bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining the extracellular matrix in non-cartilage soft tissues in osteoarthritis – a systematic review
Authors: Mimpen Jolet Y. , Raza Iwan G. A. , Snelling Sarah J. B. 
Published: September 2023

AbstractObjectiveOsteoarthritis (OA) is increasingly seen as a disease of global joint dysfunction, affecting not only cartilage but also the other joint tissues. Extracellular matrix (ECM) is a critical determinant of tissue mechanobiology, but ECM is poorly understood in osteoarthritic joint tissues beyond cartilage in human OA and animal models of OA. Therefore, we aimed to define the structural composition and architecture of non-cartilage soft joint tissue ECM in human OA, and to compare the ECM changes observed in humans to those seen in animal models of OA.DesignA systematic search strategy, devised using relevant matrix, tissue, and disease nomenclature, was run through the MEDLINE, EMBASE, and Scopus databases. Demographic, clinical, and biological data were extracted from eligible studies. Bias analysis was performed.Results142 studies were included, which covered capsule, ligaments, meniscus, skeletal muscle, synovium, and tendon in both humans and animals, and fat pad and intervertebral disc in humans only. Overall, included studies show that the expression of structural ECM components changes in disease within an ECM that becomes disorganised with increasing joint degeneration.ConclusionsThis systematic review consolidates existing knowledge of a poorly defined aspect of OA pathophysiology. Changes in ECM composition and architecture occur across soft joint tissues in OA, but most of these remain poorly defined due to the low number of studies and lack of healthy comparator groups. Further research to better understand the context within which cartilage is damaged in OA may enable a better understanding of OA and its potential treatments.Key messagesWhat is already known on this topicExtracellular matrix (ECM) is a critical determinant of tissue mechanobiology and cell behaviour, but it is poorly described in osteoarthritic joint tissues beyond cartilage.What this study addsOur study highlights the global nature of ECM dysregulation across the osteoarthritic joint. In addition, this study describes practical and methodological challenges that should be addressed to improve the contribution of future studies to define the role of ECM in non-cartilage soft tissues in osteoarthritis.How this study might affect research, practice or policyA better understanding of ECM changes and their underlying mechanisms throughout the osteoarthritic joint may assist with disease classification and patient stratification and also holds promise for the development of ECM-targeting treatments which could modify the pathogenic cell behaviour that may drive osteoarthritis progression.
Effect of lifetime exposure to depression on brain structure and function in the UK Biobank
Authors: Wang Xinyi , Hoffstaedter Felix , Kasper Jan , Eickhoff Simon , Patil Kaustubh R. , Dukart Juergen 
Published: September 2023

AbstractImportanceDespite several decades of neuroimaging studies reporting brain structural and functional alterations in depression, discrepancies in findings across various studies and limited convergence across several recent meta-analyses have raised questions about the consistency and robustness of the observed brain phenotypes.ObjectiveTo investigate the effects of six different operational criteria of lifetime exposure to depression on functional and structural neuroimaging measures.Design, Setting, ParticipantsA cross-sectional study analyzed data from the UK biobank in individuals aged 45 to 80 years enrolled from 2014 to 2018. Six operational depression criteria were defined: Help-seeking for depression, Self-reported Depression, Antidepressant usage, Depression defined by Smith, Hospital International Classification of Disease, 10th Edition (ICD-10), and short-form Composite International Diagnostic Interview. Six increasingly conservative groups of lifetime depression were defined based on the six available depression criteria from meeting only one to more restrictive meeting all six criteria. We tested the effect of these definitions on voxel-wise measures of local functional activity, global connectivity, and gray matter volume.Main Outcomes and MeasuresVoxel-wise fractional amplitude of low-frequency fluctuations, local connectivity, global connectivity, and gray matter volume.ResultsWe included 20,484 individuals with lifetime depression (12,645 women [61.73%]; mean [SD] age, 63.92 [7.6] years) and 25,462 healthy individuals (11,384 women [44.7%]; mean [SD] age, 65.05 [7.8] years) from the UK biobank. Across all depression definitions, individuals with lifetime depression displayed regionally consistent decreases in local functional activity in sensorimotor regions but not in global connectivity and gray matter volume. Previous hospital ICD10 diagnosis and antidepressant usage resulted in the most pronounced alterations.Conclusions and RelevanceLifetime exposure to depression is associated with robust functional changes with more restrictive criteria revealing more pronounced alterations. Different inclusion criteria for depression may strongly contribute to the substantial variation of imaging findings reported in the literature.
Severe preeclampsia is not associated with significant DNA methylation changes but cell proportion changes in the cord blood - caution on the importance of confounding adjustment
Authors: Liu Wenting , Yang Xiaotong , Mao Zhixin , Du Yuheng , Lassiter Cameron , AlAkwaa Fadhl M. , Benny Paula A , Garmire Lana X 
Published: September 2023

