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Find video protocols related to scientific articles indexed in Pubmed.
Exome sequencing identifies frequent mutation of MLL2 in non-small cell lung carcinoma from Chinese patients.
Sci Rep
PUBLISHED: 08-12-2014
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Lung cancer is the most common cause of cancer mortality worldwide, with an estimated 1.4 million deaths each year. Here we report whole-exome sequencing of nine tumor/normal tissue pairs from Chinese patients with non-small cell lung carcinoma (NSCLC). This allows us to identify a number of significantly mutated genes in NSCLC, which were highly enriched in DNA damage repair, NF-?B pathway, JAK/STAT signaling and chromatin modification. Notably, we identify a histone-lysine methyltransferase gene, namely, MLL2, as one of the most significantly mutated genes in our screen. In a following validation study, we identify deleterious mutations of MLL2 in 12 out of 105 (11.4%) NSCLC patients. Additionally, reduced or lost expression of MLL2 was commonly observed in tumor tissues as compared with paired adjacent non-tumor tissues regardless of mutation status. Together, our study defines the landscape of somatic mutations in Chinese NSCLC and supports the role of MLL2 mutation in the pathogenesis of the disease.
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Combined analysis with copy number variation identifies risk loci in lung cancer.
Biomed Res Int
PUBLISHED: 05-21-2014
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Lung cancer is the most important cause of cancer mortality worldwide, but the underlying mechanisms of this disease are not fully understood. Copy number variations (CNVs) are promising genetic variations to study because of their potential effects on cancer.
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De novo Structure Variations of the Y Chromosome in a 47,XXY Female with Ovarian Failure: A Case Report.
Cytogenet. Genome Res.
PUBLISHED: 03-31-2014
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We report on a patient with a 47,XXY karyotype who presents a normal female phenotype, which is an extremely rare observation worldwide. The patient is infertile. Type B ultrasound scans and other tests suggested that her ovaries had completely failed. Microsatellite DNA marker analysis revealed that the 2 X chromosomes were derived from her mother and that this abnormality was caused by non-disjunction of the maternal X chromosomes during meiosis II. Copy number variation analysis identified 2 large de novo deletions in her Y chromosome. Remarkably, one of the deleted regions includes the SRY gene locus, which might explain her female phenotype. However, the genetic mechanism of her ovarian failure remains unclear. This paper is the first report of a 47,XXY female with ovarian failure. © 2014 S. Karger AG, Basel.
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Predicting A-to-I RNA Editing by Feature Selection and Random Forest.
PLoS ONE
PUBLISHED: 01-01-2014
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RNA editing is a post-transcriptional RNA process that provides RNA and protein complexity for regulating gene expression in eukaryotes. It is challenging to predict RNA editing by computational methods. In this study, we developed a novel method to predict RNA editing based on a random forest method. A careful feature selection procedure was performed based on the Maximum Relevance Minimum Redundancy (mRMR) and Incremental Feature Selection (IFS) algorithms. Eighteen optimal features were selected from the 77 features in our dataset and used to construct a final predictor. The accuracy and MCC (Matthews correlation coefficient) values for the training dataset were 0.866 and 0.742, respectively; for the testing dataset, the accuracy and MCC were 0.876 and 0.576, respectively. The performance was higher using 18 features than all 77, suggesting that a small feature set was sufficient to achieve accurate prediction. Analysis of the 18 features was performed and may shed light on the mechanism and dominant factors of RNA editing, providing a basis for future experimental validation.
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Analysis of tumor suppressor genes based on gene ontology and the KEGG pathway.
PLoS ONE
PUBLISHED: 01-01-2014
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Cancer is a serious disease that causes many deaths every year. We urgently need to design effective treatments to cure this disease. Tumor suppressor genes (TSGs) are a type of gene that can protect cells from becoming cancerous. In view of this, correct identification of TSGs is an alternative method for identifying effective cancer therapies. In this study, we performed gene ontology (GO) and pathway enrichment analysis of the TSGs and non-TSGs. Some popular feature selection methods, including minimum redundancy maximum relevance (mRMR) and incremental feature selection (IFS), were employed to analyze the enrichment features. Accordingly, some GO terms and KEGG pathways, such as biological adhesion, cell cycle control, genomic stability maintenance and cell death regulation, were extracted, which are important factors for identifying TSGs. We hope these findings can help in building effective prediction methods for identifying TSGs and thereby, promoting the discovery of effective cancer treatments.
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Uncovering the rare variants of DLC1 isoform 1 and their functional effects in a Chinese sporadic congenital heart disease cohort.
