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1.  Identification of Two Novel Mutations of the HOMEZ Gene in Chinese Patients with Isolated Ventricular Septal Defect 
Objectives: Ventricular septal defect (VSD) is the most common congenital heart disease (CHD). Genome-wide linkage analysis revealed a potential CHD susceptibility locus in the homeodomain leucine zipper-encoding (HOMEZ) gene in a South Indian population. The present study aimed to identify potential pathogenic mutations for HOMEZ and to provide insights into the etiology of isolated VSD in the Chinese population. Methods: Case–control mutational analysis was performed in 400 patients with isolated VSD and 400 healthy controls. Protein-coding exton of HOMEZ and their flanking sequences were amplified by polymerase chain reaction and sequenced on an ABI3730 Automated Sequencer. CLC workbench software was used to compare the conservatism of the HOMEZ protein with other multiple species. The ExPASy-ProtScale online tool was used to predicate the alignment of the hydrophobic features. Results: Two novel heterozygous missense mutations (c.116 C>T; c. 630T>A) were identified in HOMEZ gene exon-2. The two mutations lead to alanine to valine substitution at position 39 and serine to arginine at position 210, which are highly conserved among many species. The hydropathicity of the valine and arginine residue at the position 39 and 210 were significantly different from the wild type. Conclusions: We have identified two novel heterozygous missense mutations in HOMEZ gene exon-2 in isolated VSD patients in the Chinese population and have found that these two mutations resulted in alteration of the hydropathicity of the HOMEZ protein. Therefore, the two missense mutations of the HOMEZ gene are directly linked with the etiology of isolated VSD in the Chinese population.
doi:10.1089/gtmb.2012.0435
PMCID: PMC3634154  PMID: 23574532
2.  Prevalence of HIV and Syphilis Infection among Men Who Have Sex with Men in China: A Meta-Analysis 
BioMed Research International  2014;2014:620431.
Objectives. To figure out the most current prevalence of HIV and syphilis in MSM in China. Methods. A meta-analysis was conducted on the studies searched through PubMed, CNKI, and Wanfang published between 1 January 2009 and 11 April 2013. Results. Eighty-four eligible studies, either in Chinese or in English, were included in this review. The pooled prevalence of HIV and syphilis infection in MSM in China was 6.5% and 11.2%, respectively. The subgroup analyses indicated that the prevalence of HIV infection was higher in the economically less developed cities than that in the developed cities (7.5% versus 6.1%, P < 0.05). In contrast, the prevalence of syphilis infection was lower in less developed cities than in developed cities (8.6% versus 15.1%). Studies with a sample size smaller than 500 had a lower prevalence of HIV and syphilis infection than those with a sample size greater than 500 (5.9% versus 7.2% for HIV; 11.0% versus 11.5% for syphilis, respectively). Conclusions. HIV and syphilis infection are prevalent in MSM in China. The different prevalence of HIV and syphilis infection between developing and developed cities underscores the need to target prevention strategies based on economic conditions.
doi:10.1155/2014/620431
PMCID: PMC4017804  PMID: 24868533
3.  A novel RT-PCR method for quantification of human papillomavirus transcripts in archived tissues and its application in oropharyngeal cancer prognosis 
Oropharyngeal squamous cell carcinoma (SCC) is strongly associated with human papillomavirus (HPV) infection, which is distinctively different from most other head and neck cancers. However, a robust quantitative reverse transcription PCR (RT-qPCR) method for comprehensive expression profiling of HPV genes in routinely fixed tissues has not been reported. To address this issue, we have established a new real-time RT-PCR method for the expression profiling of the E6 and E7 oncogenes from 13 high-risk HPV types. This method was validated in cervical cancer and by comparison with another HPV RNA detection method (in situ hybridization) in oropharyngeal tumors. In addition, the expression profiles of selected HPV-related human genes were also analyzed. HPV E6 and E7 expression profiles were then analyzed in 150 archived oropharyngeal SCC samples and compared with other variables and with patient outcomes. Our study showed that RT-qPCR and RNA in situ hybridization were 100% concordant in determining HPV status. HPV transcriptional activity was found in most oropharyngeal SCC (81.3%), a prevalence that is higher than in previous studies. Besides HPV16, three other HPV types were also detected, including 33, 35 and 18. Furthermore, HPV and p16 had essentially identical expression signatures, and both HPV and p16 were prognostic biomarkers for the prediction of disease outcome. Thus, p16 mRNA or protein expression signature is a sensitive and specific surrogate marker for HPV transcriptional activity (all genotypes combined).
doi:10.1002/ijc.27739
PMCID: PMC3498587  PMID: 22821242
human papillomavirus; oropharyngeal cancer; prognosis; expression signature
4.  A microRNA expression signature for the prognosis of oropharyngeal squamous cell carcinoma 
Cancer  2012;119(1):72-80.
