bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of cell-free DNA methylation-based blood test for colorectal cancer screening in high-risk population: a prospective cohort study
Authors: Zhao Fuqiang , Bai Ping , Xu Jianfeng , Li Zitong , Muhammad Shan , Li Diange , Zhang Zeyue , Gao Yibo , Liu Qian 
Published: September 2023

Abstract
Background
Although colonoscopy is the standard screening test for colorectal cancer (CRC), its use is limited by a poor compliance rate, the need for extensive bowel preparation, and the risk of complications. As an alternative, an FDA-approved stool-based DNA test, Cologuard, has demonstrated satisfactory detection performance for CRC, but its compliance rate remains suboptimal, primarily attributable to individuals’ reluctance to provide stool samples.

Methods
We developed a noninvasive blood-based CRC test, ColonSecure, based on cell-free DNA containing cancer-specific CpG island methylation patterns. We initially screened publicly available datasets for differentially methylated CpG sites in CRC with prediction potential. Subsequently, we performed two sequential bisulfite-free methylation sequencing on blood samples obtained from CRC patients and non-cancer controls. Through rigorous evaluation of each marker and machine learning-assisted feature selection, we identified 149 hypermethylated markers from over 193,000 CpG sites. These markers were then utilized to construct the ColonSecure model, enabling accurate CRC detection.

Results
We validated the efficacy of our cell-free DNA methylation-based blood test for CRC screening with 3493 high-risk individuals identified from 114,136 urban residents. The ColonSecure test identified 89 out of 103 CRC patients diagnosed by the follow-up colonoscopy, outperforming CEA, CRP, and CA19-9 (with a sensitivity of 86.4% compared to 45.6%, 39.8%, and 25.2% for CEA, CRP, and CA19-9 respectively; an AUROC of 0.956 compared to an AUROC of < 0.77 for other methods).

Conclusion
Our observations emphasize the potential of our multiple cfDNA methylation marker-based test for CRC screening in high-risk populations.
Critical contributions of protein cargos to the functions of macrophage-derived extracellular vesicles
Authors: Liu Baolong , Nguyen Phuong Linh , Yu Han , Li Xingzhi , Wang Huiren , Price Jeffrey , Niu Meng , Guda Chittibabu , Cheng Xiao , Sun Xinghui , Moreau Regis , Ramer-Tait Amanda , Naldrett Michael J. , Alvarez Sophie , Yu Jiujiu 
Published: September 2023

Abstract
Background
Macrophages are highly plastic innate immune cells that play key roles in host defense, tissue repair, and homeostasis maintenance. In response to divergent stimuli, macrophages rapidly alter their functions and manifest a wide polarization spectrum with two extremes: M1 or classical activation and M2 or alternative activation. Extracellular vesicles (EVs) secreted from differentially activated macrophages have been shown to have diverse functions, which are primarily attributed to their microRNA cargos. The role of protein cargos in these EVs remains largely unexplored. Therefore, in this study, we focused on the protein cargos in macrophage-derived EVs.

Results
Naïve murine bone marrow-derived macrophages were treated with lipopolysaccharide or interlukin-4 to induce M1 or M2 macrophages, respectively. The proteins of EVs and their parental macrophages were subjected to quantitative proteomics analyses, followed by bioinformatic analyses. The enriched proteins of M1-EVs were involved in proinflammatory pathways and those of M2-EVs were associated with immunomodulation and tissue remodeling. The signature proteins of EVs shared a limited subset of the proteins of their respective progenitor macrophages, but they covered many of the typical pathways and functions of their parental cells, suggesting their respective M1-like and M2-like phenotypes and functions. Experimental examination validated that protein cargos in M1- or M2-EVs induced M1 or M2 polarization, respectively. More importantly, proteins in M1-EVs promoted viability, proliferation, and activation of T lymphocytes, whereas proteins in M2-EVs potently protected the tight junction structure and barrier integrity of epithelial cells from disruption. Intravenous administration of M2-EVs in colitis mice led to their accumulation in the colon, alleviation of colonic inflammation, promotion of M2 macrophage polarization, and improvement of gut barrier functions. Protein cargos in M2-EVs played a key role in their protective function in colitis.