PLoS ONE
PUBLISHED: 01-01-2014
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Congenital heart disease (CHD) is the most common birth defect affecting the structure and function of fetal hearts. Despite decades of extensive studies, the genetic mechanism of sporadic CHD remains obscure. Deleted in liver cancer 1 (DLC1) gene, encoding a GTPase-activating protein, is highly expressed in heart and essential for heart development according to the knowledge of Dlc1-deficient mice. To determine whether DLC1 is a susceptibility gene for sporadic CHD, we sequenced the coding region of DLC1 isoform 1 in 151 sporadic CHD patients and identified 13 non-synonymous rare variants (including 6 private variants) in the case cohort. Importantly, these rare variants (8/13) were enriched in the N-terminal region of the DLC1 isoform 1 protein. Seven of eight amino acids at the N-terminal variant positions were conserved among the primates. Among the 9 rare variants that were predicted as "damaging", five were located at the N-terminal region. Ensuing in vitro functional assays showed that three private variants (Met360Lys, Glu418Lys and Asp554Val) impaired the ability of DLC1 to inhibit cell migration or altered the subcellular location of the protein compared to wild-type DLC1 isoform 1. These data suggest that DLC1 might act as a CHD-associated gene in addition to its role as a tumor suppressor in cancer.
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Genes that escape x-inactivation in humans have high intraspecific variability in expression, are associated with mental impairment but are not slow evolving.
Mol. Biol. Evol.
PUBLISHED: 09-10-2013
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In female mammals most X-linked genes are subject to X-inactivation. However, in humans some X-linked genes escape silencing, these escapees being candidates for the phenotypic aberrations seen in polyX karyotypes. These escape genes have been reported to be under stronger purifying selection than other X-linked genes. Although it is known that escape from X-inactivation is much more common in humans than in mice, systematic assays of escape in humans have to date employed only interspecies somatic cell hybrids. Here we provide the first systematic next-generation sequencing analysis of escape in a human cell line. We analyzed RNA and genotype sequencing data obtained from B lymphocyte cell lines derived from Europeans (CEU) and Yorubans (YRI). By replicated detection of heterozygosis in the transcriptome, we identified 114 escaping genes, including 76 not previously known to be escapees. The newly described escape genes cluster on the X chromosome in the same chromosomal regions as the previously known escapees. There is an excess of escaping genes associated with mental retardation, consistent with this being a common phenotype of polyX phenotypes. We find both differences between populations and between individuals in the propensity to escape. Indeed, we provide the first evidence for there being both hyper- and hypo-escapee females in the human population, consistent with the highly variable phenotypic presentation of polyX karyotypes. Considering also prior data, we reclassify genes as being always, never, and sometimes escape genes. We fail to replicate the prior claim that genes that escape X-inactivation are under stronger purifying selection than others.
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Identification of hepatocellular carcinoma related genes with k-th shortest paths in a protein-protein interaction network.
Mol Biosyst
PUBLISHED: 09-02-2013
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Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide and one of the deadliest cancers in Asia. But at present, effective targets for HCC clinical therapy are still limited. The "guilt by association" rule suggests that interacting proteins share the same or similar functions and hence may be involved in the same pathway. This assumption can be used to identify disease related genes from protein association networks constructed from existing PPI data. Given the close association between Hepatitis B virus and Hepatitis B which may lead to HCC, here we develop a computational method to identify hepatocellular carcinoma related genes based on k-th shortest paths in the protein-protein interaction (PPI) network (we set k=1, 2 in this study). Finally, we found 33 genes whose p-values were less than 0.05, and most of them have been reported to be involved in HCC tumorigenesis and development. The results also provide a new reference for research into HCC oncogenesis and for development of new strategies for HCC clinical therapies.
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MicroRNA or NMD: why have two RNA silencing systems?
J Genet Genomics
PUBLISHED: 06-14-2013
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MicroRNA (miRNA)-mediated RNA silencing and nonsense-mediated decay (NMD) are two conserved RNA-level regulatory pathways. Although they are mechanically different, both can regulate target genes by RNA degradation and translational repression. Moreover, studies of individual target genes indicated that these two pathways can be involved in the same processes (e.g., development and stress responses). These facts raise an important question that whether these two systems are cooperative, interchangeable or optimal for regulation of different sorts of genes. We addressed this by comparing miRNA and NMD targets in Arabidopsis thaliana at the genome-wide scale. We find no more overlap in the genes targeted by both systems than expected by chance. Moreover, the sorts of genes or pathways regulated by these systems are categorically different on several cross-correlating fronts. While miRNA targets show enrichment in the process of development, metabolism and transcription, NMD targets are associated with stress responses but otherwise poorly annotated. Validated miRNA targets are more highly expressed, less variably expressed and slower evolving. These differences suggest that the modes of regulation need not be interchangeable. Instead, we suggest that miRNA genes are commonly dose-sensitive and require fine control of levels through weak pull-down by miRNAs. This is consistent with miRNA-regulated genes being more likely to be involved in protein-protein interactions. Many NMD-regulated genes, by contrast, have properties consistent with them being rapid emergency response "fire-fighter" genes. If true, the lack of annotation of NMD targets suggests that we poorly understand the emergencies plants face in the wild.
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Identification of two maternal transmission ratio distortion loci in pedigrees of the Framingham heart study.
Sci Rep
PUBLISHED: 01-04-2013
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Transmission ratio distortion (TRD) is indicated by the recovery of alleles in offspring in non-Mendelian proportions. An assumption of Mendelian proportion is central to many methods to identify disease-associated markers. This seems reasonable as, while TRD cases have been occasionally observed in various species few instances have been identified in humans. Here we search for evidence of paternal or maternal TRD with genome-wide SNP data of pedigrees from the Framingham Heart Study. After excluding many examples as better explained by genotyping errors we identified two maternal-specific TRD loci for autosomal SNPs rs6733122 and rs926716 (corrected P = 0.029 and P = 0.018) on LRP2 and ZNF133, respectively. The transmission ratios were as high as 1.7~1.8:1. Genotyping validation and further replication is still necessary to confirm the TRD. This study shows that there may be large-effect maternal-specific TRD loci of common SNPs in the human genome but that these are rare.
