bluuebunny/crossref_metadata_2025_split huggingface dataset:
The specific mitochondrial unfolded protein response in fast- and slow-twitch muscles of high-fat diet-induced insulin-resistant rats
Authors: Li Can , Li Nan , Zhang Ziyi , Song Yu , Li Jialin , Wang Zhe , Bo Hai , Zhang Yong 
Published: March 2023

IntroductionSkeletal muscle insulin resistance (IR) plays an important role in the pathogenesis of type 2 diabetes mellitus. Skeletal muscle is a heterogeneous tissue composed of different muscle fiber types that contribute distinctly to IR development. Glucose transport shows more protection in slow-twitch muscles than in fast-twitch muscles during IR development, while the mechanisms involved remain unclear. Therefore, we investigated the role of the mitochondrial unfolded protein response (UPRmt) in the distinct resistance of two types of muscle in IR.MethodsMale Wistar rats were divided into high-fat diet (HFD) feeding and control groups. We measured glucose transport, mitochondrial respiration, UPRmt and histone methylation modification of UPRmt-related proteins to examine the UPRmt in the slow fiber-enriched soleus (Sol) and fast fiber-enriched tibialis anterior (TA) under HFD conditions.ResultsOur results indicate that 18 weeks of HFD can cause systemic IR, while the disturbance of Glut4-dependent glucose transport only occurred in fast-twitch muscle. The expression levels of UPRmt markers, including ATF5, HSP60 and ClpP, and the UPRmt-related mitokine MOTS-c were significantly higher in slow-twitch muscle than in fast-twitch muscle under HFD conditions. Mitochondrial respiratory function is maintained only in slow-twitch muscle. Additionally, in the Sol, histone methylation at the ATF5 promoter region was significantly higher than that in the TA after HFD feeding.ConclusionThe expression of proteins involved in glucose transport in slow-twitch muscle remains almost unaltered after HFD intervention, whereas a significant decline of these proteins was observed in fast-twitch muscle. Specific activation of the UPRmt in slow-twitch muscle, accompanied by higher mitochondrial respiratory function and MOTS-c expression, may contribute to the higher resistance to HFD in slow-twitch muscle. Notably, the different histone modifications of UPRmt regulators may underlie the specific activation of the UPRmt in different muscle types. However, future work applying genetic or pharmacological approaches should further uncover the relationship between the UPRmt and insulin resistance.
Development and validation of a tumor immune cell infiltration-related gene signature for recurrence prediction by weighted gene co-expression network analysis in prostate cancer
Authors: Xie Lin-Ying , Huang Han-Ying , Hao Yu-Lei , Yu Miaomiao , Zhang Wenju , Wei Enwei , Gao Chunfeng , Wang Chang , Zeng Lei 
Published: March 2023

Introduction: Prostate cancer (PCa) is the second most common malignancy in men. Despite multidisciplinary treatments, patients with PCa continue to experience poor prognoses and high rates of tumor recurrence. Recent studies have shown that tumor-infiltrating immune cells (TIICs) are associated with PCa tumorigenesis.Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to derive multi-omics data for prostate adenocarcinoma (PRAD) samples. The CIBERSORT algorithm was used to calculate the landscape of TIICs. Weighted gene co-expression network analysis (WGCNA) was performed to determine the candidate module most significantly associated with TIICs. LASSO Cox regression was applied to screen a minimal set of genes and construct a TIIC-related prognostic gene signature for PCa. Then, 78 PCa samples with CIBERSORT output p-values of less than 0.05 were selected for analysis. WGCNA identified 13 modules, and the MEblue module with the most significant enrichment result was selected. A total of 1143 candidate genes were cross-examined between the MEblue module and active dendritic cell-related genes.Results: According to LASSO Cox regression analysis, a risk model was constructed with six genes (STX4, UBE2S, EMC6, EMD, NUCB1 and GCAT), which exhibited strong correlations with clinicopathological variables, tumor microenvironment context, antitumor therapies, and tumor mutation burden (TMB) in TCGA-PRAD. Further validation showed that the UBE2S had the highest expression level among the six genes in five different PCa cell lines.Discussion: In conclusion, our risk-score model contributes to better predicting PCa patient prognosis and understanding the underlying mechanisms of immune responses and antitumor therapies in PCa.
Potential predictive value of circulating tumor DNA (ctDNA) mutations for the efficacy of immune checkpoint inhibitors in advanced triple-negative breast cancer
Authors: Tan Qiaorui , Chi Yajing , Su Mu , Zhou Jinxing , Zhou Dongdong , Zheng Fangchao , Man Xiaochu , Sun Shujuan , Huang Jie , Li Huihui 
Published: March 2023

