bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysregulated RNA editing of EIF2AK2 in polycystic ovary syndrome: clinical relevance and functional implications
Authors: Kong Fan-Sheng , Feng Junjie , Yao Jin-Ping , Lu Yinghua , Guo Tao , Sun Meng , Ren Chun-Yan , Jin Yun-Yun , Ma Yaping , Chen Jian-Huan 
Published: June 2024

Abstract
Background
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA editing and PCOS, yet the actual role of RNA editing, its association with clinical features, and the underlying mechanisms remain unclear.

Methods
Ten RNA-Seq datasets containing 269 samples of multiple tissue types, including granulosa cells, T helper cells, placenta, oocyte, endometrial stromal cells, endometrium, and adipose tissues, were retrieved from public databases. Peripheral blood samples were collected from twelve PCOS and ten controls and subjected to RNA-Seq. Transcriptome-wide RNA-Seq data analysis was conducted to identify differential RNA editing (DRE) between PCOS and controls. The functional significance of DRE was evaluated by luciferase reporter assays and overexpression in human HEK293T cells. Dehydroepiandrosterone and lipopolysaccharide were used to stimulate human KGN granulosa cells to evaluate gene expression.

Results
RNA editing dysregulations across multiple tissues were found to be associated with PCOS in public datasets. Peripheral blood transcriptome analysis revealed 798 DRE events associated with PCOS. Through weighted gene co-expression network analysis, our results revealed a set of hub DRE events in PCOS blood. A DRE event in the eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2:chr2:37,100,559) was associated with PCOS clinical features such as luteinizing hormone (LH) and the ratio of LH over follicle-stimulating hormone. Luciferase assays, overexpression, and knockout of RNA editing enzyme adenosine deaminase RNA specific (ADAR) showed that the ADAR-mediated editing cis-regulated EIF2AK2 expression. EIAF2AK2 showed a higher expression after dehydroepiandrosterone and lipopolysaccharide stimulation, triggering changes in the downstrean MAPK pathway.

Conclusions
Our study presented the first evidence of cross-tissue RNA editing dysregulation in PCOS and its clinical associations. The dysregulation of RNA editing mediated by ADAR and the disrupted target EIF2AK2 may contribute to PCOS development via the MPAK pathway, underlining such epigenetic mechanisms in the disease.
How do lifestyle factors modify the association between genetic predisposition and obesity-related phenotypes? A 4-way decomposition analysis using UK Biobank
Authors: Zhang Mengrong , Ward Joey , Strawbridge Rona J. , Celis-Morales Carlos , Pell Jill P. , Lyall Donald M. , Ho Frederick K. 
Published: June 2024

Abstract
Background
Obesity and central obesity are multifactorial conditions with genetic and non-genetic (lifestyle and environmental) contributions. There is incomplete understanding of whether lifestyle modifies the translation from respective genetic risks into phenotypic obesity and central obesity, and to what extent genetic predisposition to obesity and central obesity is mediated via lifestyle factors.

Methods
This is a cross-sectional study of 201,466 (out of approximately 502,000) European participants from UK Biobank and tested for interactions and mediation role of lifestyle factors (diet quality; physical activity levels; total energy intake; sleep duration, and smoking and alcohol intake) between genetic risk for obesity and central obesity. BMI-PRS and WHR-PRS are exposures and obesity and central obesity are outcomes.

Results
Overall, 42.8% of the association between genetic predisposition to obesity and phenotypic obesity was explained by lifestyle: 0.9% by mediation and 41.9% by effect modification. A significant difference between men and women was found in central obesity; the figures were 42.1% (association explained by lifestyle), 1.4% (by mediation), and 40.7% (by modification) in women and 69.6% (association explained by lifestyle), 3.0% (by mediation), and 66.6% (by modification) in men.

Conclusions
A substantial proportion of the association between genetic predisposition to obesity/central obesity and phenotypic obesity/central obesity was explained by lifestyles. Future studies with repeated measures of obesity and lifestyle would be needed to clarify causation.
Clinical features and ALDH5A1 gene findings in 13 Chinese cases with succinic semialdehyde dehydrogenase deficiency
Authors: Dong Hui , Ma Xue , Chen Zhehui , Zhang Huiting , Song Jinqing , Jin Ying , Li Mengqiu , Lu Mei , He Ruxuan , Zhang Yao , Yang Yanling 
Published: June 2024

Abstract
Background and aims
To investigate the clinical features, ALDH5A1 gene variations, treatment, and prognosis of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency.

