bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nomination of a novel plasma protein biomarker panel capable of classifying Alzheimer’s disease dementia with high accuracy in an African American cohort
Authors: Kuchenbecker Lindsey A. , Thompson Kevin J. , Hurst Cheyenne D. , Opdenbosch Bianca M. , Heckman Michael G. , Reddy Joseph S. , Nguyen Thuy , Casellas Heidi L. , Sotelo Katie D. , Reddy Delila J. , Lucas John A. , Day Gregory S. , Willis Floyd B. , Graff-Radford Neill , Ertekin-Taner Nilufer , Kalari Krishna R. , Carrasquillo Minerva M. 
Published: July 2024

AbstractIntroductionAfrican Americans (AA) are widely underrepresented in plasma biomarker studies for Alzheimer’s disease (AD) and current diagnostic biomarker candidates do not reflect the heterogeneity of AD.MethodsUntargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in a cohort of AA clinically diagnosed as AD dementia (n=183) or cognitively unimpaired (CU, n=145). Machine learning approaches were implemented to identify the set of plasma proteins that yields the best classification accuracy.ResultsA plasma protein panel achieved an area under the curve (AUC) of 0.91 to classify AD dementia vs CU. The reproducibility of this finding was observed in the ANMerge plasma and AMP-AD Diversity brain datasets (AUC=0.83; AUC=0.94).DiscussionThis study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning approaches. Our findings also highlight the potential importance of the matrisome and cerebrovascular dysfunction in AD pathophysiology.
Investigating Medin Cleavage Accessibility in MfgE8: Conformational Insights Derived from Molecular Dynamics Simulations and AlphaFold2 Models
Authors: Mesdaghi Shahram , Price Rebecca , Li Ming , Migrino Raymond Q. , Madine Jillian , Rigden Daniel J. 
Published: July 2024

AbstractRecent studies have indicated that the human amyloidogenic protein medin is associated with a range of vascular diseases, including aortic aneurysms, vascular dementia, and Alzheimer’s disease. Medin accumulates in the vasculature with age, leading to endothelial dysfunction through oxidative and nitrative stress and inducing pro-inflammatory activation. Medin is a cleavage product from the C2 domain of MfgE8. The exact mechanism of medin production from MfgE8 is unknown, with crystal structures of homologous C2 domains suggesting that the cleavage sites are buried, requiring a conformational transition for medin production. Molecular dynamics simulations can explore a wide range of conformations, from small-scale bond rotations to large-scale changes like protein folding or ligand binding. This study employed a combination of full-atom and coarse-grained molecular dynamics simulations, along with CONCOORD- and AlphaFold2-generated models, to investigate MfgE8 conformations and their implications for medin cleavage site accessibility. The simulations revealed that MfgE8 tends to adopt a compact conformation with the RGD motif, important for cell attachment within the N-terminal domain, and the medin region in the C-terminal domain close in proximity. Formation of this compact structure is facilitated by interdomain electrostatic interactions that promote stability and in turn decrease the solvent-accessible surface area of the medin region and particularly the C-terminal medin cleavage site. This data enhances current knowledge on medin generation to propose that alterations in local environmental conditions, possibly through changes in glycosylation or other post-translational modifications are required to induce MfgE8 to unfold partially or fully: this would result in enhanced accessibility of the cleavage sites and therefore enable medin generation.
Does temperature, light or inter-individual variation explain feeding motivation in a tropical freshwater predator?
Authors: Brown Lucy J. , Ioannou Christos C. 
Published: July 2024

