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1.  A Combinational Strategy upon RNA Sequencing and Peptidomics Unravels a Set of Novel Toxin Peptides in Scorpion Mesobuthus martensii 
Toxins  2016;8(10):286.
Scorpion venom is deemed to contain many toxic peptides as an important source of natural compounds. Out of the two hundred proteins identified in Mesobuthus martensii (M. martensii), only a few peptide toxins have been found so far. Herein, a combinational approach based upon RNA sequencing and Liquid chromatography-mass spectrometry/mass spectrometry (LC MS/MS) was employed to explore the venom peptides in M. martensii. A total of 153 proteins were identified from the scorpion venom, 26 previously known and 127 newly identified. Of the novel toxins, 97 proteins exhibited sequence similarities to known toxins, and 30 were never reported. Combining peptidomic and transcriptomic analyses, the peptide sequence of BmKKx1 was reannotated and four disulfide bridges were confirmed within it. In light of the comparison of conservation and variety of toxin amino acid sequences, highly conserved and variable regions were perceived in 24 toxins that were parts of two sodium channel and two potassium channel toxins families. Taking all of this evidences together, the peptidomic analysis on M. martensii indeed identified numerous novel scorpion peptides, expanded our knowledge towards the venom diversity, and afforded a set of pharmaceutical candidates.
doi:10.3390/toxins8100286
PMCID: PMC5086646  PMID: 27782050
scorpion; peptidomics; toxins; diversity
2.  PGA: an R/Bioconductor package for identification of novel peptides using a customized database derived from RNA-Seq 
BMC Bioinformatics  2016;17:244.
Background
Peptide identification based upon mass spectrometry (MS) is generally achieved by comparison of the experimental mass spectra with the theoretically digested peptides derived from a reference protein database. Obviously, this strategy could not identify peptide and protein sequences that are absent from a reference database. A customized protein database on the basis of RNA-Seq data is thus proposed to assist with and improve the identification of novel peptides. Correspondingly, development of a comprehensive pipeline, which provides an end-to-end solution for novel peptide detection with the customized protein database, is necessary.
Results
A pipeline with an R package, assigned as a PGA utility, was developed that enables automated treatment to the tandem mass spectrometry (MS/MS) data acquired from different MS platforms and construction of customized protein databases based on RNA-Seq data with or without a reference genome guide. Hence, PGA can identify novel peptides and generate an HTML-based report with a visualized interface. On the basis of a published dataset, PGA was employed to identify peptides, resulting in 636 novel peptides, including 510 single amino acid polymorphism (SAP) peptides, 2 INDEL peptides, 49 splice junction peptides, and 75 novel transcript-derived peptides. The software is freely available from http://bioconductor.org/packages/PGA/, and the example reports are available at http://wenbostar.github.io/PGA/.
Conclusions
The pipeline of PGA, aimed at being platform-independent and easy-to-use, was successfully developed and shown to be capable of identifying novel peptides by searching the customized protein database derived from RNA-Seq data.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-016-1133-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-016-1133-3
PMCID: PMC4912784  PMID: 27316337
Proteomics; RNA-Seq; MS/MS; Peptide identification; Proteogenomics
3.  MicroRNA-320a promotes 5-FU resistance in human pancreatic cancer cells 
Scientific Reports  2016;6:27641.
The drug-resistance of pancreatic cancer cells results in poor therapeutic effect. To predict the therapeutic effect of the chemotherapy drugs to specific patients and to reverse the resistance of pancreatic cancer cells are critical for chemotherapy of pancreatic cancer. MicroRNAs (miRNAs) have been reported to play important roles in the genesis of drug-resistance of various cancer types. There are also many advantages of miRNAs in diagnosis and therapy of disease. Although several miRNAs regulating 5-Fluorouracil (5-FU) resistance in human pancreatic cancer have been reported, the detailed molecular mechanism remains to be determined. In this study, we found that miR-320a was significantly up-regulated in 5-FU resistant pancreatic cancer cells. Over-expression of miR-320a strongly contributed to pathogenesis of pancreatic cancer, which was represented by the increased proliferation, invasion, metastasis, drug-resistance characteristics and the epithelial-to-mesenchymal transition. Furthermore, we demonstrated that miR-320a was able to bind to 3′UTR of PDCD4 mRNA, and mediated its down-regulation in 5-FU resistance of human pancreatic cancer cells. Whereas restoration of PDCD4 expression could partially attenuate the function of miR-320a in pancreatic cancer. Taken together, our study demonstrated that miR-320a played important role in regulating 5-FU resistance by targeting PDCD4 and might be developed as new therapeutic target for pancreatic cancer.
