bluuebunny/crossref_metadata_2025_split huggingface dataset:
WISH-BONE: Whole-mount In Situ Histology, to label osteocyte mRNA and protein in 3D adult mouse bones
Authors: Meslier Quentin A. , Duerr Timothy J. , Nguyen Brian , Monaghan James R. , Shefelbine Sandra J. 
Published: March 2024

AbstractBone is a three dimensional and highly dynamic tissue under constant remodeling. Commonly used tools to investigate bone biology require sample digestion for biomolecule extraction or only provide two-dimensional spatial information. There is a need for 3D tools to investigate spatially preserved biomarker expression in osteocytes. In this work, we present a new method, WISH-BONE, to label osteocyte mRNA and protein in whole-mount mouse bone. For mRNA labeling, we used Hybridization Chain Reaction – FluorescenceIn SituHybridization to label genes of interest in osteocytes. For protein labeling, samples were preserved using an epoxy-based solution that protects tissue structure and biomolecular components. Then an enzymatic matrix permeabilization step was performed to enable antibody penetration. Immunostaining was used to label various proteins involved in bone homeostasis. We also demonstrate the use of customized fluorescent nanobodies to target and label proteins in the cortical bone. However, the relatively dim signal observed from nanobodies staining limited detection. In this study, we share protocols, highlight opportunities, and identify the challenges of this novel 3D labeling method. They are the first protocols for whole-mount osteocyte 3D labeling of mRNA and protein in mature mouse bones. WISH-BONE will allow the investigation of molecular signaling in bone cells in their 3D environment and could be applied to various bone-related fields of research.
Hour-long, Kilohertz Sampling Rate 3D Single-virus Tracking in Live Cells Enabled by StayGold Fluorescent Protein Fusions
Authors: Lin Yuxin , Exell Jack , Lin Haoting , Zhang Chen , Welsher Kevin D. 
Published: March 2024

ABSTRACTThe viral infection process covers a large range of spatiotemporal scales. Tracking the viral infection process with fluorescent labels over long durations while maintaining a fast sampling rate requires bright and highly photostable labels. StayGold is a recently identified green fluorescent protein that has a greater photostability and higher signal intensity under identical illumination conditions as compared to existing fluorescence protein variants. Here, StayGold protein fusions were used to generate virus-like particles (StayGold-VLPs) to achieve hour-long 3D single-virus tracking (SVT) with one thousand localizations per second (kHz sampling rate) in live cells. The expanded photon budget from StayGold protein fusions prolonged the tracking duration, facilitating a comprehensive study of viral trafficking dynamics with high temporal resolution over long timescales. The development of StayGold-VLPs presents a simple and general VLP labeling strategy for better performance in SVT, enabling exponentially more information to be collected from single trajectories and allowing for the future possibility of observing the whole life cycle of a single virus.Abstract Figure
Dissecting AlphaFold’s Capabilities with Limited Sequence Information
Authors: Gut Jannik Adrian , Lemmin Thomas 
Published: March 2024

AbstractProtein structure prediction, a fundamental challenge in computational biology, aims to predict a protein’s 3D structure from its amino acid sequence. This structure is pivotal for elucidating protein functions, interactions, and driving innovations in drug discovery and enzyme engineering. AlphaFold2, a powerful deep learning model, has revolutionized this field by leveraging phylogenetic information from multiple sequence alignments (MSAs) to achieve remarkable accuracy in protein structure prediction. However, a key question remains: how well does AlphaFold2 understand protein structures? This study investigates AlphaFold2’s capabilities when relying primarily on high-quality template structures, without the additional information provided by MSAs. By designing experiments that probe local and global structural understanding, we aimed to dissect its dependence on specific features and its ability to handle missing information. Our findings revealed AlphaFold2’s reliance on sterically valid C-βatoms for correctly interpreting structural templates. Additionally, we observed its remarkable ability to recover 3D structures from certain perturbations and the negligible impact of the previous structure in recycling. Collectively, these results support the hypothesis that AlphaFold2 has learned an accurate local biophysical energy function. However, this function seems most effective for local interactions. Our work significantly advances understanding of how deep learning models predict protein structures and provides valuable guidance for researchers aiming to overcome limitations in these models. protein folding, alphafold, side-chain, interpretability
Common soil history is more important than plant history for arbuscular mycorrhizal community assembly in an experimental grassland diversity gradient
Authors: Albracht Cynthia , Solbach Marcel Dominik , Hennecke Justus , Bassi Leonardo , van der Ploeg Geert Roelof , Eisenhauer Nico , Weigelt Alexandra , Buscot François , Heintz-Buschart Anna 
Published: March 2024