Background: In recent years, tumor immunotherapy has become a viable treatment option for triple negative breast cancer (TNBC). Among these, immune checkpoint inhibitors (ICIs) have demonstrated good efficacy in advanced TNBC patients with programmed death-ligand 1 (PD-L1) positive expression. However, only 63% of PD-L1-positive individuals showed any benefit from ICIs. Therefore, finding new predictive biomarkers will aid in identifying patients who are likely to benefit from ICIs. In this study, we used liquid biopsies and next-generation sequencing (NGS) to dynamically detect changes in circulating tumor DNA (ctDNA) in the blood of patients with advanced TNBC treated with ICIs and focused on its potential predictive value.Methods: From May 2018 to October 2020, patients with advanced TNBC treated with ICIs at Shandong Cancer Hospital were included prospectively. Patient blood samples were obtained at the pretreatment baseline, first response evaluation, and disease progression timepoints. Furthermore, 457 cancer-related genes were evaluated by NGS, and patients’ ctDNA mutations, gene mutation rates, and other indicators were determined and coupled with clinical data for statistical analysis.Results: A total of 11 TNBC patients were included in this study. The overall objective response rate (ORR) was 27.3%, with a 6.1-month median progression-free survival (PFS) (95% confidence interval: 3.877–8.323 months). Of the 11 baseline blood samples, 48 mutations were found, with the most common mutation types being frame shift indels, synonymous single-nucleotide variations (SNVs), frame indel missenses, splicing, and stop gains. Additionally, univariate Cox regression analysis revealed that advanced TNBC patients with one of 12 mutant genes (CYP2D6 deletion and GNAS, BCL2L1, H3F3C, LAG3, FGF23, CCND2, SESN1, SNHG16, MYC, HLA-E, and MCL1 gain) had a shorter PFS with ICI treatment (p &lt; 0.05). To some extent, dynamic changes of ctDNA might indicate the efficacy of ICIs.Conclusion: Our data indicate that ICI efficacy in patients with advanced TNBC may be predicted by 12 mutant ctDNA genes. Additionally, dynamic alterations in peripheral blood ctDNA might be used to track the effectiveness of ICI therapy in those with advanced TNBC.
Neutrophilic inflammation promotes SARS-CoV-2 infectivity and augments the inflammatory responses in airway epithelial cells
Authors: Calvert Ben A. , Quiroz Erik J. , Lorenzana Zareeb , Doan Ngan , Kim Seongjae , Senger Christiana N. , Anders Jeffrey J. , Wallace Wiliam D. , Salomon Matthew P. , Henley Jill , Ryan Amy L. 
Published: March 2023

IntroductionIn response to viral infection, neutrophils release inflammatory mediators as part of the innate immune response, contributing to pathogen clearance through virus internalization and killing. Pre- existing co-morbidities correlating to incidence to severe COVID-19 are associated with chronic airway neutrophilia. Furthermore, examination of COVID-19 explanted lung tissue revealed a series of epithelial pathologies associated with the infiltration and activation of neutrophils, indicating neutrophil activity in response to SARS-CoV-2 infection.MethodsTo determine the impact of neutrophil-epithelial interactions on the infectivity and inflammatory responses to SARS-CoV-2 infection, we developed a co-culture model of airway neutrophilia. This model was infected with live SARS-CoV-2 virus the epithelial response to infection was evaluated.ResultsSARS-CoV-2 infection of airway epithelium alone does not result in a notable pro-inflammatory response from the epithelium. The addition of neutrophils induces the release of proinflammatory cytokines and stimulates a significantly augmented proinflammatory response subsequent SARS-CoV-2 infection. The resulting inflammatory responses are polarized with differential release from the apical and basolateral side of the epithelium. Additionally, the integrity of the \epithelial barrier is impaired with notable epithelial damage and infection of basal stem cells.ConclusionsThis study reveals a key role for neutrophil-epithelial interactions in determining inflammation and infectivity.
Comprehensive analysis of m6A RNA methylation modification patterns and the immune microenvironment in osteoarthritis
Authors: Liu Zhixin , Liu Heng , Li Deqiang , Ma Liang , Lu Tongxin , Sun Hao , Zhang Yuankai , Yang Hui 
Published: March 2023