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Predicting transcriptional activity of multiple site p53 mutants based on hybrid properties.
PLoS ONE
PUBLISHED: 04-23-2011
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As an important tumor suppressor protein, reactivate mutated p53 was found in many kinds of human cancers and that restoring active p53 would lead to tumor regression. In this work, we developed a new computational method to predict the transcriptional activity for one-, two-, three- and four-site p53 mutants, respectively. With the approach from the general form of pseudo amino acid composition, we used eight types of features to represent the mutation and then selected the optimal prediction features based on the maximum relevance, minimum redundancy, and incremental feature selection methods. The Mathews correlation coefficients (MCC) obtained by using nearest neighbor algorithm and jackknife cross validation for one-, two-, three- and four-site p53 mutants were 0.678, 0.314, 0.705, and 0.907, respectively. It was revealed by the further optimal feature set analysis that the 2D (two-dimensional) structure features composed the largest part of the optimal feature set and maybe played the most important roles in all four types of p53 mutant active status prediction. It was also demonstrated by the optimal feature sets, especially those at the top level, that the 3D structure features, conservation, physicochemical and biochemical properties of amino acid near the mutation site, also played quite important roles for p53 mutant active status prediction. Our study has provided a new and promising approach for finding functionally important sites and the relevant features for in-depth study of p53 protein and its action mechanism.
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Genome-wide interaction-based association analysis identified multiple new susceptibility Loci for common diseases.
PLoS Genet.
PUBLISHED: 02-15-2011
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Genome-wide interaction-based association (GWIBA) analysis has the potential to identify novel susceptibility loci. These interaction effects could be missed with the prevailing approaches in genome-wide association studies (GWAS). However, no convincing loci have been discovered exclusively from GWIBA methods, and the intensive computation involved is a major barrier for application. Here, we developed a fast, multi-thread/parallel program named "pair-wise interaction-based association mapping" (PIAM) for exhaustive two-locus searches. With this program, we performed a complete GWIBA analysis on seven diseases with stringent control for false positives, and we validated the results for three of these diseases. We identified one pair-wise interaction between a previously identified locus, C1orf106, and one new locus, TEC, that was specific for Crohns disease, with a Bonferroni corrected P < 0.05 (P = 0.039). This interaction was replicated with a pair of proxy linked loci (P = 0.013) on an independent dataset. Five other interactions had corrected P < 0.5. We identified the allelic effect of a locus close to SLC7A13 for coronary artery disease. This was replicated with a linked locus on an independent dataset (P = 1.09 × 10??). Through a local validation analysis that evaluated association signals, rather than locus-based associations, we found that several other regions showed association/interaction signals with nominal P < 0.05. In conclusion, this study demonstrated that the GWIBA approach was successful for identifying novel loci, and the results provide new insights into the genetic architecture of common diseases. In addition, our PIAM program was capable of handling very large GWAS datasets that are likely to be produced in the future.
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Computational analysis of HIV-1 resistance based on gene expression profiles and the virus-host interaction network.
PLoS ONE
PUBLISHED: 01-28-2011
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A very small proportion of people remain negative for HIV infection after repeated HIV-1 viral exposure, which is called HIV-1 resistance. Understanding the mechanism of HIV-1 resistance is important for the development of HIV-1 vaccines and Acquired Immune Deficiency Syndrome (AIDS) therapies. In this study, we analyzed the gene expression profiles of CD4+ T cells from HIV-1-resistant individuals and HIV-susceptible individuals. One hundred eighty-five discriminative HIV-1 resistance genes were identified using the Minimum Redundancy-Maximum Relevance (mRMR) and Incremental Feature Selection (IFS) methods. The virus protein target enrichment analysis of the 185 HIV-1 resistance genes suggested that the HIV-1 protein nef might play an important role in HIV-1 infection. Moreover, we identified 29 infection information exchanger genes from the 185 HIV-1 resistance genes based on a virus-host interaction network analysis. The infection information exchanger genes are located on the shortest paths between virus-targeted proteins and are important for the coordination of virus infection. These proteins may be useful targets for AIDS prevention or therapy, as intervention in these pathways could disrupt communication with virus-targeted proteins and HIV-1 infection.
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Evidence for OTUD-6B participation in B lymphocytes cell cycle after cytokine stimulation.
PLoS ONE
PUBLISHED: 01-18-2011
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Deubiquitinating enzymes (DUBs) are important regulators of cell proliferation. Here we identified a functional deubiquitinating enzyme, ovarian tumor domain-containing 6B (OTUD-6B). Mutation of the conserved Cys residue abolished its deubiquitinating activity in vitro. Otud-6b expression was induced with cytokine stimulation in both mouse Ba/F3 cells and primary B lymphocytes followed a rapid decrease. This rapid decrease was partially facilitated by tristetraprolin (TTP) destabilization of Otud-6b mRNA through AU-rich motifs. Enforced expression of OTUD-6B in Ba/F3 cells could block cell proliferation by arresting cells in G1 phase. In addition, cyclin D2 level was down-regulated when OTUD-6B WT was overexpressed. Therefore, down-regulation of Otud-6b expression after prolonged cytokine stimulation may be required for cell proliferation in B lymphocytes.