Conclusion
This study has yielded a comprehensive unbiased dataset of protein cargos in macrophage-derived EVs, provided a systemic view of their potential functions, and highlighted the important engagement of protein cargos in the pathophysiological functions of these EVs.
Programmable DNA hydrogel provides suitable microenvironment for enhancing autophagy-based therapies in intervertebral disc degeneration treatment
Authors: Qingxin Song , Kai Jiang , Dandan Zheng , Linyu Jin , Xiuyuan Chen , Yubo Feng , Kun Wang , Yingchao Han , Hao Chen , Jie Song , Zhi Chen , Hongxing Shen 
Published: September 2023

AbstractThe pathogenesis of intervertebral disc degeneration (IVDD) is attributed to metabolic dysregulation within the extracellular matrix and heightened apoptosis of nucleus pulposus cells (NPC). Therefore, a potential therapeutic strategy for managing IVDD involves the reestablishment of metabolic equilibrium within the extracellular matrix and the suppression of excessive myeloid cell apoptosis. The microRNA, miR-5590, displays marked differential expression in degenerative nucleus pulposus (NP) tissues and exerts a direct influence on the regulation of DDX5 expression. This, in turn, modulates mammalian target of rapamycin (mTOR) phosphorylation, thereby impacting autophagy and apoptosis. However, ensuring the smooth delivery of miRNA to a specific injury site poses a significant challenge. To address this issue, a multifunctional DNA hydrogel was developed and subsequently loaded with miR-5590 via spherical nucleic acids (SNAs) for the treatment of IVDD. The hydrogel, which exhibits versatility, has the potential to be administered through injection at the site of injury, resulting in a consistent and prolonged release of miR-5590. This leads to the creation of a genetic microenvironment within the NP, which triggers the onset of autophagy in NPCs and subsequently suppresses apoptosis. As a result, this process regulates the metabolic equilibrium within the extracellular matrix, thereby impeding the in vitro and in vivo progression of IVDD. The amalgamation of miRNAs and biomaterials offers a promising therapeutic strategy for the management of IVDD in clinical settings.
RU.521 mitigates subarachnoid hemorrhage-induced brain injury via regulating microglial polarization and neuroinflammation mediated by the cGAS/STING/NF-κB pathway
Authors: Shao Jiang , Meng Yuxiao , Yuan Kaikun , Wu Qiaowei , Zhu Shiyi , Li Yuchen , Wu Pei , Zheng Jiaolin , Shi Huaizhang 
Published: September 2023

Abstract
Background
The poor prognosis of subarachnoid hemorrhage (SAH) is often attributed to neuroinflammation. The cGAS-STING axis, a cytoplasmic pathway responsible for detecting dsDNA, plays a significant role in mediating neuroinflammation in neurological diseases. However, the effects of inhibiting cGAS with the selective small molecule inhibitor RU.521 on brain injury and the underlying mechanisms after SAH are still unclear.

Methods
The expression and microglial localization of cGAS following SAH were investigated with western blot analysis and immunofluorescent double-staining, respectively. RU.521 was administered after SAH. 2’3’-cGAMP, a second messenger converted by activated cGAS, was used to activate cGAS-STING. The assessments were carried out by adopting various techniques including neurological function scores, brain water content, blood–brain barrier permeability, western blot analysis, TUNEL staining, Nissl staining, immunofluorescence, morphological analysis, Morris water maze test, Golgi staining, CCK8, flow cytometry in the in vivo and in vitro settings.

Results
Following SAH, there was an observed increase in the expression levels of cGAS in rat brain tissue, with peak levels observed at 24 h post-SAH. RU.521 resulted in a reduction of brain water content and blood–brain barrier permeability, leading to an improvement in neurological deficits after SAH. RU.521 had beneficial effects on neuronal apoptosis and microglia activation, as well as improvements in microglial morphology. Additionally, RU.521 prompted a shift in microglial phenotype from M1 to M2. We also noted a decrease in the production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, and an increase in the level of the anti-inflammatory cytokine IL-10. Finally, RU.521 treatment was associated with improvements in cognitive function and an increase in the number of dendritic spines in the hippocampus. The therapeutic effects were mediated by the cGAS/STING/NF-κB pathway and were found to be abolished by 2’3’-cGAMP. In vitro, RU.521 significantly reduced apoptosis and neuroinflammation.

