bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-omics analysis revealed the role of CYP1A2 in the induction of mechanical allodynia in type 1 diabetes
Authors: Chen Hongjin , Liao Chenlong , Yang Xiaosheng , Zhou Han , Wu Yiwei , Sun Qiuyang , Li Shuo , Zhang Wenchuan 
Published: March 2023

Background: Mechanical allodynia (MA) is one of the leading clinical symptoms of painful diabetic peripheral neuropathy (PDPN), which is a primary reason for non-traumatic amputations, foot ulceration, and gait abnormalities in patients with diabetes. However, the pathogenic mechanisms of MA have not yet been fully elucidated, and there is no effective treatment. This study aims to study the potential pathogenetic mechanisms of MA and to provide targets for the therapy of MA.Methods: A single intraperitoneal injection of streptozotocin induced type 1 diabetes in rat models. Subsequently, rats were divided into the control group, the diabetic group without MA, and the diabetic group with MA based on weekly behavioral assays. The differentially expressed lipids in the sciatic nerve of each group were detected using untargeted lipidomics, and the differentially expressed genes in the sciatic nerve of each group were detected by transcriptomics. The pathogenesis of MA was predicted using integrated analysis and validated by immunofluorescence staining and transmission electron microscopy.Results: Untargeted lipidomics revealed the accumulation of a more severe lipid in MA rats. Transcriptomics results suggested that differentially expressed genes in MA rats were primarily related to lipid droplets and myelin sheath. Integrated analysis results indicated that the downregulation of Cytochrome P450 1A2 (CYP1A2) expression was closely linked to lipid metabolism disorders. Immunofluorescence staining demonstrated that down-regulation of CYP1A2 expression occurred in MA rats. Transmission electron microscopy results showed that more severe lipid droplet accumulation and myelin sheath degeneration occurred in MA rats.Conclusion: Our findings imply that the downregulation of CYP1A2 expression leads to disorders of lipid metabolism and further leads to lipid droplet accumulation and myelin sheath degeneration, which might ultimately lead to the development of MA. Therefore, our study contributes to promoting the understanding of the molecular mechanisms of MA and providing potential targets for the clinical treatment of MA.
Identification of berberine as a potential therapeutic strategy for kidney clear cell carcinoma and COVID-19 based on analysis of large-scale datasets
Authors: Zheng Zhihua , Li Xiushen , Nie Kechao , Wang Xiaoyu , Liang Wencong , Yang Fuxia , Zheng Kairi , Zheng Yihou 
Published: March 2023

BackgroundRegarding the global coronavirus disease 2019 (COVID)-19 pandemic, kidney clear cell carcinoma (KIRC) has acquired a higher infection probability and may induce fatal complications and death following COVID-19 infection. However, effective treatment strategies remain unavailable. Berberine exhibits significant antiviral and antitumour effects. Thus, this study aimed to provide a promising and reliable therapeutic strategy for clinical decision-making by exploring the therapeutic mechanism of berberine against KIRC/COVID-19.MethodsBased on large-scale data analysis, the target genes, clinical risk, and immune and pharmacological mechanisms of berberine against KIRC/COVID-19 were systematically investigated.ResultsIn total, 1,038 and 12,992 differentially expressed genes (DEGs) of COVID-19 and KIRC, respectively, were verified from Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively, and 489 berberine target genes were obtained from official websites. After intersecting, 26 genes were considered potential berberine therapeutic targets for KIRC/COVID-19. Berberine mechanism of action against KIRC/COVID-19 was revealed by protein-protein interaction, gene ontology, and Kyoto Encyclopedia of Genes and Genomes with terms including protein interaction, cell proliferation, viral carcinogenesis, and the PI3K/Akt signalling pathway. In COVID-19 patients, ACOX1, LRRK2, MMP8, SLC1A3, CPT1A, H2AC11, H4C8, and SLC1A3 were closely related to disease severity, and the general survival of KIRC patients was closely related to ACOX1, APP, CPT1A, PLK1, and TYMS. Additionally, the risk signature accurately and sensitively depicted the overall survival and patient survival status for KIRC. Numerous neutrophils were enriched in the immune system of COVID-19 patients, and the lives of KIRC patients were endangered due to significant immune cell infiltration. Molecular docking studies indicated that berberine binds strongly to target proteins.ConclusionThis study demonstrated berberine as a potential treatment option in pharmacological, immunological, and clinical practice. Moreover, its therapeutic effects may provide potential and reliable treatment options for patients with KIRC/COVID-19.
Optimal LC-MS metabolomic profiling reveals emergent changes to monocyte metabolism in response to lipopolysaccharide
Authors: Leacy Emma , Batten Isabella , Sanelli Laetitia , McElheron Matthew , Brady Gareth , Little Mark A. , Khouri Hania 
Published: March 2023

