bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of the threonine metabolism ofEchinococcus multilocularis: the threonine dehydrogenase as a potential drug target in alveolar echinococcosis
Authors: Kaethner Marc , Zumstein Pascal , Preza Matías , Grossenbacher Philipp , Bartetzko Anissa , Lochner Martin , Schürch Stefan , Regnault Clement , Ramírez Daniel Villalobos , Lundström-Stadelmann Britta 
Published: July 2024

AbstractAlveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of the fox tapewormEchinococcus multilocularis. We recently showed thatE. multilocularismetacestode vesicles scavenge large amounts of L-threonine from the culture medium that were neither stored nor overused for protein synthesis. This motivated us to study the effect of L-threonine on the parasite and how it is metabolized. We established a novel metacestode vesicle growth assay with an automated readout, which showed that L-threonine treatment led to significantly increased parasite growth. In addition, L-threonine increased the formation of novel metacestode vesicles from primary parasite cell cultures in contrast to the non-proteinogenic threonine analog 3-hydroxynorvaline. Tracing of [U-13C]-L-threonine and metabolites in metacestode vesicles and culture medium resulted in the detection of [U-13C]-labeling in aminoacetone and glycine, indicating that L-threonine was metabolized by threonine dehydrogenase (TDH). In addition, the detection of [13C2]-glutathione, suggested thatE. multilocularismetacestode vesicles synthesize glutathione via L-threonine-derived glycine. EmTDH-mediated threonine metabolism in theE. multilocularismetacestode stage was further confirmed by quantitative real-time PCR, which demonstrated high expression ofemtdhinin vitrocultured metacestode vesicles and also in metacestode samples obtained from infected animals. EmTDH was enzymatically active in metacestode vesicle extracts. Thus, the drugs disulfiram, myricetin, quercetin, sanguinarine and seven quinazoline carboxamides were assessed for inhibition of recombinantly expressed EmTDH, and the most potent inhibitors disulfiram, myricetin and sanguinarine were further tested for activity againstE. multilocularismetacestode vesicles and primary parasite cells. Sanguinarine exhibited significantin vitroactivity and IC50-values for metacestode vesicles, primary parasite cells, as well as mammalian cells were determined. Our results suggest that sanguinarine treatment should be further assessedin vivoemploying suitable AE mouse models. Furthermore, the EmTDH assay could serve as high-throughput target-based discovery platform for novel anti-echinococcal compounds.
Gαs-specific structural elements attenuate interactions with RGS proteins
Authors: Higazy-Mreih Sabreen , Avital-Shacham Meirav , LeGouill Christian , Bouvier Michel , Kosloff Mickey 
Published: July 2024

AbstractHeterotrimeric (αβγ) G proteins are molecular switches that are activated by G protein-coupled receptors (GPCRs) and regulate numerous intracellular signaling cascades. Most active Gα subunits are inactivated by Regulators of G protein Signaling (RGS) proteins, which determine the duration of G protein-mediated signaling by accelerating the catalytic turn-off of the Gα subunit. However, the G protein Gαsdoes not interact with known RGS proteins. To understand the molecular basis for this divergent phenomenon, we combined a comparative structural analysis of experimental and modelled structures with functional biochemical assays. This analysis showed that Gαscontains unique structural elements in both the helical and the GTPase domains. Modeling identified helical domain insertions, missing in experimental structures, that project towards the interface with RGS proteins, and residues in the GTPase domain that might interfere with RGS binding. Mutagenesis of Gαsand measurements of RGS GAP activity showed that three residues in the GαsGTPase domain are both necessary and sufficient to prevent Gαsinactivation by RGSs. Indeed, substitution of all three Gαsresidues with the corresponding residues from Gαi1enabled efficient inactivation by RGS proteins. These results shed new light on the mechanistic bases for G protein specificity towards RGS proteins.
Comparative Evaluation Of Machine Learning Classifiers For Brain Tumor Detection
Authors: Ali Umair 
Published: August 2024