Materials and methods
This retrospective study evaluated the findings in 13 Chinese patients with SSADH deficiency admitted to the Pediatric Department of Peking University First Hospital from September 2013 to September 2023.

Results
Thirteen patients (seven male and six female patients; two sibling sisters) had the symptoms aged from 1 month to 1 year. Their urine 4-hydroxybutyrate acid levels were elevated and were accompanied by mildly increased serum lactate levels. Brain magnetic resonance imaging (MRI) showed symmetric abnormal signals in both sides of the globus pallidus and other areas. All 13 patients had psychomotor retardation, with seven showing epileptic seizures. Among the 18 variants of the ALDH5A1 gene identified in these 13 patients, six were previously reported, while 12 were novel variants. Among the 12 novel variants, three (c.85_116del, c.206_222dup, c.762C > G) were pathogenic variants; five (c.427delA, c.515G > A, c.637C > T, c.755G > T, c.1274T > C) were likely pathogenic; and the remaining four (c.454G > C, c.479C > T, c.1480G > A, c.1501G > C) were variants of uncertain significance. The patients received drugs such as L-carnitine, vigabatrin, and taurine, along with symptomatic treatment. Their urine 4-hydroxybutyric acid levels showed variable degrees of reduction.

Conclusions
A cohort of 13 cases with early-onset SSADH deficiency was analyzed. Onset of symptoms occurred from 1 month to 1 year of age. Twelve novel variants of the ALDH5A1 gene were identified.
Motor skill learning modulates striatal extracellular vesicles’ content in a mouse model of Huntington’s disease
Authors: Solana-Balaguer Júlia , Garcia-Segura Pol , Campoy-Campos Genís , Chicote-González Almudena , Fernández-Irigoyen Joaquín , Santamaría Enrique , Pérez-Navarro Esther , Masana Mercè , Alberch Jordi , Malagelada Cristina 
Published: June 2024

AbstractHuntington’s disease (HD) is a neurological disorder caused by a CAG expansion in the Huntingtin gene (HTT). HD pathology mostly affects striatal medium-sized spiny neurons and results in an altered cortico-striatal function. Recent studies report that motor skill learning, and cortico-striatal stimulation attenuate the neuropathology in HD, resulting in an amelioration of some motor and cognitive functions. During physical training, extracellular vesicles (EVs) are released in many tissues, including the brain, as a potential means for inter-tissue communication. To investigate how motor skill learning, involving acute physical training, modulates EVs crosstalk between cells in the striatum, we trained wild-type (WT) and R6/1 mice, the latter with motor and cognitive deficits, on the accelerating rotarod test, and we isolated their striatal EVs. EVs from R6/1 mice presented alterations in the small exosome population when compared to WT. Proteomic analyses revealed that striatal R6/1 EVs recapitulated signaling and energy deficiencies present in HD. Motor skill learning in R6/1 mice restored the amount of EVs and their protein content in comparison to naïve R6/1 mice. Furthermore, motor skill learning modulated crucial pathways in metabolism and neurodegeneration. All these data provide new insights into the pathogenesis of HD and put striatal EVs in the spotlight to understand the signaling and metabolic alterations in neurodegenerative diseases. Moreover, our results suggest that motor learning is a crucial modulator of cell-to-cell communication in the striatum.
Elevated nuclear TDP-43 induces constitutive exon skipping
Authors: Carmen-Orozco Rogger P. , Tsao William , Ye Yingzhi , Sinha Irika R. , Chang Koping , Trinh Vickie T. , Chung William , Bowden Kyra , Troncoso Juan C. , Blackshaw Seth , Hayes Lindsey R. , Sun Shuying , Wong Philip C. , Ling Jonathan P. 
Published: June 2024

Abstract
Background
Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems.

Methods
We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease.

Results
Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43.