IntroductionImmunometabolism examines the links between immune cell function and metabolism. Dysregulation of immune cell metabolism is now an established feature of innate immune cell activation. Advances in liquid chromatography mass spectrometry (LC-MS) technologies have allowed discovery of unique insights into cellular metabolomics. Here we have studied and compared different sample preparation techniques and data normalisation methods described in the literature when applied to metabolomic profiling of human monocytes.MethodsPrimary monocytes stimulated with lipopolysaccharide (LPS) for four hours was used as a study model. Monocytes (n=24) were freshly isolated from whole blood and stimulated for four hours with lipopolysaccharide (LPS). A methanol-based extraction protocol was developed and metabolomic profiling carried out using a Hydrophilic Interaction Liquid Chromatography (HILIC) LC-MS method. Data analysis pipelines used both targeted and untargeted approaches, and over 40 different data normalisation techniques to account for technical and biological variation were examined. Cytokine levels in supernatants were measured by ELISA.ResultsThis method provided broad coverage of the monocyte metabolome. The most efficient and consistent normalisation method was measurement of residual protein in the metabolite fraction, which was further validated and optimised using a commercial kit. Alterations to the monocyte metabolome in response to LPS can be detected as early as four hours post stimulation. Broad and profound changes in monocyte metabolism were seen, in line with increased cytokine production. Elevated levels of amino acids and Krebs cycle metabolites were noted and decreases in aspartate and β-alanine are also reported for the first time. In the untargeted analysis, 154 metabolite entities were significantly altered compared to unstimulated cells. Pathway analysis revealed the most prominent changes occurred to (phospho-) inositol metabolism, glycolysis, and the pentose phosphate pathway.DiscussionThese data report the emergent changes to monocyte metabolism in response to LPS, in line with reports from later time points. A number of these metabolites are reported to alter inflammatory gene expression, which may facilitate the increases in cytokine production. Further validation is needed to confirm the link between metabolic activation and upregulation of inflammatory responses.
Development and implementation of a continuing medical education program on non-alcoholic fatty liver disease for primary care practitioners in Europe
Authors: Papadakis Sophia , Anastasaki Marilena , Gergianaki Irini , Koek Ger , Mendive Juan , Anastasiou Foteini , Heyens Leen , Garcia-Retortillo Montserrat , Muris Jean , Lionis Christos 
Published: March 2023