Conclusion
The study showed that SAH leads to neuroinflammation caused by microglial activation, which contributes to early brain injury. RU.521 improved neurological outcomes and reduced neuroinflammation by regulating microglial polarization through the cGAS/STING/NF-κB pathway in early brain injury after SAH. RU.521 may be a promising candidate for the treatment of neuroinflammatory pathology after SAH.
The effectiveness and cost-effectiveness of a group domestic abuse perpetrator programme: protocol for a randomised controlled trial
Authors: Morgan Karen , Man Mei-See , Bloomer Rachael , Cochrane Madeleine , Cole Melissa , Dheensa Sandi , Eisenstadt Nathan , Feder Gene , Gaunt Daisy M. , Leach Rwth , Kandiyali Rebecca , Noble Sian , Peters Tim J. , Shirkey Beverly A. , Cramer Helen 
Published: September 2023

Abstract
Background
In contrast to evidence for interventions supporting victim/survivors of domestic violence and abuse (DVA), the effectiveness of perpetrator programmes for reduction of abuse is uncertain. This study aims to estimate the effectiveness and cost-effectiveness of a perpetrator programme for men.

Methods
Pragmatic two-group individually randomised controlled trial (RCT) with embedded process and economic evaluation. Five centres in southwest England and South Wales aim to recruit 316 (reduced from original target of 366) male domestic abuse perpetrators. These will be randomised 2:1 to a community-based domestic abuse perpetrator programme (DAPP) or usual care comparator with 12-month follow-up. Female partners/ex-partners will be invited to join the study.
The intervention for men comprises 23 weekly sessions of a group programme delivered in voluntary sector domestic abuse services. The intervention for female partners/ex-partners is one-to-one support from a safety worker. Men allocated to usual care receive no intervention; however, they are free to access other services. Their partners/ex-partners will be signposted to support services.
Data is collected at baseline, and 4, 8 and 12 months’ follow-up. The primary outcome is men’s self-reported abusive behaviour measured by the Abusive Behaviour Inventory (ABI-29) at 12 months. Secondary measures include physical and mental health status and resource use alongside the abuse measure ABI (ABI-R) for partners/ex-partners and criminal justice contact for men.
A mixed methods process evaluation and qualitative study will explore mechanisms of effectiveness, judge fidelity to the intervention model using interviews and group observations.
The economic evaluation, over a 1-year time horizon from three perspectives (health and social care, public sector and society), will employ a cost-consequences framework reporting costs alongside economic outcomes (Quality-Adjusted Life Years derived from EQ-5D-5L, SF-12 and CHU-9D, and ICECAP-A) as well as the primary and other secondary outcomes.

Discussion
This trial will provide evidence of the (cost)effectiveness of a DAPP. The embedded process evaluation will further insights in the experiences and contexts of participants and their journey through a perpetrator programme, and the study will seek to address the omission in other studies of economic evaluations.

Trial registration
ISRCTN15804282, April 1, 2019
Effect of a telerehabilitation exercise program versus a digital booklet with self-care for patients with chronic non-specific neck pain: a protocol of a randomized controlled trial assessor-blinded, 3 months follow-up
Authors: Barbosa Juliene Corrêa , Comachio Josielli , Marques Amelia Pasqual , Saragiotto Bruno Tirotti , Magalhaes Mauricio Oliveira 
Published: September 2023

Abstract
Background
Neck pain is the fourth worldwide leading cause of disability and represents 22% of musculoskeletal disorders. Conservative intervention has been strongly recommended to treat chronic neck pain and Telerehabilitation is the alternative for the treatment of musculoskeletal conditions. There is a lack of high-quality research on the effects of telerehabilitation in patients with neck pain and functional disability. Therefore, this study aims to evaluate the effect of a telerehabilitation exercise program versus a digital booklet only with self-care information in individuals with non-specific chronic neck pain.

Methods
This is a prospectively registered, assessor-blinded, two-arm randomized controlled trial comparing a telerehabilitation exercise program versus a digital booklet with self-care information. Seventy patients will be recruited with non-specific chronic neck pain. Follow-ups will be conducted post-treatment, 6 weeks, and 3 months after randomization. The primary outcome will be disability at post-treatment (6 weeks) measured using neck pain disability. Secondary outcomes will be pain intensity levels, global perceived effect, self-efficacy, quality of life, kinesiophobia, and adherence to treatment. In our hypothesis, patients allocated to the intervention group experience outcomes that are similar to those of those assigned to the self-care digital booklet. Our hypothesis can then be approved or disapproved based on the results of the study.

