bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel method to assess motor planning deficits in patients with Parkinson’s disease and mild cognitive impairment
Authors: Maffit Natalie J , Banerjee Satwika , Sarkar Subhajit , Majumdar Suchismita , Choudhury Supriyo , Kumar Hrishikesh , Soteropoulos Demetris S , Kraskov Alexander 
Published: November 2024

AbstractIt is well established that patients with Parkinson’s disease (PD) show deficits with movement execution, however experiences of motor planning dysfunction, and how they relate to the severity of motor symptoms, remains unclear. To investigate motor planning in PD, we designed a novel precision-grip task. PD patients showed significantly higher uncertainty in task performance compared to healthy controls, indicative of motor planning deficits. Performance of PD patients did not correlate with indicators of disease severity or subtype, yet patients on a higher daily levodopa dosage showed reduced motor planning deficits. Interestingly, these deficits were present even in recently diagnosed patients, implying that this measure may have potential as an early marker of motor planning impairment. These results suggest that the motor planning deficits revealed by our task may arise from separate pathological processes to that of motor execution dysfunction in PD, though can be alleviated with higher treatment dosages.
Risk Prediction for Non-cardiac Surgery Using the 12-Lead Electrocardiogram: An Explainable Deep Learning Approach
Authors: Harris Carl , Pimpalkar Anway , Aggarwal Ataes , Yang Jiyuan , Chen Xiaojian , Schmidgall Samuel , Rapuri Sampath , Greenstein Joseph L. , Taylor Casey Overby , Stevens Robert D. 
Published: November 2024

AbstractBackgroundTo improve on existing noncardiac surgery risk scores, we propose a novel approach which leverages features of the preoperative 12-lead electrocardiogram (ECG) to predict major adverse postoperative outcomes.MethodsData acquired in 37,060 adult patients prior to major noncardiac surgery were used to train a series of convolutional neural network models in the task of predicting in-hospital acute myocardial infarction (MI), in-hospital mortality (IHM), and a composite of in-hospital MI, in-hospital stroke, and 30-day mortality. Preoperative ECG waveform features were first modeled as sole inputs then integrated with clinical variables in fusion models. Model discrimination was evaluated using area under the receiver operating characteristic (AUROC) analysis, and performances were compared with the Revised Cardiac Risk Index (RCRI), a benchmark preoperative risk score To gain interpretable insight, a generative approach using counterfactual ECGs was implemented.ResultsThe ECG fusion model had an AUROC of 0.858 (95% CI [0.845, 0.872]), 0.899 (95% CI [0.889, 0.908]), and 0.835 (95% CI [0.827, 0.843]) in predicting MI, IHM, and the composite endpoint, respectively; these AUROC values were significantly higher than in models based on ECG waveforms alone (MI:p= 0.001, IHM:p< 10−4, composite:p< 10−4). All ECG based models had significantly higher discrimination than the RCRI. Counterfactual ECG analysis revealed morphological features relevant to outcome classification.ConclusionA deep learning approach integrating preoperative ECG waveform features significantly enhances the ability to predict major outcomes after noncardiac surgery. The use of counterfactual ECGs provides plausible explanations for classifier decisions, increasing the interpretability of the models.Clinical perspectiveWhat is new?□ A deep learning approach applied to preoperative 12-lead ECG waveforms accurately predicts major outcomes after noncardiac surgery.□ This model outperforms the benchmark Revised Cardiac Risk Index (RCRI).□ The highest predictive performance was obtained with a fusion model that combines preoperative ECG waveforms with routinely collected clinical variables.□ An exploratory approach in which counterfactual ECGs are generated provides explainability for classifier decisions.What are the clinical implications?□ In adults undergoing non-cardiac surgery, ECG waveform features are predictive of postoperative cardiovascular risk□ Risk models integrating ECG waveforms with clinical variables can serve as the basis for outcome modifying interventions across the surgical continuum.□ Achieving explainability through counterfactual ECGs represents an important step towards real-world implementation.
Frequency and Longitudinal Course of Autonomic Reflex Testing Abnormalities in Isolated REM Sleep Behavior Disorder
Authors: Taha Hash Brown , Zitser Jennifer , Miglis Mitchell G. 
Published: November 2024

