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1.  Transactional Database Transformation and Its Application in Prioritizing Human Disease Genes 
Binary (0,1) matrices, commonly known as transactional databases, can represent many application data, including gene-phenotype data where “1” represents a confirmed gene-phenotype relation and “0” represents an unknown relation. It is natural to ask what information is hidden behind these “0”s and “1”s. Unfortunately, recent matrix completion methods, though very effective in many cases, are less likely to infer something interesting from these (0,1)-matrices. To answer this challenge, we propose IndEvi, a very succinct and effective algorithm to perform independent-evidence-based transactional database transformation. Each entry of a (0,1)-matrix is evaluated by “independent evidence” (maximal supporting patterns) extracted from the whole matrix for this entry. The value of an entry, regardless of its value as 0 or 1, has completely no effect for its independent evidence. The experiment on a gene-phenotype database shows that our method is highly promising in ranking candidate genes and predicting unknown disease genes.
doi:10.1109/TCBB.2011.58
PMCID: PMC4047992  PMID: 21422495
Transactional database; binary matrix; frequent item set mining; maximal biclique; phenotype; disease gene; prioritization; matrix completion
2.  Lithium Chloride Suppresses Colorectal Cancer Cell Survival and Proliferation through ROS/GSK-3β/NF-κB Signaling Pathway 
Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, has been regarded as a potential therapeutic target for multiple human cancers. In addition, oxidative stress is closely related to all aspects of cancer. We sought to determine the biological function of lithium, one kind of GSK-3β inhibitors, in the process of reactive oxygen species (ROS) production in colorectal cancer. In this study, we analyzed the cell apoptosis and proliferation by cell viability, EdU, and flow cytometry assays through administration of LiCl. We used polymerase chain reaction and Western blotting to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Results showed administration of LiCl increased apoptosis and the level of ROS in colorectal cancer cells. Furthermore, the underlying mechanisms could be mediated by the reduction of NF-κB expression and NF-κB-mediated transcription. Taken together, our results demonstrated that therapeutic targeting of ROS/GSK-3β/NF-κB pathways may be an effective way for colorectal cancer intervention, although further preclinical and clinical testing are desirable.
doi:10.1155/2014/241864
PMCID: PMC4070474
3.  Poly(ADP-Ribose) Polymerase 1 Promotes Oxidative-Stress-Induced Liver Cell Death via Suppressing Farnesoid X Receptor α 
Molecular and Cellular Biology  2013;33(22):4492-4503.
Farnesoid X receptor α (FXR) is highly expressed in the liver and regulates the expression of various genes involved in liver repair. In this study, we demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP1) promoted hepatic cell death by inhibiting the expression of FXR-dependent hepatoprotective genes. PARP1 could bind to and poly(ADP-ribosyl)ate FXR. Poly(ADP-ribosyl)ation dissociated FXR from the FXR response element (FXRE), present in the promoters of target genes, and suppressed FXR-mediated gene transcription. Moreover, treatment with a FXR agonist attenuated poly(ADP-ribosyl)ation of FXR and promoted FXR-dependent gene expression. We further established the CCl4-induced acute liver injury model in wild-type and FXR-knockout mice and identified an essential role of FXR poly(ADP-ribosyl)ation in CCl4-induced liver injury. Thus, our results identified poly(ADP-ribosyl)ation of FXR by PARP1 as a key step in oxidative-stress-induced hepatic cell death. The molecular association between PARP1 and FXR provides new insight into the mechanism, suggesting that inhibition of PARP1 could prevent liver injury.
doi:10.1128/MCB.00160-13
PMCID: PMC3838191  PMID: 24043304
4.  A Module of Human Peripheral Blood Mononuclear Cell Transcriptional Network Containing Primitive and Differentiation Markers Is Related to Specific Cardiovascular Health Variables 
PLoS ONE  2014;9(4):e95124.