BACKGROUND
Oropharyngeal squamous cell carcinoma (SCC) rates have been increasing significantly in recent years, despite a decreasing incidence of head and neck cancer in general. Oropharyngeal cancer has many characteristics that are distinctively different from other head and neck cancers, and thus it is important to focus specifically on cancers arising here, with the goal of improving patient outcomes. One important goal is to identify patients who are likely to fail standard therapy and who could potentially benefit from alternative or targeted treatments.
METHODS
In this study, we evaluated the prognostic value of microRNAs (miRNAs) in oropharyngeal SCC. miRNAs are small non-coding RNAs that are master regulators of many important biological processes. In total, 150 oropharyngeal tumors were analyzed using our recently developed quantitative PCR-based method for miRNA expression profiling. In addition, the expression of miRNAs was also correlated to human papillomavirus (HPV) transcriptional activities.
RESULTS AND CONCLUSION
Our study identified six miRNAs that were significantly associated with cancer survival. A combined expression signature of these miRNAs was prognostic of oropharyngeal SCC, independent of common clinical features or HPV status. Importantly, this new miRNA signature was experimentally validated in an independent oropharyngeal SCC cohort. Furthermore, five HPV-related miRNAs were identified which may help to characterize HPV-induced cancers including both oropharyngeal and cervical SCC.
doi:10.1002/cncr.27696
PMCID: PMC3461127  PMID: 22736309
microRNA; oropharyngeal cancer; prognosis; gene signature; human papillomavirus
5.  RBM25/LUC7L3 function in Cardiac Sodium Channel Splicing Regulation of Human Heart Failure 
Alternative splicing is a post-transcriptional mechanism that can substantially change the pattern of gene expression. Up to 95% of human genes have multi-exon alternative spliced forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Nevertheless, alternative splicing regulation has received comparatively little attention in the study of cardiac diseases. When investigating SCN5A splicing abnormalities in heart failure, we found 47 of 181 known splicing regulators were upregulated in HF when compared to controls, which indicate that splicing regulation may play a key role in heart failure. Our results shows that AngII and hypoxia, signals common to HF, result in increased LUC7L3 and RBM25 splicing regulators, increased binding of RBM25 to SCN5A mRNA, increased SCN5A splice variant abundances, decreased full-length SCN5A mRNA and protein, and decreased Na+ current. These observations could shed light on a mechanism whereby cardiac function and arrhythmic risk are associated and allow for refined predictions of which patients may be at highest arrhythmic risk or suffer from Na+ channel blocking anti-arrhythmic drug complications.
doi:10.1016/j.tcm.2012.08.003
PMCID: PMC3532530  PMID: 22939879
6.  PlantTFDB 3.0: a portal for the functional and evolutionary study of plant transcription factors 
Nucleic Acids Research  2013;42(D1):D1182-D1187.
With the aim to provide a resource for functional and evolutionary study of plant transcription factors (TFs), we updated the plant TF database PlantTFDB to version 3.0 (http://planttfdb.cbi.pku.edu.cn). After refining the TF classification pipeline, we systematically identified 129 288 TFs from 83 species, of which 67 species have genome sequences, covering main lineages of green plants. Besides the abundant annotation provided in the previous version, we generated more annotations for identified TFs, including expression, regulation, interaction, conserved elements, phenotype information, expert-curated descriptions derived from UniProt, TAIR and NCBI GeneRIF, as well as references to provide clues for functional studies of TFs. To help identify evolutionary relationship among identified TFs, we assigned 69 450 TFs into 3924 orthologous groups, and constructed 9217 phylogenetic trees for TFs within the same families or same orthologous groups, respectively. In addition, we set up a TF prediction server in this version for users to identify TFs from their own sequences.
doi:10.1093/nar/gkt1016
PMCID: PMC3965000  PMID: 24174544
7.  Systematically profiling and annotating long intergenic non-coding RNAs in human embryonic stem cell 
BMC Genomics  2013;14(Suppl 5):S3.
