Yang Y.,Shanghai JiaoTong University |
Yang Y.,Key Laboratory of Shanghai Education Commission for Intelligent Interaction and Cognitive Engineering |
Yang Y.,Shanghai Center for Systems Biomedicine |
Huang N.,Shanghai JiaoTong University |
And 2 more authors.
BMC Genomics | Year: 2017
Background: MicroRNAs (miRNAs) have great potential serving as tumor biomarkers and therapeutic targets. As the rapid development of high-throughput experimental technology, gene expression experiments have become more and more specialized and diversified. The complex data structure has brought great challenge for the identification of biomarkers. In the meantime, current statistical and machine learning methods for detecting biomarkers have the problem of low reliability and biased criteria. Results: This study aims to select combinatorial miRNA biomarkers, which have higher sensitivity and specificity than single-gene biomarkers. In order to avoid exhaustive search and redundant information, miRNAs are firstly clustered, then the combinations of representative cluster members are assessed as potential biomarkers. Both the criteria for the partition of clusters and selection of representative members are based on Fisher linear discriminant analysis (FDA). The FDA-based criterion has been demonstrated to be superior to three other criteria in selecting representative members, and also good at refining clusters. In the comparison with eight common feature selection methods, this clustering-based method performs the best with regard to the discriminative ability of selected biomarkers. Conclusions: Our experimental results demonstrate that the clustering-based method can identify microRNA combinatorial biomarkers with high accuracy and efficiency. Our method and data are available to the public upon request. © 2017 The Author(s).
Yin X.,Shanghai JiaoTong University |
Peng J.,Shanghai University of Traditional Chinese Medicine |
Zhao L.,Shanghai JiaoTong University |
Zhao L.,Shanghai Center for Systems Biomedicine |
And 7 more authors.
Systematic and Applied Microbiology | Year: 2013
Accumulating evidence indicates that disruption of the gut microbiota by a high-fat diet (HFD) may play a pivotal role in the progression of metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). In this study, the structural changes of gut microbiota were analyzed in an HFD-induced NAFLD rat model during treatment with an ancient Chinese herbal formula (CHF) used in clinical practice - Qushi Huayu Fang. CHF treatment significantly reduced body weight, alleviated hepatic steatosis, and decreased the content of triglycerides and free fatty acids in the livers of the rats. Gut microbiota of treated and control rats were profiled with polymerase chain reaction-denaturing gradient gel electrophoresis and bar-coded pyrosequencing of the V3 region of 16S rRNA genes. Both analyses indicated that the CHF-treated group harbored significantly different gut microbiota from that of model rats. Partial least squares discriminant analysis and taxonomy-based analysis were further employed to identify key phylotypes responding to HFD and CHF treatment. Most notably, the genera Escherichia/. Shigella, containing opportunistic pathogens, were significantly enriched in HFD-fed rats compared to controls fed normal chow (P< 0.05) but they decreased to control levels after CHF treatment. Collinsella, a genus with short chain fatty acid producers, was significantly elevated in CHF-treated rats compared to HFD-fed rats (P< 0.05). The results revealed that the bacterial profiles of HFD-induced rats could be modulated by the CHF. Elucidation of these differences in microbiota composition provided a basis for further understanding the pharmacological mechanism of the CHF. © 2013 Elsevier GmbH.