AbstractStudy ObjectivesAutonomic dysfunction is common across the α-synucleinopathies including isolated RBD (iRBD), however the presence, severity and distribution of autonomic dysfunction as a risk factor for phenoconversion in iRBD remains unclear. We aimed to characterize autonomic reflex testing (ART) abnormalities in a cohort of participants with iRBD and assess their potential as biomarkers for predicting phenoconversion risk.MethodsWe performed ART on 45 individuals with iRBD and evaluated the ability of individual ART components (sympathetic cholinergic, cardiovagal, sympathetic adrenergic) to predict phenoconversion using univariate and multivariate predictive models, both alone and combined with measures of olfaction, cognition, motor function, and skin biopsy assessment of dermal synuclein.ResultsForty-one individuals with iRBD were enrolled (age 66.7 ± 7.4 yrs, 27% female), and followed annually for an average of 2.9 ± 2.4 yrs, with four participants lost to follow-up. Eight participants with iRBD phenoconverted during their follow-up period (3 Parkinson’s disease, 4 dementia with Lewy bodies and 1 multiple system atrophy), yielding a phenoconversion rate of 6.6% per year. Eighty seven percent of iRBD participants had an abnormal baseline ART, and 100% had an abnormal follow-up ART. A combination of MDS-UPDRS III score and cardiovagal dysfunction (abnormal heart rate variability with deep breathing) best predicted phenoconversion (AUC = 0.77, 95% CI: 0.59–0.94).ConclusionsANS dysfunction was common and spanned all domains of autonomic function. Baseline cardiovagal dysfunction was most affected and predictive of phenoconversion, especially if combined with motor examination. Longitudinal studies with larger sample sizes are needed to confirm these findings.
DNA Methylation Signatures of Cardiovascular Health Provide Insights into Diseases
Authors: Carbonneau Madeleine , Li Yi , Qu Yishu , Zheng Yinan , Wood Alexis C. , Wang Mengyao , Liu Chunyu , Huan Tianxiao , Joehanes Roby , Guo Xiuqing , Yao Jie , Taylor Kent D. , Tracy Russell P. , Peter Durda , Liu Yongmei , Johnson W Craig , Post Wendy S. , Blackwell Tom , Rotter Jerome I. , Rich Stephen S. , Redline Susan , Fornage Myriam , Wang Jun , Ning Hongyan , Hou Lifang , Lloyd-jones Donald , Ferrier Kendra , Min Yuan-I. , Carson April P. , Raffield Laura M. , Teumer Alexander , Grabe Hans J. , Völzke Henry , Nauck Matthias , Dörr Marcus , Domingo-Relloso Arce , Fretts Amanda , Tellez-Plaza Maria , Cole Shelley , Navas-Acien Ana , Wang Meng , Murabito Joanne M. , Heard-Costa Nancy L. , Prescott Brenton , Xanthakis Vanessa , Mozaffarian Dariush , Levy Daniel , Ma Jiantao 
Published: November 2024

AbstractBackgroundThe association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.MethodsWe calculated the American Heart Association’s Life’s Essential 8 (LE8) score to reflect CVH in five cohorts with diverse ancestry backgrounds. Epigenome-wide association studies (EWAS) for LE8 score were conducted, followed by bioinformatic analyses. DNAm loci significantly associated with LE8 score were used to calculate a CVH DNAm score. We examined the association of the CVH DNAm score with incident CVD, CVD-specific mortality, and all-cause mortality.ResultsWe identified 609 CpGs associated with LE8 score at false discovery rate (FDR) < 0.05 in the discovery analysis and at Bonferroni correctedP< 0.05 in the multi-cohort replication stage. Most had low-to-moderate heterogeneity (414 CpGs [68.0%] with I2< 0.2) in replication analysis. Pathway enrichment analyses and phenome-wide association study (PheWAS) search associated these CpGs with inflammatory or autoimmune phenotypes. We observed enrichment for phenotypes in the EWAS catalog, with 29-fold enrichment for stroke (P= 2.4e-15) and 21-fold for ischemic heart disease (P= 7.4e-38). Two-sample Mendelian randomization (MR) analysis showed significant association between 141 CpGs and ten phenotypes (261 CpG-phenotype pairs) at FDR < 0.05. For example, hypomethylation at cg20544516 (MIR33B;SREBF1) associated with lower risk of stroke (P= 8.1e-6). In multivariable prospective analyses, the CVH DNAm score was consistently associated with clinical outcomes across participating cohorts, the reduction in risk of incident CVD, CVD mortality, and all-cause mortality per standard deviation increase in the DNAm score ranged from 19% to 32%, 28% to 40%, and 27% to 45%, respectively.ConclusionsWe identified new DNAm signatures for CVH across diverse cohorts. Our analyses indicate that immune response-related pathways may be the key mechanism underpinning the association between CVH and clinical outcomes.
Effectiveness of aerobic physical exercise on depression symptoms in adults: A protocol for a systematic review and meta-analysis of randomized clinical trials
Authors: de Souza Larissa Nayara , de Araújo Silvana Medeiros , da Silva Paiva Eva , Eliege da Silva Alícia , da Costa Neto Joel Florêncio , Lima Assis Juvêncio César , dos Santos Isis Kelly , Mesquita Soares Themis Cristina , Pinto Edson Fonseca , da Silva Júnior Roque Ribeiro , Knackfuss Maria Irany 
Published: November 2024

