bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation
Authors: Tsai Dung-Jang , Fang Wen-Hui , Wu Li-Wei , Tai Ming-Cheng , Kao Chung-Cheng , Huang Shih-Ming , Chen Wei-Teing , Hsiao Po-Jen , Chiu Chih-Chien , Su Wen , Wu Chia-Chun , Su Sui-Lung 
Published: December 2021

PurposeGenome-wide association studies have identified numerous genetic variants that are associated with osteoporosis risk; however, most of them are present in the non-coding regions of the genome and the functional mechanisms are unknown. In this study, we aimed to investigate the potential variation in runt domain transcription factor 2 (RUNX2), which is an osteoblast-specific transcription factor that normally stimulates bone formation and osteoblast differentiation, regarding variants within RUNX2 binding sites and risk of osteoporosis in postmenopausal osteoporosis (PMOP).MethodsWe performed bioinformatics-based prediction by combining whole genome sequencing and chromatin immunoprecipitation sequencing to screen functional SNPs in the RUNX2 binding site using data from the database of Taiwan Biobank; Case-control studies with 651 postmenopausal women comprising 107 osteoporosis patients, 290 osteopenia patients, and 254 controls at Tri-Service General Hospital between 2015 and 2019 were included. The subjects were examined for bone mass density and classified into normal and those with osteopenia or osteoporosis by T-scoring with dual-energy X-ray absorptiometry. Furthermore, mRNA expression and luciferase reporter assay were used to provide additional evidence regarding the associations identified in the association analyses. Chi-square tests and logistic regression were mainly used for statistical assessment.ResultsThrough candidate gene approaches, 3 SNPs in the RUNX2 binding site were selected. A novel SNP rs6086746 in the PLCB4 promoter was identified to be associated with osteoporosis in Chinese populations. Patients with AA allele had higher risk of osteoporosis than those with GG+AG (adjusted OR = 6.89; 95% confidence intervals: 2.23–21.31, p = 0.001). Moreover, the AA genotype exhibited lower bone mass density (p &lt; 0.05). Regarding mRNA expression, there were large differences in the correlation between PLCB4 and different RUNX2 alleles (Cohen’s q = 0.91). Functionally, the rs6086746 A allele reduces the RUNX2 binding affinity, thus enhancing the suppression of PLCB4 expression (p &lt; 0.05).ConclusionsOur results provide further evidence to support the important role of the SNP rs6086746 in the etiology of osteopenia/osteoporosis, thereby enhancing the current understanding of the susceptibility to osteoporosis. We further studied the mechanism underlying osteoporosis regulation by PLCB4.
Comprehensive Analyses of Type 1 Diabetes Ketosis- or Ketoacidosis-Related Genes in Activated CD56+CD16+ NK Cells
Authors: Shi Ruifeng , Dai Fang , He Yong , Sun Li , Xu Min , Deng Datong , Zhang Qiu 
Published: December 2021

ObjectivesAlterations in natural killer (NK) cells activity cause damage to pancreatic islets in type 1 diabetes mellitus (T1DM). The aim of this study is to identify T1DM ketosis- or ketoacidosis-related genes in activated CD56+CD16+ NK cells.MethodsMicroarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were analyzed using the GEO2R tool. Enrichment analyses were performed using Metascape online database and GSEA software. Cell-specific gene co-expression network was built using NetworkAnalyst tools. Cytoscape software was used to identify hub genes and construct co-expressed networks. Target miRNAs were predicted based on the DIANA-micro T, miRDB, and miRWalk online databases.ResultsA total of 70 DEGs were identified between T1DM patients recovered from ketosis or ketoacidosis and healthy control blood samples in GSE44314. Among the DEGs, 10 hub genes were screened out. The mature NK cell-specific gene co-expression network for DEGs in T1DM was built using NetworkAnalyst tools. DEGs between activated CD56+CD16+ NK cells and CD56brightCD16- NK cells were identified from GSE1511. After intersection, 13 overlapping genes between GSE44314 and GSE1511 microarray datasets were screened out, in which 7 hub genes were identified. Additionally, 59 target miRNAs were predicted according to the 7 hub genes. After validating with the exosome miRNA expression profile dataset of GSE97123, seven differentially expressed miRNAs (DEmiRNAs) in plasma-derived exosome were selected. Finally, a mRNA–miRNA network was constructed, which was involved in the T1DM ketosis or ketoacidosis process.ConclusionThis work identified seven hub genes in activated CD56+CD16+ NK cells and seven miRNAs in plasma-derived exosome as potential predictors of T1DM ketoacidosis, which provided a novel insight for the pathogenesis at the transcriptome level.
Transition of Lipid Accumulation Product Status and the Risk of Type 2 Diabetes Mellitus in Middle-Aged and Older Chinese: A National Cohort Study
Authors: Yu Jinyue , Yi Qian , Hou Leying , Chen Ge , Shen Yaojia , Song Yuan , Zhu Yimin , Song Peige 
Published: December 2021