AbstractThis study evaluates the effectiveness of six machine learning classifiers—Support Vector Classifier (SVC), Logistic Regression, K-Nearest Neighbors (KNN), Naive Bayes, Decision Tree, and Random Forest—in detecting brain tumors using numerical data rather than traditional imaging techniques like MRI. The results emphasize the importance of data preprocessing, particularly feature scaling, in enhancing model performance. Among the classifiers, Random Forest emerged as the top performer, achieving an accuracy of 98.27% on both original and scaled data, demonstrating its robustness and reliability. The study highlights the potential of Random Forest as a valuable tool for automated brain tumor detection in clinical settings, offering a cost-effective and accessible alternative for resource-constrained environments. The paper suggests that future research should explore advanced deep learning models, such as 3D Convolutional Neural Networks (CNNs) and Generative Adversarial Networks (GANs), to further improve diagnostic accuracy and support early intervention and personalized treatment strategies for brain tumor patients.
Genetic associations with human longevity are enriched for oncogenic genes
Authors: Park Junyoung , Peña-Tauber Andrés , Talozzi Lia , Greicius Michael D. , Guen Yann Le 
Published: August 2024

AbstractHuman lifespan is shaped by both genetic and environmental exposures and their interaction. To enable precision health, it is essential to understand how genetic variants contribute to earlier death or prolonged survival. In this study, we tested the association of common genetic variants and the burden of rare non-synonymous variants in a survival analysis, using age-at-death (N = 35,551, median [min, max] = 72.4 [40.9, 85.2]), and last-known-age (N = 358,282, median [min, max] = 71.9 [52.6, 88.7]), in European ancestry participants of the UK Biobank. The associations we identified seemed predominantly driven by cancer, likely due to the age range of the cohort. Common variant analysis highlighted three longevity-associated loci:APOE, ZSCAN23, andMUC5B. We identified six genes whose burden of loss-of-function variants is significantly associated with reduced lifespan:TET2,ATM,BRCA2, CKMT1B,BRCA1andASXL1. Additionally, in eight genes, the burden of pathogenic missense variants was associated with reduced lifespan:DNMT3A, SF3B1, CHL1,TET2, PTEN, SOX21, TP53andSRSF2. Most of these genes have previously been linked to oncogenic-related pathways and some are linked to and are known to harbor somatic variants that predispose to clonal hematopoiesis. A direction-agnostic (SKAT-O) approach additionally identified significant associations withC1orf52, TERT, IDH2,andRLIM, highlighting a link between telomerase function and longevity as well as identifying additional oncogenic genes.Our results emphasize the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one’s susceptibility to cancer and/or early death.
“Leveraging AI Tools to Bridge the Healthcare Gap in Rural Areas in India”
Authors: Kerketta Ajit , Balasundaram Sathiyaseelan 
Published: August 2024

AbstractIntroductionDespite considerable progress in the healthcare sector, rural regions continue to grapple with healthcare deficiencies. However, the emergence of AI technology offers promising solutions to overcome these hurdles. Hence, the study explores the potential and efficacy of introducing artificial intelligence (AI) tools to address the healthcare disparity in rural India.MethodsThe research employed a literature review method and gathered data from various databases such as Science Direct, PubMed, and Google Scholar. The screening process was aided by the “Rayyan” electronic software. Articles published in English between January 2020 and December 2022 were selected, followed by a thematic analysis of the findings.ResultsResults indicate the potential of AI in rural healthcare settings, showing AI-driven solutions addressing healthcare access gaps and contributing to their bridging. The study also highlights hurdles related to AI tool adoption in rural healthcare and proposes collaborative efforts among policymakers, healthcare providers, and technology developers to integrate AI tools effectively. This necessitates advocating for digital infrastructure investments, capacity-building initiatives, and conducive regulatory frameworks for AI implementation.ConclusionThe study underscores AI’s transformative role in bridging the healthcare gap in rural India. By harnessing AI technologies, healthcare providers and policymakers can surmount barriers, empower local healthcare workers, and improve health outcomes for rural communities. The insights and recommendations contribute to the evolving knowledge base on leveraging AI for adequate healthcare delivery, guiding future initiatives in similar contexts.
The glymphatic system clears amyloid beta and tau from brain to plasma in humans
Authors: Iliff Jeffrey J. , Elbert Donald L. , Giovangrandi Laurent , Singh Tarandeep , Venkatesh Venky V. , Corbellini Alejandro , Kaplan Robert M. , Ludington Elizabeth , Yarasheski Kevin , Lowenkron Jeffrey , VandeWeerd Carla , Lim Miranda M. , Dagum Paul 
Published: August 2024

