Evaluation of graphical models for multi-group metabolomics data.

Gaussian graphical model is a strong tool for identifying interactions from metabolomics data based on conditional correlation. However, data may be collected from different stages or subgroups of subjects with heterogeneity or hierarchical structure. There are different integrating strategies of graphical models for multi-group data proposed by data scientists. It is challenging to select the methods for metabolism data analysis. This study aimed to evaluate the performance of several different integrating graphical models for multi-group data and provide support for the choice of strategy for similar characteristic data. We compared the performance of seven methods in estimating graph structures through simulation study. We also applied all the methods in breast cancer metabolomics data grouped by stages to illustrate the real data application. The method of Shaddox et al. achieved the highest average area under the receiver operating characteristic curve and area under the precision-recall curve across most scenarios, and it was the only approach with all indicators ranked at the top. Nevertheless, it also cost the most time in all settings. Stochastic search structure learning tends to result in estimates that focus on the precision of identified edges, while BEAM, hierarchical Bayesian approach and birth-death Markov chain Monte Carlo may identify more potential edges. In the real metabolomics data analysis from three stages of breast cancer patients, results were in line with that in simulation study.

Exosome-derived miR-5p-72106_14 in vascular endothelial cells regulates fate determination of BMSCs.

Vascular endothelial cells have recently been shown to be associated with osteogenic activity. However, the mechanism of vascular endothelial cells promoting osteogenesis is unclear. Here, we found that exosomes secreted from human microvascular endothelial cells (HMEC-1) promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and inhibited adipogenic differentiation. Aged and ovariectomy mice treated with exosomes showed increased bone formation and decreased lipid accumulation in the bone marrow cavity. Additionally, we screened out novel exosomal miR-5p-72106_14 by miRNA-seq and confirmed that miR-5p-72106_14 promoted osteogenic differentiation and inhibited adipogenic differentiation of BMSCs by inhibiting STAT1. Our results suggest that vascular endothelial cell-derived exosomes are involved in BMSC differentiation and exosomal miR-5p-72106_14 is a major factor in regulating fate determination of BMSCs.

Implementing mind mapping in small-group learning to promote student engagement in the medical diagnostic curriculum: a pilot study.

BACKGROUND: Medical diagnostics is a pivotal bridge curriculum that receives much less attention from undergraduates in non-clinical medicine health profession programs with less student engagement and poor performance. Mind mapping is an active learning strategy for graphically presenting radiant thinking to culture clinical reasoning. The purpose of this study was to explore whether students' comprehensive diagnostic skills are enhanced through increased student engagement by employing mind mapping. METHODS: We implemented mind mapping in small-grouped workshops with 86 junior undergraduates from preventive medicine program, for physical diagnostic sessions including physical examination (PE) maneuver, electrocardiogram (ECG) interpretation and medical history collection. We also conducted assessments of the above skills, as well as online surveys regarding their expectation on this course, self-evaluation of mind mapping in teaching and the learning process of all the modules. RESULTS: Group members employing mind mapping in all PE sessions obtained higher scores in the heart and lung systems during the PE maneuver exam. Similarly, groups that made more in-depth mind maps achieved higher scores on the ECG quiz. In addition, groups displaying mind maps for history taking from normal classes and reformed class exhibited greater completeness of medical history with both standardized patients and real patients, which was consistent with increased collection of accompanying symptoms. Mind mapping was valued by the majority of students for its benefits in terms of acquiring PE maneuver, theoretical knowledge, medical history collection and medical records writing, clinical reasoning, communication skills, sense of teamwork and cooperation, professionalism and humanistic literacy. DISCUSSION: The visual feature of mind mapping evoked extensive behavioral engagement in all groups, as did cognitive and emotional engagement, as the majority of students expressed their willingness and affective reactions. In the short term, the positive feedbacks encourage growing engagement. The continuous benefits of mind mapping require long-term observation.