BackgroundLipid accumulation product (LAP), a product of waist circumference (WC) and fasting triglycerides (TG), is a measure of lipid accumulation and an effective predictor of metabolic syndrome. This study aimed to evaluate the associations of LAP and its longitudinal transitions with type 2 diabetes mellitus (T2DM) among middle-aged and older Chinese.MethodsData were extracted from the China Health and Retirement Longitudinal Study (2011, 2013, 2015, and 2018). LAP was defined as (WC-65) ×TG for men, and (WC-58) ×TG for women. Participants were classified into high- and low-LAP groups at baseline, and subsequently into four transition patterns during 2011-2015: maintained-high, maintained-low, high-to-low, and low-to-high LAP. The longitudinal transition patterns of LAP on the development of T2DM were assessed by multivariable Cox frailty models.ResultsOverall, 7397 participants were included for analysis, among whom 849 (11.5%) developed T2DM between 2011 and 2018. Women with high-LAP levels at baseline presented a higher risk of T2DM (hazard ratios [HR]=1.37, 95% confidence interval [CI]: 1.07-1.77), while no significant association was found in men. Compared with women with maintained-low LAP pattern, those with transition patterns of low-to-high LAP and maintained-high LAP were at higher risk of T2DM (HR =1.99 and 1.98, both P&lt;0.05); however, for men, the significantly positive association was only observed in maintained-high LAP transition pattern (HR=1.53, 95% CI: 1.04-2.23).ConclusionsElevated LAP levels and the transition patterns of maintained-high LAP and low-to-high LAP are significant risk factors for T2DM in women. Preventions are needed to combat T2DM at an early dyslipidemic stage.
Characterizing the Influence of Organic Polymers on the Specific Reactivity of Particulate Remedial Amendments
Authors: Muller Katherine A. , Zhong Lirong , Bagwell Christopher E. 
Published: December 2021

Commercially available particulate amendments demonstrate high reactivity for effective treatment of water soluble organic and inorganic contaminants in laboratory studies; however, transport of these particles is constrained in the subsurface. In many field applications, particulate amendments are mixed with organic polymers to enhance mobility for direct push applications or stabilize suspensions for high mass loadings. As such, the interactions between particulate amendments, organic polymers and contaminant species need to be systematically investigated to properly understand mechanistic processes that facilitate predictive performance metrics for specific applications in situ. In this study, batch experiments were conducted to quantify the effects of organic polymers (xanthan gum, guar gum, and sodium alginate), polymer concentration (800 and 4,000 mg/L), and aging (up to 28 days) on chromate treatment rate and capacity by two classes of amendments: reductants [granular zero-valent iron (gZVI), micron-ZVI (mZVI), sulfur modified iron (SMI)], and an adsorbent (bismuth sub-nitrate). When particulate amendments were suspended in polymer solutions, reductants retained between 84–100% of the amendment treatment capacity. Conversely, the adsorbent maintained 63–97% relative treatment capacity of the no-polymer control. Polymer solutions had a more pronounced impact on the rate of chromate removal; first order rates of chemical reduction decreased by as much as 70% and adsorption by up to 81% relative to the no-polymer controls. Polymer–amendment aging experiments also showed decreased Cr(VI) treatment capacity; reductants decreased by as much as 24% and adsorption decreased by as much as 44% after 28 days of incubation. While polymer suspensions are needed to aid the injection of particulate amendments into the subsurface, the results from this study indicate potential losses of treatment capacity and a decrease in the rate of remedial performance due to the physical and chemical interactions between polymer suspensions and reactive particulate amendments. Simple batch systems provide baseline characterization of tripartite interactions for the removal of Cr(VI). Additional work is needed to quantify the full impact of polymers on remedial outcomes under site relevant conditions at field scale.
Estimating Nitrogen Flows and Nitrogen Footprint for Agro-Food System of Rwanda Over the Last Five Decades: Challenges and Measures
Authors: Harerimana Barthelemy , Zhou Minghua , Shaaban Muhammad , Zhu Bo 
Published: December 2021