ABSTRACTPoor sleep is implicated in the development of Alzheimer’s disease (AD) pathology and cognitive impairment. The glymphatic system has been proposed as a link between sleep disruption and AD, and in animal models glymphatic impairment is sufficient to drive the development of AD pathology. It remains unknown whether the glymphatic system clears amyloid beta (Aβ) and tau from the brain in humans. In a multi-site randomized crossover clinical trial (N=39), participants underwent overnight in-laboratory conditions of normal sleep and sleep deprivation following instrumentation that included a novel device to measure brain parenchymal resistance to glymphatic flow (RP) by transcranial multifrequency impedance spectroscopy and sleep electroencephalography (EEG). This study directly tested the hypothesis that sleep-active glymphatic clearance increases morning plasma AD biomarker levels. The primary outcomes were the change in plasma levels of AD biomarkers (Aβ40, Aβ42, np-tau181, np-tau217 and p-tau181) from evening to morning predicted by RP, sleep EEG features, and heart rate. We found that changes in RP, heart rate and EEG delta power predicted changes in Aβ42 (p<0.001), np-tau181 (p=0.002), np-tau217 (p<0.001) and p-tau181 (p<0.001). The predicted changes replicated those from a multicompartment model based on published data on Aβ and tau efflux from brain to plasma. Our findings show that elements of sleep-active physiology, in particular decreased brain parenchymal resistance, facilitates the clearance of AD biomarkers to plasma, supporting a role for glymphatic clearance in these processes, and suggesting the enhancement of glymphatic function as a therapeutic target to reduce the development and progression of AD pathology in at-risk populations.
JM-20 administration to animals with lesion of the nigrostriatal dopamine pathway induced by 6-hydroxydopamine, partially reverses motor damage and oxidative stress
Authors: Fonseca-Fonseca Luis Arturo , Taño Portuondo Laura Reina , Ramírez-Sánchez Jeney , Pavón Fuentes Nancy , Mondelo Rodríguez Abel , Amaral da Silva Víctor Diogenes , Lima Costa Silvia , Núñez-Figueredo Yanier 
Published: August 2024

AbstractPrevious studies have shown that JM-20, a new chemical hybrid molecule, protects against rotenone and 6-hydroxydopamine neurotoxicity. Also, we demonstrated that JM-20 blocks the formation of toxic alpha-synuclein aggregated species and aminochrome cytotoxicity. The present study sought to determine the neuroprotective property of JM-20 in animals with a partial lesion of the nigrostriatal dopamine pathway induced by 6-hydroxydopamine (6-OHDA). Forin vivostudies, adult male Wistar rats were lesioned in the rightsubstantia nigra pars compacta(SNpc) with 6-OHDA administration. Fifteen days after surgery, the animals asymmetry levels were assessed. Those with asymmetry values higher than 50% were divided into two groups: animals that did not receive any treatment and those that were administered with JM-20 (40 mg/kg, intragastric via gavage) for 27 days. Every seven days, the asymmetry values of the animals were analyzed until day 42 after the surgery. At the end of the experiment, the animals were euthanized and the SNpc and striatum were taken out for the analysis of oxidative stress. Our results reveal a behavioral function progressively recovered in the JM-20-treated animals, diminishing the percentage of motor asymmetry. Also, it improves some oxidative stress markers in the SNpc and the striatum of these animals. Our study provides the preclinical evidence to support the long-term neuroprotective potential of JM-20 in 6-OHDA hemiparkinson rat model, pointing out to its possible use as a disease-modifying agent in PD.
Experience instructs the refinement of feature-selectivity in the mouse primary visual thalamus
Authors: Sonoda Takuma , Stephany Céleste-Élise , Kelley Kaleb , Kang Di , Wu Rui , Uzgare Meghna R. , Fagiolini Michela , Greenberg Michael E. , Chen Chinfei 
Published: August 2024

