bluuebunny/crossref_metadata_2025_split huggingface dataset:
The BRoccoli In Osteoarthritis (BRIO study) - A randomised controlled feasibility trial to examine the potential protective effect of broccoli bioactives, (specifically sulforaphane), on osteoarthritis
Authors: Davidson Rose K , Watts Laura , Beasy Gemma , Saha Shikha , Kroon Paul , Cassidy Aedin , Clark Allan , Fraser William , Mcnamara Iain , Kingsbury Sarah R , Conaghan Philip G , Clark Ian M , Macgregor Alex 
Published: June 2024

AbstractObjectiveThe Broccoli in Osteoarthritis (BRIO Study) was conducted to determine whether dietary sulforaphane (SFN), consumed as broccoli, improves pain and/or physical function in participants with knee osteoarthritis (OA). This was a proof of principle study to test the feasibility of the trial to optimise the design of an appropriately powered study.DesignTwo-centre, double-blind, two-arm parallel, randomised placebo-controlled, dietary intervention feasibility trial. Patients with radiographic knee osteoarthritis (Kellgren-Lawrence score 2-3), with pain of at least 4 on a scale of 0-10 were recruited. The intervention was a high glucoraphanin broccoli, (source of SFN), or a matched placebo (no SFN) soup. Pain and measures of physical function were measured at baseline, 6 and 12 weeks.ResultsThe mean WOMAC pain score (scale 0 - 20) was decreased by 4.2 (95% CI: 1.03,7.38) following intervention, Similar patterns of improvement were observed for other pain and function outcome measures. Study data, sample collections and intervention adherence were 100% compliant except where COVID restrictions applied. Acceptability for randomisation was 100% and acceptability for the intervention was 92%. There were three related adverse events, two of which were expected.ConclusionsHigh glucosinolate broccoli soup is a novel approach to managing OA that is widely accessible and can be used on a large scale. This study shows that it is an acceptable way of delivering dietary bioactives and has potential for therapeutic benefit. The primary outcome of pain improved in the intervention group compared to the placebo and the confidence interval encompassed the minimal clinically important difference. The data provide justification for proceeding to a large scale, appropriately powered intervention trial.
Sleep and long COVID: Preexisting sleep issues and the risk of PASC in a large general population using 3 different model definitions
Authors: Quan Stuart F. , Weaver Matthew D. , Czeisler Mark É. , Barger Laura K. , Booker Lauren A. , Howard Mark E. , Jackson Melinda L. , Lane Rashon I. , McDonald Christine F. , Ridgers Anna , Robbins Rebecca , Varma Prerna , Wiley Joshua F. , Rajaratnam Shantha M.W. , Czeisler Charles A. 
Published: June 2024

AbstractStudy ObjectivesInsomnia, poor sleep quality and extremes of sleep duration are associated with COVID-19 infection. This study assessed whether these factors are related to Post-Acute Sequelae of SARS-CoV-2 infection (PASC).MethodsCross-sectional survey of a general population of 24,803 U.S. adults to determine the association of insomnia, poor sleep quality and sleep duration with PASC.ResultsPrevalence rates of PASC among previously COVID-19 infected participants for three definitions of PASC were COPE (21.9%), NICE (38.9%) and RECOVER PASC Score (15.3%). PASC was associated with insomnia in all 3 models in fully adjusted models with adjusted odds ratios (aORs) and 95% confidence intervals (CI) ranging from 1.30 (95% CI: 1.11-1.52, p≤0.05, PASC Score) to 1.52 (95% CI: 1.34-1.71, p≤0.001, (NICE). Poor sleep quality was related to PASC in all models with aORs ranging from 1.77 (95% CI: 1.60-1.97, p≤0.001, NICE) to 2.00 (95% CI: 1.77-2.26, p≤0.001, COPE). Sleep <6 hours was associated with PASC with aORs between 1.59 (95% CI: 1.40-1.80, p≤0.001, PASC Score) to 1.70 (95% CI: 1.53-1.89, p≤0.001, COPE). Sleep>9 hours was not associated with PASC in any model. Although vaccination with COVID-19 booster decreased the likelihood of developing PASC, it did not attenuate associations between insomnia, poor sleep quality and short sleep duration with PASC in any of the models.ConclusionsInsomnia, poor sleep quality and short sleep duration are potential risk factors for PASC. Interventions to improve sleep may decrease the development of PASC.Brief SummaryCurrent Knowledge/Study RationaleInsomnia, poor sleep quality, and extremes of sleep duration have been associated with a higher likelihood of COVID-19 infection. However, evidence implicating an association with the development of Post-Acute Sequelae of SARS-CoV-2 infection (PASC) is scant.Study ImpactResults indicate that insomnia, poor sleep quality and sleep duration<6 hours are associated with an increase in the prevalence of PASC among persons who have previously had a COVID-19 infection. The findings provide support for employing interventions to improve sleep as a means to decrease the development of PASC.
Localized K63 ubiquitin signaling is regulated by VCP/p97 during oxidative stress
Authors: Maduka Austin O. , Manohar Sandhya , Foster Matthew W. , Silva Gustavo M. 
Published: June 2024

