bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking myelin and Epstein-Barr virus specific immune responses in multiple sclerosis: insights from integrated public T cell receptor repertoires
Authors: Valkiers Sebastiaan , Dams Amber , Kuznetsova Maria , Ha My , Janssens Ibo , Willekens Barbara , Laukens Kris , Ogunjimi Benson , Cools Nathalie , Meysman Pieter 
Published: October 2024

AbstractThe autoimmune responses in multiple sclerosis (MS), particularly those mediated by T cells targeting CNS-derived antigens, are broadly recognized. However, the defining triggers underlying these responses remain poorly understood. Epstein-Barr virus (EBV) infection has emerged as a primary risk factor for MS, suggesting a potential role for molecular mimicry in which EBV-specific immune responses cross-react with myelin antigens.In this study, we analyzed the T cell receptor (TCR) repertoires of MS patients (n = 129) and controls (n = 94) from public datasets, to explore the relationship between EBV-specific and myelin-specific T cell responses. Our analysis identified clusters of TCRs that were significantly depleted among MS patients, many of which were associated with cytomegalovirus (CMV). By generating a library of myelin-reactive TCRs from stimulated peripheral blood mononuclear cells (PBMCs) obtained from MS patients and mapping these sequences to the public TCR repertoire database, we also uncovered a lower frequency of myelin-reactive TCRs in MS samples compared to controls in the public datasets. In addition, epitope-specificity prediction revealed a broader response to EBV-, but not CMV-derived epitopes.Collectively, these findings underscore the complex role of chronic viral infections in MS. Particularly, they suggest that EBV-specific immune responses contribute to the dysregulation of the immune system in MS patients, potentially through mechanisms of molecular mimicry. While the broader response to EBV-derived epitopes and the lower frequency of myelin-reactive TCRs in MS samples are both associated with the disease, further research is needed to clarify the nature of this relationship. These observations suggest that viral and autoimmune mechanisms may contribute independently or interact in MS pathogenesis.
TheSaccharomyces cerevisiaecell lysis mutantcly8is a temperature-sensitive allele ofESP1
Authors: Putnam Christopher D. , Li Bin-zhong , Broderick Lori 
Published: October 2024

ABSTRACTTheSaccharomyces cerevisiaemutants designatedcly(celllysis) cause cell lysis at elevated temperatures. Thecly8mutation, previously localized to an 80 kilobase region betweenGCD2andSPT6on the right arm of chromosome VII, has been used for mutation mapping and in recombination assays, but its genetic identity has remained unknown. Whole genome sequencing ofcly8mutant andCLY8wild-type strains revealed four missense mutations specific to thecly8mutant strain in theGCD2-SPT6interval, three of these missense mutations affected essential genes. Theesp1-G543Emutation, but not the two other missense mutations, recapitulated the temperature-sensitive growth, the cell lysis phenotype, and recessive nature of thecly8mutation. TheESP1gene encodesS. cerevisiaeseparase and is required for normal chromosome segregation during mitosis. Shifting cells containing theesp1-G543Emutation to the non-permissive temperature caused chromosome missegregation based on the analysis of DNA content by flow cytometry analysis. Taken together, these results indicate that the temperature-sensitivecly8mutation is an allele of the essentialESP1gene.
β-Amyloid impairs Proteasome structure and function. Proteasome activation mitigates amyloid induced toxicity and cognitive deficits
Authors: Davidson Kanisa , Bano Mehar , Parker Danitra , Osmulski Pawel , Gaczynska Maria , Pickering Andrew M. 
Published: October 2024