BackgroundPrimary care has a crucial role to play in the prevention, early detection, referral, and risk factor management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH). In 2021, a team of European collaborators developed a continuing medical education (CME) program on NAFLD/NASH that consolidates evidence and clinical best practices tailored to the primary care setting. This article reports on the methodology used to design and develop the CME and the results of a feasibility study.MethodsAn expert advisory group representing both European specialists and general practitioners supported the design of the CME to be implemented in three European settings (Greece, Spain, and Netherlands). The CME features four training modules and problem-based learning using clinical case studies. The CME was tested regarding feasibility and acceptability among a sample of primary care providers (PCPs) in Greece (n = 28) with measurements occurring before, immediately after, and 1 month following the training. Outcome measures included satisfaction with the CME, changes in PCPs’ knowledge, attitudes, confidence, and self-reported clinical practices related to NAFLD/NASH.ResultsThe CME is available as an open-access e-learning course on the European Society for Primary Care Gastroenterology education platform1 in English, Greek, Spanish, and Dutch. The feasibility study documented high levels of satisfaction, with 96% of PCPs reporting they were extremely or very satisfied with the overall training. Statistically significant increases in PCPs’ confidence in NAFLD/NASH-related clinical practices were documented between the pre- and post-assessments. At the follow-up, 62% of GPs reported that the CME had changed their clinical practices related to NAFLD/NASH to a great extent.ConclusionThis CME intervention developed by experts and tailored to PCPs in European settings may serve as an asset for increasing knowledge, confidence, and practice behaviors related to NAFLD/NASH.
The Neolithic site “La Marmotta”: DNA metabarcoding to identify the microbial deterioration of waterlogged archeological wood
Authors: Beccaccioli Marzia , Moricca Claudia , Faino Luigi , Reale Rita , Mineo Mario , Reverberi Massimo 
Published: March 2023

IntroductionThe evaluation of biological degradation of waterlogged archeological wood is crucial to choose the conservative and protective treatments to be applied to the wooden material. The waterlogged environmental conditions are characterized by oxygen scarcity, only allowing the growth of adapted microbes capable to degrade the organic wooden material, mainly erosion bacteria and soft-rot fungi. In this work, we characterized and evaluated the biodegradation state and the microbial communities of wooden fragments preserved in storage tanks. These were preserved by waterlogging within the Neolithic village “La Marmotta,” currently found under the Bracciano Lake (Lazio, Italy).MethodsThe waterlogged wood samples were first identified taxonomically with an optical microscope, also allowing an evaluation of their preservation state. The microbial community was then evaluated through the sequencing of Internal Transcribed Spacer sequences for fungi and 16S for bacteria with the Oxford Nanopore Technologies (ONT) MinION platform.ResultsThe identified microbial community appears to be consistent with the waterlogged samples, as many bacteria attributable to the erosion of wood and ligninolytic fungi have been sequenced.DiscussionThe reported results highlight the first use of targeted metabarcoding by ONT applied to study the biodeterioration of waterlogged archeological wood.
First report of coexistence of blaKPC-2-, blaNDM-1- and mcr-9-carrying plasmids in a clinical carbapenem-resistant Enterobacter hormaechei isolate
Authors: Yuan Qian , Xia Peiyuan , Xiong Lirong , Xie Linli , Lv Shan , Sun Fengjun , Feng Wei 
Published: March 2023

IntroductionColistin is regarded as one of the last-resort antibiotics against severe infections caused by carbapenem-resistant Enterobacteriaceae. Strains with cooccurrence of mcr-9 and carbapenemase genes are of particular concern. This study aimed to investigate the genetic characteristics of a blaKPC-2-carrying plasmid, blaNDM-1-carrying plasmid and mcr-9-carrying plasmid coexisting in a carbapenem-resistant Enterobacter hormaechei isolate.MethodsE. hormaechei strain E1532 was subjected to whole-genome sequencing, and the complete nucleotide sequences of three resistance plasmids identified in the strain were compared with related plasmid sequences. The resistance phenotypes mediated by these plasmids were analyzed by plasmid transfer, carbapenemase activity and antimicrobial susceptibility testing.ResultsWhole-genome sequencing revealed that strain E1532 carries three different resistance plasmids, pE1532-KPC, pE1532-NDM and pE1532-MCR. pE1532-KPC harboring blaKPC-2 and pE1532-NDM harboring blaNDM-1 are highly identical to the IncR plasmid pHN84KPC and IncX3 plasmid pNDM-HN380, respectively. The mcr-9-carrying plasmid pE1532-MCR possesses a backbone highly similar to that of the IncHI2 plasmids R478 and p505108-MDR, though their accessory modules differ. These three coexisting plasmids carry a large number of resistance genes and contribute to high resistance to almost all antibiotics tested, except for amikacin, trimethoprim/sulfamethoxazole, tigecycline and polymyxin B. Most of the plasmid-mediated resistance genes are located in or flanked by various mobile genetic elements, facilitating horizontal transfer of antibiotic resistance genes.DiscussionThis is the first report of a single E. hormaechei isolate with coexistence of three resistance plasmids carrying mcr-9 and the two most common carbapenemase genes, blaKPC-2 and blaNDM-1. The prevalence and genetic features of these coexisting plasmids should be monitored to facilitate the establishment of effective strategies to control their further spread.
Identification of anoikis-related genes classification patterns and immune infiltration characterization in ischemic stroke based on machine learning
Authors: Qin Xiaohong , Yi Shangfeng , Rong Jingtong , Lu Haoran , Ji Baowei , Zhang Wenfei , Ding Rui , Wu Liquan , Chen Zhibiao 
Published: March 2023