Risk factors of primary Sjögren's syndrome combined with osteoporosis. / åŽŸå‘æ€§å¹²ç‡¥ç»¼åˆå¾åˆå¹¶éª¨è´¨ç–æ¾çš„å±é™©å› ç´ .

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that is prevalent in middle-aged and elderly women, characterized by dry mouth, dry eyes, fatigue, and joint pain. Nearly one-third pSS patients have been suffering with osteoporosis (OP), displaying symptoms of lumbago, back pain, and even fracture, all of which severely affect their life quality. Common risk factors for pSS and OP include gender and age, persistent state of inflammation, immune disorders, intestinal flora imbalance, vitamin D deficiency, dyslipidemia and sarcopenia. Meanwhile, the comorbidities of pSS, such as renal tubular acidosis, primary biliary cholangitis, autoimmune thyroid diseases, and drugs (glucocorticoids, methotrexate, and cyclophosphamide) are unique risk factors for pSS complicated with OP. Education, guidance of healthy lifestyle, and OP screening are recommended for bone management of pSS patients. Early detection and intervention are crucial for keeping bone health and life quality in pSS patients.

Utilizing biochar to decorate nanoscale FeS for the highly effective decontamination of Se(IV) from simulated wastewater.

Selenium (Se) as an essential nutrient for human beings at trace concentrations, the allowable concentration for the human is only 40 µg/L. Iron sulfide (FeS) nanoparticles have been applied for excessive of selenium (Se) remediation in surface water and groundwater. In this study, FeS nanoparticles were anchored onto biochar (BC) to reduce agglomeration of FeS and prepared into the composite of FeS-BC by pyrolysis to economically and efficiently remove Se(IV) from simulated wastewater based on the excellent performance of FeS and the low cost of BC. Characterizations presented the uniform anchorage of FeS on the BC surface to prevent agglomeration. The results of batch experiments revealed that the removal of Se(IV) by FeS-BC nanomaterials significantly depended on the pH value, with the maximum removal of ∼174.96 mg/g at pH 3.0. A pseudo-second-order kinetic model well reflected the kinetic removal of Se(IV) in pure Se(IV) solution with different concentration, as well as the coexistence of K+, Ca2+, Cl-, and SO42- ions. The presence of K+ ions significantly inhibited the removal of Se(IV) with the increase of K+ ion concentration compared with the effect of the other three ions. SEM-EDS and XPS analyses indicated that the removal process was achieved through adsorption by surface complexation, and reductive precipitation of Se(IV) into Se0 with the electron donor of Fe(II) and S(-II) ions. The FeS-BC nanomaterial exhibited an excellent application prospect in the remediation of Se(IV).

Integration of multi-omics data reveals cis-regulatory variants that are associated with phenotypic differentiation of eastern from western pigs.

BACKGROUND: The genetic mechanisms that underlie phenotypic differentiation in breeding animals have important implications in evolutionary biology and agriculture. However, the contribution of cis-regulatory variants to pig phenotypes is poorly understood. Therefore, our aim was to elucidate the molecular mechanisms by which non-coding variants cause phenotypic differences in pigs by combining evolutionary biology analyses and functional genomics. RESULTS: We obtained a high-resolution phased chromosome-scale reference genome with a contig N50 of 18.03 Mb for the Luchuan pig breed (a representative eastern breed) and profiled potential selective sweeps in eastern and western pigs by resequencing the genomes of 234 pigs. Multi-tissue transcriptome and chromatin accessibility analyses of these regions suggest that tissue-specific selection pressure is mediated by promoters and distal cis-regulatory elements. Promoter variants that are associated with increased expression of the lysozyme (LYZ) gene in the small intestine might enhance the immunity of the gastrointestinal tract and roughage tolerance in pigs. In skeletal muscle, an enhancer-modulating single-nucleotide polymorphism that is associated with up-regulation of the expression of the troponin C1, slow skeletal and cardiac type (TNNC1) gene might increase the proportion of slow muscle fibers and affect meat quality. CONCLUSIONS: Our work sheds light on the molecular mechanisms by which non-coding variants shape phenotypic differences in pigs and provides valuable resources and novel perspectives to dissect the role of gene regulatory evolution in animal domestication and breeding.