AbstractVariability in environmental conditions in freshwater ecosystems are increasingly driven by human activity. Increased temperature and light intensity are among the anthropogenic stressors dramatically altering these ecosystems, for example through deforestation that reduces canopy cover of riparian vegetation. Simultaneous exposure to multiple stressors complicates predictions of responses to environmental stressors due to potential interactions, yet the interaction between temperature and light intensity on feeding motivation remains poorly understood. Here, a fully factorial design was employed to investigate the combined effect of increased temperature and light intensity on the feeding motivation of a freshwater predator, the pike cichlidSaxatilia proteus. Strikes toward food items were used to quantify the subjects’ motivation to feed. We found no effect of temperature or light intensity on feeding motivation, either individually or as an interaction. Our repeated measures design allowed us to test whether the predatory fish showed personality variation, i.e. consistent inter-individual differences, in their motivation to feed. While the time taken to make the first strike was not consistently different between individuals, the number of strikes in 1 minute, 3 minutes and the time taken for the 10thstrike (which were strongly correlated to one another), was consistently different between individuals. This variation could not be explained by variation in body length, which had no effect as a main effect. Variation between individuals is likely to be magnified in wild predators that are likely to vary more in experience and genetic background than the captive subjects in our study. Thus, we suggest that anthropogenic effects that alter the composition of individuals in a population of predators, for example selective harvesting, will have a greater ecological effect than direct short-term effects of variability in environmental factors.
Differential Patterns of Gut and Oral Microbiomes in Hispanic Individuals with Cognitive Impairment
Authors: Wadop Yannick N. , Vasquez Erin L. , Mathews Julia J. , Muhammad Jazmyn A. S. , Mavarez Rosa Pirela , Satizabal Claudia , Gonzales Mitzi M , Tanner Jeremy , Maestre Gladys , Fonteh Alfred N. , Seshadri Sudha , Kautz Tiffany F. , Fongang Bernard 
Published: July 2024

AbstractAlzheimer’s disease and related dementias (ADRD) have been associated with alterations in both oral and gut microbiomes. While extensive research has focused on the role of gut dysbiosis in ADRD, the contribution of the oral microbiome remains relatively understudied. Furthermore, the potential synergistic interactions between oral and gut microbiomes in ADRD pathology are largely unexplored. This study aims to evaluate distinct patterns and potential synergistic effects of oral and gut microbiomes in a cohort of predominantly Hispanic individuals with cognitive impairment (CI) and without cognitive impairment (NC). We conducted 16S rRNA gene sequencing on stool and saliva samples from 32 participants (17 CI, 15 NC; 62.5% female, mean age = 70.4 ± 6.2 years) recruited in San Antonio, Texas, USA. Correlation analysis through MaAslin2 assessed the relationship between participants’ clinical measurements (e.g., fasting glucose and blood cholesterol) and their gut and saliva microbial contents. Differential abundance analysis evaluated taxa with significant differences between CI and NC groups, and alpha and beta diversity metrics assessed within-sample and group compositional differences. Our analyses revealed no significant differences between NC and CI groups in fasting glucose or blood cholesterol levels. However, a clear association was observed between gut microbiome composition and levels of fasting glucose and blood cholesterol. While alpha and beta diversity metrics showed no significant differences between CI and NC groups, differential abundance analysis revealed an increased presence of oral genera such asDialister,Fretibacterium, andMycoplasmain CI participants. Conversely, CI individuals exhibited a decreased abundance of gut genera, includingShuttleworthia,Holdemania, andSubdoligranulum, which are known for their anti-inflammatory properties. No evidence was found for synergistic contributions between oral and gut microbiomes in the context of ADRD. Our findings suggest that similar to the gut microbiome, the oral microbiome undergoes significant modifications as individuals transition from NC to CI. Notably, the identified oral microbes have been previously associated with periodontal diseases and gingivitis. These results underscore the necessity for further investigations with larger sample sizes to validate our findings and elucidate the complex interplay between oral and gut microbiomes in ADRD pathogenesis.
Single-nucleus and spatial transcriptomic analysis identified molecular features of neuronal heterogeneity and distinct glial responses in Parkinson’s disease
Authors: Yoo Sooyeon , Lee Kwanghoon , Seo Junseo , Choi Hwisoo , Kim Seong-Ik , Chang Junyoung , Shim Yu-Mi , Kim Junil , Won Jae-Kyung , Park Sung-Hye 
Published: July 2024