This study presents the first detailed estimate of Rwanda’s nitrogen (N) flows and N footprint for food (NFfood) from 1961 to 2018. Low N fertilizer inputs, substandard production techniques, and inefficient agricultural management practices are focal causes of low crop yields, environmental pollution, and food insecurity. We therefore assessed the N budget, N use efficiency (NUE), virtual N factors (VNFs), soil N mining factors (SNMFs), and N footprint for the agro-food systems of Rwanda with consideration of scenarios of fertilized and unfertilized farms. The total N input to croplands increased from 14.6 kg N ha−1 yr−1 (1960s) to 34.1 kg N ha−1 yr−1 (2010–2018), while the total crop N uptake increased from 18 kg N ha−1yr−1 (1960s) to 28.2 kg N ha−1yr−1 (2010–2018), reflecting a decline of NUE from 124% (1960s) to 85% (2010–2018). Gaseous N losses of NH3, N2O, and NO increased from 0.45 (NH3), 0.03 (N2O), and 0.00 (NO) Gg N yr−1 (1960s) to 6.98 (NH3), 0.58 (N2O), and 0.10 (NO) Gg N yr−1 (2010–2018). Due to the low N inputs, SNMFs were in the range of 0.00 and 2.99 and the rice production, cash-crop production, and livestock production systems have greater SNMFs in Rwanda. The weighted NFfood per capita that presents the actual situation of fertilized and unfertilized croplands increased from 4.0 kg N cap−1 yr−1 (1960s) to 6.3 kg N cap−1 yr−1 (2010–2018). The NFfood per capita would increase from 3.5 kg N cap−1 yr−1 to 4.8 kg N cap−1 yr−1 under a scenario of all croplands without N fertilizer application and increase from 6.0 to 8.7 kg N cap−1 yr−1 under the situation of all croplands receiving N fertilizer. The per capita agro-food production accounted for approximately 58% of the national NFfood. The present study indicates that Rwanda is currently suffering from low N inputs, high soil N depletion, food insecurity, and environmental N losses. Therefore, suggesting that the implementation of N management policies of increasing agricultural N inputs and rehabilitating the degraded soils with organic amendments of human and animal waste needs to be carefully considered in Rwanda.
TGF-Beta Induced Key Genes of Osteogenic and Adipogenic Differentiation in Human Mesenchymal Stem Cells and MiRNA–mRNA Regulatory Networks
Authors: Du Genfa , Cheng Xinyuan , Zhang Zhen , Han Linjing , Wu Keliang , Li Yongjun , Lin Xiaosheng 
Published: December 2021

Background: The clinical efficacy of osteoporosis therapy is unsatisfactory. However, there is currently no gold standard for the treatment of osteoporosis. Recent studies have indicated that a switch from osteogenic to adipogenic differentiation in human bone marrow mesenchymal stem cells (hMSCs) induces osteoporosis. This study aimed to provide a more comprehensive understanding of the biological mechanisms involved in this process and to identify key genes involved in osteogenic and adipogenic differentiation in hMSCs to provide new insights for the prevention and treatment of osteoporosis.Methods: Microarray and bioinformatics approaches were used to identify the differentially expressed genes (DEGs) involved in osteogenic and adipogenic differentiation, and the biological functions and pathways of these genes were analyzed. Hub genes were identified, and the miRNA–mRNA interaction networks of these hub genes were constructed.Results: In an optimized microenvironment, transforming growth factor-beta (TGF-beta) could promote osteogenic differentiation and inhibit adipogenic differentiation of hMSCs. According to our study, 98 upregulated genes involved in osteogenic differentiation and 66 downregulated genes involved in adipogenic differentiation were identified, and associated biological functions and pathways were analyzed. Based on the protein–protein interaction (PPI) networks, the hub genes of the upregulated genes (CTGF, IGF1, BMP2, MMP13, TGFB3, MMP3, and SERPINE1) and the hub genes of the downregulated genes (PPARG, TIMP3, ANXA1, ADAMTS5, AGTR1, CXCL12, and CEBPA) were identified, and statistical analysis revealed significant differences. In addition, 36 miRNAs derived from the upregulated hub genes were screened, as were 17 miRNAs derived from the downregulated hub genes. Hub miRNAs (hsa-miR-27a/b-3p, hsa-miR-128-3p, hsa-miR-1-3p, hsa-miR-98-5p, and hsa-miR-130b-3p) coregulated both osteogenic and adipogenic differentiation factors.Conclusion: The upregulated hub genes identified are potential targets for osteogenic differentiation in hMSCs, whereas the downregulated hub genes are potential targets for adipogenic differentiation. These hub genes and miRNAs play important roles in adipogenesis and osteogenesis of hMSCs. They may be related to the prevention and treatment not only of osteoporosis but also of obesity.
Exploring Pathway-Based Group Lasso for Cancer Survival Analysis: A Special Case of Multi-Task Learning
Authors: Malenová Gabriela , Rowson Daniel , Boeva Valentina 
Published: December 2021