Background
While more and more long intergenic non-coding RNAs (lincRNAs) were identified to take important roles in both maintaining pluripotency and regulating differentiation, how these lincRNAs may define and drive cell fate decisions on a global scale are still mostly elusive. Systematical profiling and comprehensive annotation of embryonic stem cells lincRNAs may not only bring a clearer big picture of these novel regulators but also shed light on their functionalities.
Results
Based on multiple RNA-Seq datasets, we systematically identified 300 human embryonic stem cell lincRNAs (hES lincRNAs). Of which, one forth (78 out of 300) hES lincRNAs were further identified to be biasedly expressed in human ES cells. Functional analysis showed that they were preferentially involved in several early-development related biological processes. Comparative genomics analysis further suggested that around half of the identified hES lincRNAs were conserved in mouse. To facilitate further investigation of these hES lincRNAs, we constructed an online portal for biologists to access all their sequences and annotations interactively. In addition to navigation through a genome browse interface, users can also locate lincRNAs through an advanced query interface based on both keywords and expression profiles, and analyze results through multiple tools.
Conclusions
By integrating multiple RNA-Seq datasets, we systematically characterized and annotated 300 hES lincRNAs. A full functional web portal is available freely at http://scbrowse.cbi.pku.edu.cn. As the first global profiling and annotating of human embryonic stem cell lincRNAs, this work aims to provide a valuable resource for both experimental biologists and bioinformaticians.
doi:10.1186/1471-2164-14-S5-S3
PMCID: PMC3852230  PMID: 24564552
8.  Progressive Changes in Inflammatory and Matrix Adherence of Bronchial Epithelial Cells with Persistent Respiratory Syncytial Virus (RSV) Infection (Progressive Changes in RSV Infection) 
In addition to the acute manifestations of respiratory syncytial virus (RSV), persistent infection may be associated with long-term complications in the development of chronic respiratory diseases. To understand the mechanisms underlying RSV-induced long-term consequences, we established an in vitro RSV (strain A2) infection model using human bronchial epithelial (16HBE) cells that persists over four generations and analyzed cell inflammation and matrix adherence. Cells infected with RSV at multiplicity of infection (MOI) 0.0067 experienced cytolytic or abortive infections in the second generation (G2) or G3 but mostly survived up to G4. Cell morphology, leukocyte and matrix adherence of the cells did not change in G1 or G2, but subsequently, leukocyte adherence and cytokine/chemokine secretion, partially mediated by intercellular adhesion molecule-1 (ICAM-1), increased drastically, and matrix adherence, partially mediated by E-cadherin, decreased until the cells died. Tumor necrosis factor-α (TNF-α) secretion was inhibited by ICAM-1 antibody in infected-16HBE cells, suggesting that positive feedback between TNF-α secretion and ICAM-1 expression may be significant in exacerbated inflammation. These data demonstrate the susceptibility of 16HBE cells to RSV and their capacity to produce long-term progressive RSV infection, which may contribute to inflammation mobilization and epithelial shedding.
doi:10.3390/ijms140918024
PMCID: PMC3794767  PMID: 24005865
respiratory syncytial virus; human bronchial epithelial cells; adherence; adhesive molecule; cytokine; chemokine
9.  Identification of Altered Plasma Proteins by Proteomic Study in Valvular Heart Diseases and the Potential Clinical Significance 
PLoS ONE  2013;8(8):e72111.
Background
Little is known about genetic basis and proteomics in valvular heart disease (VHD) including rheumatic (RVD) and degenerative (DVD) valvular disease. The present proteomic study examined the hypothesis that certain proteins may be associated with the pathological changes in the plasma of VHD patients.
Methods and Results
Differential protein analysis in the plasma identified 18 differentially expressed protein spots and 14 corresponding proteins or polypeptides by two-dimensional electrophoresis and mass spectrometry in 120 subjects. Two up-regulated (complement C4A and carbonic anhydrase 1) and three down-regulated proteins (serotransferrin, alpha-1-antichymotrypsin, and vitronectin) were validated by ELISA in enlarging samples. The plasma levels (n = 40 for each) of complement C4A in RVD (715.8±35.6 vs. 594.7±28.2 ng/ml, P = 0.009) and carbonic anhydrase 1 (237.70±15.7 vs. 184.7±10.8 U/L, P = 0.007) in DVD patients were significantly higher and that of serotransferrin (2.36±0.20 vs. 2.93±0.16 mg/ml, P = 0.025) and alpha-1-antichymotrypsin (370.0±13.7 vs. 413.0±11.6 µg/ml, P = 0.019) in RVD patients were significantly lower than those in controls. The plasma vitronectin level in both RVD (281.3±11.0 vs. 323.2±10.0 µg/ml, P = 0.006) and DVD (283.6±11.4 vs. 323.2±10.0 µg/ml, P = 0.011) was significantly lower than those in normal controls.