Functional interplay between long non-coding RNAs and the Wnt signaling cascade in osteosarcoma.

Osteosarcoma is a common and highly malignant bone tumor among children, adolescents and young adults. However, the underlying molecular mechanisms remain largely unexplored. LncRNAs are transcripts with no or limited protein-coding capacity in human genomes, and have been demonstrated to play crucial functions in initiation, progression, therapeutic resistance, recurrence and metastasis of tumor. Considerable studies revealed a dysregulated lncRNA expression pattern in osteosarcoma, which may act as oncogenes or suppressors to regulate osteosarcoma progression. Wnt signaling pathway is an important cascade in tumorigenesis by modulation of pleiotropic biological functions including cell proliferation, apoptosis, differentiation, stemness, genetic stability and chemoresistance. Hyperactivation or deficiency of key effectors in Wnt cascade is a common event in many osteosarcoma patients. Recently, increasing evidences have suggested that lncRNAs could interplay with component of Wnt pathway, and thereby contribute to osteosarcoma onset, progression and dissemination. In this review, we briefly summarize Wnt signaling-related lncRNAs in osteosarcoma progression, aiming to gain insights into their underlying crosstalk as well as clinical application in osteosarcoma therapeutic modalities.

Emerging landscape of circular RNAs as biomarkers and pivotal regulators in osteosarcoma.

Osteosarcoma represents the most prevailing primary bone tumor and the third most common cancer in children and adolescents worldwide. Among noncoding RNAs, circular RNAs (circRNAs) refer to a unique class in the shape of a covalently closed continuous loop with neither 5' caps nor 3'-polyadenylated tails, which are generated through back-splicing. Recently, with the development of whole-genome and transcriptome sequencing technologies, a growing number of circRNAs have been found aberrantly expressed in multiple diseases, including osteosarcoma. circRNA are capable of various biological functions including miRNA sponge, mediating alternatives, regulating genes at posttranscriptional levels, and interacting with proteins, indicating a pivotal role of circRNA in cancer initiation, progression, chemoresistance, and immune response. Moreover, circRNAs have been thrust into the spotlight as potential biomarkers and therapeutic targets in osteosarcoma. Herein, we briefly summarize the origin and biogenesis of circRNA with current knowledge of circRNA in tumorigenesis of osteosarcoma, aiming to elucidate the specific role and clinical implication of circRNAs in osteosarcoma.

The predictive value of lncRNA MIR31HG expression on clinical outcomes in patients with solid malignant tumors.

BACKGROUND: Emerging studies have explored the prognostic value of MIR31HG in cancers, but its role remains elusive. Herein, we aimed to summarize the prognostic potential of MIR31HG in this study. METHODS: Several databases were searched for literature retrieval on Dec 5, 2019. Overall and subgroup analyses were conducted to measure the relationship between MIR31HG expression and clinical outcomes. Moreover, GEPIA was applied for validation of prognostic value of MIR31HG in tumor patients in TCGA dataset. RESULTS: Overall, seventeen studies with 2573 patients were enrolled. Compared to counterparts, those patients with high MIR31HG expression tended to have shorter RFS. Notably, MIR31HG overexpression predicted unfavorable OS in lung cancer. By contrast, gastrointestinal cancer patients with elevated MIR31HG expression predicted better OS and disease-free survival. Additionally, MIR31HG overexpression was significantly associated with worse clinicopathological features including advanced tumor stage and LNM in lung cancer, but favorable clinical characteristics in gastrointestinal cancer. Moreover, the positive association between MIR31HG and OS in lung cancer was further confirmed in TCGA dataset. CONCLUSION: Overexpression of MIR31HG suggested remarkable association with poor prognosis in terms of OS, tumor stage, and LNM in lung cancer, but favorable prognosis in gastrointestinal cancer. Therefore, MIR31HG may serve as a promising prognostic biomarker in multiple cancers.