AbstractThe relationship between biodiversity and ecosystem functioning strengthens with ecosystem age. However, the interplay between the plant diversity - ecosystem functioning relationship and Glomeromycotinian arbuscular mycorrhizal fungi (AMF) community assembly has not yet been scrutinized in this context, despite AMF’s role in plant survival and niche exploration.We study the development of AMF communities by disentangling soil- and plant-driven effects from year effects. Within a long-term grassland biodiversity experiment, the pre-existing plant communities of varying plant diversity were re-established as split plots with combinations of common plant and soil histories: split plots with neither common plant nor soil history, with only soil but no plant history, and with both common plant and soil history.We found that bulk soil AMF communities were primarily shaped by common soil history and additional common plant history had little effect. Further, the steepness of AMF diversity and plant diversity relationship did not strengthen over time, but AMF community evenness increased with common history. Specialisation of AMF towards plant species was low throughout giving no indication of AMF communities specialising or diversifying over time. The potential of bulk soil AMF as mediators of variation in plant and microbial biomass over time and hence as drivers of BEF relationships was low.Our results suggest that soil processes may be key for the build-up of plant community-specific mycorrhizal communities with likely feedback effects on ecosystem productivity, but the plant-available mycorrhizal pool in bulk soil itself does not explain the strengthening of BEF relationships over time.
BMI Variability and Cardiovascular Outcomes Within Clinical Trial and Real-World Environments in Type 2 Diabetes: An IMI2 SOPHIA study
Authors: Massey Robert J , Chen Yu , Panova-Noeva Marina , Mattheus Michaela , Siddiqui Moneeza K , Schloot Nanette C , Ceriello Antonio , Pearson Ewan R , Dawed Adem Y 
Published: March 2024

AbstractAimsBMI variability has been associated with increased cardiovascular disease risk in individuals with type 2 diabetes, however comparison between clinical studies and real-world observational evidence has been lacking. Furthermore, it is not known whether BMI variability has an effect independent of HbA1c variability.Methods and ResultsWe investigated the association between BMI variability and 3P-MACE risk in the Harmony Outcomes trial (n = 9198), and further analysed placebo arms of REWIND (n = 4440) and EMPA-REG OUTCOME (n = 2333) trials, followed by real-world data from the Tayside Bioresource (n = 6980) using Cox regression modelling. BMI variability was determined using average successive variability (ASV), with first major adverse cardiovascular event of non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death (3P-MACE) as the primary outcome.After adjusting for cardiovascular risk factors, a +1 SD increase in BMI variability was associated with increased 3P-MACE risk in Harmony Outcomes (HR 1.12, 95% CI 1.08 – 1.17, P < 0.001). The most variable quartile of participants experienced an 87% higher risk of 3P-MACE (P <0.001) relative to the least variable. Similar associations were found in REWIND and Tayside Bioresource. Further analyses in the EMPA-REG OUTCOME trial did not replicate this association. BMI variability’s impact on 3P-MACE risk was independent of HbA1c variability.ConclusionIn individuals with type 2 diabetes, increased BMI variability was found to be an independent risk factor for 3P-MACE across cardiovascular outcome trials and real-world datasets. Future research should attempt to establish a causal relationship between BMI variability and cardiovascular outcomes.
Defining tumor growth in vestibular schwannomas: a volumetric inter-observer variability study in contrast-enhanced T1-weighted MRI
Authors: Cornelissen Stefan , Schouten Sammy M. , Langenhuizen Patrick P.J.H. , Lie Suan Te , Kunst Henricus P.M. , de With Peter H.N. , Verheul Jeroen B. 
Published: March 2024