BackgroundOsteoarthritis (OA) is the most common joint degenerative disease, and so far, there is no effective therapy to prevent or delay its development. Considerable attention is now being given to the impact of m6A RNA methylation modification on the disease immune regulation. However, much remains unknown about the function of m6A modification in OA.MethodsA total of 63 OA and 59 healthy samples were applied to comprehensively examine the m6A regulators mediated RNA methylation modification pattern in OA, and evaluate the impacts of distinct patterns on the characteristics of OA immune microenvironment, including immune infiltration cells, immune responses and human leukocyte antigen (HLAs) genes expression. In addition, we screened out the m6A phenotype-related genes and further explored their potential biological functions. At last, we verified the expression of key m6A regulators and their associations with immune cells, in vitro.ResultsMost of m6A regulators was differentially expressed in OA samples compared to the normal tissues. Based on six hub-m6A regulators identified as abnormally expressed in OA samples, we developed a classifier to distinguish OA patients from healthy individuals. We noted that immune characteristics of OA were correlated with m6A regulators. For instance, YTHDF2 had a strongest significantly positive correlation with regulatory T cells (Tregs) and IGFBP2 was strongest negatively associated with dendritic cells (DCs), which were confirmed by the immunohistochemistry (IHC) staining. Two distinct m6A modification patterns were determined: pattern B had higher infiltrating immunocytes and more active immune responses than pattern A, and two patterns differed in the expression of HLA genes. We also identified 1,592 m6A phenotype-related genes that could mediate the OA synovitis and cartilage degradation by the PI3K-Akt signaling pathway. Quantitative real-time polymerase chain reaction (qRT-PCR) results indicated that IGFBP2 was significantly overexpressed, while YTHDF2 mRNA expression was decreased in OA samples, which was consistent with our findings.ConclusionOur research proves the essential impact of m6A RNA methylation modification on the OA immune microenvironment, and helps to explain the regulatory mechanism behind it, which may open up a new direction for more precise immunotherapy of osteoarthritis.
Fucosylated TLR4 mediates communication between mutualist fucotrophic microbiota and mammalian gut mucosa
Authors: Nanthakumar Nanda N. , Meng Di , Newburg David S. 
Published: March 2023

ObjectiveThe glycans on the mucosa of suckling mice are predominantly sialylated; upon weaning, fucosylated glycans preponderate. This manifestation of mutualism between fucotrophic bacteria and the mature host utilizes a sentinel receptor in the intestinal mucosa; this receptor was isolated to distinguish its structural and functional features.DesignProvisional identification of the sentinel gut receptor as fuc-TLR4 was through colonization of germ-free mutant mice. Conventional mice whose microbiota was depleted with a cocktail of antibiotics were used to further define the nature and functions of fuc-TLR4 sentinel, and to define the role of the fucotrophic microbiota in gut homeostasis and recovery from insult. The nature of the sentinel was confirmed in cultured human HEL cells.ResultsFuc-TLR4 activity is distinct from that of TLR4. Activated mucosal fuc-TLR4 induces a fuc-TLR4 dependent non-inflammatory (ERK and JNK dependent, NF-κB independent) signaling cascade, initiating induction of fucosyltransferase 2 (secretor) gene transcription. In vitro, either defucosylation or TLR4 knockdown abrogates FUT2 induction, indicating that fuc-TLR4 activity requires both the peptide and glycan moieties. In vivo, fucose-utilizing bacteria and fucose-binding ligands induce mucosal fucosylation. Activation of this pathway is essential for recovery from chemically induced mucosal injury in vivo.ConclusionIn mature mice, fucosyl-TLR4 mediated gut fucosylation creates a niche that supports the healthy fucose-dependent mutualism between the mammalian gut and its fucotrophic microbes. Such microbiota-induced Fuc-TLR4 signaling supports initial colonization of the secretor gut, recovery from dysbiosis, and restoration or preservation of intestinal homeostasis.
Relationship between fibrinogen level and advanced colorectal adenoma among inpatients: A retrospective case-control study
Authors: Wang Huijie , Zheng Huanwei , Cao Xu , Meng Ping , Liu Jinli , Wang Zhichao , Zhang Teng , Zuo Haiying 
Published: March 2023

