Conserved Disease Modules Extracted From Multilayer Heterogeneous Disease and Gene Networks for Understanding Disease Mechanisms and Predicting Disease Treatments

Disease relationship studies for understanding the pathogenesis of complex diseases, diagnosis, prognosis, and drug development are important. Traditional approaches consider one type of disease data or aggregating multiple types of disease data into a single network, which results in important temporal- or context-related information loss and may distort the actual organization. Therefore, it is necessary to apply multilayer network model to consider multiple types of relationships between diseases and the important interplays between different relationships. Further, modules extracted from multilayer networks are smaller and have more overlap that better capture the actual organization. Here, we constructed a weighted four-layer disease-disease similarity network to characterize the associations at different levels between diseases. Then, a tensor-based computational framework was used to extract Conserved Disease Modules (CDMs) from the four-layer disease network. After filtering, nine significant CDMs were reserved. The statistical significance test proved the significance of the nine CDMs. Comparing with modules got from four single layer networks, CMDs are smaller, better represent the actual relationships, and contain potential disease-disease relationships. KEGG pathways enrichment analysis and literature mining further contributed to confirm that these CDMs are highly reliable. Furthermore, the CDMs can be applied to predict potential drugs for diseases. The molecular docking techniques were used to provide the direct evidence for drugs to treat related disease. Taking Rheumatoid Arthritis (RA) as a case, we found its three potential drugs Carvedilol, Metoprolol, and Ramipril. And many studies have pointed out that Carvedilol and Ramipril have an effect on RA. Overall, the CMDs extracted from multilayer networks provide us with an impressive understanding disease mechanisms from the perspective of multi-layer network and also provide an effective way to predict potential drugs for diseases based on its neighbors in a same CDM

HPV E6 induces eIF4E transcription to promote the proliferation and migration of cervical cancer

AbstractIncreasing evidence has placed eukaryotic translation initiation factor 4E (eIF4E) at the hub of tumor development and progression. Several studies have reported that eIF4E is over-expressed in cervical cancer; however, the mechanism remains elusive. The results of this study further confirm over-expression of eIF4E in cervical cancer tumors and cell lines, and we have discovered that the transcription of eIF4E is induced by protein E6 of the human papillomavirus (HPV). Moreover, regulation of eIF4E by E6 significantly influences cell proliferation, the cell cycle, migration, and apoptosis. Therefore, eIF4E emerges as a key player in tumor development and progression and a potential target for CC treatment and prevention

A global view of the oncogenic landscape in nasopharyngeal carcinoma : an integrated analysis at the genetic and expression levels

Previous studies have reported that the tumour cells of nasopharyngeal carcinoma (NPC) exhibit recurrent chromosome abnormalities. These genetic changes are broadly assumed to lead to changes in gene expression which are important for the pathogenesis of this tumour. However, this assumption has yet to be formally tested at a global level. Therefore a genome wide analysis of chromosome copy number and gene expression was performed in tumour cells micro-dissected from the same NPC biopsies. Cellular tumour suppressor and tumour-promoting genes (TSG, TPG) and Epstein-Barr Virus (EBV)-encoded oncogenes were examined. The EBV-encoded genome maintenance protein EBNA1, along with the putative oncogenes LMP1, LMP2 and BARF1 were expressed in the majority of NPCs that were analysed. Significant downregulation of expression in an average of 76 cellular TSGs per tumour was found, whilst a per-tumour average of 88 significantly upregulated, TPGs occurred. The expression of around 60% of putative TPGs and TSGs was both up-and down-regulated in different types of cancer, suggesting that the simplistic classification of genes as TSGs or TPGs may not be entirely appropriate and that the concept of context-dependent onco-suppressors may be more extensive than previously recognised. No significant enrichment of TPGs within regions of frequent genomic gain was seen but TSGs were significantly enriched within regions of frequent genomic loss. It is suggested that loss of the FHIT gene may be a driver of NPC tumourigenesis. Notwithstanding the association of TSGs with regions of genomic loss, on a gene by gene basis and excepting homozygous deletions and high-level amplification, there is very little correlation between chromosomal copy number aberrations and expression levels of TSGs and TPGs in NPC

Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors

Background Epstein-Barr Virus (EBV)-encoded RNAs (EBERs) are non-polyadenylated RNA molecules transcribed from the EBV genome by RNA polymerase III (pol III). EBERs are the most abundant viral latent gene products, although the precise mechanisms by which EBV is able to achieve such high levels of EBER expression are not fully understood. Previously EBV has been demonstrated to induce transcription factors associated with EBER expression, including pol III transcription factors and ATF-2. We have recently demonstrated that EBV-encoded nuclear antigen-1 (EBNA1) induces cellular transcription factors, and given these findings, we investigated the role of EBNA1 in induction of EBER-associated transcription factors. Results Our data confirm that in epithelial cells EBNA1 can enhance cellular pol III transcription. Transient expression of EBNA1 in Ad/AH cells stably expressing the EBERs led to induction of both EBER1 and EBER2 and conversely, expression of a dominant negative EBNA1 led to reduced EBER expression in EBV-infected Ad/AH cells. EBNA1 can induce transcription factors used by EBER genes, including TFIIIC, ATF-2 and c-Myc. A variant chromatin precipitation procedure showed that EBNA1 is associated with the promoters of these genes but not with the promoters of pol III-transcribed genes, including the EBERs themselves. Using shRNA knock-down, we confirm the significance of both ATF-2 and c-Myc in EBER expression. Further, functional induction of a c-Myc fusion protein led to increased EBER expression, providing c-Myc binding sites upstream of EBER1 were intact. In vivo studies confirm elevated levels of the 102 kD subunit of TFIIIC in the tumour cells of EBV-positive nasopharyngeal carcinoma biopsies. Conclusions Our findings reveal that EBNA1 is able to enhance EBER expression through induction of cellular transcription factors and add to the repertoire of EBNA1's transcription-regulatory properties

Complete Chloroplast Genome Sequence of the Avocado: Gene Organization, Comparative Analysis, and Phylogenetic Relationships with Other Lauraceae

The complete chloroplast sequence of the avocado (Persea americana Mill.), a popular tropical fruit tree, was determined in this study. The plastome consists of 152,723 bp, with a typical circular structure including inverted repeats (IRs) 40,104 bp in length separated by a large single-copy region (LSC) and a small single-copy region (SSC) of 93,795 bp and 18,824 bp, respectively. Potential mutation sites including 61 repeats and 679 SSRs were accurately located in the avocado plastome. Compared with the plastomes of five other related Lauraceae, 25 highly variable regions and six micro-inversions were identified and the contraction event of the IR regions was observed. However, the plastomes of Lauraceae are extremely evolutionarily conservative with only 0.32% sequence divergence, which is surprisingly low for angiosperms. Further phylogenetic analyses were conducted using eight complete plastomes of Lauraceae and seven barcoding sequences from 23 Persea species. These data support a close relationship between the genera Persea and Machilus, and suggest that Persea is polyphyletic.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Complete plastid genome sequences of three tropical Alseodaphne trees in the family Lauraceae

Alseodaphne is a genus of timber trees (ca. 40 spp.) belonging to the Persea group of the Lauraceae. It is widely distributed in tropical Asia, but is often confused with Dehaasia and Nothaphoebe, and the systematics of the genus is unclear. Here, the complete chloroplast genome sequences of A. semecarpifolia will be reported, the type species of Alseodaphne, and two China-endemic species, A. gracilis and A. huanglianshanensis. The three plastomes were 153 051 bp, 153 099 bp and 153 070 bp, respectively. Comparative genomic analyses indicate that the three Alseodaphne plastomes have similar genome size and those are very different with previously published plastomes of Lauraceae in length. The length difference is directly caused by inverted repeats expansion/contraction. Four highly variable loci including psbD-trnM, ndhF-rpl32, rpl32-trnL and ycf1 among the three Alseodaphne species were identified as useful plastid candidate barcodes for Alseodaphne and Lauraceae species. Phylogenetic analyses based on 12 complete plastomes of Lauraceae species confirm a monophyletic Persea group comprising species of Alseodaphne, Phoebe, Persea and Machilus