes. These alternatives have been tested with introgression lines, where small regions of genome are scored in the heterospecific background. We develop predictions for introgression line data under a simple model of phenotypic selection, where parents diverge by fixing deleterious mutations via genetic drift. We show that this simple process can generate complex patterns in the data, misleading tests for both overdominance and coadaptation. We also suggest new ways to analyse the data to overcome these difficulties. Reanalyses of published data fromSolanumandGossypiumsuggest that the model can account for the qualitative patterns observed, though not the extent of apparent overdominance.
Mild uncoupling of mitochondria synergistically enhances senolytic specificity and sensitivity of BH3 mimetics
Authors: Fielder Edward , Ishaq Abbas , Low Evon , Laws Joseph , Calista Aisha , Castle Jemma , von Zglinicki Thomas , Miwa Satomi 
Published: August 2023

AbstractAnti-senescence interventions are exceptionally effective in alleviating a wide range of age-associated diseases and disabilities. However, the sensitivity and specificity of current senolytic interventions are limited. Mitochondrial dysfunction is an integral part of the senescent phenotype and we demonstrate that specific loss of complex I-linked coupled respiration and the inability to maintain mitochondrial membrane potential upon respiratory stimulation are early and persistent features in a cell’s progression towards senescence.We thus identify senescence-associated mitochondrial dysfunction as a targetable vulnerability of senescent cells and show that further decreasing mitochondrial membrane potential of senescent cells with a low concentration of a mitochondrial uncoupler synergistically enhances thein vitrosenolytic efficacy of BH3 mimetic drugs, including Navitoclax, by up two orders of magnitude.Moreover, in anin vivomouse model of radiation-induced premature ageing, we show that a short-term intervention combining the mitochondrial uncoupler BAM15 with Navitoclax at a dose two orders of magnitude lower than typically used reduces frailty and improves cognitive function for at least 8 months after irradiation. Therefore our study shows that compromised mitochondrial functional capacity is a specific vulnerability of senescent cells which can be targeted by mild uncouplingin vitroandin vivo.
The H3K27 acetyltransferase p300 is dispensable for thermogenic adipose tissue formation and function
Authors: Gamu Daniel , Cameron Makenna S. , Gibson William T. 
Published: August 2023

AbstractBrown adipose tissue (BAT) is specialized for thermogenesis because it contains uncoupling protein (UCP)-1. BAT is also an endocrine organ, producing many signalling molecules important for regulating the metabolism of peripheral organs. Mounting evidence suggest that histone modifying enzymes are integral for the development, tissue maintenance, and postnatal functioning of brown and beige adipocytes. p300 and its functional homologue CREB-binding protein (CBP) are histone acetyltransferases that form the transcriptionally activating histone 3 acetyl-lysine 27 (H3K27ac) mark. UsingUcp1-Cre, we examined the requirement of p300 activity specifically within thermogenic adipocytes. We hypothesized that loss of p300 activity would impair gene programming integral for BAT development/function, rendering knockouts susceptible to metabolic dysfunction and unable to form beige adipocytes. Despite successful knockdown, brown fat was completely unaffected by p300 deletion. As such, knockout mice showed a comparable metabolic profile to littermate controls in response to diet-induced obesity. Furthermore,de novobeige adipogenesis within subcutaneous fat by a β3adrenergic agonist remained intact in knockout mice. Although p300 and CBP have non-overlapping roles in other tissues, our results indicate p300 HAT activity is dispensable within thermogenic fats, likely due to functional compensation by CBP.
RAD52 and ERCC6L/PICH have a compensatory relationship for genome stability in mitosis
Authors: Osia Beth , Merkell Arianna , Lopezcolorado Felicia Wednesday , Ping Xiaoli , Stark Jeremy M. 
Published: August 2023

ABSTRACTThe mammalian RAD52 protein is a DNA repair factor that has both strand annealing and recombination mediator activities, yet is dispensable for cell viability. To characterize genetic contexts that reveal dependence on RAD52 to sustain cell viability (i.e., synthetic lethal relationships), we performed genome-wide CRISPR knock-out screens. Subsequent secondary screening found that depletion of ERCC6L in RAD52-deficient cells causes reduced viability and elevated genome instability, measured as accumulation of 53BP1 into nuclear foci. Furthermore, loss of RAD52 causes elevated levels of anaphase ultrafine bridges marked by ERCC6L, and conversely depletion of ERCC6L causes elevated RAD52 foci both in prometaphase and interphase cells. These effects were enhanced with combination treatments using hydroxyurea and the topoisomerase IIα inhibitor ICRF-193, and the timing of these treatments are consistent with defects in addressing such stress in mitosis. Thus, loss of RAD52 appears to cause an increased reliance on ERCC6L in mitosis, and vice versa. Consistent with this notion, combined depletion of ERCC6L and disrupting G2/M progression via CDK1 inhibition causes a marked loss of viability in RAD52-deficient cells. We suggest that RAD52 and ERCC6L play compensatory roles in protecting genome stability in mitosis.