AbstractObjectiveDepression is a chronic condition that affects millions of people and requires effective interventions. Studies suggest that aerobic exercise can improve mental health and reduce depression symptoms, despite variations in exercise type and intensity. The aim of this study will be to analyze the effect of aerobic exercise on reducing depression in adults.MethodsThis is a systematic review protocol, which will follow the PRISMA-P 2020 guidelines and has been registered in PROSPERO (no. CRD42024592700). The study search will be conducted in five databases: PubMed, Embase, Cochrane, BVS, and SPORTDiscus, using MeSH-based descriptors. Studies will be selected independently by two researchers using the Rayyan ‘QCRI’ software. Data extraction will be conducted with specific forms, and the methodological quality of the studies will be assessed using the Cochrane RoB 2.0 method. The certainty of evidence will be evaluated through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).ConclusionsThe systematic review is expected to identify the effective dose-response for reducing depression levels and provide understanding of the mechanisms through which aerobic exercise influences depression.
AZIN2-dependent polyamine metabolism determines adipocyte progenitor fate and protects against obesity and dysmetabolism
Authors: Mund Christine , Sinha Anupam , Aderhold Anika , Mateska Ivona , Hagag Eman , Traikov Sofia , Gercken Bettina , Soto Andres , Pollock Jonathan , Arndt Lilli , Wölk Michele , Werner Natalie , Fodelianaki Georgia , Subramanian Pallavi , Chung Kyoung-Jin , Grossklaus Sylvia , Langner Mathias , Elgendy Mohamed , Grinenko Tatyana , Wielockx Ben , Dahl Andreas , Gericke Martin , Blüher Matthias , Coskun Ünal , Voehringer David , Fedorova Maria , Peitzsch Mirko , Murray Peter J. , Chavakis Triantafyllos , Alexaki Vasileia Ismini 
Published: November 2024

SummaryAdipose tissue homeostasis plays a critical role in metabolic disease but the metabolic circuitry regulating adipose tissue dynamics remains unclear. In this study, polyamine metabolism emerges as an important regulator of adipose tissue pathophysiology. We identify AZIN2 (Antizyme inhibitor 2), a protein promoting polyamine synthesis and acetylation, as a major regulator of total acetyl-CoA in adipocyte progenitors (APs). AZIN2 deficient APs demonstrate increased H3K27 acetylation marks in genes related to lipid metabolism, cell cycle arrest and cellular senescence, and enhanced adipogenesis compared to wild-type counterparts. Upon high-fat diet (HFD)-induced obesity, global AZIN2 deficiency in mice provokes adipose tissue hypertrophy, AP senescence, lipid storage perturbations, inflammation and insulin resistance. IL4 promotesAzin2expression in APs but not mature adipocytes due to diminished IL4 receptor expression in the latter. In human visceral and subcutaneous adipose tissue,AZIN2expression positively correlates with expression of early progenitor markers and genes associated with protection against insulin resistance, while it negatively correlates with markers of lipogenesis. In sum, AZIN2-driven polyamine metabolism preserves adipose tissue health, a finding that could be therapeutically harnessed for the management of obesity-associated metabolic disease.
Scalable cell-free production of active T7 RNA polymerase
Authors: Rezvani Ryan N. , Aw Rochelle , Chan Wei , Satish Krishnathreya , Chen Han , Lavy Adi , Rimal Swechha , Patel Divyesh A. , Kvam Erik , Karim Ashty S. , Krüger Antje , Kightlinger Weston K. , Jewett Michael C. 
Published: November 2024