Conclusions
We have for the first time identified alterations of 14 differential proteins or polypeptides in the plasma of patients with various VHD. The elevation of plasma complement C4A in RVD and carbonic anhydrase 1 in DVD and the decrease of serotransferrin and alpha-1-antichymotrypsin in RVD patients may be useful biomarkers for these valvular diseases. The decreased plasma level of vitronectin – a protein related to the formation of valvular structure – in both RVD and DVD patients might indicate the possible genetic deficiency in these patients.
doi:10.1371/journal.pone.0072111
PMCID: PMC3754973  PMID: 24015209
10.  A Novel Variation of PLAGL1 in Chinese Patients with Isolated Ventricular Septal Defect 
Aims
Ventricular septal defect (VSD) is the most common congenital heart disease (CHD). A number of genetic studies have linked the gene of PLAGL1 to the etiology of CHD. The present study aimed to identify potential pathogenic mutations for PLAGL1 and to provide insights into the etiology of isolated VSD. Methods: Case–control mutational analysis was performed in 300 patients with isolated VSD and 300 healthy controls. Two protein-coding extons of PLAGL1 and their partial flanking intron sequences were amplified by polymerase chain reaction and sequenced on an ABI3730 Automated Sequencer. CLC workbench software was used to compare the conservatism of PLAGL1 protein with other multiple species. Results: Neither missense nor frame-shift mutations were detected in two protein-coding extons of PLAGL1. But a novel synonymous variation (c.486A>G, p. E162E) was detected in protein-coding exon-2. The glutamic that translated with the mutational codon is conservative when compared with other species. Conclusions: We detected a synonymous variation in the protein-coding exon-2 of PLAGL1 in isolated VSD patients. It is possible that the etiology of isolated VSD might not be directly linked with this mutation, but might be associated with other patterns of gene expression regulation in PLAGL1, such as in the methylation-dependent manner.
doi:10.1089/gtmb.2012.0003
PMCID: PMC3422556  PMID: 22784302
11.  Detection and significance of human papillomavirus, CDKN2A (p16) and CDKN1A (p21) expression in squamous cell carcinoma of the larynx 
While a strong etiologic relationship between human papillomavirus and a majority of oropharyngeal squamous cell carcinomas has been established, the role of human papillomavirus in non-oropharyngeal head and neck carcinomas is much less clear. Here, we investigated the prevalence and clinicopathologic significance of human papillomavirus and its reported biomarkers, CDKN2A(p16) and CDKN1A(p21), in laryngeal squamous cell carcinomas in patients treated either with primary surgery and postoperative radiation or with definitive radiation-based therapy. Nearly all of 76 tumors were keratinizing and none displayed the nonkeratinizing morphology that is typically associated with human papillomavirus infection in the oropharynx. However, CDKN2A(p16) immunohistochemistry was positive in 21 cases (28%), and CDKN1A(p21) in 34 (45%). CDKN2A(p16) and CDKN1A(p21) status strongly correlated with each other (p = 0.0038). Yet, only four cases were human papillomavirus positive by DNA in situ hybridization or by reverse transcriptase polymerase chain reaction E6/E7 mRNA [all four were CDKN2A(p16) and CDKN1A(p21) positive]. Unexpectedly, 9 additional tumors out of 20 CDKN2A(p16) positive cases harbored high-risk human papillomavirus DNA by polymerase chain reaction. For further investigation of this unexpected result, in situ hybridization for E6/E7 mRNA was performed on these 9 cases and all were negative, confirming the absence of transcriptionally active virus. Patients with CDKN1A(p21) positive tumors did have better overall survival (69% at 3 years) than those with CDKN1A(p21) negative tumors (51% at 3 years) [p = 0.045]. There was also a strong trend towards better overall survival in the CDKN2A(p16) positive group (p=0.058). Thus, it appears that the role of human papillomavirus is more complex in the larynx than in the oropharynx and that CDKN2A(p16) and CDKN1A(p21) expression may not reflect human papillomavirus driven tumors in most cases. Because of this, CDKN2A(p16) should not be used as a definitive surrogate marker of human papillomavirus driven tumors in the larynx.
doi:10.1038/modpathol.2012.159
PMCID: PMC3529982  PMID: 22996374
Human papillomavirus; CDKN2A(p16); CDKN1A(p21); larynx; in situ hybridization; polymerase chain reaction
12.  Controllable immobilization of polyacrylamide onto glass slide: synthesis and characterization 
Colloid and Polymer Science  2013;291:2359-2364.