IntroductionIschemic stroke (IS) is a type of stroke that leads to high mortality and disability. Anoikis is a form of programmed cell death. When cells detach from the correct extracellular matrix, anoikis disrupts integrin junctions, thus preventing abnormal proliferating cells from growing or attaching to an inappropriate matrix. Although there is growing evidence that anoikis regulates the immune response, which makes a great contribution to the development of IS, the role of anoikis in the pathogenesis of IS is rarely explored.MethodsFirst, we downloaded GSE58294 set and GSE16561 set from the NCBI GEO database. And 35 anoikis-related genes (ARGs) were obtained from GSEA website. The CIBERSORT algorithm was used to estimate the relative proportions of 22 infiltrating immune cell types. Next, consensus clustering method was used to classify ischemic stroke samples. In addition, we used least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) algorithms to screen the key ARGs in ischemic stroke. Next, we performed receiver operating characteristics (ROC) analysis to assess the accuracy of each diagnostic gene. At the same time, the nomogram was constructed to diagnose IS by integrating trait genes. Then, we analyzed the correlation between gene expression and immune cell infiltration of the diagnostic genes in the combined database. And gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis were performed on these genes to explore differential signaling pathways and potential functions, as well as the construction and visualization of regulatory networks using NetworkAnalyst and Cytoscape. Finally, we investigated the expression pattern of ARGs in IS patients across age or gender.ResultsOur study comprehensively analyzed the role of ARGs in IS for the first time. We revealed the expression profile of ARGs in IS and the correlation with infiltrating immune cells. And The results of consensus clustering analysis suggested that we can classify IS patients into two clusters. The machine learning analysis screened five signature genes, including AKT1, BRMS1, PTRH2, TFDP1 and TLE1. We also constructed nomogram models based on the five risk genes and evaluated the immune infiltration correlation, gene-miRNA, gene-TF and drug-gene interaction regulatory networks of these signature genes. The expression of ARGs did not differ by sex or age.DiscussionThis study may provide a beneficial reference for further elucidating the pathogenesis of IS, and render new ideas for drug screening, individualized therapy and immunotherapy of IS.
Construction and evaluation of Alzheimer’s disease diagnostic prediction model based on genes involved in mitophagy
Authors: Pei Yongyan , Chen Sijia , Zhou Fengling , Xie Tao , Cao Hua 
Published: March 2023

