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1.  Detection of extracellular RNAs in cancer and viral infection via tethered cationic lipoplex nanoparticles containing molecular beacons 
Analytical chemistry  2013;85(23):11265-11274.
Non-invasive early detection methods have the potential to reduce mortality rates of both cancer and infectious diseases. Here, we present a novel assay by which tethered cationic lipoplex nanoparticles containing molecular beacons (MBs) can capture cancer cell-derived exosomes or viruses, and identify encapsulated RNAs in a single step. A series of ultracentrifugation and Exoquick™ isolation kit were first used to isolate exosomes from the cell culture medium and human serum respectively. Cationic lipoplex nanoparticles linked onto the surface of a thin glass plate capture negatively charged viruses or cell-secreted exosomes by electrostatic interactions to form larger nanoscale complexes. Lipoplex/virus or lipoplex/exosome fusion leads to the mixing of viral/exosomal RNAs and MBs within the lipoplexes. After the target RNAs specially bind to the MBs, exosomes enriched in target RNAs are readily identified by the fluorescence signals of MBs. The in situ detection of target extracellular RNAs without diluting the samples leads to high detection sensitivity not achievable by existing methods, e.g. qRT-PCR. Here we demonstrate this concept using lentivirus and serum from lung cancer patients.
PMCID: PMC4121114  PMID: 24102152
lipoplex nanoparticles; exosome; extracellular RNA; cancer detection; viral infection
2.  Conversion of bone marrow mesenchymal stem cells into type II alveolar epithelial cells reduces pulmonary fibrosis by decreasing oxidative stress in rats 
Molecular Medicine Reports  2014;11(3):1685-1692.
Pulmonary fibrosis is an irreversible chronic progressive fibroproliferative lung disease, which usually has a poor prognosis. Previous studies have confirmed that the transplantation of bone marrow mesenchymal stem cells (MSCs) significantly reduces lung damage in a number of animal models. However, the underlying mechanism involved in this process remains to be elucidated. In the present study, a bleomycin (BLM)-induced female Wister rat model of fibrosis was established. At 0 or 7 days following BLM administration, rats were injected into the tail vein with 5-bromo-2-deoxyuridine-labeled MSCs extracted from male Wistar rats. The lung tissue of the rats injected with MSCs expressed the sex-determining region Y gene. The level surfactant protein C (SP-C), a marker for type II alveolar epithelial cells (AEC II), was higher in the group injected with MSCs at day 0 than that in the group injected at day 7. Furthermore, SP-C mRNA, but not aquaporin 5 mRNA, a marker for type I alveolar epithelial cells, was expressed in fresh bone marrow aspirates and the fifth generation of cultured MSCs. In addition, superoxide dismutase activity and total antioxidative capability, specific indicators of oxidative stress, were significantly increased in the lung tissue of the MSC-transplanted rats (P<0.05). In conclusion, to alleviate pulmonary fibrosis, exogenous MSCs may be transplanted into damaged lung tissue where they differentiate into AEC II and exert their effect, at least in part, through blocking oxidative stress.
PMCID: PMC4270324  PMID: 25411925
pulmonary fibrosis; bone marrow mesenchymal stem cells; type II alveolar epithelial cells; oxidative stress
3.  Increased expression and possible role of chitinase 3-like-1 in a colitis-associated carcinoma model 
World Journal of Gastroenterology : WJG  2014;20(42):15736-15744.
AIM: To investigate the possible role of chitinase 3-like-1 (CHI3L1) in the progression of colitis-associated carcinoma (CAC).
METHODS: Thirty-four Balb/c mice were randomly assigned to five groups, including the control, CAC control, CAC + caffeine, colitis control and colitis + caffeine. Three animals were sacrificed every two weeks for blinded macroscopic inspection, histological analysis, and total RNA extraction. An immunofluorescent assay was performed using specimens from the colitis control and colitis + caffeine groups to investigate whether the protective effect of caffeine was associated with less oxidative DNA damage. In vitro, HT29 cells pre-stimulated with different concentrations of recombinant CHI3L1 protein and H2O2 were loaded with the DCFH-DA fluorescent probe to determine the effect of CHI3L1 on intracellular reactive oxygen species production.