AbstractFor patients with vestibular schwannomas (VS), a conservative observational approach is increasingly used. Therefore, the need for accurate and reliable volumetric tumor monitoring is important. Currently, a volumetric cutoff of 20% increase in tumor volume is widely used to define tumor growth in VS. The goal of this study is to investigate the tumor volume dependency on the limits of agreement (LoA) for volumetric measurements of VS by means of an inter-observer study.This retrospective study included 100 VS patients who underwent contrast-enhanced T1-weighted MRI. Five observers volumetrically annotated the images. Observer agreement and reliability was measured using the LoA, estimated using the limits of agreement with the mean (LOAM) method, and the intraclass correlation coefficient (ICC). Influence of imaging parameters and tumor characteristics were assessed using univariable and multivariable linear regression analysis.The 100 patients had an average median tumor volume of 903 mm3(IQR: 193-3101). Peritumoral cysts were found in 6 (6%) patients. Patients were divided into four volumetric size categories based on tumor volume quartile. The smallest tumor volume quartile showed a LOAM relative to the mean of 26.8% (95% CI: 23.7, 33.6), whereas for the largest tumor volume quartile this figure was found to be 7.3% (95% CI: 6.5, 9.7) and when excluding peritumoral cysts: 4.8% (95% CI: 4.2, 6.2). Of all imaging parameters and tumor characteristics, only tumor volume was associated with the LoA (adjusted B=-0.001 [95% CI: -0.001, 0.000;P=0.003]).Agreement limits within volumetric annotation of VS are affected by tumor volume, since the LoA improves with increasing tumor volume. As a result, for tumors larger than 200 mm3, growth can reliably be detected at an earlier stage, compared to the currently widely used cutoff of 20%. However, for very small tumors, growth should be assessed with higher agreement limits than previously thought.
Comparative safety and effectiveness of Pfizer BA.4-5 versus Sanofi during the spring 2023 COVID-19 booster vaccination programme in England: a matched cohort study in OpenSAFELY-TPP
Authors: Andrews Colm D , Prestige Em , Parker Edward PK , Walker Venexia , Palmer Tom , Schaffer Andrea L , Green Amelia CA , Curtis Helen J , Walker Alex , Smith Rebecca M , Wood Christopher , Bates Chris , Mehrkar Amir , MacKenna Brian , Bacon Sebastian CJ , Goldacre Ben , Hernán Miguel A , Sterne Jonathan AC ,   the OpenSAFELY collaborative, Hulme William J 
Published: March 2024

