bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteostasis as a fundamental principle of Tau immunotherapy
Authors: Cruz Esteban , Nisbet Rebecca M. , Padmanabhan Pranesh , van Waardenberg Ashley J. , Graham Mark E. , Nkajja Godfrey , Tapaswi Swara , Robinson Phil , Götz Jürgen 
Published: February 2024

AbstractThe microtubule-associated protein Tau is a driver of neuronal dysfunction in Alzheimer’s disease and numerous other tauopathies. In this process, Tau initially undergoes subtle changes to its abundance, subcellular localisation and a vast array of post-translational modifications including phosphorylation, that progressively result in the protein’s aggregation and dysregulation of multiple Tau-dependent cellular processes.Given the various loss- and gain-of-functions of Tau in disease and the brain-wide changes in the proteome that characterise tauopathies, we asked whether targeting Tau would restore the alterations in proteostasis observed in disease.To this end, we generated a novel pan-Tau antibody, RNJ1, that preferentially binds human Tau and neutralises proteopathic seeding activity in multiple cell lines and benchmarked it against a clinically tested pan-Tau antibody, HJ8.5 (murine version of tilavonemab). We next evaluated both antibodies, alone and in combination, in the K3 mouse model of tauopathy, showing reduced Tau pathology and improvements in neuronal function following 14 weekly treatments, without obtaining synergistic effects for the combination treatment.To gain insight into molecular mechanisms contributing to improvements in neuronal function, we employed quantitative proteomics and phosphoproteomics to first establish alterations in K3 mice relative to WT controls at the proteome level. This revealed 342 proteins with differential abundance in K3 mice, which are predominantly involved in metabolic and microtubule-associated processes, strengthening previously reported findings of defects in several functional domains in multiple tauopathy models. We next asked whether antibody-mediated Tau target engagement indirectly affects levels of deregulated proteins in the K3 model. Importantly, both immunotherapies, in particular RNJ1, induced abundance shifts in this protein subset towards a restoration to wild-type levels (proteostasis). A total of 257 of 342 (∼75.1%) proteins altered in K3 were closer in abundance to WT levels after RNJ1 treatment. The same analysis indicated a similar response in K3 mice treated with HJ8.5, with approximately 72.5% of these altered proteins also showing changes in the same direction as wild-type. Furthermore, analysis of the phosphoproteome showed an even stronger restoration effect with RNJ1, with ∼82.1% of altered phosphopeptides in K3 showing a shift to WT levels, and 75.4% with HJ8.5. Gene set over-representation analysis (ORA) further confirmed that proteins undergoing restoration are involved in biological pathways affected in K3 mice. Together, our study suggests that a Tau immunotherapy-induced restoration of proteostasis links target engagement and treatment efficacy.
Unveiling Tryptophan Dynamics and Functions Across Model Organisms via Quantitative Imaging
Authors: Wang Kui , Chen Tian-lun , Zhang Xin-xin , Cao Jian-bin , Wang Pengcheng , Wang Mingcang , Du Jiu-lin , Mu Yu , Tao Rongkun 
Published: February 2024

ABSTRACTTryptophan is an essential amino acid involved in many cellular processes in vertebrates. Systemic and quantitative measurement of tryptophan is crucial for evaluating its essential role as a precursor of serotonin and kynurenine, key neuromodulators affecting neural and immune functions. We utilized a robust and highly responsive ratiometric indicator for tryptophan (GRIT) to quantitatively measure tryptophan dynamics in bacteria, mitochondria of mammalian cell cultures, and human serum. At the cellular scale, these analyses uncovered differences in tryptophan dynamics across cell types and organelles. At the whole-organism scale, we revealed that inflammation-induced tryptophan concentration increases in zebrafish brain led to elevated tryptophan metabolites serotonin and kynurenine levels, which is associated with the prolonged sleep duration. The reduction of zebrafish plasma tryptophan was mirrored in patients with inflammation symptoms and could serve as a biochemical marker of inflammation. In summary, this study introduces GRIT as a powerful method for studying tryptophan metabolism and functions across scales and species and suggests that tryptophan metabolic processes link the immune response and animal behavior.
Ageing Biomarkers Derived From Retinal Imaging: A Scoping Review
Authors: Grimbly Michaela , Koopowitz Sheri-Michelle , Chen Alice Ruiye , Sun Zihan , Foster Paul , He Mingguang , Stein Dan J. , Ipser Jonathan , Zhu Lisa Zhuoting 
Published: February 2024