RESULTS: CHI3L1 mRNA was increased during the progression of colon carcinogenesis. Tumors were mostly located in the distal end of the colon where the expression of CHI3L1 was higher than in the proximal colon. Caffeine-treated mice developed fewer tumors and milder inflammation than untreated mice. CHI3L1 protein increased reactive oxygen species in HT29 cells when exposed to H2O2.
CONCLUSION: Caffeine reduces tumor incidence by decreasing oxidative DNA damage. CHI3L1 may contribute to CAC by increasing reactive oxygen species production.
PMCID: PMC4229538  PMID: 25400457
Inflammatory bowel disease; Ulcerative colitis; Colitis-associated carcinoma; Murine model; Chitinase 3-like-1; Oxidative stress; Colorectal cancer
4.  Discovery and characterization of a novel extremely acidic bacterial N-glycanase with combined advantages of PNGase F and A 
Bioscience Reports  2014;34(6):e00149.
Peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidases [PNGases (peptide N-glycosidases), N-glycanases, EC] are essential tools in the release of N-glycans from glycoproteins. We hereby report the discovery and characterization of a novel bacterial N-glycanase from Terriglobus roseus with an extremely low pH optimum of 2.6, and annotated it therefore as PNGase H+. The gene of PNGase H+ was cloned and the recombinant protein was successfully expressed in Escherichia coli. The recombinant PNGase H+ could liberate high mannose-, hybrid- and complex-type N-glycans including core α1,3-fucosylated oligosaccharides from both glycoproteins and glycopeptides. In addition, PNGase H+ exhibited better release efficiency over N-glycans without core α1,3-fucose compared with PNGase A. The facile expression, non-glycosylated nature, unusual pH optimum and broad substrate specificity of this novel type of N-glycanase makes recombinant PNGase H+ a versatile tool in N-glycan analysis.
PNGase H+, from T. roseus was successfully cloned and expressed in E. coli. It shows activity in extremely acidic conditions and can release all types of N-glycans including core α1,3-fucosylated N-glycans from glycoproteins and glycopeptides in high efficiency.
PMCID: PMC4231336  PMID: 25294009
carbohydrate processing; core fucosylation; glycoprotein structure; N-linked glycosylation; PNGase; Terriglobus; 2-AB, 2-aminobenzamide; Asn, asparagine; CBB, Coomassie Brilliant Blue; HRP, horseradish peroxidase; MMXF3, Manα1-6(Manα1-3)(Xylβ1-2)Manα1-4GlcNAcα1-4(Fucα1-3)GlcNAc; MMX, Manα1-6(Manα1-3)(Xylβ1-2)Manα1-4GlcNAcα1-4GlcNAc; Ni-NTA, Ni2+-nitrilotriacetate; PMSF, phenyl-methylsulfonyl fluoride; PNGase, peptide N-glycosidase; UPLC, ultra-performance liquid chromatography
5.  Impacts of Diffuse Radiation on Light Use Efficiency across Terrestrial Ecosystems Based on Eddy Covariance Observation in China 
PLoS ONE  2014;9(11):e110988.
Ecosystem light use efficiency (LUE) is a key factor of production models for gross primary production (GPP) predictions. Previous studies revealed that ecosystem LUE could be significantly enhanced by an increase on diffuse radiation. Under large spatial heterogeneity and increasing annual diffuse radiation in China, eddy covariance flux data at 6 sites across different ecosystems from 2003 to 2007 were used to investigate the impacts of diffuse radiation indicated by the cloudiness index (CI) on ecosystem LUE in grassland and forest ecosystems. Our results showed that the ecosystem LUE at the six sites was significantly correlated with the cloudiness variation (0.24≤R2≤0.85), especially at the Changbaishan temperate forest ecosystem (R2 = 0.85). Meanwhile, the CI values appeared more frequently between 0.8 and 1.0 in two subtropical forest ecosystems (Qianyanzhou and Dinghushan) and were much larger than those in temperate ecosystems. Besides, cloudiness thresholds which were favorable for enhancing ecosystem carbon sequestration existed at the three forest sites, respectively. Our research confirmed that the ecosystem LUE at the six sites in China was positively responsive to the diffuse radiation, and the cloudiness index could be used as an environmental regulator for LUE modeling in regional GPP prediction.