Xiao S.,Shanghai JiaoTong University |
Zhao L.,Shanghai JiaoTong University |
Zhao L.,Shanghai Center for Systems Biomedicine
FEMS Microbiology Ecology | Year: 2014
In the face of the global epidemic of metabolic syndrome (MetS) and its strong association with the increasing rate of cardiovascular morbidity and mortality, it is critical to detect MetS at an early stage in the clinical setting to implement preventive intervention long before the complications arise. Lipopolysaccharide, the cell wall component of Gram-negative bacteria produced from diet-disrupted gut microbiota, has been shown to induce metabolic endotoxemia, chronic low-grade inflammation, and ultimately insulin resistance. Therefore, ameliorating the inflammation and insulin resistance underlying MetS by gut microbiota-targeted, dietary intervention has gained increasing attention. In this review, we propose using dynamic monitoring of a set of translational biomarkers related with the etiological role of gut microbiota, including lipopolysaccharide binding protein (LBP), C-reactive protein (CRP), fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR), for early detection and prevention of MetS via nutritional modulation. LBP initiates the recognition and monomerization of lipopolysaccharide and amplifies host immune responses, linking the gut-derived antigen load and inflammation indicated by the plasma levels of CRP. Fasting plasma insulin and HOMA-IR are measured to evaluate insulin sensitivity that is damaged by pro-inflammatory cytokines. The dynamic monitoring of these biomarkers in high-risk populations may provide translational methods for the quantitative and dynamic evaluation of dysbiosis-induced insulin resistance and the effectiveness of dietary treatment for MetS. Monitoring of gut microbiota-based host biomarkers to prevent MetS and evaluate the effectiveness of dietary intervention. © 2014 Federation of European Microbiological Societies.
Zhang C.,Shanghai JiaoTong University |
Zhang M.,Shanghai JiaoTong University |
Pang X.,Shanghai JiaoTong University |
Zhao Y.,Shanghai Center for Systems Biomedicine |
And 3 more authors.
ISME Journal | Year: 2012
Disruption of the gut microbiota by high-fat diet (HFD) has been implicated in the development of obesity. It remains to be elucidated whether the HFD-induced shifts occur at the phylum level or whether they can be attributed to specific phylotypes; additionally, it is unclear to what extent the changes are reversible under normal chow (NC) feeding. One group (diet-induced obesity, DIO) of adult C57BL/6J mice was fed a HFD for 12 weeks until significant obesity and insulin resistance were observed, and then these mice were switched to NC feeding for 10 weeks. Upon switching to NC feeding, the metabolic deteriorations observed during HFD consumption were significantly alleviated. The second group (control, CHO) remained healthy under continuous NC feeding. UniFrac analysis of bar-coded pyrosequencing data showed continued structural segregation of DIO from CHO on HFD. At 4 weeks after switching back to NC, the gut microbiota in the DIO group had already moved back to the CHO space, and continued to progress along the same age trajectory and completely converged with CHO after 10 weeks. Redundancy analysis identified 77 key phylotypes responding to the dietary perturbations. HFD-induced shifts of these phylotypes all reverted to CHO levels over time. Some of these phylotypes exhibited robust age-related changes despite the dramatic abundance variations in response to dietary alternations. These findings suggest that HFD-induced structural changes of the gut microbiota can be attributed to reversible elevation or diminution of specific phylotypes, indicating the significant structural resilience of the gut microbiota of adult mice to dietary perturbations. © 2012 International Society for Microbial Ecology. All rights reserved.
Zhang C.,Shanghai JiaoTong University |
Li S.,Chinese Academy of Sciences |
Yang L.,Chinese Academy of Sciences |
Huang P.,Chinese Academy of Sciences |
And 9 more authors.
Nature Communications | Year: 2013
Calorie restriction has been regarded as the only experimental regimen that can effectively lengthen lifespan in various animal models, but the actual mechanism remains controversial. The gut microbiota has been shown to have a pivotal role in host health, and its structure is mostly shaped by diet. Here we show that life-long calorie restriction on both high-fat or low-fat diet, but not voluntary exercise, significantly changes the overall structure of the gut microbiota of C57BL/6 J mice. Calorie restriction enriches phylotypes positively correlated with lifespan, for example, the genus Lactobacillus on low-fat diet, and reduces phylotypes negatively correlated with lifespan. These calorie restriction-induced changes in the gut microbiota are concomitant with significantly reduced serum levels of lipopolysaccharide-binding protein, suggesting that animals under calorie restriction can establish a structurally balanced architecture of gut microbiota that may exert a health benefit to the host via reduction of antigen load from the gut. © 2013 Macmillan Publishers Limited. All rights reserved.