[Evaluation of key production processes of Schizonepetae Herba formula granules based on characteristic chromatogram and quantitative transfer relationship].

The aim of this paper was to evaluate the key production processes of Schizonepetae Herba formula granules based on the new model of combining characteristic chromatogram with quantitative transfer relationship. The rationality of production process design was evaluated by studying the intermediates in different processes of formula granules, analyzing the loss of index component pulegone in each step, and establishing the characteristic chromatogram. The content of pulegone in 10 batches of standard decoction ranged between 0.067% and 0.124%(70%-130% of the average value), and the transfer rate of pulegone was 44.58%-93.97%. After the improvement of the production process, the content of pulegone in Schizonepetae Herba formula granules was 0.093%, and the transfer rate of pulegone was 68.38%, which was consistent with the parameters range of standard decoction. This study emphasized the integrality of the research process of traditional Chinese medicine(TCM) formula granules, and provided a new idea for the quality control of TCM with content determination as the main evaluation index for a long time.

shinyBN: an online application for interactive Bayesian network inference and visualization.

BACKGROUND: High-throughput technologies have brought tremendous changes to biological domains, and the resulting high-dimensional data has also posed enormous challenges to computational science. A Bayesian network is a probabilistic graphical model represented by a directed acyclic graph, which provides concise semantics to describe the relationship between entities and has an independence assumption that is suitable for sparse omics data. Bayesian networks have been broadly used in biomedical research fields, including disease risk assessment and prognostic prediction. However, the inference and visualization of Bayesian networks are unfriendly to the users lacking programming skills. RESULTS: We developed an R/Shiny application, shinyBN, which is an online graphical user interface to facilitate the inference and visualization of Bayesian networks. shinyBN supports multiple types of input and provides flexible settings for network rendering and inference. For output, users can download network plots, prediction results and external validation results in publication-ready high-resolution figures. CONCLUSION: Our user-friendly application (shinyBN) provides users with an easy method for Bayesian network modeling, inference and visualization via mouse clicks. shinyBN can be used in the R environment or online and is compatible with three major operating systems, including Windows, Linux and Mac OS. shinyBN is deployed at https://jiajin.shinyapps.io/shinyBN/. Source codes and the manual are freely available at https://github.com/JiajinChen/shinyBN.

An extensive review regarding the adipokines in the pathogenesis and progression of osteoarthritis.

Osteoarthritis is the most prevalent form of aging-related joint diseases, and its etiology is still not fully understood. Obesity has been recognized as one of the most significant and potentially preventable risk factors for osteoarthritis. Beyond mechanical loading, adipokines, including leptin, visfatin, adiponectin, resistin and others, are demonstrated to have metabolic implications in the pathogenesis and progression in obesity-induced osteoarthritis by modulating the pro/anti-inflammatory and anabolic/catabolic balance, apoptosis, matrix remodeling and subchondral bone ossification. Accordingly, adipokines emerge as potential candidates to link these two entities, and may serve as putative targets for disease-modifying drugs for osteoarthritis, especially for obese patients. Here we summarize studies over the past decades on the pivotal role of adipokine family in osteoarthritis, and aim to shed a light on the causative link between obesity and osteoarthritis. Notably, due to difficulties in separation of the metabolic effect from the mechanical effect of fat excess, researches on osteoarthritis in non-weight-bearing joints may provide a promising direction and more emphasis shall be put on them in future.

The prognostic value of long noncoding RNA SNHG16 on clinical outcomes in human cancers: a systematic review and meta-analysis.