doi:10.1038/srep27641
PMCID: PMC4899709  PMID: 27279541
4.  The levels of serine proteases in colon tissue interstitial fluid and serum serve as an indicator of colorectal cancer progression 
Oncotarget  2016;7(22):32592-32606.
The proteins in tissue interstitial fluids (TIFs) can spread into the blood and have been proposed as an ideal material to find blood biomarkers. The colon TIFs were collected from 8-, 13-, 18-, and 22-week ApcMin/+, a typical mouse model of colorectal cancer (CRC), and wild-type mice. iTRAQ-based quantification proteomics was conducted to survey the TIF proteins whose abundance appeared to depend on tumor progression. A total of 46 proteins that exhibited consecutive changes in abundance were identified, including six serine proteases, chymotrypsin-like elastase 1 (CELA1), chymotrypsin-like elastase 2A (CEL2A), chymopasin, chymotrypsinogen B (CTRB1), trypsin 2 (TRY2), and trypsin 4 (TRY4). The observed increases in the abundance of serine proteases were supported in another quantitative evaluation of the individual colon TIFs using a multiple reaction monitor (MRM) assay. Importantly, the increases in the abundance of serine proteases were also verified in the corresponding sera. The quantitative verification of the serine proteases was further extended to the clinical sera, revealing significantly higher levels of CELA1, CEL2A, CTRL/chymopasin, and TRY2 in CRC patients. The receiver operating characteristic analysis illustrated that the combination of CELA1 and CTRL reached the best diagnostic performance, with 90.0% sensitivity and 80.0% specificity. Thus, the quantitative target analysis demonstrated that some serine proteases are indicative of CRC progression.
doi:10.18632/oncotarget.8693
PMCID: PMC5078036  PMID: 27081040
tissue interstitial fluid; serum; colorectal cancer; biomarker; serine proteases
5.  The roles of AKR1C1 and AKR1C2 in ethyl-3,4-dihydroxybenzoate induced esophageal squamous cell carcinoma cell death 
Oncotarget  2016;7(16):21542-21555.
The aldo-keto reductase (AKR) superfamily of enzymes is critical for the detoxification of drugs and toxins in the human body; these enzymes are involved not only in the development of drug resistance in cancer cells but also in the metabolism of polycyclic aromatic hydrocarbons. Here, we demonstrated that AKR1C1/C2 increased the metabolism of ethyl-3,4-dihydroxybenzoate (EDHB) in esophageal squamous cell carcinoma (ESCC) cells. Previous studies have shown that EDHB can effectively induce esophageal cancer cell autophagy and apoptosis, and the AKR1C family represents one set of highly expressed genes after EDHB treatment. To explore the cytotoxic effects of EDHB, esophageal cancer cells with higher (KYSE180) or lower (KYSE510) AKR1C expression levels were evaluated in this study. The proliferation of KYSE180 cells was inhibited more effectively than that of KYSE510 cells by EDHB treatment. Furthermore, the effective subunits of the AKR superfamily, AKR1C1/C2, were quantitatively identified using multiple reaction monitoring (MRM) assays. The sensitivity of esophageal cancer cells to EDHB was significantly attenuated by the siRNA knockdown of AKR1C1/C2. Moreover, the expression of autophagy inducers (Beclin, LC3II and BNIP3) and NDRG1 was significantly elevated in KYSE180 cells, but not in KYSE510 cells, after EDHB treatment. When autophagy was inhibited by 3-methyladenine, KYSE180 cells exhibited an increased sensitivity to EDHB, which may be a metabolic substrate of AKR1C1/C2. These results indicated that ESCC patients with high AKR1C1/C2 expression may be more sensitive to EDHB, and AKR1C1/C2 may facilitate EDHB-induced autophagy and apoptosis, thus providing potential guidance for the chemoprevention of ESCC.
doi:10.18632/oncotarget.7775
PMCID: PMC5008304  PMID: 26934124
aldo-keto reductase 1C1/C2; ethyl-3; 4-dihydroxybenzoate; MRM; ESCC
6.  Photo-induced transformation process at gold clusters-semiconductor interface: Implications for the complexity of gold clusters-based photocatalysis 
Scientific Reports  2016;6:22742.