PMCID: PMC4230921  PMID: 25393629
6.  Deterministic Progenitor Behavior and Unitary Production of Neurons in the Neocortex 
Cell  2014;159(4):775-788.
Radial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ∼8–9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ∼1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.
Graphical Abstract
•Radial glial progenitors (RGPs) progress through a coherent proliferation program•Individual RGPs produce a unitary output of neurons during the neurogenic phase•OTX1 deletion in RGPs leads to a reduction in neuronal unit size•A defined fraction of about one in six RGPs proceeds to gliogenesis after neurogenesis
Individual radial glial progenitors divide a defined number of times to produce excitatory neurons that initially enter the deep layers of the neocortex before populating the more superficial layers. A constant fraction of these neurons go on to produce glia, thereby maintaining the balance between the two cell types.
PMCID: PMC4225456  PMID: 25417155
7.  Genetic variants in ADAM33 are associated with airway inflammation and lung function in COPD 
BMC Pulmonary Medicine  2014;14(1):173.
Genetic factors play a role in the development and severity of chronic obstructive pulmonary disease (COPD). The pathogenesis of COPD is a multifactorial process including an inflammatory cell profile. Recent studies revealed that single nucleotide polymorphisms (SNPs) within ADAM33 increased the susceptibility to COPD through changing the airway inflammatory process and lung function.
In this paper, we investigated associations of four polymorphisms (T1, T2, S2 and Q-1) of ADAM33 as well as their haplotypes with pulmonary function and airway inflammatory process in an East Asian population of patients with COPD.
We found that T1, T2 and Q-1 were significantly associated with the changes of pulmonary function and components of cells in sputum of COPD, and T1 and Q-1 were significantly associated with cytokines and mediators of inflammation in airway of COPD in recessive models. 10 haplotypes were significantly associated with transfer factor of the lung for carbon monoxide in the disease state, 4 haplotypes were significantly associated with forced expiratory volume in one second, and other haplotypes were associated with airway inflammation.
We confirmed for the first time that ADAM33 was involved in the pathogenesis of COPD by affecting airway inflammation and immune response in an East Asian population. Our results made the genetic background of COPD, a common and disabling disease, more apparent, which would supply genetic support for the study of the mechanism, classification and treatment for this disease.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-173) contains supplementary material, which is available to authorized users.
PMCID: PMC4228268  PMID: 25369941
Chronic obstructive pulmonary disease; SNP; ADAM33; Haplotype; Pulmonary function; Airway inflammatory process
8.  Regulation of 53BP1 Protein Stability by RNF8 and RNF168 Is Important for Efficient DNA Double-Strand Break Repair 
PLoS ONE  2014;9(10):e110522.
53BP1 regulates DNA double-strand break (DSB) repair. In functional assays for specific DSB repair pathways, we found that 53BP1 was important in the conservative non-homologous end-joining (C-NHEJ) pathway, and this activity was dependent upon RNF8 and RNF168. We observed that 53BP1 protein was diffusely abundant in nuclei, and upon ionizing radiation, 53BP1 was everywhere degraded except at DNA damage sites. Depletion of RNF8 or RNF168 blocked the degradation of the diffusely localized nuclear 53BP1, and ionizing radiation induced foci (IRIF) did not form. Furthermore, when 53BP1 degradation was inhibited, a subset of 53BP1 was bound to DNA damage sites but bulk, unbound 53BP1 remained in the nucleoplasm, and localization of its downstream effector RIF1 at DSBs was abolished. Our data suggest a novel mechanism for responding to DSB that upon ionizing radiation, 53BP1 was divided into two populations, ensuring functional DSB repair: damage site-bound 53BP1 whose binding signal is known to be generated by RNF8 and RNF168; and unbound bulk 53BP1 whose ensuing degradation is regulated by RNF8 and RNF168.
PMCID: PMC4206297  PMID: 25337968
9.  Non-rigid Registration for Large Sets of Microscopic Images on Graphics Processors 
Journal of signal processing systems  2008;55(1-3):229-250.