AbstractBackground/AimsThe emerging concept of retinal age, a biomarker derived from retinal images, holds promise in estimating biological age. The retinal age gap (RAG) represents the difference between retinal age and chronological age which serves as an indicator of deviations from normal ageing. This scoping review aims to collate studies on retinal age to determine its potential clinical utility and to identify knowledge gaps for future research.MethodsUsing the PRISMA checklist, eligible non-review, human studies were identified, selected, and appraised. Pubmed, Scopus, SciELO, PsycINFO, Google Scholar, Cochrane, CINAHL, Africa Wide EBSCO, MedRxiv, and BioRxiv databases were searched to identify literature pertaining to retinal age, the RAG, and their associations. No restrictions were imposed on publication date.ResultsThirteen articles published between 2022 and 2023 were analysed, revealing four models capable of determining biological age from retinal images. Three models, ‘Retinal Age’, ‘EyeAge’ and a ‘convolutional network-based model,’ achieved comparable mean absolute errors (MAE): 3.55, 3.30 and 3.97 respectively. A fourth model, ‘RetiAGE’, predicting the probability of being older than 65 years, also demonstrated strong predictive ability with respect to clinical outcomes. In the models identified, a higher predicted RAG demonstrated an association with negative occurrences, notably mortality and cardiovascular health outcomes.ConclusionThis review highlights the potential clinical application of retinal age and RAG, emphasising the need for further research to establish their generalisability for clinical use, particularly in neuropsychiatry. The identified models showcase promising accuracy in estimating biological age, suggesting its viability for evaluating health status.Key MessageWhat is already known on this topicRetinal age has emerged as a promising ageing biomarker capable of determining biological age from retinal images.What this study addsThis study presents a comprehensive scoping review of current literature concerning retinal age and the RAG, highlighting the reproducible association between advanced retinal age gap and increased mortality and cardiovascular disease risk.How this study might affect research, practice, or policyThe findings underscore the paucity of knowledge on this topic, advocating for further research in this area to determine the potential clinical use of retinal age as a biomarker.SynopsisThis scoping review explores retinal age, a biological ageing marker derived from retinal images. Findings from 13 articles reveal links between advanced retinal ageing gaps and adverse outcomes, emphasizing its potential for improving health outcomes.
Trends and spatial distribution of pneumonia admissions and deaths among children <5 years, Uganda, 2013–2021
Authors: Wanyana Mercy Wendy , Migisha Richard , King Patrick , Bulage Lilian , Kwesiga Benon , Kadobera Daniel , Ario Alex Riolexus , Harris Julie R. 
Published: February 2024