Motivation: The Cox proportional hazard models are widely used in the study of cancer survival. However, these models often meet challenges such as the large number of features and small sample sizes of cancer data sets. While this issue can be partially solved by applying regularization techniques such as lasso, the models still suffer from unsatisfactory predictive power and low stability.Methods: Here, we investigated two methods to improve survival models. Firstly, we leveraged the biological knowledge that groups of genes act together in pathways and regularized both at the group and gene level using latent group lasso penalty term. Secondly, we designed and applied a multi-task learning penalty that allowed us leveraging the relationship between survival models for different cancers.Results: We observed modest improvements over the simple lasso model with the inclusion of latent group lasso penalty for six of the 16 cancer types tested. The addition of a multi-task penalty, which penalized coefficients in pairs of cancers from diverging too greatly, significantly improved accuracy for a single cancer, lung squamous cell carcinoma, while having minimal effect on other cancer types.Conclusion: While the use of pathway information and multi-tasking shows some promise, these methods do not provide a substantial improvement when compared with standard methods.
Epigenetic Alteration and its Association With Downregulated FOXP3 Gene in Indian Breast Cancer Patients
Authors: Sadaf  , Akhter Naseem , Alharbi Raed A. , Sindi Abdulmajeed A. A. , Najm Mohammad Zeeshan , Alhumaydhi Fahad A. , Khan Mohammad Aasif , Deo S.V.S , Husain Syed Akhtar 
Published: December 2021

Background:FOXP3 gene, known to be a potential tumor suppressor, has been identified to interact with HER2 in mammary cancer. Moreover, the high expression of FOXP3 serves as a good predictor of the survival of patients in breast cancer, prostate cancer, and gastric cancer. The expression and epigenetic alterations were evaluated in female breast cancer patients.Material and Methods: Expression studies at the mRNA level and protein level were conducted in 140 breast cancer cases by real-time PCR and immunohistochemistry, respectively. Epigenetic studies were also conducted by analyzing the methylation status at the promoter region of the gene using MS-PCR.Results:FOXP3 mRNA expression and protein expression were downregulated in breast cancer patients. The absence of FOXP3 protein expression is significantly associated with promoter methylation, where 70 methylated cases exhibited protein loss (70/95, 73.6%). Statistically, we also found a significant correlation between FOXP3 protein expression and TNM stage, promoter methylation, and histological grade. The methylated FOXP3 cases that did not express protein were also significantly associated with positive lymph node metastasis and HER-2 status.Conclusion: The expression profile of FOXP3 may serve as a prognostic factor. In short, FOXP3 may stand in the most crucial list of biomarkers for breast cancer, bringing compelling results in terms of treatment and management of the disease.
Identification and Validation of a Novel Six-Gene Expression Signature for Predicting Hepatocellular Carcinoma Prognosis
Authors: Yan Zongcai , He Meiling , He Lifeng , Wei Liuxia , Zhang Yumei 
Published: December 2021