Peripheral blood mononuclear cells (PBMCs), including rare circulating stem and progenitor cells (CSPCs), have important yet poorly understood roles in the maintenance and repair of blood vessels and perfused organs. Our hypothesis was that the identities and functions of CSPCs in cardiovascular health could be ascertained by analyzing the patterns of their co-expressed markers in unselected PBMC samples. Because gene microarrays had failed to detect many stem cell-associated genes, we performed quantitative real-time PCR to measure the expression of 45 primitive and tissue differentiation markers in PBMCs from healthy and hypertensive human subjects. We compared these expression levels to the subjects' demographic and cardiovascular risk factors, including vascular stiffness. The tested marker genes were expressed in all of samples and organized in hierarchical transcriptional network modules, constructed by a bottom-up approach. An index of gene expression in one of these modules (metagene), defined as the average standardized relative copy numbers of 15 pluripotency and cardiovascular differentiation markers, was negatively correlated (all p<0.03) with age (R2 = −0.23), vascular stiffness (R2 = −0.24), and central aortic pressure (R2 = −0.19) and positively correlated with body mass index (R2 = 0.72, in women). The co-expression of three neovascular markers was validated at the single-cell level using mRNA in situ hybridization and immunocytochemistry. The overall gene expression in this cardiovascular module was reduced by 72±22% in the patients compared with controls. However, the compactness of both modules was increased in the patients' samples, which was reflected in reduced dispersion of their nodes' degrees of connectivity, suggesting a more primitive character of the patients' CSPCs. In conclusion, our results show that the relationship between CSPCs and vascular function is encoded in modules of the PBMCs transcriptional network. Furthermore, the coordinated gene expression in these modules can be linked to cardiovascular risk factors and subclinical cardiovascular disease; thus, this measure may be useful for their diagnosis and prognosis.
doi:10.1371/journal.pone.0095124
PMCID: PMC3997360  PMID: 24759906
5.  New Insight into Onset of Lactation: Mediating the Negative Effect of Multiple Perinatal Biopsychosocial Stress on Breastfeeding Duration 
Breastfeeding Medicine  2013;8(2):151-158.
Abstract
Background
Many perinatal stressors, including high prepregnancy body mass index, preterm birth, and cesarean section, increase the risk for short breastfeeding duration. Few studies, however, have investigated the mechanism in the relationship between perinatal determinants and breastfeeding duration. This study aimed to test the hypothesis that delayed onset of lactation (OL) could mediate the negative effect of perinatal biopsychosocial stress on breastfeeding duration and to evaluate the impact of new perinatal factors with potentially hazardous effects.
Subjects and Methods
Maternal demographic characteristics, health status, and psychological stress during pregnancy were assessed by structured questionnaires and medical records. The information of lactation was collected in the hospital within 1–3 days after delivery. Data on breastfeeding behaviors were obtained through the telephone interview at 2 months after delivery.
Results
The risk of delayed OL increased in women who had experienced severe life event stress in the first trimester of pregnancy (adjusted risk ratio [RR] 2.59, 95% confidence interval [CI] 1.52, 4.40), had undergone cesarean section (adjusted RR 2.11, 95% CI 1.46, 3.05), whose gestational body mass index gain were not less than 7.62 (adjusted RR 1.90, 95% CI 1.27, 2.86), and whose breastfeeding frequency was less than three times in the first day after childbirth (adjusted RR 2.14, 95% CI 1.57, 2.91). The final model of structural equation modeling indicated that women with cesarean section, preterm birth, greater gestational body mass index gain, higher scores of stressful life events in the first trimester, and less breastfeeding frequency in the first day after delivery were more likely to experience delayed OL, which could result in an earlier breastfeeding termination.
Conclusions
Delayed OL, as a negative biological event resulted from the perinatal biopsychosocial stress, is a key mediator linking perinatal factors to breastfeeding duration. More attention should to be paid to underweight before pregnancy and severe life events during pregnancy, which are regarded as novel and remarkable risk factors of delayed OL and short breastfeeding duration.
doi:10.1089/bfm.2012.0010
PMCID: PMC3616404  PMID: 23057642
6.  Autonomic Dysreflexia Causes Chronic Immune Suppression after Spinal Cord Injury 
The Journal of Neuroscience  2013;33(32):12970-12981.
Autonomic dysreflexia (AD), a potentially dangerous complication of high-level spinal cord injury (SCI) characterized by exaggerated activation of spinal autonomic (sympathetic) reflexes, can cause pulmonary embolism, stroke, and, in severe cases, death. People with high-level SCI also are immune compromised, rendering them more susceptible to infectious morbidity and mortality. The mechanisms underlying postinjury immune suppression are not known. Data presented herein indicate that AD causes immune suppression. Using in vivo telemetry, we show that AD develops spontaneously in SCI mice with the frequency of dysreflexic episodes increasing as a function of time postinjury. As the frequency of AD increases, there is a corresponding increase in splenic leucopenia and immune suppression. Experimental activation of spinal sympathetic reflexes in SCI mice (e.g., via colorectal distension) elicits AD and exacerbates immune suppression via a mechanism that involves aberrant accumulation of norepinephrine and glucocorticoids. Reversal of postinjury immune suppression in SCI mice can be achieved by pharmacological inhibition of receptors for norepinephrine and glucocorticoids during the onset and progression of AD. In a human subject with C5 SCI, stimulating the micturition reflex caused AD with exaggerated catecholamine release and impaired immune function, thus confirming the relevance of the mouse data. These data implicate AD as a cause of secondary immune deficiency after SCI and reveal novel therapeutic targets for overcoming infectious complications that arise due to deficits in immune function.