AbstractBackgroundPneumonia is the second leading cause of hospital admissions and deaths among children <5 years old in Uganda. In 2013, Uganda adopted various interventions to protect, prevent, and improve the treatment of pneumonia under the Global Action Plan for Prevention and Control of Pneumonia and Diarrhoea (GAPPD), including the introduction of the pneumococcal conjugate vaccine (PCV) into routine immunization schedule. However, little is known about the impact of these interventions on pneumonia admissions and deaths. We described the trends and spatial distribution of pneumonia hospital admissions and mortality among children <5 years in Uganda, 2013–2021.MethodsWe analysed secondary data on pneumonia admissions and deaths from the District Health Information System version 2 during 2013–2021. Reporting rates were calculated as the percentage of expected complete monthly health facility reports submitted to the national surveillance database. The proportion of pneumonia cases admitted and case-fatality rates (CFRs) for children <5 years were calculated for children <5 years presenting at the outpatient department. At national, regional, and district levels, pneumonia mortality rates were calculated per 100,000 children <5 years. The Mann-Kendall Test was used to assess trend significance.ResultsThere were 753,978 pneumonia admissions and 13,632 (2%) deaths during 2013–2021. Reporting rates ranged from 78–92%. The overall proportion of pneumonia cases admitted among children <5 years was 23%. The overall CFR was 0.41%, and the overall pneumonia mortality rate among children <5 years was 21 deaths per 100,000. From 2013 to 2021, there were declines in the proportion of pneumonia cases admitted (33% to 15%; p=0.051), mortality rates (26/100,000 to 13 per 100,000; p=0.01), and CFR (0.61% to 0.24%; p=0.01), concomitant with increasing PCV coverage. Kotido District had a persistently high proportion of pneumonia cases that were admitted (>30%) every year while Kasese District had persistently high mortality rates (68-150 deaths per 100,000 children <5 years).ConclusionPneumonia admissions, mortality, and case fatality among children <5 years declined during 2013–2021 in Uganda after the introduction of PCV. However, with these trends it is unlikely that Uganda will meet the 2025 GAPPD targets. There is therefore a need to review implementation of existing interventions, identify gaps in order to highlight priority actions to further accelerate declines.
Prevalence of Mendelian kidney disease among patients with high-riskAPOL1genotypes undergoing commercial genetic testing in the United States
Authors: Francisco Ronaldo da Silva , Punj Sumit , Vincent Lisa , Sanapareddy Nina , Bhalla Vivek , Chertow Glenn M. , Keen-Kim Dianne , Charu Vivek 
Published: February 2024

ABSTRACTBackgroundAmong individuals with high-riskAPOL1genotypes, the lifetime risk of developing kidney failure is ∼15%, indicating that other genetic variants or non-genetic modifiers likely contribute substantially to an individual patient’s risk of progressive kidney disease. Here we estimate the prevalence and distribution of molecularly diagnosed Mendelian kidney diseases among patients with high-riskAPOL1genotypes undergoing commercial genetic testing in the United States.MethodsWe analyzed clinical exome sequencing data from 15,181 individuals undergoing commercial genetic testing for Mendelian kidney disease in the United States from 2020-2021. We identified patients with high-riskAPOL1genotypes by the presence of G1/G1, G1/G2, or G2/G2 alleles. Patients carrying single riskAPOL1alleles were identified as G1/G0, G2/G0; the remainder of patients were G0/G0. We estimated the prevalence and distribution of molecularly diagnosed Mendelian kidney disease stratified byAPOL1genotype.ResultsOf 15,181 patients, 3119 had genetic testing results consistent with a molecular diagnosis of Mendelian kidney disease (20.5%). 1035 (6.8%) had high-riskAPOL1genotypes. The prevalence of molecularly diagnosed Mendelian kidney diseases was lower in individuals with high-riskAPOL1genotypes (9.2%; n=95/1035) compared to single riskAPOL1allele carriers (14.4%; n=243/1687) and those with G0/G0APOL1genotypes (22.3%; n=2781/12459). The distribution of molecularly diagnosed Mendelian kidney diseases was broadly similar among patients with and without high-riskAPOL1genotypes.ConclusionsAmong patients undergoing clinical genetic testing, we found a relatively high rate of molecularly diagnosed Mendelian kidney disease in patients with high-riskAPOL1genotypes. Mendelian kidney disease may contribute to wide variation in rates of progression observed among patients with high-riskAPOL1genotypes.
Investigating the relationship of serum vitamin D levels with blood pressure and hypertension risk in The HUNT Study: Using traditional observational and Mendelian randomization approaches
Authors: Jiang Lin , Sun Yi-Qian , Denos Marion , Brumpton Ben Michael , Chen Yue , Malmo Vegard , Sanderson Eleanor , Mai Xiao-Mei 
Published: February 2024