A novel route was introduced to synthesize dense polyacrylamide (PAM) onto the glass slide surface. To investigate the surface chemistry of the PAM on the glass slides, X-ray photoelectron spectroscopy (XPS) was utilized to obtain detailed chemical state information on the PAM layer constituents. The XPS peak data were consistent with the presented model of the PAM on the glass slide surface. Scanning electron microscopy and atomic force microscope data indicated the presence of PAM on the glass slides, which consist of nodules. The results showed that PAM was successfully immobilized onto glass slides with a two-tier structure under aqueous condition and a monolayer structure under anhydrous condition. Compared with those under aqueous condition, the controllability of the molecular layer on glass slides and the reproducibility under anhydrous condition were much better, which makes anhydrous condition an advisable condition for the study of the reaction mechanisms of glass slides modified by PAM.
doi:10.1007/s00396-013-2981-2
PMCID: PMC3776275  PMID: 24058247
Glass slide; Polyacrylamide; Surface analysis; XPS; SEM; AFM
13.  Identification of four serum microRNAs from a genome-wide serum microRNA expression profile as potential non-invasive biomarkers for endometrioid endometrial cancer 
Oncology Letters  2013;6(1):261-267.
Serum microRNAs (miRNAs), with their remarkable stability and unique concentration profiles in patients with various diseases, are promising non-invasive biomarkers for tumor detection. The present study investigated the altered profiles of serum microRNAs in patients with endometrioid endometrial cancer (EEC) in order to predict the malignancy of the disease at a relatively early stage. TaqMan® low-density arrays (TDLAs) were used to perform an analysis in the initial screening phase using serum samples pooled from seven EEC patients and 20 controls. The differential expression was validated using a hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (qRT-PCR) in samples taken from 26 EEC patients and 22 age- and gender-matched healthy controls. The data obtained from the TLDAs demonstrated that 22 serum miRNAs were markedly upregulated in the EEC patients compared with the controls. The qRT-PCR analysis further identified a profile of four serum miRNAs (miR-222, miR-223, miR-186 and miR-204) as a fingerprint for EEC detection. The area under the receiver operating characteristic (ROC) curve of this four-serum miRNA signature was 0.927, which was markedly higher than that of carbohydrate antigen 125 (CA-125; 0.673). The four-miRNA signature identified by genome-wide serum miRNA expression profiling analysis provides a novel, non-invasive approach for EEC diagnosis.
doi:10.3892/ol.2013.1338
PMCID: PMC3742699  PMID: 23946815
endometrioid endometrial cancer; serum microRNAs; biomarker; diagnosis
14.  Complete Genome Sequence of Mycobacterium vaccae Type Strain ATCC 25954 
Journal of Bacteriology  2012;194(22):6339-6340.
Mycobacterium vaccae is a rapidly growing, nontuberculous Mycobacterium species that is generally not considered a human pathogen and is of major pharmaceutical interest as an immunotherapeutic agent. We report here the annotated genome sequence of the M. vaccae type strain, ATCC 25954.
doi:10.1128/JB.01462-12
PMCID: PMC3486380  PMID: 23105074
15.  Recent Adaptive Events in Human Brain Revealed by Meta-Analysis of Positively Selected Genes 
PLoS ONE  2013;8(4):e61280.
Background and Objectives
Analysis of positively-selected genes can help us understand how human evolved, especially the evolution of highly developed cognitive functions. However, previous works have reached conflicting conclusions regarding whether human neuronal genes are over-represented among genes under positive selection.
Methods and Results
We divided positively-selected genes into four groups according to the identification approaches, compiling a comprehensive list from 27 previous studies. We showed that genes that are highly expressed in the central nervous system are enriched in recent positive selection events in human history identified by intra-species genomic scan, especially in brain regions related to cognitive functions. This pattern holds when different datasets, parameters and analysis pipelines were used. Functional category enrichment analysis supported these findings, showing that synapse-related functions are enriched in genes under recent positive selection. In contrast, immune-related functions, for instance, are enriched in genes under ancient positive selection revealed by inter-species coding region comparison. We further demonstrated that most of these patterns still hold even after controlling for genomic characteristics that might bias genome-wide identification of positively-selected genes including gene length, gene density, GC composition, and intensity of negative selection.