ABSTRACTBackgroundAlzheimer’s Disease (AD) is the leading cause of dementia globally, affecting around 50 million people and marked by cognitive decline and the accumulation of β-amyloid plaques and hyperphosphorylated tau. The limited treatment options and numerous failed clinical trials targeting β-amyloid (Aβ) highlight the need for novel approaches. Lowered proteasome activity is a consistent feature in AD, particularly in the hippocampus. Impaired proteasome function in AD is hypothesized to stem from direct inhibition by β-amyloid or hyperphosphorylated tau, disrupting critical neuronal processes such as memory formation and synaptic plasticity.ObjectivesThis study tests the hypothesis that AD related deficits are driven in part by impaired proteasome function as a consequence of inhibition by Aβ. We evaluated how proteasome function is modulated by Aβ and the capacity of two proteasome-activating compounds, TAT1-8,9-TOD and TAT1-DEN to rescue Aβ-induced impairment in vitro, as well as survival deficits in cell culture and Aβ-induced cognitive deficits in Drosophila and mouse models.ResultsOur study demonstrates that oligomeric β-amyloid binds to the 20S proteasome and impairs its activity and conformational stability. The oligomers also destabilize the 26S proteasome to release the free 20S proteasome. Treatment with proteasome activators TAT1-8,9TOD and TAT1-DEN rescue the 20S proteasome function and reduces cell death caused by Aβ42 toxicity in SK-N-SH cells. In Drosophila models overexpressing Aβ42, oral administration of proteasome agonists delayed mortality and restored cognitive function. Chronic treatment with TAT1-DEN protected against deficits in working memory caused by Aβ42 in mice and in hAPP(J20) mice with established deficits, acute TAT1-DEN treatment significantly improved spatial learning, with treated mice performing comparably to controls.ConclusionsAβ has dual impacts on 20S and 26S proteasome function and stability. Proteasome activation using TAT1-8,9TOD and TAT1-DEN shows promise in mitigating AD-like deficits by protecting against amyloid toxicity and enhancing proteasome function. These findings suggest that targeting proteasome activity could be a viable therapeutic approach for AD, warranting further investigation into the broader impacts of proteasome modulation on AD pathology.
Soil microbes influence the ecology and evolution of plant plasticity
Authors: Bolin Lana G. 
Published: October 2024

SUMMARYStress often induces plant trait plasticity, and microbial communities also alter plant traits. Therefore, it is unclear how much plasticity results from direct plant responses to stress versus indirect responses due to stress-induced changes to soil microbial communities.To test how microbes and microbial community responses to stress affect the ecology and potentially the evolution of plant plasticity, I grew plants in four stress environments (salt, herbicide, herbivory, no stress) with microbes that had responded to these same environments or with sterile inoculant.Plants delayed flowering under stress only in the presence of live microbial communities, and this plasticity was maladaptive. However, microbial communities responded to stress in ways that accelerated flowering across all environments. Microbes also affected the expression of genetic variation for plant flowering time and specific leaf area, as well as genetic variation for plasticity of both traits, and disrupted a positive genetic correlation for plasticity in response to herbicide and herbivory stress, suggesting that microbes may affect the pace of plant evolution.Together, these results highlight an important role for soil microbes in plant plastic responses to stress and suggest that microbes may alter the evolution of plant plasticity.
Imaging synaptic density in ageing and Alzheimer’s Disease with [18F]-SynVesT-1
Authors: Giorgio Joseph , Soleimani-Meigooni David N. , Janabi Mustafa , Baker Suzanne L. , Chen Xi , Toueg Tyler N. , Weimer Robby , Zinnhardt Bastian , Green Ari , Rabinovici Gil D. , Jagust William J. 
Published: October 2024

AbstractMonitoring synaptic injury in neurodegenerative diseases may provide new insights into the evolution of the degenerative process as well as a potential mechanism to target for preservation of function. Synaptic density imaging with PET is a relatively new approach to this issue. However, there are remaining questions about technical approaches to data analysis including reference region selection, and how specific phenotypic presentations and symptoms of Alzheimer’s Disease (AD) are reflected in alterations in synaptic density.MethodsUsing an SV2A PET ligand radiolabeled with the18F isotope ([18F]-SynVesT-1) we performed sensitivity analyses to determine the optimal reference tissue modelling approach to derive whole brain ratio images. Using these whole brain images from a sample of young adults, older adults, and patients with varied phenotypic presentations of AD we then contrast regional SV2A density andin vivoAD biomarkers.ResultReference tissue optimisation concluded that a cerebellar grey matter reference region is best for deriving whole brain ratio images. Using these whole brain ratio images, we find a strong inverse association between [18F]-SynVesT-1 PET uptake and amyloid beta and tau PET deposition. Finally, we find that individuals with lower temporal grey matter volume but higher temporal [18F]-SynVesT-1 PET uptake show preserved performance on the MMSE.Conclusions[18F]-SynVesT-1 PET shows a close association within vivoAD pathology and preserved SV2A density may be a possible marker for resilience to neurodegeneration.
Mental Schema Reduces Cognitive Load and Facilitates Emergence of Novel Responses in Mice and Artificial Neural Networks
Authors: Singh Vikram Pal , Shridhar Shruti , Kundu Shankanava , Bhatt Richa , Jayaprakash Balaji 
Published: October 2024