doi:10.1523/JNEUROSCI.1974-13.2013
PMCID: PMC3735880  PMID: 23926252
7.  Identification of Poly(ADP-Ribose) Polymerase-1 as a Cell Cycle Regulator through Modulating Sp1 Mediated Transcription in Human Hepatoma Cells 
PLoS ONE  2013;8(12):e82872.
The transcription factor Sp1 is implicated in the activation of G0/G1 phase genes. Modulation of Sp1 transcription activities may affect G1-S checkpoint, resulting in changes in cell proliferation. In this study, our results demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP-1) promoted cell proliferation by inhibiting Sp1 signaling pathway. Cell proliferation and cell cycle assays demonstrated that PARP inhibitors or PARP-1 siRNA treatment significantly inhibited proliferation of hepatoma cells and induced G0/G1 cell cycle arrest in hepatoma cells, while overexpression of PARP-1 or PARP-1 activator treatment promoted cell cycle progression. Simultaneously, inhibition of PARP-1 enhanced the expression of Sp1-mediated checkpoint proteins, such as p21 and p27. In this study, we also showed that Sp1 was poly(ADP-ribosyl)ated by PARP-1 in hepatoma cells. Poly(ADP-ribosyl)ation suppressed Sp1 mediated transcription through preventing Sp1 binding to the Sp1 response element present in the promoters of target genes. Taken together, these data indicated that PARP-1 inhibition attenuated the poly(ADP-ribosyl)ation of Sp1 and significantly increased the expression of Sp1 target genes, resulting in G0/G1 cell cycle arrest and the decreased proliferative ability of the hepatoma cells.
doi:10.1371/journal.pone.0082872
PMCID: PMC3868549  PMID: 24367566
8.  Maternal depressive symptoms related to Epstein-Barr virus reactivation in late pregnancy 
Scientific Reports  2013;3:3096.
We examined the relationship between maternal depressive symptoms in late pregnancy and Epstein-Barr virus reactivation before delivery. In this prospective observational study, prevalence of Epstein-Barr virus reactivation within one week before delivery was compared between 163 pregnant women with depressive symptoms at 33 to 34 weeks of gestation and a computer-generated control group of 163 pregnant healthy women without depressive symptoms. Depressive symptoms at 33 to 34 weeks of gestation were significantly related to the prevalence of Epstein-Barr virus reactivation before delivery after adjustment for potential confounders (adjusted OR = 2.74, 95%CI: 1.23–6.08). Compared to that in the control group, the prevalence of Epstein-Barr virus reactivation was higher in women with depressive symptoms accompanied by higher negative coping (24.2% compared with 7.9%; adjusted OR = 3.67, 95%CI: 1.47–9.16). Maternal depressive symptoms in late pregnancy are associated with Epstein-Barr virus reactivation, and this association could be moderated by maternal coping style.
doi:10.1038/srep03096
PMCID: PMC3813936  PMID: 24172862
9.  Two-Point Correlation as a Feature for Histology Images: Feature Space Structure and Correlation Updating 
The segmentation of tissues in whole-slide histology images is a necessary step for the morphological analyses of tissues and cellular structures. Previous works have demonstrated the potential of two-point correlation functions (TPCF) as features for tissue segmentation, however the feature space is not yet well understood and computational methods are lacking. This paper illustrates several fundamental aspects of TPCF feature space and contributes a fast algorithm for deterministic feature computation. Despite the high-dimensionality of TPCF feature space, the features corresponding to different tissues are shown to be characterized by low-dimensional manifolds. The relationship between TPCF and the familiar co-occurrence matrix is highlighted, and it is shown that costly cross correlations are not necessary to achieve an accurate segmentation. For computation, the method of correlation updating, based on the linearity of the correlation operator, is proposed and shown to achieve up to a 67X speedup over frequency domain computation methods. Segmentation results are demonstrated on multiple tissues and natural texture images.
doi:10.1109/CVPRW.2010.5543453
PMCID: PMC3803159  PMID: 24154808
10.  Mining the tissue-tissue gene co-expression network for tumor microenvironment study and biomarker prediction 
BMC Genomics  2013;14(Suppl 5):S4.