The recent thrust in utilizing atomically precise organic ligands protected gold clusters (Au clusters) as photosensitizer coupled with semiconductors for nano-catalysts has led to the claims of improved efficiency in photocatalysis. Nonetheless, the influence of photo-stability of organic ligands protected-Au clusters at the Au/semiconductor interface on the photocatalytic properties remains rather elusive. Taking Au clusters–TiO2 composites as a prototype, we for the first time demonstrate the photo-induced transformation of small molecular-like Au clusters to larger metallic Au nanoparticles under different illumination conditions, which leads to the diverse photocatalytic reaction mechanism. This transformation process undergoes a diffusion/aggregation mechanism accompanied with the onslaught of Au clusters by active oxygen species and holes resulting from photo-excited TiO2 and Au clusters. However, such Au clusters aggregation can be efficiently inhibited by tuning reaction conditions. This work would trigger rational structural design and fine condition control of organic ligands protected-metal clusters-semiconductor composites for diverse photocatalytic applications with long-term photo-stability.
doi:10.1038/srep22742
PMCID: PMC4780007  PMID: 26947754
7.  sapFinder: an R/Bioconductor package for detection of variant peptides in shotgun proteomics experiments 
Bioinformatics  2014;30(21):3136-3138.
Summary: Single nucleotide variations (SNVs) located within a reading frame can result in single amino acid polymorphisms (SAPs), leading to alteration of the corresponding amino acid sequence as well as function of a protein. Accurate detection of SAPs is an important issue in proteomic analysis at the experimental and bioinformatic level. Herein, we present sapFinder, an R software package, for detection of the variant peptides based on tandem mass spectrometry (MS/MS)-based proteomics data. This package automates the construction of variation-associated databases from public SNV repositories or sample-specific next-generation sequencing (NGS) data and the identification of SAPs through database searching, post-processing and generation of HTML-based report with visualized interface.
Availability and implementation: sapFinder is implemented as a Bioconductor package in R. The package and the vignette can be downloaded at http://bioconductor.org/packages/devel/bioc/html/sapFinder.html and are provided under a GPL-2 license.
Contact: siqiliu@genomics.cn
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu397
PMCID: PMC4609003  PMID: 25053745
8.  Multimodal neuroimaging computing: the workflows, methods, and platforms 
Brain Informatics  2015;2:181-195.
The last two decades have witnessed the explosive growth in the development and use of noninvasive neuroimaging technologies that advance the research on human brain under normal and pathological conditions. Multimodal neuroimaging has become a major driver of current neuroimaging research due to the recognition of the clinical benefits of multimodal data, and the better access to hybrid devices. Multimodal neuroimaging computing is very challenging, and requires sophisticated computing to address the variations in spatiotemporal resolution and merge the biophysical/biochemical information. We review the current workflows and methods for multimodal neuroimaging computing, and also demonstrate how to conduct research using the established neuroimaging computing packages and platforms.
doi:10.1007/s40708-015-0020-4
PMCID: PMC4737665  PMID: 26870630
Multimodal; Neuroimaging; Medical image computing
9.  Multimodal neuroimaging computing: the workflows, methods, and platforms 
Brain Informatics  2015;2(3):181-195.
The last two decades have witnessed the explosive growth in the development and use of noninvasive neuroimaging technologies that advance the research on human brain under normal and pathological conditions. Multimodal neuroimaging has become a major driver of current neuroimaging research due to the recognition of the clinical benefits of multimodal data, and the better access to hybrid devices. Multimodal neuroimaging computing is very challenging, and requires sophisticated computing to address the variations in spatiotemporal resolution and merge the biophysical/biochemical information. We review the current workflows and methods for multimodal neuroimaging computing, and also demonstrate how to conduct research using the established neuroimaging computing packages and platforms.
doi:10.1007/s40708-015-0020-4
PMCID: PMC4737665  PMID: 26870630
Multimodal; Neuroimaging; Medical image computing
10.  Multimodal neuroimaging computing: a review of the applications in neuropsychiatric disorders 
Brain Informatics  2015;2:167-180.