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Analysis and prediction of translation rate based on sequence and functional features of the mRNA.
PLoS ONE
PUBLISHED: 01-06-2011
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Protein concentrations depend not only on the mRNA level, but also on the translation rate and the degradation rate. Prediction of mRNAs translation rate would provide valuable information for in-depth understanding of the translation mechanism and dynamic proteome. In this study, we developed a new computational model to predict the translation rate, featured by (1) integrating various sequence-derived and functional features, (2) applying the maximum relevance & minimum redundancy method and incremental feature selection to select features to optimize the prediction model, and (3) being able to predict the translation rate of RNA into high or low translation rate category. The prediction accuracies under rich and starvation condition were 68.8% and 70.0%, respectively, evaluated by jackknife cross-validation. It was found that the following features were correlated with translation rate: codon usage frequency, some gene ontology enrichment scores, number of RNA binding proteins known to bind its mRNA product, coding sequence length, protein abundance and 5UTR free energy. These findings might provide useful information for understanding the mechanisms of translation and dynamic proteome. Our translation rate prediction model might become a high throughput tool for annotating the translation rate of mRNAs in large-scale.
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Nonsense-mediated decay targets have multiple sequence-related features that can inhibit translation.
Mol. Syst. Biol.
PUBLISHED: 08-13-2010
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Nonsense-mediated mRNA decay (NMD) is a surveillance system that eliminates transcripts with premature termination codons. In this study, we show that mRNAs targeted by NMD are also suppressed at the translational level. The low translational efficiency (TE) is a consequence of multiple features acting in concert, including low translation initiation rate, mediated by 5 secondary structure and by use of weak initiation sites, and low translation elongation speed, mediated by low codon usage bias. Despite low elongation rates, NMD transcripts show low ribosome density in the coding sequence, probably owing to low initiation rates, high abortion rates or rapid transit of the ribosome following initiation failure. The low TE is observed in the absence of NMD and is not explained by low transcript abundance. Translational inefficiency is flexible, such that NMD targets have increased TE upon starvation. We propose that the low TE predisposes to NMD and/or that it is part of a mechanism for regulation of NMD transcripts.
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Prediction of deleterious non-synonymous SNPs based on protein interaction network and hybrid properties.
PLoS ONE
PUBLISHED: 06-01-2010
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Non-synonymous SNPs (nsSNPs), also known as Single Amino acid Polymorphisms (SAPs) account for the majority of human inherited diseases. It is important to distinguish the deleterious SAPs from neutral ones. Most traditional computational methods to classify SAPs are based on sequential or structural features. However, these features cannot fully explain the association between a SAP and the observed pathophysiological phenotype. We believe the better rationale for deleterious SAP prediction should be: If a SAP lies in the protein with important functions and it can change the protein sequence and structure severely, it is more likely related to disease. So we established a method to predict deleterious SAPs based on both protein interaction network and traditional hybrid properties. Each SAP is represented by 472 features that include sequential features, structural features and network features. Maximum Relevance Minimum Redundancy (mRMR) method and Incremental Feature Selection (IFS) were applied to obtain the optimal feature set and the prediction model was Nearest Neighbor Algorithm (NNA). In jackknife cross-validation, 83.27% of SAPs were correctly predicted when the optimized 263 features were used. The optimized predictor with 263 features was also tested in an independent dataset and the accuracy was still 80.00%. In contrast, SIFT, a widely used predictor of deleterious SAPs based on sequential features, has a prediction accuracy of 71.05% on the same dataset. In our study, network features were found to be most important for accurate prediction and can significantly improve the prediction performance. Our results suggest that the protein interaction context could provide important clues to help better illustrate SAPs functional association. This research will facilitate the post genome-wide association studies.
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Prediction of nucleosome positioning based on transcription factor binding sites.
PLoS ONE
PUBLISHED: 05-24-2010
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The DNA of all eukaryotic organisms is packaged into nucleosomes, the basic repeating units of chromatin. The nucleosome consists of a histone octamer around which a DNA core is wrapped and the linker histone H1, which is associated with linker DNA. By altering the accessibility of DNA sequences, the nucleosome has profound effects on all DNA-dependent processes. Understanding the factors that influence nucleosome positioning is of great importance for the study of genomic control mechanisms. Transcription factors (TFs) have been suggested to play a role in nucleosome positioning in vivo.
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Alterations to proteins in the lens of hereditary Crygs-mutated cataractous mice.
Mol. Vis.
PUBLISHED: 04-27-2010
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To investigate the altered expression of proteins in the lens of mice with inherited cataracts.
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The inhibition of CMV promoter by heat shock factor 4b is regulated by Daxx.
Int. J. Biochem. Cell Biol.