Background
Recent discovery in tumor development indicates that the tumor microenvironment (mostly stroma cells) plays an important role in cancer development. To understand how the tumor microenvironment (TME) interacts with the tumor, we explore the correlation of the gene expressions between tumor and stroma. The tumor and stroma gene expression data are modeled as a weighted bipartite network (tumor-stroma coexpression network) where the weight of an edge indicates the correlation between the expression profiles of the corresponding tumor gene and stroma gene. In order to efficiently mine this weighted bipartite network, we developed the Bipartite subnetwork Component Mining algorithm (BCM), and we show that the BCM algorithm can efficiently mine weighted bipartite networks for dense Bipartite sub-Networks (BiNets) with density guarantees.
Results
We applied BCM to the tumor-stroma coexpression network and find 372 BiNets that demonstrate statistical significance in survival tests. A good number of these BiNets demonstrate strong prognosis powers on at least one breast cancer patient cohort, which suggests that these BiNets are potential biomarkers for breast cancer prognosis. Further study on these 372 BiNets by the network merging approach reveals that they form 10 macro bipartite networks which show orchestrated key biological processes in both tumor and stroma. In addition, by further examining the BiNets that are significant in ER-negative breast cancer patient prognosis, we discovered a ubiquitin C (UBC) gene network that demonstrates strong prognosis power in nearly all types of breast cancer subtypes we used in this study.
Conclusions
The results support our hypothesis that the UBC gene network plays an important role in breast cancer prognosis and therapy and it is a potential prognostic biomarker for multiple breast cancer subtypes.
doi:10.1186/1471-2164-14-S5-S4
PMCID: PMC3852209  PMID: 24564578
11.  Protective Effect of Hypercapnic Acidosis in Ischemia-Reperfusion Lung Injury Is Attributable to Upregulation of Heme Oxygenase-1 
PLoS ONE  2013;8(9):e74742.
Hypercapnic acidosis (HCA) has protective effects in animal models of acute lung injury, but the mechanism underlying the effect of HCA is unclear. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that protects tissue from inflammation injury. We investigated whether HO-1 contributes to the protective effects of HCA in ischemia-reperfusion (IR)-induced lung injury. Typical acute lung injury in rats was successfully induced by 40 min of ischemia and 90 min of reperfusion in an isolated perfused lung model. The rat lungs were randomly assigned to the control group, IR group or IR + HCA group with or without zinc protoporphyrin IX (ZnPP), an HO-1 activity inhibitor. At the end of the experiment, bronchoalveolar lavage fluid (BALF) and lung tissues were collected to evaluate the degree of lung injury. In in vitro experiments, HO-1 siRNA transfected A549 cells were exposed to a normoxic or hypoxia-reoxygenation (H/R) environment in the presence or absence of HCA. IR caused significant increases in the pulmonary arterial pressure, lung weight to body weight and wet/dry ratios, lung weight gain, capillary filtration coefficient, lung injury scores, neutrophil infiltration, and concentrations of protein and TNF-α in the BALF. IR also induced degradation of inhibitor of nuclear factor (NF)-κB-α, increased IκB kinase (IKK)-β phosphorylation and nuclear translocation of NF-κB, and up-regulated HO-1 expression and activity. Furthermore, IR decreased Bcl-2 protein expression and increased the number of active caspase-3 stained cells. HCA treatment enhanced HO-1 expression and activity, and accordingly reduced IKK-NF-κB signaling, inhibited apoptosis, and significantly attenuated IR-induced changes. Treatment with ZnPP partially blocked the protective effect of HCA. In addition, HO-1 siRNA significantly reversed HCA-mediated inhibition of NF-κB signaling in A549 cells subjected to H/R. In conclusion, the protective effect of HCA in IR lung injury in rats was mediated in part by the anti-inflammatory and anti-apoptotic action of HO-1.
doi:10.1371/journal.pone.0074742
PMCID: PMC3769390  PMID: 24040332
12.  JNK3 perpetuates metabolic stress induced by Abeta peptides 
Neuron  2012;75(5):824-837.