ObjectiveThis study was to explore the relationship between fibrinogen and advanced colorectal adenoma among inpatients.MethodsFrom April 2015 to June 2022, 3738 participants (566 case subjects and 3172 control subjects) who underwent colonoscopies enrolled, and smooth curve fitting and logistic regression models were applied to explore the association between fibrinogen and advanced colorectal adenoma. In addition, sensitivity and subgroup analyses were performed to assess the stability of the results.ResultsCompared with lower fibrinogen quantile 1 (&lt; 2.4 g/L), the adjusted OR values for fibrinogen and advanced colorectal adenoma in quantile 2 (2.4–2.75 g/L), quantile 3 (2.76–3.15 g/L), and quantile 4 (≥3.16 g/L) were 1.03 (95% confidence interval [CI]: 0.76–1.41), 1.37 (95% CI: 1.01–1.85), and 1.43 (95% CI: 1.06–1.94), respectively. A linear relationship between fibrinogen and advanced colorectal adenoma was observed. Sensitivity and subgroup analyses showed stable results.ConclusionComplements the evidence that fibrinogen was positively associated with advanced adenomas, suggesting that fibrinogen may play a role in the adenoma-carcinoma sequence.
Molecular analysis of clinical Citrobacter spp. isolates: Acquisition of the Yersinia high-pathogenicity island mediated by ICEkp in C. freundii
Authors: Zhang Guangcun , Zhao Qiang , Ye Kun , Ye Liyan , Ma Yanning , Yang Jiyong 
Published: March 2023

BackgroundStudies on Citrobacter spp. are limited, hindering our understanding of its species evolution and medical relevance.MethodsA total of 164 clinical Citrobacter spp. isolates were collected from 2017 to 2020 and identified by VITEK MALDI-TOF MS or VITEK-2 Gram-Negative Identification Card. All isolates were further analyzed by whole-genome sequencing using a HiSeq sequencer. All sequences were processed using different modules of the PGCGAP integrated package: Prokka and fastANI were used for annotation and average nucleotide identification (ANI), respectively. Antibiotic resistance and virulence genes were identified by searching CARD, ResFinder, and VFDB databases, respectively. Strains were identified using Ribosomal Multi-locus Sequence Typing (rMLST) classification based on 53 ribosome protein subunits (rps). The evolutionary relationship was analyzed using kSNP3 and visualized by iTOL editor v1_1. Genetic environments were compared by BLAST and visualized by Easyfig 2.2.5. The pathogenicity of some Citrobacter freundii isolates was confirmed by Galleria mellonella larvae infection test.ResultsA total of 14 species of Citrobacter spp. were identified from 164 isolates. However, 27 and 11 isolates were incorrectly identified as C. freundii and Citrobacter braakii by MALDI-TOF MS, respectively. In addition, MS also failed to identify Citrobacter portucalensis. The virulence genes mainly encoded proteins related to flagella and iron uptake systems. Citrobacter koseri isolates (n = 28) contained two iron uptake systems, coding yersiniabactin and aerobactin, respectively. C. braakii isolates (n = 32), like Salmonella, carried Vi capsule polysaccharide synthesis genes. The yersiniabactin gene clusters identified in five C. freundii isolates are located on various ICEkp elements and have not been reported previously. Moreover, ICEkp-carrying C. freundii showed diverse pathogenic features.ConclusionConventional methods have significant defects in identifying Citrobacter spp. ICEkp-like elements-mediated acquirement of the Yersinia high-pathogenicity island was identified for the first time in C. freundii.
Structural and oxidative investigation of a recombinant high-yielding fetal hemoglobin mutant
Authors: Kettisen Karin , Nyblom Maria , Smeds Emanuel , Fago Angela , Bülow Leif 
Published: March 2023