AbstractBackgroundLimited studies have triangulated the relationship between serum vitamin D [25(OH)D] levels and systolic blood pressure (SBP), diastolic blood pressure (DBP) or hypertension risk using traditional observational and Mendelian randomization (MR) approaches.Methods and resultsData were obtained from the Norwegian Trøndelag Health Study (HUNT). A cross-sectional study was performed among 5854 participants from HUNT2. Among them, 3592 participants were followed over 11 years for a prospective analysis. Furthermore, a one-sample MR was conducted with 86,324 participants from HUNT. An externally weighted genetic risk score based on 19 genetic variants for 25(OH)D was used as instrument and the Wald ratio method was applied to evaluate causal associations. Additionally, two-sample MR were performed using updated publicly available data. Our cross-sectional analyses showed a 25 nmol/L increase in 25(OH)D was associated with a 1.73 mmHg decrease in SBP (95 % CI -2.46 to -1.01), a 0.91 mmHg decrease in DBP (95% CI - 1.35 to -0.47) and 19% lower prevalence of hypertension (OR 0.81, 95% CI 0.74 to 0.90) after adjusting for important confounders. However, these associations disappeared in prospective analyses. Both one-sample and two-sample MR results suggested no causal associations.ConclusionsCross-sectional findings of inverse associations between serum 25(OH)D levels and blood pressure or hypertension were not supported by results from the prospective and MR analyses, suggesting no causal links.Clinical Perspective What Is New?We triangulated the potential relationships of serum 25(OH)D with blood pressure and hypertension using several observational methods such as cross-sectional, prospective cohort, one-sample and two-sample Mendelian randomization (MR) approaches.What Are the Clinical Implications?The consistency across the prospective, one-sample MR and two-sample MR analyses enhanced the robustness of the findings of no causal association between vitamin D and blood pressure or hypertension.Clinicians should be cautious when recommending vitamin D supplementation to the general population for the prevention of cardiovascular diseases.
Association of Mobile Stroke Unit Care and Spending, Utilization, and Mortality in New York City
Authors: Khullar Dhruv , Navi Babak B. , Mir Saad , Fink Matthew E. , Tinapay Luisa , Asaeda Glenn , Kaushal Rainu , Pareek Eshani , Bond Amelia M. 
Published: February 2024

AbstractBackgroundTransport by mobile stroke units (MSUs), which provide access to computed tomography scanning and intravenous blood pressure medications and thrombolytics, reduces time to treatment and may improve short-term functional outcomes for patients with acute stroke. The longer-term clinical and financial impacts remain incompletely understood.ObjectiveDetermine whether MSU care is associated with better health, utilization, and spending outcomes for patients with suspected acute stroke.DesignRetrospective, observational study of Medicare patients transported by MSUs versus traditional ambulances in New York City, from October 2016 to December 2019.Eligibility167 Medicare patients with suspected acute stroke transported by MSU and 2,518 propensity-score matched controls.Main OutcomesPrimary outcomes included length of stay and discharge destination at index hospitalization, as well as risk of repeat hospitalization, number of emergency department visits, total costs of care, and mortality at 1 year.ResultsOf 167 patients (mean age, 79.9 years;56.3% women) transported by a MSU for suspected acute stroke, 61.1% had an ischemic stroke/TIA, 7.8% had an intracerebral hemorrhage, and 31.1% had a stroke mimic or other diagnosis. Compared to propensity-score matched control patients, MSU patients experienced similar lengths of stay (5.9 vs 6.7 days,p=0.13) and were similarly likely to be discharged to a skilled nursing facility (15.6% vs 15.1%,p=0.86). They had clinically but marginally significant lower rates of mortality at 1 year (21.6% vs 28.4%; difference, 6.8 percentage points [95% CI -13.3 to 0.3,p=0.058). They had similar rates of any repeat hospitalization (24% vs 23.2%,p=0.82) and ED visits without hospitalization (14% vs 12%,p=0.86), and there were no significant differences in total spending or specific types of spending.ConclusionsIn this study of patients presenting with suspected acute stroke in New York City, transport by MSUs, compared with traditional ambulances, was associated with a trend toward lower mortality at 1 year. Prospective trials and replication in other regions are warranted.
Investigating 3D microbial community dynamics in the rhizosphere using complex-field and fluorescence microscopy
Authors: Zhang Oumeng , Alcalde Reinaldo E. , Zhou Haowen , Yin Siyuan , Newman Dianne K. , Yang Changhuei 
Published: February 2024