SUMMARY
Although Aβ peptides are causative agents in Alzheimer's disease (AD), the underlying mechanisms are still elusive. We report that Aβ42 induces a translational block by activating AMPK, thereby inhibiting the mTOR pathway. This translational block leads to widespread ER stress, which activates JNK3. JNK3 in turn phosphorylates APP at T668, thereby facilitating its endocytosis and subsequent processing. In support, pharmacologically blocking translation results in a significant increase in Aβ42 in a JNK3-dependent manner. Thus, JNK3 activation, which is increased in human AD cases and a familial AD (FAD) mouse model, is integral to perpetuating Aβ42 production. Concomitantly, deletion of JNK3 from FAD mice results in a dramatic reduction in Aβ42 levels and overall plaque loads and increased neuronal number and improved cognition. This reveals AD as a metabolic disease that is under tight control by JNK3.
doi:10.1016/j.neuron.2012.06.024
PMCID: PMC3438522  PMID: 22958823
13.  Successful Treatment of Vasculo-Behcet’s Disease Presenting as Recurrent Pseudoaneurysms: the Importance of Medical Treatment 
Dermatology and Therapy  2013;3(1):107-112.
Introduction
Vasculo-Behcet’s disease is a subtype of Behcet’s disease, characterized by cases in which vascular complications are present and often dominate the clinical features. In this disease, there are four different vascular complications: arterial occlusion, arterial aneurysm or pseudoaneurysm, venous thrombosis, and variceal formation. It is rare that arterial lesions are multiple, but without venous involvement. So far, the optimal treatment of the disease has not been established.
Case Report
The authors report a rare case of vasculo-Behcet’s disease with multiple and recurrent pseudoaneurysms in large arteries, but without affecting the venous system. The patient underwent three rounds of surgery, but developed a new pseudoaneurysm after each operation in short term. However, the patient was successfully treated with a combination of prednisone and immunosuppressive agents.
Conclusion
For Vasculo-Behcet’s disease, surgical and endovascular interventions alone increased the incidence of pseudoaneurysm. Early diagnosis and early initiation of prednisone in combination with immunosuppressive therapy are critical for inhibiting the progression of vascular lesions and provide a good prognosis.
doi:10.1007/s13555-013-0024-z
PMCID: PMC3680642  PMID: 23888260
Azathioprine; Behcet’s disease; Immunosuppressive agents; Intravenous pulse cyclophosphamide; Prednisone; Pseudoaneurysms; Surgical therapy; Vasculo-Behcet’s disease
14.  Successful Treatment of Vasculo-Behcet’s Disease Presenting as Recurrent Pseudoaneurysms: the Importance of Medical Treatment 
Dermatology and Therapy  2013;3(1):107-112.
Introduction
Vasculo-Behcet’s disease is a subtype of Behcet’s disease, characterized by cases in which vascular complications are present and often dominate the clinical features. In this disease, there are four different vascular complications: arterial occlusion, arterial aneurysm or pseudoaneurysm, venous thrombosis, and variceal formation. It is rare that arterial lesions are multiple, but without venous involvement. So far, the optimal treatment of the disease has not been established.
Case Report
The authors report a rare case of vasculo-Behcet’s disease with multiple and recurrent pseudoaneurysms in large arteries, but without affecting the venous system. The patient underwent three rounds of surgery, but developed a new pseudoaneurysm after each operation in short term. However, the patient was successfully treated with a combination of prednisone and immunosuppressive agents.
Conclusion
For Vasculo-Behcet’s disease, surgical and endovascular interventions alone increased the incidence of pseudoaneurysm. Early diagnosis and early initiation of prednisone in combination with immunosuppressive therapy are critical for inhibiting the progression of vascular lesions and provide a good prognosis.
doi:10.1007/s13555-013-0024-z
PMCID: PMC3680642  PMID: 23888260
Azathioprine; Behcet’s disease; Immunosuppressive agents; Intravenous pulse cyclophosphamide; Prednisone; Pseudoaneurysms; Surgical therapy; Vasculo-Behcet’s disease
15.  Canonical and Atypical E2Fs Regulate the Mammalian Endocycle 
Nature cell biology  2012;14(11):1192-1202.