PUBLISHED: 03-29-2010
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Heat shock factor 4 (Hsf4b) has been identified as a novel cataractogenic protein whose mutation has been closely associated with hereditary cataracts in humans and animals. It acts both as a transcription activator and a transcription inhibitor in the regulation of its downstream targets during lens development. However, the signaling factors that regulate Hsf4b transcription activity are still not completely defined. Here, we found that Hsf4b, not Hsf4a (another isoform of Hsf4), acts as the inhibitor of CMV promoter as well as the activator of Hsp25 in the Hsf4-/- mouse lens epithelial cell line (mLEC/hsf4-/-). Hsf4b inhibits CMV-promoter activity by directly binding to TTCC (HSE motif) at 173-176bps in the CMV promoter. The phosphorylation of Hsf4b/S299 in the PDSM motif, which is absent in Hsf4a, participates in the negative regulation of the CMV promoter. The transcriptional inhibition of Hsf4b is associated with transcriptional inhibitor Daxx. Hsf4b can interact and co-localize with Daxx in the nucleus, and their association is regulated by the phosphorylation of Hsf4b/S299. In addition, we found that Hsf4a and Hsf1 were also associated with Daxx. However, in contrast to activating Hsf1, Daxx can repress Hsf4b-induced expression of Hsp25 in the mLEC/hsf4-/- cell line. Our results demonstrate that the transcription-inhibitory function of Hsf4b is regulated by the phosphorylation of Hsf4b/S299 and phosphorylation-dependent association with Daxx.
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Analysis and prediction of the metabolic stability of proteins based on their sequential features, subcellular locations and interaction networks.
PLoS ONE
PUBLISHED: 03-29-2010
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The metabolic stability is a very important idiosyncracy of proteins that is related to their global flexibility, intramolecular fluctuations, various internal dynamic processes, as well as many marvelous biological functions. Determination of proteins metabolic stability would provide us with useful information for in-depth understanding of the dynamic action mechanisms of proteins. Although several experimental methods have been developed to measure proteins metabolic stability, they are time-consuming and more expensive. Reported in this paper is a computational method, which is featured by (1) integrating various properties of proteins, such as biochemical and physicochemical properties, subcellular locations, network properties and protein complex property, (2) using the mRMR (Maximum Relevance & Minimum Redundancy) principle and the IFS (Incremental Feature Selection) procedure to optimize the prediction engine, and (3) being able to identify proteins among the four types: "short", "medium", "long", and "extra-long" half-life spans. It was revealed through our analysis that the following seven characters played major roles in determining the stability of proteins: (1) KEGG enrichment scores of the protein and its neighbors in network, (2) subcellular locations, (3) polarity, (4) amino acids composition, (5) hydrophobicity, (6) secondary structure propensity, and (7) the number of protein complexes the protein involved. It was observed that there was an intriguing correlation between the predicted metabolic stability of some proteins and the real half-life of the drugs designed to target them. These findings might provide useful insights for designing protein-stability-relevant drugs. The computational method can also be used as a large-scale tool for annotating the metabolic stability for the avalanche of protein sequences generated in the post-genomic age.
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Novel association strategy with copy number variation for identifying new risk Loci of human diseases.
PLoS ONE
PUBLISHED: 03-09-2010
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Copy number variations (CNV) are important causal genetic variations for human disease; however, the lack of a statistical model has impeded the systematic testing of CNVs associated with disease in large-scale cohort.
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Predicting drug-target interaction networks based on functional groups and biological features.
PLoS ONE
PUBLISHED: 02-16-2010
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Study of drug-target interaction networks is an important topic for drug development. It is both time-consuming and costly to determine compound-protein interactions or potential drug-target interactions by experiments alone. As a complement, the in silico prediction methods can provide us with very useful information in a timely manner.
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Length of the ORF, position of the first AUG and the Kozak motif are important factors in potential dual-coding transcripts.
Cell Res.
PUBLISHED: 02-16-2010
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A single mammalian transcript normally encodes one protein, but the transcript of GNAS (G-protein alpha-subunit) contains two reading frames and produces two structurally unrelated proteins, XLalphas and ALEX. No other confirmed GNAS-like dual-coding transcripts have been reported to date, even though many such candidate genes have been predicted by bioinformatics analysis. In this study, we constructed a series of vectors to test how two protein products were translated from a single transcript in vitro. The length of the ORF (open reading frame), position of the first AUG and the Kozak motif were found to be important factors. These factors, as well as 55-bp NMD (nonsense-mediated mRNA decay) rule, were used in a bioinformatics search for candidate dual-coding transcripts. A total of 1307, 750 and 474 two-ORF-containing transcripts were found in human, mouse and rat, respectively, of which 170, 89 and 70, respectively, were found to be potential dual-coding transcripts. Most transcripts showed low conservation among species. Interestingly, dual-coding transcripts were significantly enriched for transcripts from the zinc-finger protein family, which are usually DNA-binding proteins involved in regulation of the transcription process.
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Screening of Kozak-motif-located SNPs and analysis of their association with human diseases.
Biochem. Biophys. Res. Commun.