AbstractMammalian brain has evolved to infer from past experiences and elicit context relevant novel behavioural responses hitherto unexpressed by the animal. However, little is known about how prior knowledge influences the emergence of such responses. Remarkably, the brain not only arrives at these responses through logical inferences based on previous leanings, but also acquire new related information, without causing catastrophic interference. Mental schemas have often been proposed as the framework for this phenomenon. In this study, using mice as a model animal, we show that schematic networks not only enhance the cognitive load handling capacity (CLHC) and prevent catastrophic interference, but also facilitate the generation of novel, contextually relevant responses. Interestingly, when the animals were trained in a paradigm that did not invoke the pre-formed mental schema, we observed neither an enhancement to CLHC nor a generation of novel context relevant responses. Based on the principles of mental schemas discovered in our animal experiments, we developed a biologically plausible artificial neural network (ANN) that avoids catastrophic interference and captures the learning properties observed in our experiments. The custom architecture of this ANN enables it to generate responses similar to those of animals in novel scenarios.Significance StatementLittle is known about the role of mental schemas in preventing memory interference—a process in which overlapping or similar memories hinder the acquisition and retention of related information. In this study, we demonstrate that mental schemas enhance cognitive load handling capacity and improve the ability to solve novel but related problems. Using mice as a model, we show that the mere existence of a mental schema is not enough for improved cognitive load handling; instead, the relationship between existing and new information must be explicitly established during the learning process. Based on these findings, we developed a minimalistic artificial neural network (ANN) that effectively mimics this behaviour. These insights pave the way for developing more efficient learning and teaching strategies.
Site of breast cancer metastasis is independent of single nutrient levels
Authors: Abbott Keene L. , Subudhi Sonu , Ferreira Raphael , Gültekin Yetiş , Steinbuch Sophie C. , Munim Muhammad Bin , Honeder Sophie E. , Kumar Ashwin S. , Ramesh Diya L. , Wu Michelle , Hansen Jacob A. , Sivanand Sharanya , Riedmayr Lisa M. , Duquette Mark , Ali Ahmed , Henning Nicole , Shevzov-Zebrun Anna , Gourgue Florian , Barbeau Anna M. , Waite Millenia , Kunchok Tenzin , Ferraro Gino B. , Do Brian T. , Spanoudaki Virginia , Sánchez-Rivera Francisco J. , Jin Xin , Church George M. , Jain Rakesh K. , Vander Heiden Matthew G. 
Published: October 2024

AbstractCancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. In this study, we quantify the absolute levels of over 100 nutrients available across multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different organs. We then asked how tumor growth in different tissues relates to nutrient availability and tumor biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. Additionally, we identify purine synthesis as a requirement for tumor growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumor de novo nucleotide synthesis activity. These data suggest that a complex interplay of multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.
Auditory Working Memory Mediates the Relationship Between Musicianship and Auditory Stream Segregation
Authors: Liu Martha , Arseneau-Bruneau Isabelle , Franch Marcel Farrés , Latorre Marie-Elise , Samuels Joshua , Issa Emily , Payumo Alexandre , Rahman Nayemur , Loureiro Naíma , Leung Tsz Chun Matthew , Nave Karli M. , von Handorf Kristi M. , Hoddinott Joshua D. , Coffey Emily B.J. , Grahn Jessica , Zatorre Robert J. 
Published: October 2024