AbstractThe heterogeneity of Parkinson’s disease (PD) is increasingly recognized as an important aspect of understanding the disorder. Among the factors contributing to this heterogeneity, ethnic differences are primary sources, significantly influencing the likelihood of PD developing and its initial symptoms’ nature. While there have been numerous reports related to PD in East Asia, there has been a lack of contribution from single-cell (or nucleus) transcriptome studies, which have been making significant contributions to understanding PD. In this study, a total of 33,293 nuclei obtained from the substantia nigra (SN) of confirmed pathological PD and control patients in South Korea were profiled, revealing 8 different cell types through cluster analysis. Monocle-based pseudotime analysis identified two disease-associated trajectories for each astrocyte and microglia and identified genes that differentiate them. Interestingly, we uncovered the inflammatory intervention in the early PD-associated transition in microglia and identified the molecular features of this intermediate state of microglia. In addition, gene regulatory networks (GRNs) based on TENET analysis revealed the detrimental effect of anHSPA5-led module in microglia andMSRB3- and HDAC8-led modules specifying the two different astrocyte trajectories. In SN neurons, we observed population changes, a decrease in dopaminergic and glutamatergic neurons and a proportional increase in GABAergic neurons. By deconvolution in spatial transcriptome obtained the PD sample, we confirmed spatiotemporal heterogeneity of neuronal subpopulations and PD-associated progressive gliosis specific to dopaminergic nuclei, SN and ventral tegmental areas (VTAs). In conclusion, our approach has enabled us to identify the genetic and spatial characterization of neurons and to demonstrate different glial fates in PD. These findings advance our molecular understanding of cell type-specific changes in the progression of Korean PD, providing an important foundation for predicting and validating interventions or drug effects for future treatments.
Lipid-directed covalent fluorescent labeling of plasma membranes for long-term imaging, barcoding and manipulation of cells
Authors: Aknine Nathan , Pelletier Remi , Klymchenko Andrey S. 
Published: July 2024

AbstractFluorescent probes for cell plasma membrane (PM) are generally based on amphiphilic anchors that incorporate non-covalently into biomembranes. Therefore, they are not compatible with fixation and permeabilization, presence of serum, or cell co-culture because of their exchange with the medium. Here, we report a concept of lipid-directed covalent labeling of PM, which exploits transient binding to lipid membrane surface generating high local dye concentration, thus favoring covalent ligation to random proximal membrane proteins. This concept yielded a class of fluorescent probes for PM (MemGraft), where a cyanine dye (Cy3 and Cy5) bears at its two ends low-affinity membrane anchor and reactive group: an activated ester or a maleimide. We found that MemGraft probes with these reactive groups provide efficient PM labelling, in contrast to a series of control compounds, including commercial Cy3-based labels of amino and thiol groups, revealing the crucial role of the membrane anchor combined with high reactivity of activated ester and a maleimide groups. In contrast to conventional PM probes, based on non-covalent interactions, MemGraft labelling approach is compatible with cell fixation, permeabilization, trypsinization and presence of serum. The latter allows long-term cell tracking and video imaging of cell PM dynamics without signs of phototoxicity. The covalent strategy also enables staining and long-term tracking of co-cultured cells labelled in different colors without probes exchange. Moreover, combination of different ratios of MemGraft-Cy3 and MemGraft-Cy5 probes enabled long-term cell barcoding in at least 5 color codes, important for tracking and visualizing multiple cells populations. Ultimately, we found that MemGraft strategy enables efficient biotinylation of cell surface, opening the path to cell surface engineering and cell manipulation.
AraRoot - A Comprehensive Genome-Scale Metabolic Model for the Arabidopsis Root System
Authors: Esterhuizen Lohani , Ampimah Nicholas , Yandeau-Nelson Marna D , Nikolau Basil J , Sparks Erin E , Saha Rajib 
Published: July 2024

AbstractBeing the first plant to have its genome sequenced,Arabidopsis thaliana(Arabidopsis) is a well-established genetic model plant system. Studies on Arabidopsis have provided major insights into plants’ physiological and biochemical nature. Methods that allow us to computationally study the metabolism of organisms include the use of genome-scale metabolic models (GEMs). Despite its popularity, currently no GEM maps the metabolic activity in the roots of Arabidopsis, which is the organ that faces and responds to stress conditions in the soil. We’ve developed a comprehensive GEM of the Arabidopsis root system - AraRoot. The final model includes 2,682 reactions, 2,748 metabolites, and 1,310 genes. Analyzing the metabolic pathways in the model identified 158 possible bottleneck genes that impact biomass production, most of which were found to be related to phosphorous-containing- and energy-related pathways. Further insights into tissue-specific metabolic reprogramming conclude that the cortex layer in the roots is likely responsible for root growth under prolonged exposure to high salt conditions, while the endodermis and epidermis are responsible for producing metabolites responsible for increased cell wall biosynthesis. The epidermis was found to have a very poor ability to regulate its metabolism during exposure to high salt concentrations. Overall, AraRoot is the first GEM that accurately captures the comprehensive biomass formation and stress responses of the tissues in the Arabidopsis root system.
Selective Effects of Ongoing Alpha-Band Activity on Magno- and Parvo-Mediated Detection
Authors: Pilipenko April , Samaha Jason 
Published: July 2024