AbstractMicrobial interactions in the rhizosphere contribute to soil health. Understanding these interactions thus has the potential to advance sustainable agriculture, ecosystem management, and environmental stewardship. Yet it is difficult to understand what we cannot see; amongst the limitations in rhizosphere imaging are challenges associated with rapidly and non-invasively imaging microbial cells over field depths relevant to plant roots. Here, we present a novel bimodal imaging technique called Complex-field and Fluorescence microscopy using the Aperture Scanning Technique (CFAST) that begins to address these limitations by integrating quantitative phase and 3D fluorescence imaging. We showcase CFAST’s practicality and versatility in two ways. First, by harnessing its depth of field of more than 100 microns, we significantly reduce the number of captures required for 3D imaging of plant roots and bacteria in the rhizoplane, thereby minimizing potential photobleaching and phototoxicity. Second, by leveraging CFAST’s phase sensitivity and fluorescence specificity, we track early bacterial aggregate development, bacterial competition, and gene expression under varying environmental conditions. Specifically, we resolve bacterial growth dynamics of mixed populations at the early stages of colonization without the need for genetically labeling environmental isolates. Moreover, we find that the expression of genes of interest to rhizosphere chemistry (e.g. representative genes involved in phosphorus-sensing and antibiotic production) varies spatiotemporally within microbial populations that are surface-attached and appears distinct from their expression in planktonic cultures. Together, CFAST’s attributes overcome commercial imaging platform limitations and enable new insights to be gained into microbial behavioral dynamics in experimental systems of relevance to the rhizosphere.
Task-guided Generative Adversarial Networks for Synthesizing and Augmenting Structural Connectivity Matrices for Connectivity-Based Prediction
Authors: Yamamoto Tatsuya , Sugiura Tomoki , Hiroyasu Tomoyuki , Hiwa Satoru 
Published: February 2024

AbstractRecent machine learning techniques have improved connectome-based predictions by modelling complex dependencies between brain connectivity and cognitive traits. However, they typically require large datasets that are costly and time-consuming to collect. To address this, we propose Task-guided GAN II, a novel data augmentation method that uses generative adversarial networks (GANs) to expand sample sizes in connectome-based prediction tasks. Our method incorporates a task-guided branch within the Wasserstein GAN framework, specifically designed to synthesize structural connectivity matrices and improve prediction accuracy by capturing task-relevant features. We evaluated Task-guided GAN II on the prediction of fluid intelligence using the NIMH Health Research Volunteer Dataset. Results showed that data augmentation improved prediction accuracy. To further assess whether augmentation can substitute for increasing real-world sample sizes, we conducted additional validation using the HCP WU-Minn S1200 dataset. Task-guided GAN II improved prediction performance with limited real data, with gains of up to twofold augmentation observed. However, excessive augmentation did not result in further improvements, suggesting that augmentation complements, but does not fully replace, real data augmentation. These results suggest that Task-guided GAN II is a promising tool for harnessing small datasets in human connectomics research, improving predictive modelling where large-scale data collection is impractical.
A new paradigm considering multicellular adhesion, repulsion and attraction represents diverse cellular tile patterns
Authors: Carrillo Jose A. , Murakawa Hideki , Sato Makoto , Wang Miaoxing 
Published: February 2024

AbstractCell sorting by differential adhesion is one of the basic mechanisms explaining spatial organization of neurons in early stage brain development of fruit flies. The columnar arrangements of neurons determine the large scale patterns in the fly visual center. Experimental studies indicate that hexagonal configurations regularly appear while tetragonal configurations can be induced in mutants. Mathematical models based on macroscopic approximations of agent based models (ARA models) are shown to produce a similar behavior changing from hexagonal to tetragonal steady configurations when medium range repulsion and longer-range attraction between individuals is incorporated in previous successful models for cell sorting based on adhesion and volume constraints. We analyse the angular configurations of these patterns based on angle summary statistics and compare between experimental data and parameter fitted ARA models showing that intermediate patterns between hexagonal and tetragonal configuration are common in experimental data as well as in our ARA mathematical model. Our studies indicate an overall qualitative agreement of ARA models in tile patterning and pave the way for their quantitative studies.2010 MSC92C17, 92C37, 35Q92