IntroductionAlzheimer’s disease (AD) is a common neurodegenerative disease. The concealment of the disease is the difficulty of its prevention and treatment. Previous studies have shown that mitophagy is crucial to the development of AD. However, there is a lack of research on the identification and clinical significance of mitophagy-related genes in AD. Therefore, the purpose of this study was to identify the mitophagy-related genes with the diagnostic potential for AD and establish a diagnostic model for AD.MethodsFirstly, we download the AD gene expression profile from Gene Expression Omnibus (GEO). Limma, PPI, functional enrichment analysis and WGCNA were used to screen the differential expression of mitophagy-related AD gene. Then, machine learning methods (random forest, univariate analysis, support vector machine, LASSO regression and support vector machine classification) were used to identify diagnostic markers. Finally, the diagnostic model was established and evaluated by ROC, multiple regression analysis, nomogram, calibration curve and other methods. Moreover, multiple independent datasets, AD cell models and AD clinical samples were used to verify the expression level of characteristic genes in the diagnostic model.ResultsIn total, 72 differentially expressed mitophagy-related related genes were identified, which were mainly involved in biological functions such as autophagy, apoptosis and neurological diseases. Four mitophagy-related genes (OPTN, PTGS2, TOMM20, and VDAC1) were identified as biomarkers. A diagnostic prediction model was constructed, and the reliability of the model was verified by receiver operating characteristic (ROC) curve analysis of GSE122063 and GSE63061. Then, we combine four mitophagy-related genes with age to establish a nomogram model. The ROC, C index and calibration curve show that the model has good prediction performance. Finally, multiple independent datasets, AD cell model samples and clinical peripheral blood samples confirmed that the expression levels of four mitophagy-related genes were consistent with the results of bioinformatics analysis.DiscussionThe analysis results and diagnostic model of this study are helpful for the follow-up clinical work and mechanism research of AD.
Neurodegenerative disease and antioxidant biomarkers: A bidirectional Mendelian randomization study
Authors: Zhang Qianqian , Li Qingyang , Zhao Huihui , Shu Mingzhu , Luo Maotao , Li Yanan , Ding Yu , Shi Shiyu , Cheng Xi , Niu Qi 
Published: March 2023

ObjectivePrevious observational studies have suggested that antioxidant imbalance is correlated with neurodegenerative diseases, while its cause–effect remains unclear. Thus, the goal of the present study is to explore the causal relationship between 11 antioxidant biomarkers and 3 most common neurodegenerative diseases [Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s disease (PD)].MethodsA bidirectional Mendelian randomization (MR) study was performed to investigate the causal effects by using 3 main methods (Variance Weighted (IVW), Weighted Median (WM), and MR-Egger regression) in the European population. The data of 11 antioxidant biomarkers were obtained from the open database by the most up-to-date Genome-Wide Association Studies (GWAS), the summary statistics of PD and ALS were obtained from the International Parkinson’s Disease Genomics Consortium (IPDGC) (33,674 cases, and 449,056 controls), and the International Amyotrophic Lateral Sclerosis Genomics Consortium (IALSC) (20,806 cases and 59,804 controls), respectively. For AD, we specifically used two recently published GWAS data, one from the International Genomics of Alzheimer’s Project (IGAP) (21,982 cases and 41,944 controls), and the other from a large meta-analysis (71,880 cases and 383,378 controls) as validation data.ResultsBased on the Bonferroni correction p &lt; 0.0015, there was no significant causal evidence for the antioxidant biomarkers on neurodegenerative diseases, however, the reverse analysis found that AD was significantly related to the decrease in retinol (IVW: beta = −0.023, p = 0.0007; WM: beta = −0.025, p = 0.0121), while the same analysis was carried out between the AD validation database and retinol, the results were consistent (IVW: beta = −0.064, p = 0.025). Moreover, AD on Glutathione S-transferase (GST), PD on Glutathione Peroxidase (GPX) as well as PD on uric acid (UA) also indicated potential causal-and-effect associations (IVW: p = 0.025; p = 0.027; p = 0.021, respectively).ConclusionsThere was no sufficient evidence that antioxidant imbalance has a significant causal effect on neurodegenerative diseases. However, this study revealed that genetically predicted AD was significantly related to the decrease in retinol, which provides a new insight into previous research and indicates the possibility to regard retinol as potential biomarker for the diagnosis and progress of AD.