BackgroundHepatocellular carcinoma (HCC) is a highly lethal disease. Effective prognostic tools to guide clinical decision-making for HCC patients are lacking.ObjectiveWe aimed to establish a robust prognostic model based on differentially expressed genes (DEGs) in HCC.MethodsUsing datasets from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the International Genome Consortium (ICGC), DEGs between HCC tissues and adjacent normal tissues were identified. Using TCGA dataset as the training cohort, we applied the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analyses to identify a multi-gene expression signature. Proportional hazard assumptions and multicollinearity among covariates were evaluated while building the model. The ICGC cohort was used for validation. The Pearson test was used to evaluate the correlation between tumor mutational burden and risk score. Through single-sample gene set enrichment analysis, we investigated the role of signature genes in the HCC microenvironment.ResultsA total of 274 DEGs were identified, and a six-DEG prognostic model was developed. Patients were stratified into low- or high-risk groups based on risk scoring by the model. Kaplan–Meier analysis revealed significant differences in overall survival and progression-free interval. Through univariate and multivariate Cox analyses, the model proved to be an independent prognostic factor compared to other clinic-pathological parameters. Time-dependent receiver operating characteristic curve analysis revealed satisfactory prediction of overall survival, but not progression-free interval. Functional enrichment analysis showed that cancer-related pathways were enriched, while immune infiltration analyses differed between the two risk groups. The risk score did not correlate with levels of PD-1, PD-L1, CTLA4, or tumor mutational burden.ConclusionsWe propose a six-gene expression signature that could help to determine HCC patient prognosis. These genes may serve as biomarkers in HCC and support personalized disease management.
Antibiotic Prescribing and Doctor-Patient Communication During Consultations for Respiratory Tract Infections: A Video Observation Study in Out-of-Hours Primary Care
Authors: Colliers Annelies , Bombeke Katrien , Philips Hilde , Remmen Roy , Coenen Samuel , Anthierens Sibyl 
Published: December 2021

Objective: Communication skills can reduce inappropriate antibiotic prescribing, which could help to tackle antibiotic resistance. General practitioners often overestimate patient expectations for an antibiotic. In this study, we describe how general practitioners and patients with respiratory tract infections (RTI) communicate about their problem, including the reason for encounter and ideas, concerns, and expectations (ICE), and how this relates to (non-)antibiotic prescribing in out-of-hours (OOH) primary care.Methods: A qualitative descriptive framework analysis of video-recorded consultations during OOH primary care focusing on doctor-patient communication.Results: We analyzed 77 videos from 19 general practitioners. General practitioners using patient-centered communication skills received more information on the perspective of the patients on the illness period. For some patients, the reason for the encounter was motivated by their belief that a general practitioner (GP) visit will alter the course of their illness. The ideas, concerns, and expectations often remained implicit, but the concerns were expressed by the choice of words, tone of voice, repetition of words, etc. Delayed prescribing was sometimes used to respond to implicit patient expectations for an antibiotic. Patients accepted a non-antibiotic management plan well.Conclusion: Not addressing the ICE of patients, or their reason to consult the GP OOH, could drive assumptions about patient expectations for antibiotics early on and antibiotic prescribing later in the consultation.
Incidence and Risk Factors of Dry Eye in Children and Adolescents With Diabetes Mellitus: A 3-Year Follow-Up Study
Authors: Chen Zhangling , Xiao Ying , Qian Yu , Lin Qiurong , Xiang Zhaoyu , Cui Lipu , Sun Jiaqi , Li Sicong , Qin Xinran , Yang Chenhao , Zou Haidong 
Published: December 2021

Purpose: To investigate the incidence and risk factors of dry eye in children with diabetes mellitus (DM) over a period of 3 years.Methods: Children and adolescents with DM (age: 3–14 years) from the Shanghai Children and Adolescent Diabetes Eye (SCADE) study cohort who did not have dry eye in January 2018 were followed-up for 3 years and re-examined in January 2021, and the incidence rate and risk factors for dry eye were calculated.Results: Forty children and adolescents with DM came for follow-up in 2021. Nine of them were diagnosed with dry eye, resulting in a 3-year incidence rate of 22.5% and an annual mean incidence rate of 7.5% for dry eye. Univariate regression analysis confirmed that decreased corneal sensation (OR [Odds Ratio] = 25.60; 95%CI [Confidence Interval] = 1.31~501.69; P = 0.03) was the risk factor for dry eye incidence. Long course of DM (OR = 1.80; 95%CI = 0.96~3.38; P = 0.07), eye pain (OR = 12.27; 95%CI = 0.65~231.48; P = 0.09), and dry eye in parents (OR = 15.99; 95%CI = 0.76~337.75; P = 0.08) may interfere with the incidence of dry eye in them.Conclusions: The incidence of dry eye in children and adolescents with DM is high.