AbstractNeurons exhibit selectivity for specific features: a property essential for extracting and encoding relevant information in the environment. This feature-selectivity is thought to be modifiable by experience at the level of the cortex. Here, we demonstrate that selective exposure to a feature during development can instruct the population representation for that feature in the primary visual thalamus. This thalamic plasticity is not simply inherited from the cortex because it is still observed when recordings were performed in the absence of cortical feedback. Moreover, plasticity is blocked in mutant mice that exhibit deficits in retinogeniculate refinement, indicating that alterations in feature-selectivity are a direct result of changes in feedforward connectivity. These experience-dependent changes persist into older ages—highlighting the importance of this developmental period in shaping population coding in the thalamus. Our results show that salient environmental features are hard-wired into thalamic circuits during a discrete developmental window.
The Computational Auditory Signal Processing and Perception Model (CASP): A Revised Version
Authors: Paulick Lily Cassandra , Relaño-Iborra Helia , Dau Torsten 
Published: August 2024

AbstractThis study introduces a revised version of the computational auditory signal processing and perception (CASP) model (Jepsenet al., 2008), which has undergone substantial updates and refinements aimed at enhancing its accuracy and usability across various applications. A primary motivation for the revision was the integration of a more realistic non-linear inner hair cell (IHC) model to address the limitations of its more simplistic predecessor. Demonstrating backwards compatibility, the revised model exhibited similar predictive power to previous CASP implementations across conditions of intensity discrimination, simultaneous and forward masking, and modulation detection, effectively accounting for data from normal-hearing listeners. Additionally, improved decision-making strategies and a streamlined model configuration further enhance the model’s usability and accessibility. Overall, the revised CASP offers a more accurate and intuitive framework for simulating auditory processing and perception across diverse conditions and tasks. The revised model may be a useful tool in studying the influence of the ear’s nonlinear response properties on internal representations, particularly concerning the effects of sensorineural hearing loss on auditory perception.
Long axial-range double-helix point spread functions for 3D volumetric super-resolution imaging
Authors: Nakatani Yuya , Gaumer Scott , Shechtman Yoav , Gustavsson Anna-Karin 
Published: August 2024

ABSTRACTSingle-molecule localization microscopy (SMLM) is a powerful tool for observing structures beyond the diffraction limit of light. Combining SMLM with engineered point spread functions (PSFs) enables 3D imaging over an extended axial range, as has been demonstrated for super-resolution imaging of various cellular structures. However, super-resolving structures in 3D in thick samples, such as whole mammalian cells, remains challenging as it typically requires acquisition and post-processing stitching of multiple slices to cover the entire sample volume or more complex analysis of the data. Here, we demonstrate how the imaging and analysis workflows can be simplified by 3D single-molecule super-resolution imaging with long axial-range double-helix (DH)-PSFs. First, we experimentally benchmark the localization precisions of short- and long axial-range DH-PSFs at different signal-to-background ratios by imaging of fluorescent beads. The performance of the DH-PSFs in terms of achievable resolution and imaging speed was then quantified for 3D single-molecule super-resolution imaging of mammalian cells by DNA-PAINT imaging of the nuclear lamina protein lamin B1 in U-2 OS cells. Furthermore, we demonstrate how the use of a deep learning-based algorithm allows the localization of dense emitters, drastically improving the achievable imaging speed and resolution. Our data demonstrate that using long axial-range DH-PSFs offers stitching-free, 3D super-resolution imaging of whole mammalian cells, simplifying the experimental and analysis procedures for obtaining volumetric nanoscale structural information.
Self-association enhances early attentional selection through automatic prioritization of socially salient signals
Authors: Scheller Meike , Tünnermann Jan , Fredriksson Katja , Fang Huilin , Sui Jie 
Published: August 2024