ABSTRACTUnder stress conditions, cells reprogram their molecular machineries to mitigate damage and promote survival. Ubiquitin signaling is globally increased during oxidative stress, controlling protein fate and supporting stress defenses at several subcellular compartments. However, the rules driving subcellular ubiquitin localization to promote these concerted response mechanisms remain understudied. Here, we show that K63-linked ubiquitin chains, known to promote proteasome-independent pathways, accumulate primarily in non-cytosolic compartments during oxidative stress induced by sodium arsenite in mammalian cells. Our subcellular ubiquitin proteomic analyses of non-cytosolic compartments expanded 10-fold the pool of proteins known to be ubiquitinated during arsenite stress (2,046) and revealed their involvement in pathways related to immune signaling and translation control. Moreover, subcellular proteome analyses revealed proteins that are recruited to non-cytosolic compartments under stress, including a significant enrichment of helper ubiquitin-binding adaptors of the ATPase VCP that processes ubiquitinated substrates for downstream signaling. We further show that VCP recruitment to non-cytosolic compartments under arsenite stress occurs in a ubiquitin-dependent manner mediated by its adaptor NPLOC4. Additionally, we show that VCP and NPLOC4 activities are critical to sustain low levels of non-cytosolic K63-linked ubiquitin chains, supporting a cyclical model of ubiquitin conjugation and removal that is disrupted by cellular exposure to reactive oxygen species. This work deepens our understanding of the role of localized ubiquitin and VCP signaling in the basic mechanisms of stress response and highlights new pathways and molecular players that are essential to reshape the composition and function of the human subcellular proteome under dynamic environments.
Fluorescence Anisotropy Analysis of the Interaction between Doxorubicin and DNA Origami Nanostructures
Authors: Lisitsyna Ekaterina S. , Klose Anna , Vuorimaa-Laukkanen Elina , Ijäs Heini , Lajunen Tatu , Suhling Klaus , Linko Veikko , Laaksonen Timo 
Published: June 2024

AbstractOwing to doxorubicin’s high DNA binding affinity, doxorubicin-loaded DNA origami nanostructures (DOX-DONs) are promising nanocarriers against cancer. However, understanding the interactions between doxorubicin (DOX) and DNA origami nanostructures (DONs) is important to ensure the quality of DOX-DONs. This interaction is often taken for granted and the influence of DOX loading conditions is poorly characterized. Exploiting the inherent fluorescence of DOX, steady-state and time-resolved fluorescence anisotropy spectroscopy techniques are used for characterizing non-destructively the binding between DOX and DONs, and the purity of formed complexes. The difference in fluorescence anisotropy between free DOX and DOX-DONs confirms the DOX-DON complex formation. Further, at loading ratios of DOX to DNA base pairs > 0.5, homo-Förster resonance energy transfer (homo-FRET) between closely packed DOX molecules is observed. Moreover, time-resolved anisotropy reveals DOX aggregation on DONs at high loading ratios > 1. For loading ratios > 0.1, spin-filtration to remove excess free DOX is efficient and necessary, though at loading ratios > 1 some DOX aggregates remain attached to the DONs. In summary, fluorescence anisotropy analysis provides more detailed information and insight into DOX-DONs compared to regularly used fluorescence intensity-based characterization methods, and these results can help designing more efficient and safer DNA intercalator-based nanocarriers.
Mechanistic insights into RNA cleavage by bacterial RNA polymerase from a comprehensive mutational screen
Authors: Mäkinen Janne J. , Belogurov Georgiy A. 
Published: June 2024