SUMMARY
The endocycle is a variant cell cycle consisting of successive DNA synthesis and Gap phases that yield highly polyploid cells. Although essential for metazoan development, relatively little is known about its control or physiologic role in mammals. Using novel lineage-specific cre mice we identified two opposing arms of the E2F program, one driven by canonical transcription activation (E2F1, E2F2 and E2F3) and the other by atypical repression (E2F7 and E2F8), that converge on the regulation of endocycles in vivo. Ablation of canonical activators in the two endocycling tissues of mammals, trophoblast giant cells in the placenta and hepatocytes in the liver, augmented genome ploidy, whereas ablation of atypical repressors diminished ploidy. These two antagonistic arms coordinate the expression of a unique G2/M transcriptional program that is critical for mitosis, karyokinesis and cytokinesis. These results provide in vivo evidence for a direct role of E2F family members in regulating non-traditional cell cycles in mammals.
doi:10.1038/ncb2595
PMCID: PMC3616487  PMID: 23064266
16.  Using Frequent Co-expression Network to Identify Gene Clusters for Breast Cancer Prognosis 
In this paper, we investigated the use of gene co-expression network analyses to identify potential biomarkers for breast carcinoma prognosis. The network mining algorithm CODENSE is used to identify highly connected genome-wide gene co-expression networks among a variety of cancer types, and the resulted gene clusters are applied to a series of breast cancer microarray sets to categorize the patients into different groups. As a result, we have identified a set of genes that are potential biomarkers for breast cancer prognosis which can categorize the patients into two groups with distinct prognosis. We also compared the gene clusters we discovered with gene subsets identified from similar studies using other clustering algorithms.
doi:10.1109/IJCBS.2009.29
PMCID: PMC3632312  PMID: 23615925
CODENSE; breast cancer prognosis; co-expression network; gene cluster
17.  A Sparsification Approach for Temporal Graphical Model Decomposition 
Temporal causal modeling can be used to recover the causal structure among a group of relevant time series variables. Several methods have been developed to explicitly construct temporal causal graphical models. However, how to best understand and conceptualize these complicated causal relationships is still an open problem. In this paper, we propose a decomposition approach to simplify the temporal graphical model. Our method clusters time series variables into groups such that strong interactions appear among the variables within each group and weak (or no) interactions exist for cross-group variable pairs. Specifically, we formulate the clustering problem for temporal graphical models as a regression-coefficient sparsification problem and define an interesting objective function which balances the model prediction power and its cluster structure. We introduce an iterative optimization approach utilizing the Quasi-Newton method and generalized ridge regression to minimize the objective function and to produce a clustered temporal graphical model. We also present a novel optimization procedure utilizing a graph theoretical tool based on the maximum weight independent set problem to speed up the Quasi-Newton method for a large number of variables. Finally, our detailed experimental study on both synthetic and real datasets demonstrates the effectiveness of our methods.
doi:10.1109/ICDM.2009.67
PMCID: PMC3632353  PMID: 23616730
temporal graphical model decomposition; Quasi-Newton method; generalized ridge regression; maximum weight independent set
18.  Atypical E2F Repressors and Activators Coordinate Placental Development 
Developmental cell  2012;22(4):849-862.
SUMMARY
The evolutionarily ancient arm of the E2f family of transcription factors consisting of the two atypical members E2f7 and E2f8 is essential for murine embryonic development. However, the critical tissues, cellular processes and molecular pathways regulated by these two factors remain unknown. Using a series of fetal and placental lineage-specific cre mice we show that E2F7/E2F8 functions in extra-embryonic trophoblast lineages are both necessary and sufficient to carry fetuses to term. Expression profiling and biochemical approaches exposed the canonical E2F3a activator as a key family member that antagonizes E2F7/E2F8 functions. Remarkably, the concomitant loss of E2f3a normalized placental gene expression programs, corrected placental defects and fostered the survival of E2f7/E2f8 deficient embryos to birth. In summary, we identified a placental transcriptional network tightly coordinated by activation and repression through two distinct arms of the E2F family that is essential for extra-embryonic cell proliferation, placental development and fetal viability.
doi:10.1016/j.devcel.2012.01.013
PMCID: PMC3483796  PMID: 22516201
19.  Identifying survival associated morphological features of triple negative breast cancer using multiple datasets 
Background and objective
Biomarkers for subtyping triple negative breast cancer (TNBC) are needed given the absence of responsive therapy and relatively poor prediction of survival. Morphology of cancer tissues is widely used in clinical practice for stratifying cancer patients, while genomic data are highly effective to classify cancer patients into subgroups. Thus integration of both morphological and genomic data is a promising approach in discovering new biomarkers for cancer outcome prediction. Here we propose a workflow for analyzing histopathological images and integrate them with genomic data for discovering biomarkers for TNBC.
Materials and methods
We developed an image analysis workflow for extracting a large collection of morphological features and deployed the same on histological images from The Cancer Genome Atlas (TCGA) TNBC samples during the discovery phase (n=44). Strong correlations between salient morphological features and gene expression profiles from the same patients were identified. We then evaluated the same morphological features in predicting survival using a local TNBC cohort (n=143). We further tested the predictive power on patient prognosis of correlated gene clusters using two other public gene expression datasets.