Conclusions
Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.
Pediatric ultrasound practice in Italy: an exploratory survey
Authors: Musolino Anna Maria , Tei Monica , De Rose Cristina , Buonsenso Danilo , Supino Maria Chiara , Zampogna Stefania , Staiano Annamaria , Raponi Massimiliano , Amendolea Antonella , Colacino Vincenzo , Gori Laura , Manganaro Alessandro , Ricci Riccardo , D’Inzeo Victoria , Grosso Salvatore , Villani Alberto , Agostiniani Rino 
Published: June 2024

Abstract
Background
The aim of this exploratory survey is to describe the current state of US (ultrasound) technique across different pediatric settings nationwide.

Methods
A questionnaire was emailed to all members of the Italian Society of Pediatrics, including pediatric residents. The survey was open from December 2021 to March 2022.

Results
There were 1098 respondents. Seven hundred and seven pediatricians (84.1%) reported any use of US, while 51 (44.3%) residents denied it. The majority of participants (n = 956, 87.1%) reported to have a US machine available within the department, mostly cart-based (n = 516, 66.9%) and provided from 1 to 5 years prior to the survey (n = 330, 42.8%). Lung and neonatal cerebral regions were the most frequently scanned (n = 289, 18.7% and n = 218, 14.1%, respectively). The suspicion of pneumonia or respiratory distress represented the main reasons for performing US in emergency room (n = 390, 78% and n = 330, 66%, respectively). The majority of family pediatricians reported to scan lung and kidney/urinary tract regions (n = 30, 16.9%, and n = 23,12.9%, respectively). Regarding US training, the majority of respondents (n = 358, 34.6%) declared an experience-based education, with a deficient certification enabling the use of US in 71.6% (n = 552) of cases. The most common barriers included the lack of a well-defined training program (n = 627, 57.1%), unavailability of the US machine (n = 196, 17.9%) and legal responsibility concern (n = 175, 15.9%).

Conclusions
Despite the growing interest on pediatric US nationally, significant barriers still limit widespread adoption. These obstacles may be addressed through the dissemination of a specific US education plan and providing additional resources.
Registry-based randomised controlled trials: conduct, advantages and challenges—a systematic review
Authors: Shiely Frances , O Shea Niamh , Murphy Ellen , Eustace Joseph 
Published: June 2024

Abstract
Background
Registry-based randomised controlled trials (rRCTs) have been described as pragmatic studies utilising patient data embedded in large-scale registries to facilitate key clinical trial procedures including recruitment, randomisation and the collection of outcome data. Whilst the practice of utilising registries to support the conduct of randomised trials is increasing, the use of the registries within rRCTs is inconsistent. The purpose of this systematic review is to explore the conduct of rRCTs using a patient registry to facilitate trial recruitment and the collection of outcome data, and to discuss the advantages and challenges of rRCTs.

Methods
A systematic search of the literature was conducted using five databases from inception to June 2020: PubMed, Embase (through Ovid), CINAHL, Scopus and the Cochrane Controlled Register of Trials (CENTRAL). The search strategy comprised of MESH terms and key words related to rRCTs. Study selection was performed independently by two reviewers. A risk of bias for each study was completed. A narrative synthesis was conducted.

Results
A total 47,862 titles were screened and 24 rRCTs were included. Eleven rRCTs (45.8%) used more than one registry to facilitate trial conduct. Six rRCTs (25%) randomised participants via a specific randomisation module embedded within a registry. Recruitment ranged between 209 to 106,000 participants. Advantages of rRCTs are recruitment efficiency, shorter trial times, cost effectiveness, outcome data completeness, smaller carbon footprint, lower participant burden and the ability to conduct multiple trials from the same registry. Challenges are data collection/management, quality assurance issues and the timing of informed consent.

Conclusions
Optimising the design of rRCTs is dependent on the capabilities of the registry. New registries should be designed and existing registries reviewed to enable the conduct of rRCTs. At all times, data management and quality assurance of all registry data should be given key consideration. We suggest the inclusion of the term ‘registry-based’ in the title of all rRCT manuscripts and a clear simple breakdown of the registry-based conduct of the trial in the abstract to facilitate indexing in the major databases.
The integrin CD11b inhibits MSU-induced NLRP3 inflammasome activation in macrophages and protects mice against MSU-induced joint inflammation
Authors: Ehirchiou Driss , Bernabei Ilaria , Pandian Vishnuprabu Durairaj , Nasi Sonia , Chobaz Veronique , Castelblanco Mariela , So Alexander , Martinon Fabio , Li Xiaoyun , Acha-Orbea Hans , Hugle Thomas , Zhang Li , Busso Nathalie 
Published: June 2024

Abstract
Objective
In gout, monosodium urate crystals are taken up by macrophages, triggering the activation of the NLRP3 inflammasome and the maturation of IL-1β. This study aimed to investigate the role of integrin CD11b in inflammasome activation in macrophages stimulated by MSU.