AbstractRNA polymerase (RNAP) mediates the synthesis of an RNA copy of the template DNA—the first and often decisive step in gene expression. All cellular RNAPs possess an additional capacity to cleave nucleotides from the 3’ end of the nascent RNA. This ability potentially enhances the efficiency and accuracy of transcription, enabling RNAP to maintain processivity and ensure the fidelity of the RNA transcript. This study investigates the contributions of various active site regions to the RNA cleavage activity using a large collection ofEscherichia coliRNAP variants. Unlike previous studies conducted under non-physiological conditions, this research employed backtracked RNAP complexes that cleave nascent RNA on a timescale of minutes under physiological pH and low Mg2+concentrations. Our findings provide key insights into the RNA cleavage activity of the RNAP active site. Complete closure of the active site by the Trigger Loop (TL) facilitates RNA cleavage in 1-nt backtracked states, but not in 2-nt backtracked states. However, the RNA-proximal N-terminus of the TL influences the cleavage rate in both states. β subunit Asp814 plays an important role in RNA cleavage, regardless of backtracking depth, likely by coordinating the Mg2+ion responsible for generating the nucleophile. During RNA cleavage, the pre-translocated RNA nucleotide is base-paired to the template DNA, but its sugar-phosphate backbone is shifted compared to canonical pre-translocated and NTP-bound states. Bulky substitutions in the E-site (NTP entry area) stimulate RNA cleavage, suggesting that RNA binding in this site inhibits the reaction.
Prediction of exosomal miRNA-based biomarkers for liquid biopsy
Authors: Arora Akanksha , Raghava Gajendra Pal Singh 
Published: June 2024

AbstractIn this study, we investigated the properties of exosomal miRNAs to identify potential biomarkers for liquid biopsy. We collected 956 exosomal and 956 non-exosomal miRNA sequences from RNALocate and miRBase to develop predictive models. Our initial analysis reveals that specific nucleotides are preferred at certain positions in miRNAs associated with exosomes. We employed an alignment-based approach, artificial intelligence (AI) models, and ensemble methods for predicting exosomal miRNAs. For the alignment-based approach, we used a motif-based method with MERCI and a similarity-based method with BLAST, achieving high precision but low coverage of about 29%. The AI models, developed using machine learning, deep learning techniques, and large language models, achieved a maximum AUC of 0.707 and an MCC of 0.268 on an independent dataset. Finally, our ensemble method, combining alignment-based and AI-based models, reached a maximum AUC of 0.73 and an MCC of 0.352 on an independent dataset. We have developed a web server, EmiRPred, to assist the scientific community in predicting and designing exosomal miRNAs and identifying associated motifs (https://webs.iiitd.edu.in/raghava/emirpred/).Key pointsExosomal miRNAs have potential applications in liquid biopsyAn ensemble method has been developed to predict and design exosomal miRNAAn array of predictive models were built using alignment-based approaches and AI-based approaches (ML, DL, LLM)A variety of important features and motifs for exosomal miRNA have been identifiedA webserver, a python package, a github, and a standalone software have been created
Xenon plasma focused ion beam lamella fabrication on high-pressure frozen specimens for structural cell biology
Authors: Berger Casper , Watson Helena , Naismith James , Dumoux Maud , Grange Michael 
Published: June 2024

AbstractCryo focused ion beam lamella preparation is a potent tool forin situstructural biology, enabling the study of macromolecules in their native cellular environments. However, throughput is currently limited, especially for thicker, more biologically complex samples. We describe how xenon plasma focused ion beam milling can be used for routine bulk milling of thicker, high-pressure frozen samples during lamellae preparation with a high success rate and determine a 4.0 Å structure of theEscherichia coliribosome on these lamellae using sub volume averaging. We determine the effects of increased ion currents on sample integrity during bulk milling of thicker planar samples, also showing that beyond an initial region of damage, no measurable structural damage propagates beyond this. The use of xenon results in substantial structural damage to particles up to 30 nm in depth from the milled surfaces, with detectable damage observed to 45 nm. Ours results outlines how the use of high currents using xenon plasma focused ion beam milling may be integrated into FIB milling regimes for preparing thin lamellae for high-resolutionin situstructural biology.
Theta-phase locking of single neurons during human spatial memory
Authors: Guth Tim A. , Brandt Armin , Reinacher Peter C. , Schulze-Bonhage Andreas , Jacobs Joshua , Kunz Lukas 
Published: June 2024