Results and conclusion
Using TCGA data, we identified 48 pairs of significantly correlated morphological features and gene clusters; four morphological features were able to separate the local cohort with significantly different survival outcomes. Gene clusters correlated with these four morphological features further proved to be effective in predicting patient survival using multiple public gene expression datasets. These results suggest the efficacy of our workflow and demonstrate that integrative analysis holds promise for discovering biomarkers of complex diseases.
doi:10.1136/amiajnl-2012-001538
PMCID: PMC3721170  PMID: 23585272
Triple Negative Breast Cancer; Computational Biology; Image Analysis; Cancer Survival; Biomarker Identification; The Cancer Genome Atlas
20.  k-neighborhood Decentralization: A Comprehensive Solution to Index the UMLS for Large Scale Knowledge Discovery 
Journal of Biomedical Informatics  2011;45(2):323-336.
The Unified Medical Language System (UMLS) is the largest thesaurus in the biomedical informatics domain. Previous works have shown that knowledge constructs comprised of transitively-associated UMLS concepts are effective for discovering potentially novel biomedical hypotheses. However, the extremely large size of the UMLS becomes a major challenge for these applications. To address this problem, we designed a k-neighborhood Decentralization Labeling Scheme (kDLS) for the UMLS, and the corresponding method to effectively evaluate the kDLS indexing results. kDLS provides a comprehensive solution for indexing the UMLS for very efficient large scale knowledge discovery. We demonstrated that it is highly effective to use kDLS paths to prioritize disease-gene relations across the whole genome, with extremely high fold-enrichment values. To our knowledge, this is the first indexing scheme capable of supporting efficient large scale knowledge discovery on the UMLS as a whole. Our expectation is that kDLS will become a vital engine for retrieving information and generating hypotheses from the UMLS for future medical informatics applications.
doi:10.1016/j.jbi.2011.11.012
PMCID: PMC3306517  PMID: 22154838
UMLS; Knowledge Discovery; Graph Database; disease gene prioritization; fold enrichment
21.  Poly[diaqua­[μ6-4,4′-(1,4-phenyl­ene)bis­(2,6-dimethyl­pyridine-3,5-dicarboxyl­ato)]dilead(II)] 
The asymmetric unit of the title Pb-based coordination polymer, [Pb2(C24H16N2O8)(H2O)2]n, consists of one PbII cation, half of a 4,4′-(1,4-phenyl­ene)bis­(2,6-dimethyl­pyridine-3,5-di­carb­oxyl­ate (L 4−) ligand and one coordinating water mol­ecule. The centers of the benzene ring of the ligand and the four-membered Pb/O/Pb/O ring are located on centers of inversion. The PbII ion is coordinated in form of a distorted polyhedron by seven O atoms from four separate L 4− ligands and by one water O atom. The PbO7 polyhedra share O atoms, forming infinite zigzag [PbO4(H2O)]n chains along [100] that are bridged by L 4− ligands, forming a two-dimensional coordination network parallel to (001). O—H⋯O hydrogen bonds involving the water mol­ecule are observed.
doi:10.1107/S1600536813007733
PMCID: PMC3629504  PMID: 23634022
22.  Preferential electrical coupling regulates lineage-dependent microcircuit assembly in the neocortex 
Nature  2012;486(7401):113-117.
Radial glial cells are the primary neural progenitor cells in the developing neocortex 1. Consecutive asymmetric divisions of individual radial glial progenitor cells produce a number of sister excitatory neurons that migrate along the elongated radial glial fibre, resulting in the formation of ontogenetic columns 2–4. Moreover, sister excitatory neurons in ontogenetic columns preferentially develop specific chemical synapses with each other rather than with nearby non-siblings 5. While these findings provide crucial insights into the emergence of functional columns in the neocortex, little is known about the basis for this lineage-dependent assembly of excitatory neuron microcircuits with single-cell resolution. Here we show that transient electrical coupling between radially aligned sister excitatory neurons regulates the subsequent formation of specific chemical synapses in the neocortex. Multiple-electrode whole-cell recordings revealed that sister excitatory neurons preferentially form strong electrical coupling with each other rather than with adjacent non-sister excitatory neurons during early postnatal stages. This coupling allows selective electrical communication between sister excitatory neurons, promoting their action potential generation and synchronous firing. Interestingly, while this electrical communication largely disappears prior to the appearance of chemical synapses, its blockade impairs the subsequent formation of specific chemical synapses between sister excitatory neurons in ontogenetic columns. These results suggest a strong link between a lineage-dependent transient electrical coupling and the assembly of precise excitatory neuron microcircuits in the neocortex.
doi:10.1038/nature10958
PMCID: PMC3599787  PMID: 22678291
23.  A high-throughput and quantitative method to assess the mutagenic potential of translesion DNA synthesis 
Nucleic Acids Research  2013;41(8):e96.