Microscopic imaging is an important tool for characterizing tissue morphology and pathology. 3D reconstruction and visualization of large sample tissue structure requires registration of large sets of high-resolution images. However, the scale of this problem presents a challenge for automatic registration methods. In this paper we present a novel method for efficient automatic registration using graphics processing units (GPUs) and parallel programming. Comparing a C++ CPU implementation with Compute Unified Device Architecture (CUDA) libraries and pthreads running on GPU we achieve a speed-up factor of up to 4.11× with a single GPU and 6.68× with a GPU pair. We present execution times for a benchmark composed of two sets of large-scale images: mouse placenta (16K × 16K pixels) and breast cancer tumors (23K × 62K pixels). It takes more than 12 hours for the genetic case in C++ to register a typical sample composed of 500 consecutive slides, which was reduced to less than 2 hours using two GPUs, in addition to a very promising scalability for extending those gains easily on a large number of GPUs in a distributed system.
PMCID: PMC4198069  PMID: 25328635
Microscopic imaging; Image registration and segmentation; Pattern analysis; Feature detection; Graphics processors; High-performance computing
10.  Enabling Online Studies of Conceptual Relationships Between Medical Terms: Developing an Efficient Web Platform 
JMIR Medical Informatics  2014;2(2):e23.
The Unified Medical Language System (UMLS) contains many important ontologies in which terms are connected by semantic relations. For many studies on the relationships between biomedical concepts, the use of transitively associated information from ontologies and the UMLS has been shown to be effective. Although there are a few tools and methods available for extracting transitive relationships from the UMLS, they usually have major restrictions on the length of transitive relations or on the number of data sources.
Our goal was to design an efficient online platform that enables efficient studies on the conceptual relationships between any medical terms.
To overcome the restrictions of available methods and to facilitate studies on the conceptual relationships between medical terms, we developed a Web platform, onGrid, that supports efficient transitive queries and conceptual relationship studies using the UMLS. This framework uses the latest technique in converting natural language queries into UMLS concepts, performs efficient transitive queries, and visualizes the result paths. It also dynamically builds a relationship matrix for two sets of input biomedical terms. We are thus able to perform effective studies on conceptual relationships between medical terms based on their relationship matrix.
The advantage of onGrid is that it can be applied to study any two sets of biomedical concept relations and the relations within one set of biomedical concepts. We use onGrid to study the disease-disease relationships in the Online Mendelian Inheritance in Man (OMIM). By crossvalidating our results with an external database, the Comparative Toxicogenomics Database (CTD), we demonstrated that onGrid is effective for the study of conceptual relationships between medical terms.
onGrid is an efficient tool for querying the UMLS for transitive relations, studying the relationship between medical terms, and generating hypotheses.
PMCID: PMC4288067  PMID: 25600290
UMLS; ontology; conceptual relationships
11.  Gene × smoking interactions on human brain gene expression: Finding common mechanisms in adolescents and adults 
Numerous studies have examined gene × environment interactions (G×E) in cognitive and behavioral domains. However, these studies have been limited in that they have not been able to directly assess differential patterns of gene expression in the human brain. Here we assessed G×E interactions using two publically-available datasets to assess if DNA variation is associated with post-mortem brain gene expression changes based on smoking behavior, a biobehavioral construct that is part of a complex system of genetic and environmental influences.
We conducted an expression quantitative trait locus (eQTL) study on two independent human brain gene expression datasets assessing G×E for selected psychiatric genes and smoking status. We employed linear regression to model the significance of the Gene×Smoking interaction term, followed by meta-analysis across datasets.
Overall, we observed that the effect of DNA variation on gene expression is moderated by smoking status. Expression of 16 genes were significantly associated with single nucleotide polymorphisms that demonstrated G×E effects. The strongest finding (p = 1.9×10−11) was neurexin 3-alpha (NRXN3), a synaptic cell-cell adhesion molecule involved in maintenance of neural connections (such as the maintenance of smoking behavior). Other significant G×E associations include four glutamate genes.
This is one of the first studies to demonstrate G×E effects within the human brain. In particular, this study implicated NRXN3 in the maintenance of smoking. The effect of smoking on NRXN3 expression and downstream behavior is different based upon SNP genotype, indicating that DNA profiles based on SNPs could be useful in understanding the effects of smoking behaviors. These results suggest that better measurement of psychiatric conditions, and the environment in post-mortem brain studies may yield an important avenue for understanding the biological mechanisms of G×E interactions in psychiatry.