Yang Y.,Shanghai Maritime University |
Lu B.-L.,Shanghai JiaoTong University |
Lu B.-L.,Shanghai Center for Systems Biomedicine |
International Journal of Neural Systems | Year: 2010
Prediction of protein subcellular localization is an important issue in computational biology because it provides important clues for the characterization of protein functions. Currently, much research has been dedicated to developing automatic prediction tools. Most, however, focus on mono-locational proteins, i.e., they assume that proteins exist in only one location. It should be noted that many proteins bear multi-locational characteristics and carry out crucial functions in biological processes. This work aims to develop a general pattern classifier for predicting multiple subcellular locations of proteins. We use an ensemble classifier, called the min-max modular support vector machine (M3-SVM), to solve protein subcellular multi-localization problems; and, propose a module decomposition method based on gene ontology (GO) semantic information for M3-SVM. The amino acid composition with secondary structure and solvent accessibility information is adopted to represent features of protein sequences. We apply our method to two multi-locational protein data sets. The M3-SVMs show higher accuracy and efficiency than traditional SVMs using the same feature vectors. And the GO decomposition also helps to improve prediction accuracy. Moreover, our method has a much higher rate of accuracy than existing subcellular localization predictors in predicting protein multi-localization. © 2010 World Scientific Publishing Company.
Wang G.,Shanghai Center for Systems Biomedicine |
Zhu X.,Shanghai Center for Systems Biomedicine |
Gu J.,Shanghai JiaoTong University |
Ao P.,Shanghai Center for Systems Biomedicine |
Ao P.,Shanghai JiaoTong University
Interface Focus | Year: 2014
A quantitative hypothesis for cancer genesis and progression-the endogenous molecular-cellular network hypothesis, intended to include both genetic and epigenetic causes of cancer-has been proposed recently. Using this hypothesis, here we address the molecular basis for maintaining normal liver and hepatocellular carcinoma (HCC), and the potential strategy to cure or relieve HCC. First, we elaborate the basic assumptions of the hypothesis and establish a core working network of HCC according to the hypothesis. Second, we quantify the working network by a nonlinear dynamical system. We show that the working network reproduces the main known features of normal liver and HCC at both the modular and molecular levels. Lastly, the validated working network reveals that (i) specific positive feedback loops are responsible for the maintenance of normal liver and HCC; (ii) inhibiting proliferation and inflammation-related positive feedback loops and simultaneously inducing a liver-specific positive feedback loop is predicated as a potential strategy to cure or relieve HCC; and (iii) the genesis and regression of HCC are asymmetric. In light of the characteristic properties of the nonlinear dynamical system, we demonstrate that positive feedback loops must exist as a simple and general molecular basis for the maintenance of heritable phenotypes, such as normal liver and HCC, and regulating the positive feedback loops directly or indirectly provides potential strategies to cure or relieve HCC. © 2014 The Author(s) Published by the Royal Society. All rights reserved.
Zhang C.,Shanghai JiaoTong University |
Zhang M.,Shanghai JiaoTong University |
Wang S.,Chinese National Human Genome Sequencing Center |
Han R.,CAS Shanghai Institutes for Biological Sciences |
And 10 more authors.
ISME Journal | Year: 2010
Both genetic variations and diet-disrupted gut microbiota can predispose animals to metabolic syndromes (MS). This study assessed the relative contributions of host genetics and diet in shaping the gut microbiota and modulating MS-relevant phenotypes in mice. Together with its wild-type (Wt) counterpart, the Apoa-I knockout mouse, which has impaired glucose tolerance (IGT) and increased body fat, was fed a high-fat diet (HFD) or normal chow (NC) diet for 25 weeks. DNA fingerprinting and bar-coded pyrosequencing of 16S rRNA genes were used to profile gut microbiota structures and to identify the key population changes relevant to MS development by Partial Least Square Discriminate Analysis. Diet changes explained 57% of the total structural variation in gut microbiota, whereas genetic mutation accounted for no more than 12%. All three groups with IGT had significantly different gut microbiota relative to healthy Wt/NC-fed animals. In all, 65 species-level phylotypes were identified as key members with differential responses to changes in diet, genotype and MS phenotype. Most notably, gut barrier-protecting Bifidobacterium spp. were nearly absent in all animals on HFD, regardless of genotype. Sulphate-reducing, endotoxin-producing bacteria of the family, Desulfovibrionaceae, were enhanced in all animals with IGT, most significantly in the Wt/HFD group, which had the highest calorie intake and the most serious MS phenotypes. Thus, diet has a dominating role in shaping gut microbiota and changes of some key populations may transform the gut microbiota of Wt animals into a pathogen-like entity relevant to development of MS, despite a complete host genome.