AbstractThe precise timing of single-neuron activity in relation to local field potentials may support various cognitive functions. Extensive research in rodents, along with some evidence in humans, suggests that single-neuron activity at specific phases of theta oscillations plays a crucial role in memory processes. Our fundamental understanding of such theta-phase locking in humans and its dependency on basic electrophysiological properties of the local field potential is still limited, however. Here, using single-neuron recordings in epilepsy patients performing a spatial memory task, we thus aimed at improving our understanding of factors modulating theta-phase locking in the human brain. Combining a generalized-phase approach for frequency-adaptive theta-phase estimation with time-resolved spectral parameterization, our results show that theta-phase locking is a strong and prevalent phenomenon across human medial temporal lobe regions, both during spatial memory encoding and retrieval. Neuronal theta-phase locking increased during periods of elevated theta power, when clear theta oscillations were present, and when aperiodic activity exhibited steeper slopes. Theta-phase locking was similarly strong during successful and unsuccessful memory, and most neurons activated at similar theta phases between encoding and retrieval. Some neurons changed their preferred theta phases between encoding and retrieval, in line with the idea that different memory processes are separated within the theta cycle. Together, these results help disentangle how different properties of local field potentials and memory states influence theta-phase locking of human single neurons. This contributes to a better understanding of how interactions between single neurons and local field potentials may support human spatial memory.
Time-based quantitative proteomic and phosphoproteomic analysis of A549-ACE2 cells during SARS-CoV-2 infection
Authors: Milhano dos Santos Fátima , Vindel Jorge , Ciordia Sergio , Castro Victoria , Orera Irene , Garaigorta Urtzi , Gastaminza Pablo , Corrales Fernando 
Published: June 2024

AbstractThe outbreak of COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2, led to an ongoing pandemic with devastating consequences for the global economy and human health. With the global spread of SARS-CoV-2, multidisciplinary initiatives were launched to explore new diagnostic, therapeutic, and vaccination strategies. From this perspective, proteomics could help to understand the mechanisms associated with SARS-CoV-2 infection and to identify new therapeutic targets for antiviral drug repurposing and/or discovery. A TMT-based quantitative proteomics and phosphoproteomics analysis was performed to study the proteome remodeling of human lung alveolar cells transduced to express human ACE2 (A549-ACE2) after infection with SARS-CoV-2. Targeted PRM analysis was performed to assess the detectability in serum and prognostic value of selected proteins. A total of 6802 proteins and 6428 phospho-sites were identified in A549-ACE2 cells after infection with SARS-CoV-2. Regarding the viral proteome, 8 proteins were differentially expressed after 6 h of infection and reached a steady state after 9 h. In addition, we detected several phosphorylation sites of SARS-CoV-2 proteins, including two novel phosphorylation events at S410 and S416 of the viral nucleoprotein.ImportanceThe differential proteins here identified revealed that A549-ACE2 cells undergo a time-dependent regulation of essential processes, delineating the precise intervention of the cellular machinery by the viral proteins. From this mechanistic background and by applying machine learning modelling, 29 differential proteins were selected and detected in the serum of COVID-19 patients, 14 of which showed promising prognostic capacity. Targeting these proteins and the protein kinases responsible for the reported phosphorylation changes may provide efficient alternative strategies for the clinical management of COVID-19.
Privileged representational axes in biological and artificial neural networks
Authors: Khosla Meenakshi , Williams Alex H , McDermott Josh , Kanwisher Nancy 
Published: June 2024