PMCID: PMC3809890  PMID: 23909413
Genetics; environment; brain development; developmental psychopathology
12.  A mouse line for inducible and reversible silencing of specific neurons 
Molecular Brain  2014;7(1):68.
Genetic methods for inducibly and reversibly inhibiting neuronal activity of specific neurons are critical for exploring the functions of neuronal circuits. The engineered human glycine receptor, called ivermectin (IVM)-gated silencing receptor (IVMR), has been shown to possess this ability in vitro.
Here we generated a mouse line, in which the IVMR coding sequence was inserted into the ROSA26 locus downstream of a loxP-flanked STOP cassette. Specific Cre-mediated IVMR expression was revealed by mis-expression of Cre in the striatum and by crossing with several Cre lines. Behavioral alteration was observed in Rosa26-IVMR mice with unilateral striatal Cre expression after systemic administration of IVM, and it could be re-initiated when IVM was applied again. A dramatic reduction in neuron firing was recorded in IVM-treated free moving Rosa26-IVMR;Emx1-Cre mice, and neuronal excitability was reduced within minutes as shown by recording in brain slice.
This Rosa26-IVMR mouse line provides a powerful tool for exploring selective circuit functions in freely behaving mice.
Electronic supplementary material
The online version of this article (doi:10.1186/s13041-014-0068-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4177062  PMID: 25231486
Neuron silencing; Ligand-gated channel; Ivermectin; Rosa26
13.  Manipulation of acoustic focusing with an active and configurable planar metasurface transducer 
Scientific Reports  2014;4:6257.
It has a pivotal role in medical science and in industry to concentrate the acoustic energy created with piezoelectric transducers (PTs) into a specific area. However, previous researches seldom consider the focal resolution, whose focal size is much larger than one wavelength. Furthermore, there is to date no such design method of PTs that allows a large degree of freedom to achieve designed focal patterns. Here, an active and configurable planar metasurface PT prototype is proposed to manipulate the acoustic focal pattern and the focal resolution freely. By suitably optimized ring configurations of the active metasurface PT, we demonstrate the manipulation of focal patterns in acoustic far fields, such as the designed focal needle and multi foci. Our method is also able to manipulate and improve the cross-sectional focal resolution from subwavelength to the extreme case: the deep sub-diffraction-limit resolution. Via the acoustic Rayleigh-Sommerfeld diffraction integral (RSI) cum the binary particle swarm optimization (BPSO), the free manipulation of focusing properties is achieved in acoustics for the first time. Our approach may offer more initiatives where the strict control of acoustic high-energy areas is demanding.
PMCID: PMC4150112  PMID: 25174409
14.  Expression of mRNA transcripts encoding membrane transporters detected with whole transcriptome sequencing of human brain and liver 
Pharmacogenetics and genomics  2013;23(5):269-278.
Membrane transporters control the influx and efflux of endogenous and xenobiotic substrates, including nutrients and drugs, across cellular membranes.
Whole transcriptome sequencing enables simultaneous analysis of overall and allele-specific mRNA expression, and the detection of multiple RNA isoforms.
Here we characterize variation in RNA transcripts emanating from gene loci encoding transporters based on RNAseq data from 10 human brains (including cocaine overdose and normal brain tissues) and 12 normal livers.
mRNA expression was detected in 65% of transporter genes in either tissue, with many genes generating multiple mRNA transcripts. Single-nucleotide polymorphisms within transporters with previous evidence for pharmacogenomics impact were detected. We also identified noncoding RNAs in the vicinity of transporter genes with potential regulatory functions.
The results obtained with RNAseq provide detailed information on transporter mRNA expression at the molecular level, affording new avenues for the study of membrane transport, with relevance to drug efficacy and toxicity.
PMCID: PMC4132188  PMID: 23492907
alternative splicing; gene expression; RNAseq; transporters
15.  Effects of several quinones on insulin aggregation 
Scientific Reports  2014;4:5648.