AbstractIntroductionThe spring 2023 COVID-19 booster vaccination programme in England used both Pfizer BA.4-5 and Sanofi vaccines. All people aged 75 years or over and the clinically vulnerable were eligible to receive a booster dose. Direct comparisons of the effectiveness of these two vaccines in boosting protection against severe COVID-19 events have not been made in trials or observational data.MethodsWith the approval of NHS England, we used the OpenSAFELY-TPP database to compare effectiveness of the Pfizer BA.4-5 and Sanofi vaccines during the spring 2023 booster programme, between 1 April and 30 June 2023. We investigated two cohorts separately: those aged 75 or over (75+); and those aged 50 or over and clinically vulnerable (CV). In each cohort, vaccine recipients were matched on date of vaccination, COVID-19 vaccine history, age, and other characteristics. Effectiveness outcomes were COVID-19 hospital admission, COVID-19 critical care admission, and COVID-19 death up to 16 weeks after vaccination. Safety outcomes were pericarditis and myocarditis up to 4 weeks after vaccination. We report the cumulative incidence of each outcome, and compare safety and effectiveness using risk differences (RD), relative risks (RR), and incidence rate ratios (IRRs).Results492,642 people were 1-1 matched in the CV cohort, and 673,926 in the 75+ cohort, contributing a total of 7,423,251 and 10,173,230 person-weeks of follow-up, respectively. The incidence of COVID-19 hospital admission was higher for Sanofi than for Pfizer BA.4-5. In the CV cohort, 16-week risks per 10,000 people were 22.3 (95%CI 20.4 to 24.3) for Pfizer BA.4-5 and 26.4 (24.4 to 28.7) for Sanofi, with an IRR of 1.19 (95%CI 1.06 to 1.34). In the 75+ cohort, these were 17.5 (16.1 to 19.1) for Pfizer BA.4-5 and 20.4 (18.9 to 22.1) for Sanofi, with an IRR of 1.18 (1.05-1.32). These findings were similar across all pre-specified subgroups. More severe COVID-19 related outcomes (critical care admission and death), and safety outcomes at 4 weeks, were rare in both vaccines so we could not reliably compare effectiveness of the two vaccines.ConclusionThis observational study comparing effectiveness of Pfizer BA.4-5 and Sanofi vaccine during the spring 2023 programme in England in the two main eligible cohorts – people aged 75 and over and in clinically vulnerable people – found some evidence of superior effectiveness against COVID-19 hospital admission for Pfizer BA.4-5 compared with Sanofi within 16 weeks after vaccination.
Extra-axial inflammatory signal and its relation to peripheral and central immunity in depression
Authors: Eiff Brandi , Bullmore Edward T. , Clatworthy Menna R. , Fryer Tim D. , Pariante Carmine M. , Mondelli Valeria , Maccioni Lucia , Hadjikhani Nouchine , Loggia Marco L. , Moskowitz Michael A. , Bruner Emiliano , Veronese Mattia , Turkheimer Federico E. ,   NIMA Consortium, Schubert Julia J. 
Published: March 2024

AbstractAlthough both central and peripheral inflammation have been consistently observed in depression, the relationship between the two remains obscure. Extra-axial immune cells may play a role in mediating the connection between central and peripheral immunity. This study investigates the potential roles of calvarial bone marrow and parameningeal spaces in mediating interactions between central and peripheral immunity in depression.Positron emission tomography was employed to measure regional TSPO expression in the skull and parameninges as a marker of inflammatory activity. This measure was correlated with brain TSPO expression and peripheral cytokine concentrations in a cohort enriched for heightened peripheral and central immunity comprising 51 individuals with depression and 25 healthy controls.The findings reveal a complex relationship between regional skull TSPO expression and both peripheral and central immunity. Facial and parietal skull bone TSPO expression showed significant associations with both peripheral and central immunity. TSPO expression in the confluence of sinuses was also linked to both central and peripheral immune markers. Group dependant elevations in TSPO expression within the occipital skull bone marrow were also found to be significantly associated with central inflammation.Significant associations between immune activity within the skull, parameninges, parenchyma, and periphery highlight the role of the skull bone marrow and venous sinuses as pivotal sites for peripheral and central immune interactions.
Large-Scale Longitudinal Assessment of Declining Memory Function Through Individualized Modeling of Episodic Memory
Authors: Hake Holly S. , van der Velde Maarten , Leonard Bridget , Grabowski Thomas , van Rijn Hedderik , Stocco Andrea 
Published: March 2024