AbstractSpontaneous fluctuations in cortical excitability, as reflected in variation in occipital alpha-band activity (8-12 Hz), have been shown to explain trial-to-trial variability in perception. Specifically, observers typically report seeing a stimulus more often during states of weak alpha power, likely due to a shift in detection criterion. However, prior work has paid little attention to the specific stimulus properties mediating detection. In early vision, different stimulus properties are preferentially processed along the magnocellular (MC) and parvocellular (PC) pathways, which vary in their preference for spatial and temporal frequency content and chromatic information. The goal of this study was to understand how spontaneous alpha power affects the detection of stimuli which are preferentially processed by either the MC or PC pathway. To achieve this, we used the “Steady/Pulsed Paradigm’’ which presented a brief, near-threshold stimulus in two conditions intended to bias processing to one or the other pathway. Our results showed an interaction effect of pre-stimulus alpha power on detection between the two conditions. While weak alpha power was predictive of seeing the stimulus in the steady condition (MC-biased), no significant effect was found in the pulsed condition (PC-biased). This interaction was driven by a selective alpha-related criterion shift in the steady condition, with no effect of pre-stimulus alpha on sensitivity (d’) in either condition. Our results imply that alpha oscillations may differentially regulate excitability in the MC and PC pathways.
ADAR1 p150 prevents HSV-1 from triggering PKR/eIF2α-mediated translational arrest and is required for efficient viral replication
Authors: Parchure Adwait , Cesarec Mia , Ivanišević Vlatka , Čunko Marina , Bursać Slađana , de Reuver Richard , Rosani Umberto , Volarević Siniša , Maelfait Jonathan , Jurak Igor 
Published: July 2024

AbstractAdenosine deaminase acting on dsRNA 1 (ADAR1) catalyzes the deamination of adenosines to inosines in double-stranded RNAs (dsRNA) and regulates innate immunity by preventing the hyperactivation of cytosolic dsRNA sensors such as MDA5, PKR or ZBP1. ADAR1 has been shown to exert pro- and antiviral, editing-dependent and editing-independent functions in viral infections, but little is known about its function in herpesvirus replication. We now demonstrate that herpes simplex virus 1 (HSV-1) hyperactivates PKR in the absence of ADAR1, resulting in eIF2α mediated translational arrest and reduced viral replication. Silencing of PKR or inhibition of downstream signaling pathways by viral (ICP34.5) or pharmacological (ISRIB) inhibitors rescues viral replication in ADAR1-deficient cells. Upon infection, ADAR1 p150 directly interacts with PKR and prevents its overactivation. Our findings demonstrate that ADAR1 is an important proviral factor that raises the activation threshold for sensors of innate immunity.
Mechanistic basis of temperature-adaptation in microtubule dynamics across frog species
Authors: Troman Luca , de Gaulejac Ella , Biswas Abin , Stiens Jennifer , Kuropka Benno , Moores Carolyn , Reber Simone 
Published: July 2024

SUMMARYCellular processes are remarkably effective across diverse temperature ranges, even with highly conserved proteins. In the context of the microtubule cytoskeleton, which is critically involved in a wide range of cellular activities, this is particularly striking as tubulin is one of the most conserved proteins while microtubule dynamic instability is highly temperature sensitive. We thus lack a mechanistic framework that links functional adaptability with environmental pressures. Here, we leverage the diversity of natural tubulin variants from three closely related frog species that live at different temperatures: we combinein vitroreconstitution assays, quantitative biochemistry, and cryogenic electron microscopy to show how a small number of primary sequence changes influences the energy landscape of tubulin interactions and thereby mediates cold-adaptation and microtubule stability. This study thus broadens our conceptual framework for understanding microtubule dynamics and provides insights into how conserved cellular processes are tailored to different ecological niches.
Thermophilic Fungus Uses Anthraquinones to Modulate Ferrous Excretion, Sterol-Mediated Endocytosis and Iron Storage in Response to Cold Stress
Authors: Li Shuhong , Wang Donglou , He Jiangbo , Liao Chunhua , Zuo Zhangxin , Li Shenghong , Niu Xuemei 
Published: July 2024