Conclusion
Our rigorous analysis resolved previous conflicting conclusions and revealed recent adaptation of human brain functions.
doi:10.1371/journal.pone.0061280
PMCID: PMC3622023  PMID: 23593450
16.  Fabrication of Magnetic-Antimicrobial-Fluorescent Multifunctional Hybrid Microspheres and Their Properties 
Novel magnetic-antimicrobial-fluorescent multifunctional hybrid microspheres with well-defined nanostructure were synthesized by the aid of a poly(glycidyl methacrylate) (PGMA) template. The hybrid microspheres were fully characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), X-ray diffraction (XRD) and digital fluorescence microscope. The as-synthesized microspheres PGMA, amino-modified PGMA (NH2-PGMA) and magnetic PGMA (M-PGMA) have a spherical shape with a smooth surface and fine monodispersity. M-PGMA microspheres are super-paramagnetic, and their saturated magnetic field is 4.608 emu·g−1, which made M-PGMA efficiently separable from aqueous solution by an external magnetic field. After poly(haxemethylene guanidine hydrochloride) (PHGH) functionalization, the resultant microspheres exhibit excellent antibacterial performance against both Gram-positive and Gram-negative bacteria. The fluorescence feature originating from the quantum dot CdTe endowed the hybrid microspheres with biological functions, such as targeted localization and biological monitoring functions. Combination of magnetism, antibiosis and fluorescence into one single hybrid microsphere opens up the possibility of the extensive study of multifunctional materials and widens the potential applications.
doi:10.3390/ijms14047391
PMCID: PMC3645692  PMID: 23549271
poly(glycidyl methacrylate); magnetic; antibacterial; fluorescent; multifunctional; hybrid microspheres
17.  Metabolic Stress, Reactive Oxygen Species, and Arrhythmia 
Cardiac arrhythmias can cause sudden cardiac death (SCD) and add to the current heart failure (HF) health crisis. Nevertheless, the pathological processes underlying arrhythmias are unclear. Arrhythmic conditions are associated with systemic and cardiac oxidative stress caused by reactive oxygen species (ROS). In excitable cardiac cells, ROS regulate both cellular metabolism and ion homeostasis. Increasing evidence suggests that elevated cellular ROS can cause alterations of the cardiac sodium channel (Nav1.5), abnormal Ca2+ handling, changes of mitochondrial function, and gap junction remodeling, leading to arrhythmogenesis. This review summarizes our knowledge of the mechanisms by which ROS may cause arrhythmias and discusses potential therapeutic strategies to prevent arrhythmias by targeting ROS and its consequences.
doi:10.1016/j.yjmcc.2011.09.018
PMCID: PMC3264827  PMID: 21978629
reactive oxygen species; sodium channel; Ca2+ handling; mitochondria; connexin; arrhythmia
18.  EENdb: a database and knowledge base of ZFNs and TALENs for endonuclease engineering 
Nucleic Acids Research  2012;41(D1):D415-D422.
We report here the construction of engineered endonuclease database (EENdb) (http://eendb.zfgenetics.org/), a searchable database and knowledge base for customizable engineered endonucleases (EENs), including zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). EENs are artificial nucleases designed to target and cleave specific DNA sequences. EENs have been shown to be a very useful genetic tool for targeted genome modification and have shown great potentials in the applications in basic research, clinical therapies and agricultural utilities, and they are specifically essential for reverse genetics research in species where no other gene targeting techniques are available. EENdb contains over 700 records of all the reported ZFNs and TALENs and related information, such as their target sequences, the peptide components [zinc finger protein-/transcription activator-like effector (TALE)-binding domains, FokI variants and linker peptide/framework], the efficiency and specificity of their activities. The database also lists EEN engineering tools and resources as well as information about forms and types of EENs, EEN screening and construction methods, detection methods for targeting efficiency and many other utilities. The aim of EENdb is to represent a central hub for EEN information and an integrated solution for EEN engineering. These studies may help to extract in-depth properties and common rules regarding ZFN or TALEN efficiency through comparison of the known ZFNs or TALENs.
doi:10.1093/nar/gks1144
PMCID: PMC3531095  PMID: 23203870
19.  mir-35 is involved in intestine cell G1/S transition and germ cell proliferation in C. elegans 
Cell Research  2011;21(11):1605-1618.