AbstractThe detection and tracking of progressive memory impairments, particularly in the context of neurodegenerative disorders, relies predominantly on traditional neuropsychological assessment and short cognitive screening tools. These methods, however, are resource-intensive and lack the accessibility and/or the repeatability necessary for effective early identification and tracking interventions. This study addresses the critical need for reliable and efficient diagnostic tools to track and predict memory decline in clinical settings. We demonstrate that an online, remote model-based memory assessment, can identify individuals with Mild Cognitive Impairment (MCI) with an accuracy rate exceeding 84% in a single 8-minute session. Furthermore, the test can be repeated multiple times with increasing accuracy over multiple assessments. The system’s ability to monitor individual memory function inexpensively and longitudinally across various materials offers a robust and repeatable alternative to the static measures currently employed. Our findings show that traditional methods to assess memory decline could be replaced by adaptive, precise, and patient-friendly online tools based on computational modeling techniques. Moreover, our findings also open avenues for the proactive management of Alzheimer’s disease and other dementias, as well as sensitively tracking the effect of interventions in early disease.Significance StatementWe introduce, for the first time, a dependable, reliable, and repeatable model-based system for the online assessment of clinical memory impairment. Our findings demonstrate that this system can efficiently detect memory impairments using only 8 minutes of data collected online, marking a significant improvement over traditional assessments that typically require 3 hours in a clinical setting. These findings open up the possibility of inexpensive population-level monitoring of memory function.
Machine Learning-Based Prediction of Hashimoto’s Thyroiditis Development Risk
Authors: de Oliveira Andrade Luís Jesuino , Matos de Oliveira Gabriela Correia , Matos de Oliveira Luisa Correia , Vinhaes Bittencourt Alcina Maria , Matos de Oliveira Luís 
Published: March 2024

ABSTRACTIntroductionHashimoto’s Thyroiditis (HT) is a prevalent autoimmune disorder impacting thyroid function. Early detection allows for timely intervention and improved patient outcomes. Traditional diagnostic methods rely on clinical presentation and antibody testing, lacking a robust risk prediction tool.ObjectiveTo develop a high-precision machine learning (ML) model for predicting the risk of HT development.MethodData patients were acquired from PubMed. A binary classifier was constructed through data pre-processing, feature selection, and exploration of various ML models. Hyperparameter optimization and performance evaluation metrics (AUC-ROC, AUC-PR, sensitivity, specificity, precision, F1 score) were employed.ResultsOut of a total of 9,173 individuals, 400 subjects within this cohort exhibited normal thyroid function, while 436 individuals were diagnosed with HT. The mean patient age was 45 years, and 90% were female. The best performing model achieved an AUC-ROC of 0.87 and AUC-PR of 0.85, indicating high predictive accuracy. Additionally, sensitivity, specificity, precision, and F1 score reached 85%, 90%, 80%, and 83% respectively, demonstrating the model’s effectiveness in identifying individuals at risk of HT development. Hyperparameter tuning was optimized using a Random Search approach.ConclusionThis study demonstrates the feasibility of utilizing ML for accurate prediction of HT risk. The high performance metrics achieved highlight the potential for this approach to become a valuable clinical tool for early identification and risk stratification of patients susceptible to HT.
IsGBA1T369M not a risk factor for Parkinson’s disease in the Swedish population?
Authors: Brolin Kajsa Atterling , Bäckström David , Wallenius Joel , Gan-Or Ziv , Puschmann Andreas , Hansson Oskar , Swanberg Maria 
Published: March 2024

AbstractVariants inGBA1are important genetic risk factors in Parkinson’s disease (PD).GBA1T369M has been linked to an ∼80% increased PD risk but the reports are conflicting and the relevance ofGBA1variants in different populations varies. A lack of association between T369M and PD in the Swedish population was recently reported but needs further validation. We therefore investigated T369M in 1,808 PD patients and 2,183 controls and our results support that T369M is not a risk factor for PD in the Swedish population.
Assessing the Adequacy of Health Facilities for the Aging Population in Indian Cities
Authors: Anil Kumar A.H. Sruthi , Sarif Nawaj , Barman Papai 
Published: March 2024

AbstractObjectivesThe healthcare system in India is struggling to meet the needs of the current population, and the rising aging population is likely to exacerbate this problem. Therefore, this study tried to investigate the distribution of the older population’s access to improved health facilities in Indian cities.MethodsThe study uses data from the 2011 Census of India, which is the latest census round. An index was developed to understand the available health facilities and a geospatial approach was adopted to understand the aging pattern and access to health facilities across Indian cities.ResultsDespite similar aging scenarios, health infrastructure was not equally distributed across cities. The study revealed that advanced health facilities were more concentrated in specific pockets, particularly in metropolitan cities, while smaller cities lacked good health facilities and were not easily accessible.DiscussionThe results highlight the infrastructure gap in Indian cities which poses a significant challenge in achieving healthy aging.