AbstractThe SARS-CoV-2 pandemic highlighted the urgent need for biomanufacturing paradigms that are robust and fast. Here, we demonstrate the rapid process development and scalable cell-free production of T7 RNA polymerase, a critical component in mRNA vaccine synthesis. We carry out a one-liter cell-free gene expression (CFE) reaction that achieves over 80% purity, low endotoxin levels, and enhanced activity relative to commercial T7 RNA polymerase. To achieve this demonstration, we implement rolling circle amplification to circumvent difficulties in DNA template generation, and tune cell-free reaction conditions, such as temperature, additives, purification tags and agitation to boost yields. We achieve production of a similar quality and titer of T7 RNA polymerase over more than 4 orders of magnitude reaction volume. This proof of principle positions CFE as a viable solution for decentralized biotherapeutic manufacturing, enhancing preparedness for future public health crises or emergent threats.
Mirages in continuous directed enzyme evolution: A cautionary case study with plantized bacterial THI4 enzymes
Authors: Van Gelder Kristen , Gayen Anuran K. , Hanson Andrew D. 
Published: November 2024

AbstractContinuous directed evolution (CDE) improves enzyme characteristics by hypermutating the enzyme genein vivoin a microbial platform, linking enzyme activity to growth, and selecting for growth rate. Combined with genome editing, CDE can expand the gene pool for plant breeding. THI4 enzymes, essential for thiamin synthesis, are ideal targets for plant CDE. Plant THI4s are inefficient; their replacement by efficient bacterial THI4s could boost biomass yield by up to 4%. However, bacterial THI4s are O2-sensitive and unsuited to plants. Previous CDE campaigns in the yeast OrthoRep system adapted bacterial THI4s for plant-like conditions, achieving success withMucinivorans hirudinisTHI4 (MhTHI4), which acquired beneficial mutations that improved growth. Here, we increased selection pressure on MhTHI4 by reducing its expression, leading to faster-growing populations with new nonsynonymous and synonymous mutations. Surprisingly, the synonymous mutations appeared largely responsible for the growth rate improvements, providing a cautionary example for other OrthoRep CDE projects.
SARM1 Activation Promotes Axonal Degeneration Via a Two-Step Liquid-to-Solid Phase Transition
Authors: Wenbin Zhang , Qinyi Zhou , Jun Zhang , Jiachen Wang , Sanduo Zheng , Xiaodong Wang 
Published: November 2024

AbstractSARM1 protein plays a central role in axonal degeneration, a key process in many neurodegenerative diseases and nerve injuries. It mediates this by depleting axonal NAD+ through its NADase activity, catalyzed by the TIR domain. Normally, this activity is kept in an inactive state and becomes activated in response to various neuronal damage signals. However, the molecular mechanism behind SARM1 activation, particularly how activation is restricted to damaged axons, remains to be fully elucidated. In this study, using a class of pyridine-containing compounds that induce SARM1-dependent cell death and axonal degeneration, we reveal a two-step process of SARM1 activation. The first step involves sub-lethal “priming” activation of SARM1 mediated by the NAD+ precursor NMN, leading to the formation of covalent conjugates between the hydrolyzed product of NAD+, adenosine diphosphate ribose (ADPR), and the compounds catalyzed by the intrinsic base exchange activity of SARM1. In the second step, these ADPR-conjugates act as molecular glues, promoting the formation of self-proliferating superhelical filaments. On these filaments, SARM1’s TIR domains adopt an active NADase configuration. As the superhelical filaments rapidly reach their limit of solubility, they precipitate out of the liquid phase as condensates with stable, fully activated NAD hydrolysis activity. Interestingly, we found that a series of reported SARM1 inhibitors currently under clinical development, which target the TIR enzymatic domain, can paradoxically activate SARM1’s NADase activity via this mechanism. These findings provide new insights into how SARM1 activation is spatially restricted to damaged axons and offer important implications for the development of therapeutics targeting SARM1.
PTBP1 is upregulated by Zika virus infectionviaHIF-1α signal and hijacks NS1 protein to induce NS1 degradation to restrain viral replication
Authors: Rao Menglan , Lei Zhiwei , Liu Shuang , Lin Jiuxiu , Kong Yue , Liang Yicong , Luo Zhen 
Published: November 2024