Protein misfolding and aggregation are associated with more than twenty diseases, such as neurodegenerative diseases and metabolic diseases. The amyloid oligomers and fibrils may induce cell membrane disruption and lead to cell apoptosis. A great number of studies have focused on discovery of amyloid inhibitors which may prevent or treat amyloidosis diseases. Polyphenols have been extensively studied as a class of amyloid inhibitors, with several polyphenols under clinical trials as anti-neurodegenerative drugs. As oxidative intermediates of natural polyphenols, quinones widely exist in medicinal plants or food. In this study, we used insulin as an amyloid model to test the anti-amyloid effects of four simple quinones and four natural anthraquinone derivatives from rhubarb, a traditional herbal medicine used for treating Alzheimer's disease. Our results demonstrated that all eight quinones show inhibitory effects to different extent on insulin oligomerization, especially for 1,4-benzoquinone and 1,4-naphthoquinone. Significantly attenuated oligomerization, reduced amount of amyloid fibrils and reduced hemolysis levels were found after quinones treatments, indicating quinones may inhibit insulin from forming toxic oligomeric species. The results suggest a potential action of native anthraquinone derivatives in preventing protein misfolding diseases, the quinone skeleton may thus be further explored for designing effective anti-amyloidosis compounds.
PMCID: PMC4090620  PMID: 25008537
16.  iGPSe: A visual analytic system for integrative genomic based cancer patient stratification 
BMC Bioinformatics  2014;15:203.
Cancers are highly heterogeneous with different subtypes. These subtypes often possess different genetic variants, present different pathological phenotypes, and most importantly, show various clinical outcomes such as varied prognosis and response to treatment and likelihood for recurrence and metastasis. Recently, integrative genomics (or panomics) approaches are often adopted with the goal of combining multiple types of omics data to identify integrative biomarkers for stratification of patients into groups with different clinical outcomes.
In this paper we present a visual analytic system called Interactive Genomics Patient Stratification explorer (iGPSe) which significantly reduces the computing burden for biomedical researchers in the process of exploring complicated integrative genomics data. Our system integrates unsupervised clustering with graph and parallel sets visualization and allows direct comparison of clinical outcomes via survival analysis. Using a breast cancer dataset obtained from the The Cancer Genome Atlas (TCGA) project, we are able to quickly explore different combinations of gene expression (mRNA) and microRNA features and identify potential combined markers for survival prediction.
Visualization plays an important role in the process of stratifying given population patients. Visual tools allowed for the selection of possibly features across various datasets for the given patient population. We essentially made a case for visualization for a very important problem in translational informatics.
PMCID: PMC4227100  PMID: 25000928
Molecular genomic analysis; Molecular biology; Computational biology
17.  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.
PMCID: PMC4047992  PMID: 21422495
Transactional database; binary matrix; frequent item set mining; maximal biclique; phenotype; disease gene; prioritization; matrix completion
18.  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.
PMCID: PMC4070474  PMID: 25002914
19.  Effectively processing medical term queries on the UMLS Metathesaurus by layered dynamic programming 
BMC Medical Genomics  2014;7(Suppl 1):S11.
Mapping medical terms to standardized UMLS concepts is a basic step for leveraging biomedical texts in data management and analysis. However, available methods and tools have major limitations in handling queries over the UMLS Metathesaurus that contain inaccurate query terms, which frequently appear in real world applications.
To provide a practical solution for this task, we propose a layered dynamic programming mapping (LDPMap) approach, which can efficiently handle these queries. LDPMap uses indexing and two layers of dynamic programming techniques to efficiently map a biomedical term to a UMLS concept.
Our empirical study shows that LDPMap achieves much faster query speeds than LCS. In comparison to the UMLS Metathesaurus Browser and MetaMap, LDPMap is much more effective in querying the UMLS Metathesaurus for inaccurately spelled medical terms, long medical terms, and medical terms with special characters.
These results demonstrate that LDPMap is an efficient and effective method for mapping medical terms to the UMLS Metathesaurus.
PMCID: PMC4101532  PMID: 25079259
20.  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.
PMCID: PMC3838191  PMID: 24043304
21.  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.
PMCID: PMC3997360  PMID: 24759906
22.  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.
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.
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.
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.
PMCID: PMC3616404  PMID: 23057642
23.  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.
PMCID: PMC3735880  PMID: 23926252
24.  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.
PMCID: PMC3868549  PMID: 24367566
25.  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.
PMCID: PMC3813936  PMID: 24172862

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