AbstractTo date, there is no real physiological mechanisms for iron excretion in eukaryote, and no physiological “actuator” that can control all the three fundamental biologic processes of absorption, storage and excretion. Here we observed that the accumulation of anthraquinones byThermomyces dupontiiunder cold stress can achieve this process. Through mutation analysis, we found that mutant ΔAndeficiency in anthraquinones accumulated ferrous and total free iron due to adopting a rare lifestyle with no endocytosis but accumulation of membrane-derived vesicles. Anthraquinone complement indicated that the vesicles in ΔAncould coat the extrinsic anthraquinone-induced granules to prevent contact with the fungal interiors. Detailed chemical investigation on ΔAnled to characterization of a rare oxygen-free ergosterene with unstable nature in air as the major membrane steroid in ΔAn, suggesting hypoxia inner in ΔAncells, consistent with dramatically low oxygen-consuming rates in ΔAn. A series of physiological and metabolic analysis indicated anthraquinones were involved in exporting ferrous and promoting formation of oxygen-containing metabolites, including ergosterols for endocytosis and iron chelators for iron storage. Moreover, we found that both the anticancer agent mitoxantrone with well know-cardiotoxicity side effect and the major terpenoid-derived polycyclic aromatics from Danshen for treating cardiovascular disease showed potent ferrous transporting capabilities in human cancer cells. Our findings provide a novel insight into the underlying mechanisms of polycyclic aromatics in nature and pharmacology, and offer new strategy for developing potential therapeutics and agents for membrane transport, iron homestasis and anticold.Graphical AbstractUp to now, regulation of iron homeostasis by metabolites have rarely been characterized. Moreover, no excretory mechanisms for iron in fungi have been reported. In this study, we found thatThermomyces dupontiican accumulate a large amount of anthraquinones under cold stress. The anthraquinones can release free ferric ion, reduce ferric to ferrous ions, and export ferrous ions, greatly enhancing thermophilic fungus to survive in the bio-system environment. Furthermore, lack of the anthraquinones can inhibit oxygen-dependent ergosterol mediated endocytosis, leading to an self-imposed isolation via oxygen-free ergosterene-mediated cell membranes. Importantly, the well known anthraquinone compound Mitoxantraquinone for anticancer and the main terpenoid polycyclic aromatic metabolites in traditional Chinese medicine Danshen for the treatment of cardiovascular diseases both exhibit strong ferrous ions transport capabilities. Our findings provided new insights for developing potential therapies and drugs for iron homeostasis and drug delivery.
The role of training in the “school-to-work” transition in the Russian labour market
Authors: Smoliarchuk Ekaterina , Roshchin Sergey , Travkin Pavel 
Published: July 2024

PurposeThe article aims to describe the role of training and examines the impact on the wages of university and college graduates.Design/methodology/approachWe use nationwide administrative data on university and college graduates in 2019. The population includes 1.3 million observations, of which 222,000 (∼16%) received training after graduation from an educational institution (from July 2019 to 2022). We used OLS and the “difference-in-differences” methods to estimate the returns to training. Estimates obtained using the DID method turned out to be several times smaller because they consider unobserved characteristics (abilities).FindingsWe obtained several key findings. First, the participation of graduates in training is high, despite their recent education. Second, undergoing training is conditional on the existence of wage returns. The results show a wage premium of 17.8% (OLS method) and 2.0% (DID method). Third, graduates from nonselective universities (with low state exam score) try to participate more actively in training to acquire missing knowledge and skills. The wage premium for graduates from nonselective universities is 19.1% (OLS method) and 5.1% (DID method). Fourth, there is a high return to training for graduates from socially relevant fields (education and healthcare), where training is regular and mandatory.Originality/valueThis paper is one of the first to estimate the involvement and returns to training for graduates using nationwide administrative data in Russia.