Methods
BMDM from WT and CD11b KO mice were stimulated in vitro with MSU crystals. Cellular supernatants were collected to assess the expression of the inflammatory cytokines by enzyme-linked immunosorbent assay and western blot methods. The role of integrin CD11b in MSU-induced gouty arthritis in vivo was investigated by intra-articular injection of MSU crystals. Real-time extracellular acidification rate and oxygen consumption rate of BMDMs were measured by Seahorse Extracellular Flux Analyzer.

Results
We demonstrate that CD11b-deficient mice developed exacerbated gouty arthritis with increased recruitment of leukocytes in the joint and higher IL-1β levels in the sera. In macrophages, genetic deletion of CD11b induced a shift of macrophage metabolism from oxidative phosphorylation to glycolysis, thus decreasing the overall generation of intracellular ATP. Upon MSU stimulation, CD11b-deficient macrophages showed an exacerbated secretion of IL-1β. Treating wild-type macrophages with a CD11b agonist, LA1, inhibited MSU-induced release of IL-1β in vitro and attenuated the severity of experimental gouty arthritis. Importantly, LA1, was also effective in human cells as it inhibited MSU-induced release of IL-1β by peripheral blood mononuclear cells from healthy donors.

Conclusion
Our data identified the CD11b integrin as a principal cell membrane receptor that modulates NLRP3 inflammasome activation by MSU crystal in macrophages, which could be a potential therapeutic target to treat gouty arthritis in human patients.
Acute effects of multi-ingredient pre-workout dietary supplement on anaerobic performance in untrained men: a randomized, crossover, single blind study
Authors: Drwal Aleksander , Pałka Tomasz , Tota Lukasz , Wiecha Szczepan , Čech Pavol , Strzała Marek , Maciejczyk Marcin 
Published: June 2024

Abstract
Background
Multi-ingredient pre-workout dietary supplements (MIPS), which are combinations of different ingredients acting on different physiological mechanisms, can have a synergistic effect and improve performance. The aim of the study was to determine the acute effects of a multi-ingredient pre-workout supplement containing: beta-alanine, taurine, caffeine, L-tyrosine, and cayenne pepper (capsaicin) on anaerobic performance.

Methods
A randomized, crossover, single-blind study was designed. Twelve young, healthy, untrained men aged 22.4 ± 1.44 years participated in the study. The participants performed a supramaximal all-out test (20 s Wingate test) twice, day by day, in random order: test after placebo or MIPS consumption. In both trials, the following variables were measured in the exercise test: total work performed, peak power, mean power, time to reach peak power, and power decrease.

Results
MIPS was found to be effective in improving peak power (p = 0.009, ES = 0.77) and mean power (p = 0.04, ES = 0.62) in the Wingate test. However, the supplement consumption did not affect the amount of total work done (p = 0.10, ES = 0.48) in the test or power decrease (p = 0.07, ES = 0.53). The data indicate, that the improvement in anaerobic power was due to a significant improvement in pedaling speed, which was manifested in a significant improvement (i.e. shortening) in time to peak power (p = 0.003, ES = 0.88).

Conclusion
A multi-ingredient pre-workout dietary supplement was found to be effective in improving Wingate (anaerobic) performance.

Trial registration
NCT06363669, retrospectively registered on 11.04.2024 (ClinicalTrials.gov).
The value of apparent diffusion coefficient values in predicting Gleason grading of low to intermediate-risk prostate cancer
Authors: Yan Xu , Ma Ke , Zhu Li , Pan Yiqi , Wang Yuting , Shi Jiong , Mai Xiaoli 
Published: June 2024

Abstract
Objectives
To investigate the diagnostic performance of the apparent diffusion coefficient (ADC) for low to intermediate-risk prostate cancer (PCa), as well as its correlation with the prognostic Gleason score (GS).