PUBLISHED: 01-01-2010
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The Kozak motif, which is located near the translational start codon, often regulates the protein translation. Moreover, it is believed that the conserved positions -3 and +4 contribute the most. Since changes that occur in this motif have a great impact on protein yield and in some cases are associated with disease, we screened the human SNP database for all Kozak-motif-located SNPs (kSNPs) and focused on the strong-changed kSNPs (sckSNPs). Many intron-located and synonymous SNPs are reported to be associated with disease, though the mechanisms underlying these associations are poorly understood. Here, we performed haplotype analysis on sckSNP-containing genes and found that there are some sckSNPs that exist in the same haplotype blocks of reported intron-located and synonymous disease-associated SNPs, indicating that those kSNPs could be a true risk factor for disease-association by affecting the efficiency of protein expression. Our findings provide a candidate explanation for how diseases are associated with intron-located and synonymous SNPs.
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Identifying protein complexes using hybrid properties.
J. Proteome Res.
PUBLISHED: 09-22-2009
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Protein complexes, integrating multiple gene products, perform all sorts of fundamental biological functions in cells. Much effort has been put into identifying protein complexes using computational approaches. A vast majority attempt to research densely connected regions in protein-protein interaction (PPI) network/graph. In this research, we try an alterative approach to analyze protein complexes using hybrid features and present a method to determine whether multiple (more than two) proteins from yeast can form a protein complex. The data set consists of 493 positive protein complexes and 9878 negative protein complexes. Every complex is represented by graph features, where proteins in the complex form a graph (web) of interactions, and features derived from biological properties including protein length, biochemical properties and physicochemical properties. These features are filtered and optimized by Minimum Redundancy Maximum Relevance method, Incremental Feature Selection and Forward Feature Selection, established through a prediction/identification model called Nearest Neighbor Algorithm. Jackknife cross-validation test is employed to evaluate the identification accuracy. As a result, the highest accuracy for the identification of the real protein complexes using filtered features is 69.17%, and feature analysis shows that, among the adopted features, graph features play the main roles in the determination of protein complexes.
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Identification of vimentin as a novel target of HSF4 in lens development and cataract by proteomic analysis.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 07-23-2009
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To explore the target genes of HSF4, especially those involved in lens developmental processes and cataract formation.
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Divergence of exonic splicing elements after gene duplication and the impact on gene structures.
Genome Biol.
PUBLISHED: 06-15-2009
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The origin of new genes and their contribution to functional novelty has been the subject of considerable interest. There has been much progress in understanding the mechanisms by which new genes originate. Here we examine a novel way that new gene structures could originate, namely through the evolution of new alternative splicing isoforms after gene duplication.
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Prediction of interactiveness of proteins and nucleic acids based on feature selections.
Mol. Divers.
PUBLISHED: 05-18-2009
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It is important to identify which proteins can interact with nucleic acids for the purpose of protein annotation, since interactions between nucleic acids and proteins involve in numerous cellular processes such as replication, transcription, splicing, and DNA repair. This research tries to identify proteins that can interact with DNA, RNA, and rRNA, respectively. mRMR (Minimum redundancy and maximum relevance), with its elegant mathematical formulation, has been applied widely in processing biological data and feature analysis since its introduction in 2005. mRMR plus incremental feature selection (IFS) is known to be very efficient in feature selection and analysis, and able to improve both effectiveness and efficiency of a prediction model. IFS is applied to decide how many features should be selected from feature list provided by mRMR. In the end, the selected features of mRMR and IFS are further refined by a conventional feature selection method--forward feature wrapper (FFW), by reordering the features. Each protein is coded by 132 features including amino acid compositions and physicochemical properties. After the feature selection, k-Nearest Neighbor algorithm, the adopted prediction model, is trained and tested. As a result, the optimized prediction accuracies for the DNA, RNA, and rRNA are 82.0, 83.4, and 92.3%, respectively. Furthermore, the most important features that contribute to the prediction are identified and analyzed biologically. The predictor, developed for this research, is available for public access at http://chemdata.shu.edu.cn/protein_na_mrmr/.
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The impact of nucleosome positioning on the organization of replication origins in eukaryotes.
Biochem. Biophys. Res. Commun.
PUBLISHED: 05-02-2009
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The distribution of DNA replication origins (ORIs) on eukaryotic chromosomes is nonrandom, but the reasons behind this are not well understood. Previous studies have suggested a prominent role of transcriptional activity in determining the ORI organization. Here, we identify nucleosome occupancy as a likely candidate to set up ORI distribution. Combining genome-wide data on nucleosome positioning and ORI organization in yeast and humans, we demonstrate that open chromatin domains, characterized by nucleosome depletion, are preferentially permissive for replication. However, contrary to priori claims, the impact of transcriptional activity is considerably weaker than previously proposed and could partly be explained by our nucleosome exclusion model. We propose that the ORI organization imposed by nucleosome positioning is phylogenetically widespread in eukaryotes.
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Dosage compensation on the active X chromosome minimizes transcriptional noise of X-linked genes in mammals.
Genome Biol.