Multimodal neuroimaging is increasingly used in neuroscience research, as it overcomes the limitations of individual modalities. One of the most important applications of multimodal neuroimaging is the provision of vital diagnostic data for neuropsychiatric disorders. Multimodal neuroimaging computing enables the visualization and quantitative analysis of the alterations in brain structure and function, and has reshaped how neuroscience research is carried out. Research in this area is growing exponentially, and so it is an appropriate time to review the current and future development of this emerging area. Hence, in this paper, we review the recent advances in multimodal neuroimaging (MRI, PET) and electrophysiological (EEG, MEG) technologies, and their applications to the neuropsychiatric disorders. We also outline some future directions for multimodal neuroimaging where researchers will design more advanced methods and models for neuropsychiatric research.
doi:10.1007/s40708-015-0019-x
PMCID: PMC4737664  PMID: 26870629
Multimodal; Neuroimaging; Neuropsychiatric
11.  Multimodal neuroimaging computing: a review of the applications in neuropsychiatric disorders 
Brain Informatics  2015;2(3):167-180.
Multimodal neuroimaging is increasingly used in neuroscience research, as it overcomes the limitations of individual modalities. One of the most important applications of multimodal neuroimaging is the provision of vital diagnostic data for neuropsychiatric disorders. Multimodal neuroimaging computing enables the visualization and quantitative analysis of the alterations in brain structure and function, and has reshaped how neuroscience research is carried out. Research in this area is growing exponentially, and so it is an appropriate time to review the current and future development of this emerging area. Hence, in this paper, we review the recent advances in multimodal neuroimaging (MRI, PET) and electrophysiological (EEG, MEG) technologies, and their applications to the neuropsychiatric disorders. We also outline some future directions for multimodal neuroimaging where researchers will design more advanced methods and models for neuropsychiatric research.
doi:10.1007/s40708-015-0019-x
PMCID: PMC4737664  PMID: 26870629
Multimodal; Neuroimaging; Neuropsychiatric
12.  The other side of the coin 
Cell Cycle  2014;13(11):1677-1693.
Although cancer-regulatory genes are dichotomized to oncogenes and tumor-suppressor gene s, in reality they can be oncogenic in one situation but tumor-suppressive in another. This dual-function nature, which sometimes hampers our understanding of tumor biology, has several manifestations: (1) Most canonically defined genes have multiple mRNAs, regulatory RNAs, protein isoforms, and posttranslational modifications; (2) Genes may interact at different levels, such as by forming chimeric RNAs or by forming different protein complexes; (3) Increased levels of tumor-suppressive genes in normal cells drive proliferation of cancer progenitor cells in the same organ or tissue by imposing compensatory proliferation pressure, which presents the dual-function nature as a cell–cell interaction. All these manifestations of dual functions can find examples in the genes along the CCND–CDK4/6–RB axis. The dual-function nature also underlies the heterogeneity of cancer cells. Gene-targeting chemotherapies, including that targets CDK4, are effective to some cancer cells but in the meantime may promote growth or progression of some others in the same patient. Redefining “gene” by considering each mRNA, regulatory RNA, protein isoform, and posttranslational modification from the same genomic locus as a “gene” may help in better understanding tumor biology and better selecting targets for different sub-populations of cancer cells in individual patients for personalized therapy.