AbstractEfficiently processing self-related information is critical for cognition, yet the earliest mechanisms enabling this self-prioritization remain unclear. By combining a temporal order judgement task with computational modelling based on the Theory of Visual Attention (TVA), we show how mere, arbitrary associations with the self can fundamentally alter attentional selection of sensory information into short-term memory/awareness, by enhancing the attentional weights and processing capacity devoted to encoding socially loaded information. This self-prioritization in attentional selection occurs automatically at early perceptual stages but reduces when active social decoding is required. Importantly, the processing benefits obtained from attentional selection via self-relatedness and via physical salience were additive, suggesting that social and perceptual salience captured attention via separate mechanisms. Furthermore, intra-individual correlations revealed an ‘obligatory’ self-prioritization effect, whereby self-relatedness overpowered the contribution of perceptual salience in guiding attentional selection. Together, our findings provide evidence for the influence of self-relatedness during earlier, automatic stages of attentional section at the gateway to perception, distinct from later post-attentive processing stages.
Encephalomyocarditis virus protein 2B* antagonises innate immune signalling by interacting with 14-3-3 protein family members
Authors: Nguyen Samantha K. , Holmes Stephen , Barrow Henry G. , Lukhovitskaya Nina , Jahun Aminu S. , Georgana Iliana , Caller Laura G. , Edgar James R. , Emmott Edward , Firth Andrew E. , Stewart Hazel 
Published: August 2024

ABSTRACTEncephalomyocarditis virus (EMCV) has for decades served as an important model RNA virus. Although most of the EMCV proteins are obtained via proteolytic cleavage of a long polyprotein, 2B* is expressed from a short overlapping open reading frame via an unusual protein-stimulated temporally dependent ribosomal frameshifting mechanism. The function of 2B* has not yet been characterised, though mutant viruses that are unable to express 2B* have a small plaque phenotype. Here we show that 2B* binds all seven members of the 14-3-3 protein family during virus infection. Binding is dependent on the 2B* C-terminal sequence RRNSS. IFN-β and IL-6 signalling are impeded following overexpression of 2B* but not a truncated version lacking the RRNSS residues, thus suggesting a 14-3-3-dependent role for 2B* in inhibiting MAVS signalling. We also find that this function is distinct from the effect of 2B* on plaque size, as a virus in which 2B* was similarly truncated exhibited near-wildtype plaque size, thus indicating that 2B* also harbours additional functions. This work provides the first identification of a role of 2B* in innate immune antagonism and expands our knowledge of the protein complement of this important model virus.IMPORTANCEEncephalomyocarditis virus (EMCV) infects a range of species, causing economically important reproductive disorders in pigs and encephalitis and myocarditis in rodents. Due to its wide host range, it is an important model pathogen for investigating virus-host interactions. EMCV expresses an accessory protein, 2B*, from an overlapping open reading frame via an unusual ribosomal frameshifting mechanism. Although the frameshifting mechanism has been established, the function of the 2B* protein had not previously been explored. Here, we determined the host proteins to which 2B* binds and found that it specifically binds to the entire 14-3-3 protein family which, among other roles, contribute to the innate immune response to viral infection in mammalian cells. This interaction requires a specific stretch of amino acids at the end of 2B*. By interacting with the 14-3-3 proteins, 2B* blocks immune response activation. Thus, 2B* is a novel antagonist of innate immunity.