AbstractThis study investigates the interactions between musicianship and two auditory cognitive mechanisms: auditory working memory (AWM) and stream segregation. The primary hypothesis is that AWM mediates the relationship between musical training and enhanced stream segregation capabilities. Two groups of listeners were tested, the first to establish the relationship between the two variables and the second to replicate the effect in an independent sample. Music history and behavioural data were collected from a total of 145 healthy young adults with normal binaural hearing. They performed a task that requires manipulation of tonal patterns in working memory, and the Music-in-Noise Task (MINT), which measures stream segregation abilities in a musical context. The MINT task expands measurements beyond traditional Speech-in-Noise (SIN) assessments by capturing auditory subskills (e.g., rhythm, visual, spatial, prediction) relevant to stream segregation. Our results showed that musical training is associated with enhanced AWM and MINT task performance, and that this effect is replicable across independent samples. Moreover, we found in both samples that the enhancement of stream segregation was largely mediated by AWM capacity. The results suggest that musical training and/or aptitude enhances music-in-noise perception by way of improved AWM capacity.
FBXW7 alleviates c-MYC repression of pyruvate carboxylase to support metabolic flexibility
Authors: Lisci Miriam , Vericel Fanny , Gallant-Ayala Hector , Ivanisevic Julijana , Jourdain Alexis A. 
Published: October 2024

SummaryMetabolic flexibility, or the ability to adapt to environmental fluctuations, is key to the survival and growth of all living organisms. In mammals, the pathways supporting cell proliferation in nutrient-limiting conditions have not been fully elucidated, although cancers are known to display metabolic dependencies that can be targeted for therapy. Here, we combine systematic nutrient and genome-wide CRISPR/Cas9 screening to provide a comprehensive map of the signaling and metabolic pathways that support cell proliferation in glutamine-limited conditions. We focus on pyruvate anaplerosis and discover a mechanism by which the tumor suppressor FBXW7 controls a MYC-dependent cluster of epigenetic repressors that bind the pyruvate carboxylase (PC) promoter, leading to histone deacetylation, reducedPCexpression and glutamine addiction. Our work sheds light on the molecular mechanisms that support metabolic flexibility, and on the nutrients and pathways involved in glutamine dependency, a hallmark of several cancers.Graphical abstract
Testing the Tests: Using Connectome-Based Predictive Models to Reveal the Systems Standardized Tests and Clinical Symptoms are Reflecting
Authors: Samardzija Anja , Shen Xilin , Luo Wenjing , Greene Abigail , Mehta Saloni , Tokoglu Fuyuze , Arora Jagriti , Woods Scott , Katz Rachel , Sanacora Gerard , Srihari Vinod H. , Scheinost Dustin , Constable R. Todd 
Published: October 2024

AbstractBackgroundSubstantial strides have been made in developing connectome-based predictive models that establish connections between external measures of cognition and/or symptoms obtained through testing performed in a clinical setting, and the human functional connectome. Often referred to as brain-behavior modeling such models offer insights into the functional brain organization supporting the test scores of these external measures1–7. Here, we depart from the conventional feed-forward approach and introduce a feed-back approach that provides new insight into the systems the external measures are reflecting and provides a framework for developing new test instruments that better target specific brain systems.MethodsIn fMRI data from 227 demographically and clinically diverse subjects (healthy participants and patients), we a priori define connectivity networks for the six cognitive constructs and employ kernel ridge regression in a predictive modeling framework to quantify each network’s contribution to performance across a spectrum of standardized tests.ResultsThis approach provides a ranking of test scores according to the predictive power of each cognitive network, allowing one to choose the best test to probe a specific brain network. It yields a brain-driven process for forming new tests through selection of combinations of measures that probe the same brain systems. These new composite tests yield better external measures, as reflected by higher predictive power in brain-behavior modeling. We also evaluate the inclusion of specific subtests within a composite score, revealing instances where composite scores are reinforced or weakened by subtest inclusion regarding the specificity of the brain network they interrogate.ConclusionsThe brain-behavior modeling problem can be reconfigured to provide a biologically driven approach to the selection of external measures directed at specific brain systems. It opens new avenues of research by providing a framework for the development of measures, both cognitive and clinical, guided by quantitative brain metrics.
A Novel Cyanine-Based Fluorescent Dye for Targeted Mitochondrial Imaging in Neurotoxic Conditions andIn VivoBrain Studies
Authors: Yan Xin , Chen Xinqian , Hou Shanshan , Li Xiaoxu , Ju Jingyue , Shan Zhiying , Bi Lanrong 
Published: October 2024