MicroRNA (miRNA) regulates gene expression in many cellular events, yet functions of only a few miRNAs are known in C. elegans. We analyzed the function of mir-35-41 unique to the worm, and show here that mir-35 regulates the G1/S transition of intestinal cells and germ cell proliferation. Loss of mir-35 leads to a decrease of nuclei numbers in intestine and distal mitotic gonad, while re-introduction of mir-35 rescues the mutant phenotypes. Genetic analysis indicates that mir-35 may act through Rb/E2F and SCF pathways. Further bioinformatic and functional analyses demonstrate that mir-35 targets evolutionally conserved lin-23 and gld-1. Together, our study reveals a novel function of mir-35 family in cell division regulation.
doi:10.1038/cr.2011.102
PMCID: PMC3364723  PMID: 21691303
miRNA; C. elegans; mir-35; G1/S transition; germ cell proliferation
20.  The Role of RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing Regulation in Human Heart Failure 
Circulation  2011;124(10):1124-1131.
Background
Human heart failure (HF) is associated with decreased cardiac voltage-gated Na+ channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in HF. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human HF and a specific splicing pathway for SCN5A regulation were explored in this paper.
Methods and Results
Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). RBM25/LUC7L3-mediated abnormal SCN5A mRNA splicing reduced Na+ channel current 91.1 ± 9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript.
Conclusions
Of the 17 mRNA splicing factors upregulated in HF, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full length Na+ channel transcript. Since the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure.
doi:10.1161/CIRCULATIONAHA.111.044495
PMCID: PMC3172047  PMID: 21859973
heart failure; SCN5A; splicing regulation; RBM25; LUC7L3
21.  Synovial sarcoma of the buttocks presenting with a non-healing wound and rapid progression after local resection: a case report 
Synovial sarcoma is a malignant mesenchymal neoplasm that is frequently misdiagnosed as a benign condition because of its small size, slow growth, and well-delineated appearance. Rapid spread and early death occur rarely. Here we report a case of synovial sarcoma of the buttocks presenting with a non-healing wound and rapid progression after local resection in a 23-year-old woman. She initially found a slightly painful subcutaneous mass in the left buttock and underwent local excision. Postoperatively, she developed a non-healing wound that did not respond to conventional antibiotic therapy and local wound care, and pitting edema of the lower extremities. A magnetic resonance imaging scan revealed a large heterogeneous, irregular mass in the buttocks with regional lymph node involvement. Histological and immunohistochemical analyses suggested the diagnosis of a poorly differentiated synovial sarcoma. Her condition deteriorated dramatically shortly thereafter; she developed systemic edema and died of respiratory failure. This case suggests that synovial sarcoma may be fatal within months of recognition if improperly managed and stresses the importance of adequate pre-surgical evaluation and postoperative pathological analysis in the management of a subcutaneous mass.
doi:10.1186/1477-7819-10-125
PMCID: PMC3411468  PMID: 22741534
Non-healing wound; rapid progression; synovial sarcoma
22.  Transient Focal Cerebral Ischemia/Reperfusion Induces Early and Chronic Axonal Changes in Rats: Its Importance for the Risk of Alzheimer's Disease 
PLoS ONE  2012;7(3):e33722.
The dementia of Alzheimer's type and brain ischemia are known to increase at comparable rates with age. Recent advances suggest that cerebral ischemia may contribute to the pathogenesis of Alzheimer's disease (AD), however, the neuropathological relationship between these two disorders is largely unclear. It has been demonstrated that axonopathy, mainly manifesting as impairment of axonal transport and swelling of the axon and varicosity, is a prominent feature in AD and may play an important role in the neuropathological mechanisms in AD. In this study, we investigated the early and chronic changes of the axons of neurons in the different brain areas (cortex, hippocampus and striatum) using in vivo tracing technique and grading analysis method in a rat model of transient focal cerebral ischemia/reperfusion (middle cerebral artery occlusion, MCAO). In addition, the relationship between the changes of axons and the expression of β-amyloid 42 (Aβ42) and hyperphosphorylated Tau, which have been considered as the key neuropathological processes of AD, was analyzed by combining tracing technique with immunohistochemistry or western blotting. Subsequently, we found that transient cerebral ischemia/reperfusion produced obvious swelling of the axons and varicosities, from 6 hours after transient cerebral ischemia/reperfusion even up to 4 weeks. We could not observe Aβ plaques or overexpression of Aβ42 in the ischemic brain areas, however, the site-specific hyperphosphorylated Tau could be detected in the ischemic cortex. These results suggest that transient cerebral ischemia/reperfusion induce early and chronic axonal changes, which may be an important mechanism affecting the clinical outcome and possibly contributing to the development of AD after stroke.
doi:10.1371/journal.pone.0033722
PMCID: PMC3311543  PMID: 22457786
23.  ABrowse - a customizable next-generation genome browser framework 
BMC Bioinformatics  2012;13:2.