Zhen T.,CAS Shanghai Institutes for Biological Sciences |
Wu C.-F.,CAS Shanghai Institutes for Biological Sciences |
Liu P.,CAS Shanghai Institutes for Biological Sciences |
Wu H.-Y.,Shanghai Center for Systems Biomedicine |
And 19 more authors.
Science Translational Medicine | Year: 2012
Nearly 60% of acute myeloid leukemia (AML) patients with the t(8;21)(q22;q22) translocation fail to achieve long-term disease-free survival. Our previous studies demonstrated that oridonin selectively induces apoptosis of t(8;21) leukemia cells and causes cleavage of AML1-ETO oncoprotein resulting from t(8;21), but the underlying mechanisms remain unclear. We show that oridonin interacted with glutathione and thioredoxin/thioredoxin reductase to increase intracellular reactive oxygen species, which in turn activated caspase-3 in t(8;21) cells. Moreover, oridonin bound AML1-ETO, directing the enzymatic cleavage at aspartic acid 188 via caspase-3 to generate a truncated AML1-ETO (DAML1-ETO) and preventing the protein from further proteolysis. ΔAML1-ETO interacted with AML1-ETO and interfered with the trans-regulatory functions of remaining AML1-ETO oncoprotein, thus acting as a tumor suppressor that mediates the anti-leukemia effect of oridonin. Furthermore, oridonin inhibited the activity of c-Kit + leukemia-initiating cells. Therefore, oridonin is a potential lead compound for molecular target-based therapy of leukemia.
Chen S.-J.,Rui Jin Hospital |
Chen S.-J.,Shanghai Center for Systems Biomedicine |
Zhou G.-B.,CAS Institute of Zoology |
Zhang X.-W.,Rui Jin Hospital |
And 5 more authors.
Blood | Year: 2011
Arsenic had been used in treating malignancies from the 18th to mid-20th century. In the past 3 decades, arsenic was revived and shown to be able to induce complete remission and to achieve, when combined with all-trans retinoic acid and chemotherapy, a 5-year overall survival of 90% in patients with acute promyelocytic leukemia driven by the t(15;17) translocation-generated promyelocytic leukemia-retinoic acid receptor α (PMLRAR α) fusion. Molecularly, arsenic binds thiol residues and induces the formation of reactive oxygen species, thus affecting numerous signaling pathways. Interestingly, arsenic directly binds the C3HC4 zinc finger motif in the RBCC domain of PML and PML-RARα, induces their homodimerization and multimerization, and enhances their interaction with the SUMO E2 conjugase Ubc9, facilitating subsequent sumoylation/ubiquitination and proteasomal degradation. Arsenic-caused intermolecular disulfide formation in PML also contributes to PML-multimerization. All-trans retinoic acid, which targets PMLRAR α for degradation through its RARα moiety, synergizes with arsenic in eliminating leukemia-initiating cells. Arsenic perturbs a number of proteins involved in other hematologic malignancies, including chronic myeloid leukemia and adult T-cell leukemia/lymphoma, whereby it may bring new therapeutic benefits. The successful revival of arsenic in acute promyelocytic leukemia, together with modern mechanistic studies, has thus allowed a new paradigm to emerge in translational medicine. © 2011 by The American Society of Hematology.