PUBLISHED: 04-22-2009
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Theory predicts that haploid-expressed genes should have noisier expression than comparable diploid-expressed ones with the same expression level. However, in mammals there are several classes of gene that are monoallelically expressed, including X-linked genes, imprinted genes and some other autosomal genes. Does it follow that the evolution of X chromosomes in eukaryotes comes at the cost of increased transcriptional noise in the heterogametic sex? Moreover, is escaping X-inactivation in mammalian females associated with an increase in transcriptional variation? To address these questions, we analyze gene expression variation between replicate samples of diverse mammalian cell lines in steady-state using microarray data.
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Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay.
BMC Biol.
PUBLISHED: 04-21-2009
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Nonsense-mediated decay is a mechanism that degrades mRNAs with a premature termination codon. That some exons have premature termination codons at fixation is paradoxical: why make a transcript if it is only to be destroyed? One model supposes that splicing is inherently noisy and spurious transcripts are common. The evolution of a premature termination codon in a regularly made unwanted transcript can be a means to prevent costly translation. Alternatively, nonsense-mediated decay can be regulated under certain conditions so the presence of a premature termination codon can be a means to up-regulate transcripts needed when nonsense-mediated decay is suppressed.
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A novel computational approach to predict transcription factor DNA binding preference.
J. Proteome Res.
PUBLISHED: 04-07-2009
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Transcription is one of the most important processes in cell in which transcription factors translate DNA sequences into RNA sequences. Accurate prediction of DNA binding preference of transcription factors is valuable for understanding the transcription regulatory mechanism and (1) elucidating regulation network. (2-4) Here we predict the DNA binding preference of transcription factor based on the protein amino acid composition and physicochemical properties, 0/1 encoding system of nucleotide, minimum Redundancy Maximum Relevance Feature Selection method, (5) and Nearest Neighbor Algorithm. The overall prediction accuracy of Jackknife cross-validation test is 91.1%, indicating that this approach is a useful tool to explore the relation between transcription factor and its binding sites. Moreover, we find that the secondary structure and polarizability of transcriptor contribute mostly in the prediction. Especially, a 7-nt motif with AT-rich region of the DNA binding sites discovered via our method is also consistent with the statistical analysis from the TRANSFAC database. (6).
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Evidence that the nonsense-mediated mRNA decay pathway participates in X chromosome dosage compensation in mammals.
Biochem. Biophys. Res. Commun.
PUBLISHED: 03-24-2009
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Current models of X chromosome dosage compensation are usually framed by reference to how regulation in transcriptional level elevates the gene expression of the active X chromosome. This framework, however, might be oversimplified because regulation of gene expression can also act at the post-transcriptional level. Here, after a genome-wide survey, we find that autosomal genes are more likely subject to nonsense-mediated mRNA decay (NMD) than X-linked genes. Furthermore, we demonstrate that after NMD inhibition, balanced gene expression between X chromosome and autosomes is corrupted such that the global mean X/autosome gene expression ratio is decreased by 10-15%. Our results identify NMD as a post-transcription-level regulatory mechanism that contributes to the observed fine-tuning of X chromosome dosage compensation in mammals.
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Removal of Hsf4 leads to cataract development in mice through down-regulation of gamma S-crystallin and Bfsp expression.
BMC Mol. Biol.
PUBLISHED: 02-19-2009
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Heat-shock transcription factor 4 (HSF4) mutations are associated with autosomal dominant lamellar cataract and Marner cataract. Disruptions of the Hsf4 gene cause lens defects in mice, indicating a requirement for HSF4 in fiber cell differentiation during lens development. However, neither the relationship between HSF4 and crystallins nor the detailed mechanism of maintenance of lens transparency by HSF4 is fully understood.
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Stearoyl-CoA desaturase 1 deficiency protects mice from immune-mediated liver injury.
Lab. Invest.
PUBLISHED: 02-13-2009
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Immunity and metabolism are closely linked. The liver is an important metabolic organ in the body. However, the interactions between hepatocytes and the immune system are poorly understood. In mice developing concanavalin A (ConA)-induced hepatitis (CIH), we found extensive lipid accumulation in hepatocytes. Critical enzyme involved in fat synthesis such as stearoyl-CoA desaturase 1 (SCD1) was upregulated. When we injected ConA to SCD1-deficient mice, we found these mice to be highly resistant to CIH. The mechanisms of the protective effect of SCD1 deficiency might be attributed to the reduced leptin levels in those mice, which modulated critical cytokines and signaling pathways in CIH pathogenesis. In conclusion, our study suggests that SCD1 deficiency protects mice from liver injury in a leptin-dependent manner.
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miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1.
Hum. Pathol.