AbstractMitochondrial dysfunction is a key feature of neurodegenerative diseases, often preceding symptoms and influencing disease progression. However, real-timein vivoimaging of mitochondria in the brain is limited by existing dyes like MitoTrackers, which struggle with poor tissue penetration, phototoxicity, and inability to cross the blood-brain barrier (BBB). This study introduces Cy5-PEG4, a novel mitochondrial-targeting dye that overcomes these limitations, enabling high-resolution, non-invasive imaging of mitochondrial dynamics. Cy5-PEG4 effectively labels mitochondria in primary neuronal cells exposed to the SARS-CoV-2 RNYIAQVD peptide, revealing dose-dependent alterations in mitochondrial function that may contribute to COVID-19-related neurodegeneration. Importantly, Cy5-PEG4 crosses the BBB without causing neuroinflammation or toxicity, making it a safe tool forin vivobrain imaging and detailed studies of mitochondrial responses. In 3D cultured cells, Cy5-PEG4 captures dynamic changes in mitochondrial distribution and morphology as cell structures mature, highlighting its potential in neurobiological research, diagnostics, and therapeutic development. These findings support Cy5-PEG4 as a powerful tool for studying disease progression, identifying early biomarkers, and evaluating therapeutic strategies in neurodegenerative disorders and COVID-19.
Prediction of the reaction mechanisms of sesquiterpene coumarin synthases supports a direct evolutionary link with triterpene biosynthesis
Authors: Stephenson Michael J. , Brodelius Peter E. 
Published: October 2024

AbstractSesquiterpene coumarins are primarily produced by plants of the Apiaceae and Asteraceae families. Farnesylation of 7-hydroxycoumarins such as umbelliferone, scopoletin or isofraxidin yield linear 7-farnesyloxycoumarins that are converted to various cyclic sesquiterpene coumarins by sesquiterpene coumarin synthases (cyclases). The terminal double bond of the linear 7-farnesyloxycoumarins is epoxidized by a sesquiterpene coumarin epoxidase. The diverse 7-(10′,11′-oxidofarnesyloxy)-coumarins produced are protonated by various sesquiterpene coumarin synthases to generate a carbocation that initiates cyclization of the farnesyl moiety (A process analogous to the carbocation cascades observed with sesquiterpene synthases and other cyclases involved in the biosynthesis of additional terpene classes, such as the triterpenes). These reaction mechanisms typically include Wagner-Meerwein rearrangements, such as hydride, methyl, and other alkyl shifts, but can also involve more complex processes including Grob fragmentations. Around 260 sesquiterpene coumarins based on 7-farnesyloxycoumarins have been described, but essentially nothing is known about the biosynthetic enzymes involved,i.e., farnesyltransferase, sesquiterpene coumarin epoxidase and synthase. In this review, putative reaction pathways for formation of the carbon skeletons of all known 7-farnesyloxycoumarins-derived sesquiterpene coumarins are presented.
G-quadruplex ligand RHPS4 compromises cellular radio-resistance by blocking the increase in mitochondrial mass and activity induced by ionising irradiation
Authors: Tricot S. , Siberchicot C. , Bontemps I. , Desmaze C. , Kratassiouk G. , Vandamme M. , Pinna G. , Radicella J.Pablo , Lenaers G. , Lebeau J. , Campalans A. 
Published: October 2024

ABSTRACTA major challenge in radiotherapy is to enhance tumor cell sensitivity to radiation while minimizing damage to healthy tissues. Ionising radiation (IR) induces mitochondrial DNA (mtDNA) alterations that can impair mitochondrial function and cell survival. Since mitochondria play a key role in tumor cell proliferation, they represent a promising therapeutic target for cancer treatment. In this study, we characterized the impact of different IR sources on mitochondrial function in radioresistant cancer cells. Our findings revealed several adaptive responses that may contribute to radioresistance, including increased mtDNA content, mitochondrial mass, enhanced activity, and hyperfusion of the mitochondrial network. Notably, the use of mitochondrial-targeted G-quadruplex (G4) ligands, which block mtDNA replication and transcription, disrupted these responses, reducing cancer cell survival in an mtDNA-dependent manner. These results demonstrate that mitochondrial adaptations contribute to radioresistance and highlight mitochondria as a novel target for the radiosensitizing effects of G4-ligands, extending their potential beyond telomere destabilization.