AbstractZika virus (ZIKV), belonging to theFlaviviridaefamily, has been a severe threat to human health since the worldwide outbreak. ZIKV is capable of inducing fetal microcephaly, Guillain-Barré syndrome, and other serious neurological complications. Polypyrimidine tract-binding protein 1 (PTBP1) is a key member of the heterogeneous nuclear ribonucleoproteins (hnRNPs) family, functioning in selective mRNA splicing and gene expression regulation. Our previous study has indicated that the expression of PTBP1 increases in astrocytes upon ZIKV infection, yet the precise regulatory mechanisms underlying its role in viral replication remain elusive. In this study, we elucidated the specific pathway by which ZIKV upregulates PTBP1 expression through the activation of Hypoxia-inducible factor-1α (HIF-1α) expression. Further investigation revealed that overexpression of PTBP1 effectively inhibits viral replication, whereas knockdown of PTBP1 significantly enhances viral replication. Mechanistically, using co-immunoprecipitation assays for protein interaction screening, we identified an interaction between PTBP1 and ZIKV non-structural protein NS1. Detailed studies demonstrated that PTBP1 bound and colocalized with NS1 to lead to the degradation of NS1 protein via a lysosomal pathway. Collectively, our findings unveil a novel mechanism underlying that ZIKV infection induces the expression of PTBP1 via the HIF-1α pathway, subsequently the accumulated PTBP1 binds to ZIKV NS1 protein to promote NS1 degradation, thereby effectively inhibiting viral replication. The study illustrates a distinct restricted cellular factor that regulates ZIKV replication, which provides a potential target for the control of the viral replication and pathogenesis during the ZIKV epidemic.ImportanceSince the outbreak of ZIKV infection among human in 2014, a Zika epidemic has caused Zika fever accompanied with fetal microcephaly, Guillain-Barré syndrome, and other neurological symptoms. Emerging evidence reveals that ZIKV infects astrocytes to specially induce the expression of polypyrimidine tract-binding protein 1 (PTBP1), one of hnRNPs members. However, the interplay between PTBP1 and ZIKV replication is highly concerned. Here, we uncover a distinct manner that ZIKV infection induces PTBP1 expression through the activation of hypoxia-inducible factor-1α (HIF-1α) signal. Additionally, activation of HIF-1α signal hinders ZIKV replication relying on PTBP1 accumulation. Further investigations suggest that PTBP1 restrains ZIKV replication by interacting with ZIKV NS1 protein, thereby leading to the degradation of NS1 protein via a lysosomal pathway. Collectively, our findings illustrate a novel restricted cellular factor PTBP1 mediated by HIF-1α that regulates ZIKV replication, which provides a potential therapeutic target of the viral replication and pathogenesis against ZIKV pandemic.
Integrative Metagenomic and Blood Biomarker Analysis Reveals Distinct Metabolic Responses to Aerobic and Anaerobic Interventions in Athletic and Non-Athletic Individuals
Authors: Zielińska Kinga , Michałowska-Sawczyn Monika , Kosciolek Tomasz , Łabaj Paweł P. , Bicakci Barkin , Proia Patrizia , Cięszczyk Paweł , Kochanowicz Andrzej , Mieszkowski Jan , Humińska-Lisowska Kinga 
Published: November 2024

AbstractBackgroundThe gut microbiome influences physiological responses to exercise through interactions with inflammatory markers and metabolite production. Athletes often exhibit a more diverse gut microbiome that is associated with improved performance, but the mechanisms, particularly in relation to different training modalities, are not fully understood. This study aims to integrate blood serum markers with metagenomic data to explore the interplay between exercise type, gut microbiome, and biochemical responses in athletic and non-athletic individuals.MethodsFifty-two male participants (endurance athletes, strength athletes, and controls) underwent two maximal exercise tests: the anaerobic Wingate test and the aerobic Bruce treadmill test. Blood and stool samples were collected at multiple time points for biochemical analysis and metagenomic sequencing. Blood markers were correlated with shifts in microbiome composition and function.ResultsWhile most biochemical parameters showed similar trends across all groups post-exercise, SPARC and adiponectin levels showed distinct responses depending on the exercise modality. The strength group showed unique microbiome associations with blood markers after the Wingate test. Baseline enrichment of specific bacteria (Clostridium phoceensisandCatenibacterium spp.) was associated with an inhibited response to the Bruce test in strength athletes.ConclusionsThe integration of metagenomic and blood serum analyses reveals that exercise modality and training background elicit complex physiological and biochemical responses mediated by the gut microbiome. These findings suggest that specific microbial species may play significant roles in recovery and adaptation processes following acute exercise. Further research with larger cohorts is needed to validate these findings and explore microbiome-targeted interventions to improve performance and recovery.