doi:10.4161/cc.29082
PMCID: PMC4111714  PMID: 24799665
CDK4; cyclin D1; oncogenes; tumor-suppressor gene s; targeted chemotherapy; radiation therapy
13.  Multi-Modal Neuroimaging Feature Learning for Multi-Class Diagnosis of Alzheimer’s Disease 
The accurate diagnosis of Alzheimers disease (AD) is essential for patient care and will be increasingly important as disease modifying agents become available, early in the course of the disease. Although studies have applied machine learning methods for the computer aided diagnosis (CAD) of AD, a bottleneck in the diagnostic performance was shown in previous methods, due to the lacking of efficient strategies for representing neuroimaging biomarkers. In this study, we designed a novel diagnostic framework with deep learning architecture to aid the diagnosis of AD. This framework uses a zero-masking strategy for data fusion to extract complementary information from multiple data modalities. Compared to the previous state-of-the-art workflows, our method is capable of fusing multi-modal neuroimaging features in one setting and has the potential to require less labelled data. A performance gain was achieved in both binary classification and multi-class classification of AD. The advantages and limitations of the proposed framework are discussed.
doi:10.1109/TBME.2014.2372011
PMCID: PMC4394860  PMID: 25423647
Alzheimer’s Disease; Classification; Neuroimaging; MRI; PET; Deep Learning
14.  Prion-like Polymerization Underlies Signal Transduction in Antiviral Immune Defense and Inflammasome Activation 
Cell  2014;156(6):1207-1222.
SUMMARY
Pathogens and cellular danger signals activate sensors such as RIG-I and NLRP3 to produce robust immune and inflammatory responses through respective adaptor proteins MAVS and ASC, which harbor essential N-terminal CARD and PYRIN domains, respectively. Here, we show that CARD and PYRIN function as bona fide prions in yeast and their prion forms are inducible by their respective upstream activators. Likewise, a yeast prion domain can functionally replace CARD and PYRIN in mammalian cell signaling. Mutations in MAVS and ASC that disrupt their prion activities in yeast also abrogate their ability to signal in mammalian cells. Furthermore, fibers of recombinant PYRIN can convert ASC into functional polymers capable of activating caspase-1. Remarkably, a conserved fungal NOD-like receptor and prion pair can functionally reconstitute signaling of NLRP3 and ASC PYRINs in mammalian cells. These results indicate that prion-like polymerization is a conserved signal transduction mechanism in innate immunity and inflammation.
doi:10.1016/j.cell.2014.01.063
PMCID: PMC4034535  PMID: 24630723
15.  The S-Nitrosylation Status of PCNA Localized in Cytosol Impacts the Apoptotic Pathway in a Parkinson’s Disease Paradigm 
PLoS ONE  2015;10(2):e0117546.
It is generally accepted that nitric oxide (NO) or its derivatives, reactive nitrogen species (RNS), are involved in the development of Parkinson’s disease (PD). Recently, emerging evidence in the study of PD has indicated that protein S-nitrosylation triggers the signaling changes in neurons. In this study, SH-SY5Y cells treated with rotenone were used as a model of neuronal death in PD. The treated cells underwent significant apoptosis, which was accompanied by an increase in intracellular NO in a rotenone dose-dependent manner. The CyDye switch approach was employed to screen for changes in S-nitrosylated (SNO) proteins in response to the rotenone treatment. Seven proteins with increased S-nitrosylation were identified in the treated SH-SY5Y cells, which included proliferating cell nuclear antigen (PCNA). Although PCNA is generally located in the nucleus and participates in DNA replication and repair, significant PCNA was identified in the SH-SY5Y cytosol. Using immunoprecipitation and pull-down approaches, PCNA was found to interact with caspase-9; using mass spectrometry, the two cysteine residues PCNA-Cys81 and -Cys162 were identified as candidate S-nitrosylated residues. In addition, the evidence obtained from in vitro and the cell model studies indicated that the S-nitrosylation of PCNA-Cys81 affected the interaction between PCNA and caspase-9. Furthermore, the interaction of PCNA and caspase-9 partially blocked caspase-9 activation, indicating that the S-nitrosylation of cytosolic PCNA may be a mediator of the apoptotic pathway.
doi:10.1371/journal.pone.0117546
PMCID: PMC4326459  PMID: 25675097
16.  Hypothesis: Artifacts, Including Spurious Chimeric RNAs with a Short Homologous Sequence, Caused by Consecutive Reverse Transcriptions and Endogenous Random Primers 
Journal of Cancer  2015;6(6):555-567.