AbstractHow do neurons code information? Recent work emphasizes properties of population codes, such as their geometry and decodable information, using measures that are blind to the native tunings (or ‘axes’) of neural responses. But might these representational axes matter, with some privileged systematically over others? To find out, we developed methods to test for alignment of neural tuning across brains and deep convolutional neural networks (DCNNs). Across both vision and audition, both brains and DCNNs consistently favored certain axes for representing the natural world. Moreover, the representational axes of DCNNs trained on natural inputs were aligned to those in perceptual cortices, such that axis-sensitive model-brain similarity metrics better differentiated competing models of biological sensory systems. We further show that coding schemes that privilege certain axes can reduce downstream wiring costs and improve generalization. These results motivate a new framework for understanding neural tuning in biological and artificial networks and its computational benefits.
Association of age-friendly communities with health and well-being among older adults: an ecological and multilevel analysis from the Japan Gerontological Evaluation Study
Authors: Noguchi Taiji , Fujihara Satoko , Ide Kazushige , Jeong Seungwon , Saito Tami , Kondo Katsunori , Ojima Toshiyuki 
Published: June 2024

AbstractWe examined the association of age-friendly communities with health and well-being among older adults in Japan. Ecological and multilevel analyses of 71,824 older adults across 145 communities revealed that the community’s age-friendliness consistently showed associations with health and well-being. Age-friendly physical environments (accessibility to barrier-free outdoor spaces, buildings, and transportation resources) exhibited an inverse association with functional health deficits. Social engagement and communication (participation in community groups, volunteer engagement, and information use) were inversely associated with depressive symptoms. Social inclusion and dementia-friendliness (respect and inclusion for older adults and positive attitudes toward people with dementia) were positively associated with happiness. The community’s age-friendliness reflected well the multiple aspects of older adults’ health and well-being.
Brain Cell-based Genetic Subtyping and Drug Repositioning for Alzheimer Disease
Authors: Sahelijo Nathan , Rajagopalan Priya , Qian Lu , Rahman Rufuto , Priyadarshi Dhawal , Goldstein Daniel , Thomopoulos Sophia I. , Bennett David A. , Farrer Lindsay A. , Stein Thor D. ,   AI4AD Consortium, Shen Li , Huang Heng , Nho Kwangsik , Andrew Saykin J. , Davatzikos Christos , Thompson Paul M. , TCW Julia , Jun Gyungah R. 
Published: June 2024

AbstractAlzheimer’s Disease (AD) is characterized by its complex and heterogeneous etiology and gradual progression, leading to high drug failure rates in late-stage clinical trials. In order to better stratify individuals at risk for AD and discern potential therapeutic targets we employed a novel procedure utilizing cell-based co-regulated gene networks and polygenic risk scores (cbPRSs). After defining genetic subtypes using extremes of cbPRS distributions, we evaluated correlations of the genetic subtypes with previously defined AD subtypes defined on the basis of domain-specific cognitive functioning and neuroimaging biomarkers. Employing a PageRank algorithm, we identified priority gene targets for the genetic subtypes. Pathway analysis of priority genes demonstrated associations with neurodegeneration and suggested candidate drugs currently utilized in diabetes, hypertension, and epilepsy for repositioning in AD. Experimental validation utilizing human induced pluripotent stem cell (hiPSC)-derived astrocytes demonstrated the modifying effects of estradiol, levetiracetam, and pioglitazone on expression ofAPOEand complementC4genes, suggesting potential repositioning for AD.
Personalized Heart Disease Detection via ECG Digital Twin Generation
Authors: Hu Yaojun , Chen Jintai , Hu Lianting , Li Dantong , Yan Jiahuan , Ying Haochao , Liang Huiying , Wu Jian 
Published: June 2024

AbstractHeart diseases rank among the leading causes of global mortality, demonstrating a crucial need for early diagnosis and intervention. Most traditional electrocardiogram (ECG) based automated diagnosis methods are trained at population level, neglecting the customization of personalized ECGs to enhance individual healthcare management. A potential solution to address this limitation is to employ digital twins to simulate symptoms of diseases in real patients. In this paper, we present an innovativeprospective learningapproach for personalized heart disease detection, which generates digital twins of healthy individuals’ anomalous ECGs and enhances the model sensitivity to the personalized symptoms. In our approach, avector quantized feature separatoris proposed to locate and isolate the disease symptom and normal segments in ECG signals with ECG report guidance. Thus, the ECG digital twins can simulate specific heart diseases used to train a personalized heart disease detection model. Experiments demonstrate that our approach not only excels in generating high-fidelity ECG signals but also improves personalized heart disease detection. Moreover, our approach ensures robust privacy protection, safeguarding patient data in model development. The code can be found athttps://github.com/huyjj/LAVQ-Editor.