PUBLISHED: 02-11-2009
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Given that miR-124 is preferentially expressed in differentiating and mature neurons and external granule cells of cerebellum are thought to be cells-of-origins of medulloblastomas, we investigated if miR-124 played a role in the development of medulloblastomas. Quantitative expression analysis of 29 medulloblastomas demonstrated significant down-regulation of miR-124 in 21 (72%) tumors by at least 2-fold, with 11 of them exhibiting greater than 10-fold reduced level compared to normal cerebella (P < .01). Ectopic expression of miR-124 in medulloblastoma cell lines, ONS-76 and DAOY, inhibited cell proliferation. Using computational and expression analyses, solute carrier family 16, member 1 (SLC16A1) was identified as a candidate target of miR-124. Transfection of miR-124 resulted in down-regulation of SLC16A1 at both transcript and protein levels. Reporter assay with 3 untranslated region of SLC16A1 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-124, providing strong evidence that miR-124 is a direct regulator of SLC16A1. Expression analysis further revealed that SLC16A1 transcript was elevated in 26 (90%) of 29 tumors examined. Knockdown of SLC16A1 by siRNA induced cell death in medulloblastoma cells. SLC16A1 functions to efflux lactic acid during aerobic glycolysis. We speculated that inhibition of SLC16A1 function resulted in a decrease of intracellular pH to a lethal level. In conclusion, our study demonstrates that miR-124 deregulation is common in medulloblastomas, and restoration of its function inhibits cell proliferation, suggesting that miR-124 may act as a growth suppressor. Our findings also raise the possibility that the miR-124/SLC16A1 pathway may represent a novel therapeutic target for treatment of malignant medulloblastomas.
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Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation.
Am. J. Hum. Genet.
PUBLISHED: 01-10-2009
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Familial progressive hyperpigmentation (FPH) is an autosomal-dominantly inherited disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age. The genetic basis for FPH remains unknown. In this study, a six-generation Chinese family with FPH was subjected to a genome-wide scan for linkage analysis. Two-point linkage analysis mapped the locus for FPH at chromosome 12q21.31-q23.1, with a maximum two-point LOD score of 4.35 (Ø = 0.00) at D12S81. Haplotype analysis confined the locus within an interval of 9.09 cM, flanked by the markers D12S1667 and D12S2081. Mutation profiling of positional candidate genes detected a heterozygous transversion (c. 107A-->G) in exon 2 of the KIT ligand (KITLG) gene, predicted to result in the substitution of a serine residue for an asparagine residue at codon 36 (p.N-->S). This mutant "G" allele cosegregated perfectly with affected, but not with unaffected, members of the FPH family. Function analysis of the soluble form of sKITLG revealed that mutant sKITLGN36S increased the content of the melanin by 109% compared with the wild-type sKITLG in human A375 melanoma cells. Consistent with this result, the tyrosinase activity was significantly increased by mutant sKITLGN36S compared to wild-type control. To our knowledge, these data provided the first genetic evidence that the FPH disease is caused by the KITLGN36S mutation, which has a gain-of-function effect on the melanin synthesis and opens a new avenue for exploration of the genetic mechanism of FPH.
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Systematic analysis of human lysine acetylation proteins and accurate prediction of human lysine acetylation through bi-relative adapted binomial score Bayes feature representation.
Mol Biosyst
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Lysine acetylation is a reversible post-translational modification (PTM) which has been linked to many biological and pathological implications. Hence, localization of lysine acetylation is essential for deciphering the mechanism of such implications. Whereas many acetylated lysines in human proteins have been localized through experimental approaches in wet lab, it still fails to reach completion. In the present study, we proposed a novel feature extraction approach, bi-relative adapted binomial score Bayes (BRABSB), combined with support vector machines (SVMs) to construct a human-specific lysine acetylation predictor, which yields, on average, a sensitivity of 83.91%, a specificity of 87.25% and an accuracy of 85.58%, in the case of 5-fold cross validation experiments. Results obtained through the validation on independent data sets show that the proposed approach here outperforms other existing lysine acetylation predictors. Furthermore, due to the fact that global analysis of human lysine acetylproteins, which would ultimately facilitate the systematic investigation of the biological and pathological consequences associated with lysine acetylation events, remains to be resolved, we made an attempt to systematically analyze human lysine acetylproteins, demonstrating their diversity with respect to subcellular localization as well as biological process and predominance by "binding" in terms of molecular function. Our analysis also revealed that human lysine acetylproteins are significantly enriched in neurodegenerative disorders and cancer pathways. Remarkably, lysine acetylproteins in mitochondria are significantly related to neurodegenerative disorders and those in the nucleus are instead significantly involved in pathways in cancers, all of which might ultimately provide novel global insights into such pathological processes for the therapeutic purpose. The web server is deployed at http://www.bioinfo.bio.cuhk.edu.hk/bpbphka.
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Dysfunctions associated with methylation, microRNA expression and gene expression in lung cancer.
PLoS ONE
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Integrating high-throughput data obtained from different molecular levels is essential for understanding the mechanisms of complex diseases such as cancer. In this study, we integrated the methylation, microRNA and mRNA data from lung cancer tissues and normal lung tissues using functional gene sets. For each Gene Ontology (GO) term, three sets were defined: the methylation set, the microRNA set and the mRNA set. The discriminating ability of each gene set was represented by the Matthews correlation coefficient (MCC), as evaluated by leave-one-out cross-validation (LOOCV). Next, the MCCs in the methylation sets, the microRNA sets and the mRNA sets were ranked. By comparing the MCC ranks of methylation, microRNA and mRNA for each GO term, we classified the GO sets into six groups and identified the dysfunctional methylation, microRNA and mRNA gene sets in lung cancer. Our results provide a systematic view of the functional alterations during tumorigenesis that may help to elucidate the mechanisms of lung cancer and lead to improved treatments for patients.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.