AbstractEpigenome-wide DNA methylation analysis (EWAS) is an important approach to identify biomarkers for early disease detection and prognosis prediction, yet its results could be confounded by other factors such as cell-type heterogeneity and patient characteristics. In this study, we address the importance of confounding adjustment by examining DNA methylation patterns in cord blood exposed to severe preeclampsia (PE), a prevalent and potentially fatal pregnancy complication. Without such adjustment, a misleading global hypomethylation pattern is obtained. However, after adjusting cell type proportions and patient clinical characteristics, most of the so-called significant CpG methylation changes associated with severe PE disappear. Rather, the major effect of PE on cord blood is through the proportion changes in different cell types. These results are validated using a previously published cord blood DNA methylation dataset, where global hypomethylation pattern was also wrongfully obtained without confounding adjustment. Additionally, several cell types significantly change as gestation progress (eg. granulocyte, nRBC, CD4T, and B cells), further confirming the importance of cell type adjustment in EWAS study of cord blood tissues. Our study urges the community to perform confounding adjustments in EWAS studies, based on cell type heterogeneity and other patient characteristics.
An Individualized Tractography Pipeline for the Nucleus Basalis of Meynert Lateral Tract
Authors: Crockett Rachel A. , Wilkins Kevin B. , Zeineh Michael M. , McNab Jennifer A. , Henderson Jaimie M. , Buch Vivek P. , Brontë-Stewart Helen M. 
Published: September 2023

AbstractBackgroundAt the center of the cortical cholinergic network, the nucleus basalis of Meynert (NBM) is crucial for the cognitive domains most vulnerable in PD. Preclinical evidence has demonstrated the positive impact of NBM deep brain stimulation (DBS) on cognition but early human trials have had mixed results. It is possible that DBS of the lateral NBM efferent white matter fiber bundle may be more effective at improving cognitive-motor function. However, precise tractography modelling is required to identify the optimal target for neurosurgical planning. Individualized tractography approaches have been shown to be highly effective for accurately identifying DBS targets but have yet to be developed for the NBM.MethodsUsing structural and diffusion weighted imaging, we developed a tractography pipeline for precise individualized identification of the lateral NBM target tract. Using dice similarity coefficients, the reliability of the tractography outputs was assessed across three cohorts to investigate: 1) whether this manual pipeline is more reliable than an existing automated pipeline currently used in the literature; 2) the inter- and intra-rater reliability of our pipeline in research scans of patients with PD; and 3) the reliability and practicality of this pipeline in clinical scans of DBS patients.ResultsThe individualized manual pipeline was found to be significantly more reliable than the existing automated pipeline for both the segmentation of the NBM region itself (p<0.001) and the reconstruction of the target lateral tract (p=0.002). There was also no significant difference between the reliability of two different raters in the PD cohort (p=0.25), which showed high inter- (mean Dice coefficient >0.6) and intra-rater (mean Dice coefficient >0.7) reliability across runs. Finally, the pipeline was shown to be highly reliable within the clinical scans (mean Dice coefficient = 0.77). However, accurate reconstruction was only evident in 7/10 tracts.ConclusionWe have developed a reliable tractography pipeline for the identification and analysis of the NBM lateral tract in research and clinical grade imaging of healthy young adult and PD patient scans.
A comparison of large language model versus manual chart review for extraction of data elements from the electronic health record
Authors: Ge Jin , Li Michael , Delk Molly B. , Lai Jennifer C. 
Published: September 2023

Structured AbstractImportanceLarge language models (LLMs) have proven useful for extracting data from publicly available sources, but their uses in clinical settings and with clinical data are unknown.ObjectiveTo determine the accuracy of data extraction using “Versa Chat,” a chat implementation of the general-purpose OpenAI gpt-35-turbo LLM model, versus manual chart review for hepatocellular carcinoma (HCC) imaging reports.DesignWe engineered a prompt for the data extraction task of six distinct data elements and input 182 abdominal imaging reports that were also manually tagged. We evaluated performance by calculating accuracy, precision, recall, and F1 scores.Setting/ParticipantsCross-sectional abdominal imaging reports of patients diagnosed with hepatocellular carcinoma enrolled in the Functional Assessment in Liver Transplantation (FrAILT) study.
Tracer-based lipidomics identifies novel disease-specific biomarkers in mitochondrial β-oxidation disorders
Authors: Schwantje Marit , Mosegaard Signe , Knottnerus Suzan JG , van Klinken Jan Bert , Wanders Ronald J , van Lenthe Henk , Hermans Jill , IJlst Lodewijk , Denis Simone W , Jaspers Yorrick RJ , Fuchs Sabine A , Houtkooper Riekelt H , Ferdinandusse Sacha , Vaz Frédéric M 
Published: September 2023

AbstractCarnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and possible influence on cellular lipid homeostasis are, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore new disease markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two new candidate disease markers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second biomarker is an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. These are hypothesized to be degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two new disease markers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.
Full-length direct RNA sequencing uncovers stress-granule dependent RNA decay upon cellular stress
Authors: Dar Showkat A. , Malla Sulochan , Martinek Vlastimil , Payea Matthew J. , Lee Christopher T. , Martin Jessica , Khandeshi Aditya J. , Martindale Jennifer L. , Belair Cedric , Maragkakis Manolis 
Published: September 2023

AbstractCells react to stress by triggering response pathways, leading to extensive alterations in the transcriptome to restore cellular homeostasis. The role of RNA metabolism in shaping the cellular response to stress is vital, yet the global changes in RNA stability under these conditions remain unclear. In this work, we employ direct RNA sequencing with nanopores, enhanced by 5’ end adaptor ligation, to comprehensively interrogate the human transcriptome at single-molecule and nucleotide resolution. By developing a statistical framework to identify robust RNA length variations in nanopore data, we find that cellular stress induces prevalent 5’ end RNA decay that is coupled to translation and ribosome occupancy. Unlike typical RNA decay models in normal conditions, we show that stress-induced RNA decay is dependent on XRN1 but does not depend on deadenylation or decapping. We observed that RNAs undergoing decay are predominantly enriched in the stress granule transcriptome while inhibition of stress granule formation via genetic ablation of G3BP1 and G3BP2 rescues RNA length. Our findings reveal RNA decay as a key determinant of RNA metabolism upon cellular stress and dependent on stress-granule formation.
Precision Proteoform Design for 4R Tau Isoform Selective Templated Aggregation
Authors: Longhini Andrew P. , DuBose Austin , Lobo Samuel , Vijayan Vishnu , Bai Yeran , Rivera Erica Keane , Sala-Jarque Julia , Nikitina Arina , Carrettiero Daniel C. , Unger Matthew , Sclafani Olivia , Fu Valerie , Vigers Michael , Buee Luc , Landrieu Isabelle , Shell Scott , Shea Joan E. , Han Songi , Kosik Kenneth S. 
Published: September 2023

AbstractPrion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau, folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high β- sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting β-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19- residue peptide. These peptide fibrils function as partial prions to recruit naïve 4R tau—ten times the length of the peptide—and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform-specific therapeutic interventions.Significance StatementA structural motif corresponding to a short junction sequence spanning R2 and R3 forms fibrils that adopt a fold characteristic of 4R tauopathy fibrils and induces misfolding of the larger tau protein with loss of microtubule binding and a prion-like specificity for 4R tau. Simulations, validated experimentally, pinpointed the specific amino acids in the peptide that can toggle its properties between aggregation competent and incompetent. The modifications suggest design principles for a therapeutic intervention potentially capable of disaggregating tau or preventing its aggregation in the 4R tauopathies.
EfpA is required for re-growth ofMycobacterium tuberculosisfollowing isoniazid exposure
Authors: Roberts Adam H. , Moon Christopher W. , Faulkner Valwynne , Kendall Sharon L. , Waddell Simon , Bacon Joanna 
Published: September 2023

AbstractEfflux of antibiotics is a survival strategy in bacteria.Mycobacterium tuberculosishas approximately sixty efflux pumps, but little is known about the role of each pump, or which moieties that they efflux. The putative efflux pump, EfpA, is a member of the major facilitator superfamily that has been shown to be essential by saturation transposon mutagenesis studies. It has been implicated in the efflux of the frontline drug isoniazid (INH) inM. tuberculosis. This is supported by evidence from transcriptional profiling thatefpAis induced in response to INH exposure. However, its role in physiology and adaptation ofM. tuberculosisto antibiotics, have yet to be determined. Here, we describe the repression ofefpAusing CRISPR interference and the direct effect of this on the ability ofM. tuberculosisto survive exposure to INH over a 45-day time-course. We determined that wild-type levels ofefpAwere required for the recovery ofM. tuberculosiscultures following INH exposure and that, after 45-days of INH exposure, no viable colonies were recoverable fromefpA-repressedM. tuberculosiscultures. We postulate that EfpA is required for the recovery ofM. tuberculosisfollowing INH-exposure and that EfpA may have a role in the development of resistance, during treatment and contributes to relapse in patients.
Ultralow background membrane editors for spatiotemporal control of lipid metabolism and signaling
Authors: Li Xiang-Ling , Tei Reika , Uematsu Masaaki , Baskin Jeremy M. 
Published: September 2023