Materials and methods
Retrospective analysis of MRI images and relevant clinical data from patients with prostate disease. The differences in ADC between different GS groups were compared, and the efficacy of ADC in PCa diagnosis were analyzed. Furthermore, the diagnostic performance of the mean ADC (ADCmean) and minimum ADC (ADCmin) values was compared.

Results
There were 1414 patients with 1631 lesions. In terms of GS, both ADCmin and ADCmean values of the GS 4 + 3 group were significantly lower than those of the GS 3 + 4 group, GS 3 + 3 group, and the benign group, with all differences being statistically significant (p < 0.01). The AUC values for diagnosing PCa based on ADCmin and ADCmean were 0.914 and 0.944, respectively. The corresponding diagnostic thresholds were 0.703 × 10−3 mm2/s for ADCmin and 0.927 × 10−3 mm2/s for ADCmean. The magnitudes of ADCmin and ADCmean values exhibited a negative correlation with GS values (ρ = −0.750, p < 0.001; ρ = −0.752, p < 0.001).

Conclusions
ADC values demonstrate an inverse relationship with the invasiveness of PCa, indicating that higher invasiveness is associated with lower ADC values. Additionally, ADC values exhibit high diagnostic potential, sensitivity, and specificity for distinguishing between GS 3 + 4 and GS 4 + 3 lesions. Moreover, the diagnostic value of ADCmean is even more significant, highlighting its crucial role in the diagnosis of low to intermediate-risk PCa.

Critical relevance statement
ADC values are a valuable tool for distinguishing different levels of aggressiveness in PCa. They help in the preoperative assessment of the biological characteristics of PCa, allowing clinicians to develop personalized treatment strategies, effectively mitigating the risk of unnecessary interventions.

Key Points

The preoperative GS is crucial for planning the clinical treatment of PCa.

The invasiveness of PCa is inversely correlated with ADC values.

ADC values play a crucial role in the accurate preoperative evaluation of low to intermediate-risk PCa, thus aiding clinicians in developing tailored treatment plans.

Graphical Abstract
Unlocking the potential: T1-weighed MRI as a powerful predictor of levodopa response in Parkinson’s disease
Authors: Yan Junyi , Luo Xufang , Xu Jiahang , Li Dongsheng , Qiu Lili , Li Dianyou , Cao Peng , Zhang Chencheng 
Published: June 2024

Abstract
Background
The efficacy of levodopa, the most crucial metric for Parkinson’s disease diagnosis and treatment, is traditionally gauged through the levodopa challenge test, which lacks a predictive model. This study aims to probe the predictive power of T1-weighted MRI, the most accessible modality for levodopa response.

Methods
This retrospective study used two datasets: from the Parkinson’s Progression Markers Initiative (219 records) and the external clinical dataset from Ruijin Hospital (217 records). A novel feature extraction method using MedicalNet, a pre-trained deep learning network, along with three previous approaches was applied. Three machine learning models were trained and tested on the PPMI dataset and included clinical features, imaging features, and their union set, using the area under the curve (AUC) as the metric. The most significant brain regions were visualized. The external clinical dataset was further evaluated using trained models. A paired one-tailed t-test was performed between the two sets; statistical significance was set at p < 0.001.

Results
For 46 test set records (mean age, 62 ± 9 years, 28 men), MedicalNet-extracted features demonstrated a consistent improvement in all three machine learning models (SVM 0.83 ± 0.01 versus 0.73 ± 0.01, XgBoost 0.80 ± 0.04 versus 0.74 ± 0.02, MLP 0.80 ± 0.03 versus 0.70 ± 0.07, p < 0.001). Both feature sets were validated on the clinical dataset using SVM, where MedicalNet features alone achieved an AUC of 0.64 ± 0.03. Key responsible brain regions were visualized.

Conclusion
The T1-weighed MRI features were more robust and generalizable than the clinical features in prediction; their combination provided the best results. T1-weighed MRI provided insights on specific regions responsible for levodopa response prediction.

Critical relevance statement
This study demonstrated that T1w MRI features extracted by a deep learning model have the potential to predict the levodopa response of PD patients and are more robust than widely used clinical information, which might help in determining treatment strategy.

Key Points

This study investigated the predictive value of T1w features for levodopa response.

MedicalNet extractor outperformed all other previously published methods with key region visualization.

T1w features are more effective than clinical information in levodopa response prediction.

Graphical Abstract