Background
With the rapid growth of genome sequencing projects, genome browser is becoming indispensable, not only as a visualization system but also as an interactive platform to support open data access and collaborative work. Thus a customizable genome browser framework with rich functions and flexible configuration is needed to facilitate various genome research projects.
Results
Based on next-generation web technologies, we have developed a general-purpose genome browser framework ABrowse which provides interactive browsing experience, open data access and collaborative work support. By supporting Google-map-like smooth navigation, ABrowse offers end users highly interactive browsing experience. To facilitate further data analysis, multiple data access approaches are supported for external platforms to retrieve data from ABrowse. To promote collaborative work, an online user-space is provided for end users to create, store and share comments, annotations and landmarks. For data providers, ABrowse is highly customizable and configurable. The framework provides a set of utilities to import annotation data conveniently. To build ABrowse on existing annotation databases, data providers could specify SQL statements according to database schema. And customized pages for detailed information display of annotation entries could be easily plugged in. For developers, new drawing strategies could be integrated into ABrowse for new types of annotation data. In addition, standard web service is provided for data retrieval remotely, providing underlying machine-oriented programming interface for open data access.
Conclusions
ABrowse framework is valuable for end users, data providers and developers by providing rich user functions and flexible customization approaches. The source code is published under GNU Lesser General Public License v3.0 and is accessible at http://www.abrowse.org/. To demonstrate all the features of ABrowse, a live demo for Arabidopsis thaliana genome has been built at http://arabidopsis.cbi.edu.cn/.
doi:10.1186/1471-2105-13-2
PMCID: PMC3265404  PMID: 22222089
24.  Rice-Map: a new-generation rice genome browser 
BMC Genomics  2011;12:165.
Background
The concurrent release of rice genome sequences for two subspecies (Oryza sativa L. ssp. japonica and Oryza sativa L. ssp. indica) facilitates rice studies at the whole genome level. Since the advent of high-throughput analysis, huge amounts of functional genomics data have been delivered rapidly, making an integrated online genome browser indispensable for scientists to visualize and analyze these data. Based on next-generation web technologies and high-throughput experimental data, we have developed Rice-Map, a novel genome browser for researchers to navigate, analyze and annotate rice genome interactively.
Description
More than one hundred annotation tracks (81 for japonica and 82 for indica) have been compiled and loaded into Rice-Map. These pre-computed annotations cover gene models, transcript evidences, expression profiling, epigenetic modifications, inter-species and intra-species homologies, genetic markers and other genomic features. In addition to these pre-computed tracks, registered users can interactively add comments and research notes to Rice-Map as User-Defined Annotation entries. By smoothly scrolling, dragging and zooming, users can browse various genomic features simultaneously at multiple scales. On-the-fly analysis for selected entries could be performed through dedicated bioinformatic analysis platforms such as WebLab and Galaxy. Furthermore, a BioMart-powered data warehouse "Rice Mart" is offered for advanced users to fetch bulk datasets based on complex criteria.
Conclusions
Rice-Map delivers abundant up-to-date japonica and indica annotations, providing a valuable resource for both computational and bench biologists. Rice-Map is publicly accessible at http://www.ricemap.org/, with all data available for free downloading.
doi:10.1186/1471-2164-12-165
PMCID: PMC3072960  PMID: 21450055
25.  PlantTFDB 2.0: update and improvement of the comprehensive plant transcription factor database 
Nucleic Acids Research  2010;39(Database issue):D1114-D1117.
We updated the plant transcription factor (TF) database to version 2.0 (PlantTFDB 2.0, http://planttfdb.cbi.pku.edu.cn) which contains 53 319 putative TFs predicted from 49 species. We made detailed annotation including general information, domain feature, gene ontology, expression pattern and ortholog groups, as well as cross references to various databases and literature citations for these TFs classified into 58 newly defined families with computational approach and manual inspection. Multiple sequence alignments and phylogenetic trees for each family can be shown as Weblogo pictures or downloaded as text files. We have redesigned the user interface in the new version. Users can search TFs with much more flexibility through the improved advanced search page, and the search results can be exported into various formats for further analysis. In addition, we now provide web service for advanced users to access PlantTFDB 2.0 more efficiently.
doi:10.1093/nar/gkq1141
PMCID: PMC3013715  PMID: 21097470

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