AbstractPhosphatidic acid (PA) is a multifunctional lipid with important metabolic and signaling functions, and efforts to dissect its pleiotropy demand strategies for perturbing its levels with spatiotemporal precision. Previous membrane editing approaches for generating local PA pools used light-mediated induced proximity to recruit a PA-synthesizing enzyme, phospholipase D (PLD), from the cytosol to the target organelle membrane. Whereas these optogenetic PLDs exhibited high activity, their residual activity in the dark led to undesired chronic lipid production. Here, we report ultralow background membrane editors for PA wherein light directly controls PLD catalytic activity, as opposed to localization and access to substrates, exploiting a LOV domain-based conformational photoswitch inserted into the PLD sequence and enabling their stable and non-perturbative targeting to multiple organelle membranes. By coupling organelle-targeted LOVPLD activation to lipidomics analysis, we discovered different rates of metabolism for PA and its downstream products depending on the subcellular location of PA production. We also elucidated signaling roles for PA pools on different membranes in conferring local activation of AMP-activated protein kinase signaling. This work illustrates how membrane editors featuring acute, optogenetic conformational switches can provide new insights into organelle-selective lipid metabolic and signaling pathways.TOC Graphic
High prevalence of asymptomatic malaria in Forest Guinea: Results from a rapid community survey
Authors: Hammer Charlotte C , Diallo Mariama Dalanda , Kann Boubacar , Sanoh Fatoumata , Leno Tamba N’fantoma , Mansare Oumar , Diakité Ismail , Sow Abdoulaye Djibril , Konate Yacouba , Ryan-Castillo Emilie , Barry Alpha Mahmoud , Standley Claire J 
Published: September 2023

SummaryMalaria is endemic in Guinea, however, the extent and role in transmission of asymptomatic malaria are not well understood. In May 2023, we conducted a rapid community survey to determinePlasmodium falciparumprevalence among asymptomatic individuals in Middle Guinea (Dalaba) and Forest Guinea (Guéckédou). We used a cluster sampling approach with purposive selection of two prefectures and four communities and full enrolment of all individuals in the selected communities. Prevalence was calculated with a 95% confidence interval (CI). In Dalaba, 6/239 (2.1%, CI 0.9-4.8%) individuals tested positive for P.falciparumby rapid diagnostic test, while in Guéckédou, 147/235 (60.9%, CI 54.5-66.9%) of participants tested positive. Asymptomatic malaria needs to be considered more strongly as a driver for transmission when designing control strategies, especially in Forest Guinea and potentially other hyper-endemic settings.Key results and their importancePrevalence of asymptomatic malaria was very high (60.9%, CI 54.5-66.9%) in the selected communities in Forest Guinea.Prevalence was expectedly low (2.1%, CI 0.9-4.8%) in the selected communities in Middle Guinea.Current control strategies in Forest Guinea seem insufficient to reduce malaria prevalence, and likely also transmission.Both policies and control strategies need to more proactively consider asymptomatic malaria in hyper-endemic settings.
The impacts of social needs and game playing type on esports consumers' positive eWOM sharing: applying the FIRO theory
Authors: Ock Deokkyung , Hwang Yongjin 
Published: September 2023

PurposeThe current study aims to examine esports consumers' social needs (inclusion, affection and control) as antecedents of positive eWOM intention. Additionally, the moderating effects of game playing type (individual-based competition vs. team-based competition) were tested to determine whether the inherent socializing opportunities provided by each game playing type have different effects on the relationship between social needs and eWOM communication of esports consumers.Design/methodology/approachA cross-sectional survey design was applied to 387 responses collected from an online survey platform. After checking several assumptions, a series of regression analyses were performed to test the suggested hypotheses.FindingsThe results revealed that the needs for inclusion, affection and control were positively associated with eWOM intention. Furthermore, the relationships between inclusion and eWOM intention and affection and eWOM intention were moderated by game playing type.Originality/valueThe current study extended the fundamental interpersonal relations orientation theory from conventional interpersonal relationships to interpersonal communication in online platforms. This research also suggested that eWOM communication in esports could be supplemental social opportunities, especially for individual-based competition games.