Discussion
This randomized clinical trial will provide reliable information on the use of telerehabilitation to treat patients with chronic non-specific neck pain.

Trial registration
The study was prospectively registered at the Brazilian Registry of Clinical Trials (number: RBR-10h7khvk). Registered on 16 September 2022.
Solving singularly perturbed fredholm integro-differential equation using exact finite difference method
Authors: Badeye Solomon Regasa , Woldaregay Mesfin Mekuria , Dinka Tekle Gemechu 
Published: September 2023

Abstract
Objectives
In this paper, a numerical scheme is designed for solving singularly perturbed Fredholm integro-differential equation. The scheme is constructed via the exact (non-standard) finite difference method to approximate the differential part and the composite Simpson’s 1/3 rule for the integral part of the equation.

Result
The stability and uniform convergence analysis are demonstrated using solution bound and the truncation error bound. For three model examples, the maximum absolute error and the rate of convergence for different values of the perturbation parameter and mesh size are tabulated. The computational result shows, the proposed method is second-order uniformly convergent which is in a right agreement with the theoretical result.
Burden and predictors of diabetic kidney disease in an adult Ugandan population with new-onset diabetes
Authors: Kibirige Davis , Sekitoleko Isaac , Lumu William 
Published: September 2023

Abstract
Background
Despite the growing evidence of diabetic kidney disease (DKD) in adult patients with long-standing diabetes in sub-Saharan Africa, data on its burden and correlates in adult African patients with new-onset diabetes are limited. We, therefore, undertook this study to determine the burden and predictors of DKD in an adult population with new-onset diabetes in Uganda.

Methods
We collected data on the relevant sociodemographic, clinical, anthropometric, and metabolic characteristics in 519 participants with newly diagnosed diabetes recruited from seven tertiary hospitals. A spot mid-stream urine sample was collected for determination of the urine albumin creatinine ratio (UACR) using Clinitek® microalbumin strips and a point-of-care Clinitek® status analyser. The estimated glomerular filtration rate (e-GFR) was determined using the Chronic Kidney Disease Epidemiology formula. The presence of DKD was defined as a spot UACR ≥ 3 mg/mmol with or without an e-GFR < 60 ml/min/1.73m2.

Results
The median (IQR) age, UACR, and e-GFR of the participants were 48 years (39–57), 2.27 mg/mmol (1.14–3.41), and 121.8 ml/min/1.73m2 (105.4-133.9). UACR ≥ 3 mg/mmol and e-GFR < 60 ml/min/1.73m2 was noted in 175 (33.7%) and 7 (1.4%) participants, respectively. DKD was documented in 175 participants (33.7%). Compared with those without DKD, participants with DKD were more likely to be ≥ 50 years of age (53.7% vs. 43%, p = 0.02) and to have co-existing hypertension at the time of diagnosis (40.6% vs. 30.1%, p = 0.02). On multivariate analysis, self-reported hypertension comorbidity (OR 1.76 95% CI 1.24–2.48, p = 0.002) and body mass index (BMI) ≥ 30 kg/m2 (OR 0.61 95% CI 0.41–0.91, p = 0.02) were noted to independently predict DKD.

Conclusion
In this study population, DKD was relatively common and was independently associated with self-reported hypertension comorbidity and BMI ≥ 30 kg/m2.
Effect of women’s fertility and sexual development on epigenetic clock: Mendelian randomization study
Authors: Zhang Boxin , Yuan Qizhi , Luan Yining , Xia Jian 
Published: September 2023

Abstract
Background and objectives
In observational studies, women’s fertility and sexual development traits may have implications for DNA methylation patterns, and pregnancy-related risk factors can also affect maternal DNA methylation patterns. The aim of our study is to disentangle any potential causal associations between women’s fertility and sexual development traits and epigenetic clocks, as well as to search for probable mediators by using the Mendelian randomization (MR) method.

Methods
Instrumental variables for exposures, mediators, and outcomes were adopted from genome-wide association studies data of European ancestry individuals. The potential causal relationship between women’s fertility and sexual development traits and four epigenetic clocks were evaluated by inverse variance weighted method and verified by other two methods. Furthermore, we employed multivariable MR (MVMR) adjusting for hypertension, hyperglycemia, BMI changes, and insomnia. Then, combining the MVMR results and previous research, we performed two-step MR to explore the mediating effects of BMI, AFS, and AFB. Multiple sensitivity analyses were further performed to verify the robustness of our findings.