Cellular genomes are constantly damaged by endogenous and exogenous agents that covalently and structurally modify DNA to produce DNA lesions. Although most lesions are mended by various DNA repair pathways in vivo, a significant number of damage sites persist during genomic replication. Our understanding of the mutagenic outcomes derived from these unrepaired DNA lesions has been hindered by the low throughput of existing sequencing methods. Therefore, we have developed a cost-effective high-throughput short oligonucleotide sequencing assay that uses next-generation DNA sequencing technology for the assessment of the mutagenic profiles of translesion DNA synthesis catalyzed by any error-prone DNA polymerase. The vast amount of sequencing data produced were aligned and quantified by using our novel software. As an example, the high-throughput short oligonucleotide sequencing assay was used to analyze the types and frequencies of mutations upstream, downstream and at a site-specifically placed cis–syn thymidine–thymidine dimer generated individually by three lesion-bypass human Y-family DNA polymerases.
doi:10.1093/nar/gkt141
PMCID: PMC3632128  PMID: 23470999
24.  Genome-wide analysis uncovers high frequency, strong differential chromosomal interactions and their associated epigenetic patterns in E2-mediated gene regulation 
BMC Genomics  2013;14:70.
Background
An emerging Hi-C protocol has the ability to probe three-dimensional (3D) architecture and capture chromatin interactions in a genome-wide scale. It provides informative results to address how chromatin organization changes contribute to disease/tumor occurrence and progression in response to stimulation of environmental chemicals or hormones.
Results
In this study, using MCF7 cells as a model system, we found estrogen stimulation significantly impact chromatin interactions, leading to alteration of gene regulation and the associated histone modification states. Many chromosomal interaction regions at different levels of interaction frequency were identified. In particular, the top 10 hot regions with the highest interaction frequency are enriched with breast cancer specific genes. Furthermore, four types of E2-mediated strong differential (gain- or loss-) chromosomal (intra- or inter-) interactions were classified, in which the number of gain-chromosomal interactions is less than the number of loss-chromosomal interactions upon E2 stimulation. Finally, by integrating with eight histone modification marks, DNA methylation, regulatory elements regions, ERα and Pol-II binding activities, associations between epigenetic patterns and high chromosomal interaction frequency were revealed in E2-mediated gene regulation.
Conclusions
The work provides insight into the effect of chromatin interaction on E2/ERα regulated downstream genes in breast cancer cells.
doi:10.1186/1471-2164-14-70
PMCID: PMC3599885  PMID: 23368971
25.  Bisphenol A Accelerates Toxic Amyloid Formation of Human Islet Amyloid Polypeptide: A Possible Link between Bisphenol A Exposure and Type 2 Diabetes 
PLoS ONE  2013;8(1):e54198.
Bisphenol A (BPA) is a chemical compound widely used in manufacturing plastic products. Recent epidemiological studies suggest BPA exposure is positively associated with the incidence of type 2 diabetes mellitus (T2DM), however the mechanisms underlying this link remain unclear. Human islet amyloid polypeptide (hIAPP) is a hormone synthesized and secreted by the pancreatic β-cells. Misfolding of hIAPP into toxic oligomers and mature fibrils can disrupt cell membrane and lead to β-cell death, which is regarded as one of the causative factors of T2DM. To test whether there are any connections between BPA exposure and hIAPP misfolding, we investigated the effects of BPA on hIAPP aggregation using thioflavin-T based fluorescence, transmission electronic microscopy, circular dichroism, dynamic light scattering, size-exclusion chromatography,fluorescence-dye leakage assay in an artificial micelle system and the generation of reactive oxygen species in INS-1 cells. We demonstrated that BPA not only dose-dependently promotes the aggregation of hIAPP and enhances the membrane disruption effects of hIAPP, but also promotes the extent of hIAPP aggregation related oxidative stress. Taken together, our results suggest that BPA exposure increased T2DM risk may involve the exacerbated toxic aggregation of hIAPP.
doi:10.1371/journal.pone.0054198
PMCID: PMC3553173  PMID: 23372685

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