BACKGROUND: Cancer has been a worldwide health problem with a high risk of morbidity and mortality, however ideal biomarkers for effective screening and diagnosis of cancer patients are still lacking. Small nucleolar RNA host gene 16 (SNHG16) is newly identified lncRNA with abnormal expression in several human malignancies. However, its prognostic value remains controversial. This meta-analysis aimed to synthesize available data to clarify the association between SNHG16 expression levels and clinical prognosis value in multiple cancers. METHODS: Extensive literature retrieval was conducted to identify eligible studies, and data regarding SNHG16 expression levels on survival outcomes and clinicopathological features were extracted and pooled for calculation of the hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Forest plots were applied to show the association between SNHG16 expression and survival prognosis. Additionally, The Cancer Genome Atlas (TCGA) dataset was screened and extracted for validation of the results in this meta-analysis. RESULTS: A total of eight studies comprising 568 patients were included in the final meta-analysis according to the inclusion and exclusion criteria. In the pooled analysis, high SNHG16 expression significantly predicted worse overall survival (OS) in various cancers (HR = 1.87, 95% CI 1.54-2.26, P < 0.001), and recurrence-free survival (RFS) in bladder cancer (HR = 1.68, 95% CI 1.01-2.79, P = 0.045). Meanwhile, stratified analyses revealed that the survival analysis method, tumor type, sample size, and cut-off value did not alter the predictive value of SNHG16 for OS in cancer patients. In addition, compared to the low SNHG16 expression group, patients with high SNHG16 expression were more prone to worse clinicopathological features, such as larger tumor size, advanced clinical stage, lymph node metastasis (LNM) and distant metastasis (DM). Exploration of TCGA dataset further validated that the upregulated SNHG16 expression predicted unfavorable OS and disease-free survival (DFS) in cancer patients. CONCLUSIONS: The present study implicated that aberrant expression of lncRNA SNHG16 was strongly associated with clinical survival outcomes in various cancers, and therefore might serve as a promising biomarker for predicting prognosis of human cancers.

Association between renal function and bone mineral density in healthy postmenopausal Chinese women.

BACKGROUND: The relationship between renal function and bone mineral density (BMD) is controversial. The aim of this study was to determine the relationship of renal function with BMD and osteoporosis risk in healthy postmenopausal Chinese women. METHODS: A cross-sectional study was conducted in 776 healthy postmenopausal Chinese women. Dual-energy X-ray absorptiometry was used to measure BMDs. Clinical, demographic, and biochemical data were obtained at the time of image acquisition. Estimated glomerular filtration rate (eGFR) was calculated using a Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: Women with eGFR levels of at least 90 ml/min/1.73m2 had a lower prevalence of osteoporosis compared with women with decreased eGFR levels (60 ml/min/1.73 m2 ≤ eGFR < 90.0 ml/min/1.73 m2). BMDs at femoral neck and total hip were significantly lower in the lower eGFR class than the higher class (0.717 ± 0.106 vs 0.744 ± 0.125 g/cm2, P < 0.01; 0.796 ± 0.116 vs 0.823 ± 0.129 g/cm2, P < 0.01, respectively). eGFR was positively correlated with BMDs at femoral neck and total hip in unadjusted analysis (P < 0.05). After controlling for age, menopausal duration and body mass index (BMI), decreased eGFR was not associated with osteoporosis risk. CONCLUSIONS: After adjustments for age, menopausal duration and BMI, the decline in renal function was not independently associated with osteoporosis risk in healthy postmenopausal Chinese women.

Exenatide can inhibit calcification of human VSMCs through the NF-kappaB/RANKL signaling pathway.