Results
Leveraging two-sample MR analysis, we observed statistically significant associations between earlier age at first birth (AFB) with a higher HannumAge, PhenoAge and GrimAge acceleration(β = − 0.429, 95% CI [− 0.781 to − 0.077], p = 0.017 for HannumAge; β = − 0.571, 95% CI [− 1.006 to − 0.136], p = 0.010 for PhenoAge, and β = − 1.136, 95% CI [− 1.508 to − 0.765], p = 2.03E−09 for GrimAge respectively) and age at first sexual intercourse (AFS) with a higher HannumAge and GrimAge acceleration(β = − 0.175, 95% CI [− 0.336 to − 0.014], p = 0.033 for HannumAge; β = − 0.210, 95% CI [− 0.350 to − 0.070], p = 0.003 for GrimAge, respectively). Further analyses indicated that BMI, AFB and AFS played mediator roles in the path from women’s fertility and sexual development traits to epigenetic aging.

Conclusions
Our study suggested that AFS and AFB are associated with epigenetic aging. These findings may prove valuable in informing the development of prevention strategies and interventions targeted towards women’s fertility and sexual development experiences and their relationship with epigenetic aging-related diseases.
Sexual differences in locus coeruleus neurons and related behavior in C57BL/6J mice
Authors: Mariscal Patricia , Bravo Lidia , Llorca-Torralba Meritxell , Razquin Jone , Miguelez Cristina , Suárez-Pereira Irene , Berrocoso Esther 
Published: September 2023

Abstract
Background
In addition to social and cultural factors, sex differences in the central nervous system have a critical influence on behavior, although the neurobiology underlying these differences remains unclear. Interestingly, the Locus Coeruleus (LC), a noradrenergic nucleus that exhibits sexual dimorphism, integrates signals that are related to diverse activities, including emotions, cognition and pain. Therefore, we set-out to evaluate sex differences in behaviors related to LC nucleus, and subsequently, to assess the sex differences in LC morphology and function.

Methods
Female and male C57BL/6J mice were studied to explore the role of the LC in anxiety, depressive-like behavior, well-being, pain, and learning and memory. We also explored the number of noradrenergic LC cells, their somatodendritic volume, as well as the electrophysiological properties of LC neurons in each sex.

Results
While both male and female mice displayed similar depressive-like behavior, female mice exhibited more anxiety-related behaviors. Interestingly, females outperformed males in memory tasks that involved distinguishing objects with small differences and they also showed greater thermal pain sensitivity. Immunohistological analysis revealed that females had fewer noradrenergic cells yet they showed a larger dendritic volume than males. Patch clamp electrophysiology studies demonstrated that LC neurons in female mice had a lower capacitance and that they were more excitable than male LC neurons, albeit with similar action potential properties.

Conclusions
Overall, this study provides new insights into the sex differences related to LC nucleus and associated behaviors, which may explain the heightened emotional arousal response observed in females.
Reliable and accurate prediction of basic pK$$_a$$ values in nitrogen compounds: the pK$$_a$$ shift in supramolecular systems as a case study
Authors: Alcázar Jackson J. , Misad Saide Alessandra C. , Campodónico Paola R. 
Published: September 2023

Abstract
This article presents a quantitative structure–activity relationship (QSAR) approach for predicting the acid dissociation constant (pK

$$_a$$

a

) of nitrogenous compounds, including those within supramolecular complexes based on cucurbiturils. The model combines low-cost quantum mechanical calculations with QSAR methodology and linear regressions to achieve accurate predictions for a broad range of nitrogen-containing compounds. The model was developed using a diverse dataset of 130 nitrogenous compounds and exhibits excellent predictive performance, with a high coefficient of determination (R

$$^2$$

2

) of 0.9905, low standard error (s) of 0.3066, and high Fisher statistic (F) of 2142. The model outperforms existing methods, such as Chemaxon software and previous studies, in terms of accuracy and its ability to handle heterogeneous datasets. External validation on pharmaceutical ingredients, dyes, and supramolecular complexes based on cucurbiturils confirms the reliability of the model. To enhance usability, a script-like tool has been developed, providing a streamlined process for users to access the model. This study represents a significant advancement in pK

$$_a$$

a

prediction, offering valuable insights for drug design and supramolecular system optimization.

Graphical Abstract