Human fetal hemoglobin (HbF) is an attractive starting protein for developing an effective agent for oxygen therapeutics applications. This requires that HbF can be produced in heterologous systems at high levels and in a homogeneous form. The introduction of negative charges on the surface of the α-chain in HbF can enhance the recombinant production yield of a functional protein in Escherichia coli. In this study, we characterized the structural, biophysical, and biological properties of an HbF mutant carrying four additional negative charges on each α-chain (rHbFα4). The 3D structure of the rHbFα4 mutant was solved with X-ray crystallography at 1.6 Å resolution. Apart from enabling a higher yield in recombinant protein production in E. coli, we observed that the normal DNA cleavage activity of the HbF was significantly lowered, with a four-time reduced rate constant for the rHbFα4 mutant. The oxygen-binding properties of the rHbFα4 mutant were identical to the wild-type protein. No significant difference between the wild-type and rHbFα4 was observed for the investigated oxidation rates (autoxidation and H2O2-mediated ferryl formation). However, the ferryl reduction reaction indicated some differences, which appear to be related to the reaction rates linked to the α-chain.
The factors influencing postoperative efficacy of anterior clinoidal meningioma treatment and an analysis of best-suited surgical strategies
Authors: Chen Li-Hua , Xia Yong , Wei Fan , Sun Kai , Huang Hong-Zhi , Xu Ru-Xiang 
Published: March 2023

ObjectiveTo explore the influence of the type of anterior clinoidal meningioma on surgical strategy planning, surgical approach selection, and postoperative efficacy.Patients and methodsWe conducted a retrospective analysis of the clinical data of 63 cases, including data on visual function, extent of tumor resection, and postoperative follow-up. Grade I and II approaches were selected according to the type of tumor. A univariate analysis of the factors influencing the extent of tumor resection, postoperative visual function, and postoperative relapse and complications was conducted.ResultsSimpson Grade I–II total resection was seen in 48 cases (76.2%), with an overall relapse/progression rate of 12.7%. The tumor type and texture and the relationship between the tumors and adjacent structures were the main factors influencing total tumor resection (P &lt; 0.01). The overall postoperative visual acuity improvement, stabilization rate, and deterioration rate were 76.2, 15.9, and 7.9%, respectively. Postoperative visual acuity level was significantly correlated with preoperative visual acuity level and tumor type (P &lt; 0.01).ConclusionsDetermining the type of tumor at a preoperative level and whether the optic canal and cavernous sinus are invaded can aid in the planning of detailed individualized surgical strategies.
Economic and health impacts of the Change4Life Food Scanner app: Findings from a randomized pilot and feasibility study
Authors: Mahdi Sundus , Buckland Nicola J. , Chilcott Jim 
Published: March 2023

IntroductionThe UK Government developed the Change4Life Food Scanner app to provide families with engaging feedback on the nutritional content of packaged foods. There is a lack of research exploring the cost-effectiveness of dietary health promotion apps.MethodsThrough stakeholder engagement, a conceptual model was developed, outlining the pathway by which the Food Scanner app leads to proximal and distal outcomes. The conceptual model informed the development of a pilot randomized controlled trial which investigated the feasibility and acceptability of evaluating clinical outcomes in children and economic effectiveness of the Food Scanner app through a cost-consequence analysis. Parents of 4–11 years-olds (n = 126) were randomized into an app exposure condition (n = 62), or no intervention control (n = 64). Parent-reported Child Health Utility 9 Dimension (CHU9D) outcomes were collected alongside child healthcare resource use and associated costs, school absenteeism and parent productivity losses at baseline and 3 months follow up. Results for the CHU9D were converted into utility scores based on UK adult preference weights. Sensitivity analysis accounted for outliers and multiple imputation methods were adopted for the handling of missing data.Results64 participants (51%) completed the study (intervention: n = 29; control: n = 35). There was a mean reduction in quality adjusted life years between groups over the trial period of –0.004 (SD = 0.024, 95% CI: –0.005; 0.012). There was a mean reduction in healthcare costs of –£30.77 (SD = 230.97; 95% CI: –£113.80; £52.26) and a mean reduction in workplace productivity losses of –£64.24 (SD = 241.66, 95% CI: –£147.54; £19.07) within the intervention arm, compared to the control arm, over the data collection period. Similar findings were apparent after multiple imputation.DiscussionModest mean differences between study arms may have been due to the exploration of distal outcomes over a short follow-up period. The study was also disrupted due to the coronavirus pandemic, which may have confounded healthcare resource data. Although measures adopted were deemed feasible, the study highlighted difficulties in obtaining data on app development and maintenance costs, as well as the importance of economic modeling to predict long-term outcomes that may not be reliably captured over the short-term.Clinical trial registrationhttps://osf.io/, identifier 62hzt.