BACKGROUND: Arterial calcification is an important pathological change of diabetic vascular complication. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) plays an important cytopathologic role in arterial calcification. The glucagon-like peptide-1 receptor agonists (GLP-1RA), a novel type of antidiabetic drugs, exert cardioprotective effects through the GLP-1 receptor (GLP-1R). However, the question of whether or not GLP-1RA regulates osteoblastic differentiation and calcification of VSMCs has not been answered, and the associated molecular mechanisms have not been examined. METHODS: Calcifying VSMCs (CVSMCs) were isolated from cultured human arterial smooth muscle cells through limiting dilution and cloning. The extent of matrix mineralization was measured by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot. Gene expression of receptor activator of nuclear factor-κB ligand (RANKL) was silenced by small interference RNA (siRNA). RESULTS: Exenatide, an agonist of GLP-1 receptor, attenuated ß-glycerol phosphate (ß-GP) induced osteoblastic differentiation and calcification of human CVSMCs in a dose- and time-dependent manner. RANKL siRNA also inhibited osteoblastic differentiation and calcification. Exenatide decreased the expression of RANKL in a dose-dependent manner. 1,25 vitD3 (an activator of RANKL) upregulated, whereas BAY11-7082 (an inhibitor of NF-κB) downregulated RANKL, alkaline phosphatase (ALP), osteocalcin (OC), and core binding factor α1 (Runx2) protein levels and reduced mineralization in human CVSMCs. Exenatide decreased p-NF-κB and increased p-AMPKα levels in human CVSMCs 48 h after treatment. Significant decrease in p-NF-κB (p-Ser(276), p-Ser(536)) level was observed in cells treated with exenatide or exenatide + BAY11-7082. CONCLUSION: GLP-1RA exenatide can inhibit human VSMCs calcification through NF-κB/RANKL signaling.

FAM19A5 in vascular aging and osteoporosis: Mechanisms and the "calcification paradox".

Aging induces a progressive decline in the vasculature's structure and function. Vascular aging is a determinant factor for vascular ailments in the elderly. FAM19A5, a recently identified adipokine, has demonstrated involvement in multiple vascular aging-related pathologies, including atherosclerosis, cardio-cerebral vascular diseases and cognitive deficits. This review summarizes the current understanding of FAM19A5' role and explores its putative regulatory mechanisms in various aging-related disorders, including cardiovascular diseases (CVDs), metabolic diseases, neurodegenerative diseases and malignancies. Importantly, we provide novel insights into the underlying therapeutic value of FAM19A5 in osteoporosis. Finally, we outline future perspectives on the diagnostic and therapeutic potential of FAM19A5 in vascular aging-related diseases.

Vascular endothelial cells-derived exosomes synergize with curcumin to prevent osteoporosis development.

Osteoporosis has gradually become a major public health problem. Further elucidation of the pathophysiological mechanisms that induce osteoporosis and identification of more effective therapeutic targets will have important clinical significance. Experiments in vitro on bone marrow stem cells (BMSCs) subjected to osteogenic and adipogenic differentiation and in vivo on surgical bilateral ovariectomy (OVX) mouse models revealed that exosomes of vascular endothelial cells (EC-EXOs) can promote osteogenic differentiation of BMSCs and inhibit BMSC adipogenic differentiation through miR-3p-975_4191. Both miR-3p-975_4191 and curcumin can target tumor necrosis factor (TNF) and act synergistically to regulate BMSCs fate differentiation and delay the progression of osteoporosis. Our findings suggest that EC-EXOs may exert a synergistic effect with curcumin in reversing the progression of osteoporosis by targeting TNF via miR-3p-975_4191. Our study may provide therapeutic options and potential therapeutic targets for osteoporosis and thus has important clinical implications.

Novel insights into the multifaceted roles of m6A-modified LncRNAs in cancers: biological functions and therapeutic applications.

N6-methyladenosine (m6A) is considered as the most common and important internal transcript modification in several diseases like type 2 diabetes, schizophrenia and especially cancer. As a main target of m6A methylation, long non-coding RNAs (lncRNAs) have been proved to regulate cellular processes at various levels, including epigenetic modification, transcriptional, post-transcriptional, translational and post-translational regulation. Recently, accumulating evidence suggests that m6A-modified lncRNAs greatly participate in the tumorigenesis of cancers. In this review, we systematically summarized the biogenesis of m6A-modified lncRNAs and the identified m6A-lncRNAs in a variety of cancers, as well as their potential diagnostic and therapeutic applications as biomarkers and therapeutic targets, hoping to shed light on the novel strategies for cancer treatment.