Recent RNA-sequencing technology and associated bioinformatics have led to identification of tens of thousands of putative human chimeric RNAs, i.e. RNAs containing sequences from two different genes, most of which are derived from neighboring genes on the same chromosome. In this essay, we redefine “two neighboring genes” as those producing individual transcripts, and point out two known mechanisms for chimeric RNA formation, i.e. transcription from a fusion gene or trans-splicing of two RNAs. By our definition, most putative RNA chimeras derived from canonically-defined neighboring genes may either be technical artifacts or be cis-splicing products of 5'- or 3'-extended RNA of either partner that is redefined herein as an unannotated gene, whereas trans-splicing events are rare in human cells. Therefore, most authentic chimeric RNAs result from fusion genes, about 1,000 of which have been identified hitherto. We propose a hypothesis of “consecutive reverse transcriptions (RTs)”, i.e. another RT reaction following the previous one, for how most spurious chimeric RNAs, especially those containing a short homologous sequence, may be generated during RT, especially in RNA-sequencing wherein RNAs are fragmented. We also point out that RNA samples contain numerous RNA and DNA shreds that can serve as endogenous random primers for RT and ensuing polymerase chain reactions (PCR), creating artifacts in RT-PCR.
doi:10.7150/jca.11997
PMCID: PMC4439942  PMID: 26000048
artifacts; chimeric RNAs; endogenous random primers
17.  Identification of Differentially-expressed Genes in Intestinal Gastric Cancer by Microarray Analysis 
Gastric cancer (GC) is one of the most frequent malignant tumors. In order to systematically characterize the cellular and molecular mechanisms of intestinal GC development, in this study, we used 22 K oligonucleotide microarrays and bioinformatics analysis to evaluate the gene expression profiles of GC in 45 tissue samples, including 20 intestinal GC tissue samples, 20 normal appearing tissues (NATs) adjacent to tumors and 5 noncancerous gastric mucosa tissue samples. These profiles allowed us to explore the transcriptional characteristics of GC and determine the change patterns in gene expression that may be of clinical significance. 1519 and 1255 differentially-expressed genes (DEGs) were identified in intestinal GC tissues and NATs, respectively, as determined by Bayesian analysis (P < 0.001). These genes were associated with diverse functions such as mucosa secretion, metabolism, proliferation, signaling and development, which occur at different stages of GC development.
doi:10.1016/j.gpb.2014.09.004
PMCID: PMC4411479  PMID: 25500430
Gastric cancer development; Microarray; Gene expression profile
18.  Genetic diversity and population structure of Rheum tanguticum (Dahuang) in China 
Chinese Medicine  2014;9:26.
Background
Wild Rheum tanguticum (Dahuang in Chinese) has becoming endangered in China. This study aims to examine the genetic structure and genetic diversity of R. tanguticum within species, and the genetic differentiation within and among populations in China.
Methods
The variability and structure of 19 populations of R. tanguticum were investigated by their chloroplast DNA matK sequences. The genetic diversity index was calculated by Dnasp, PERMUT, and Arlequin 3.0 software, and a neighbor-joining (NJ)-tree was constructed by MEGA 5.0 software.
Results
Fifteen haplotypes were obtained based on the matK sequence analysis. The mean genetic diversity within species was 0.894, and the genetic variability among populations (67.6%) was relatively higher than that within populations (13.88%) according to the AMOVA and PERMUT analyses. The NJ-tree and a pairwise difference analysis indicated geographical isolation of R. tanguticum. The gene flow among populations was 0.05, indicating a genetic drift among some populations, which was also confirmed by the NJ-tree and haplotype distributions. Furthermore, a mismatch distribution analysis revealed the molecular evolution of R. tanguticum.
Conclusion
Genetic diversity among and within populations of R. tanguticum in China was demonstrated.
doi:10.1186/1749-8546-9-26
PMCID: PMC4223855  PMID: 25383092
19.  Just like the rest of evolution in Mother Nature, the evolution of cancers may be driven by natural selection, and not by haphazard mutations 
Oncoscience  2014;1(9):580-590.
Sporadic carcinogenesis starts from immortalization of a differentiated somatic cell or an organ-specific stem cell. The immortalized cell incepts a new or quasinew organism that lives like a parasite in the patient and usually proceeds to progressive simplification, constantly engendering intermediate organisms that are simpler than normal cells. Like organismal evolution in Mother Nature, this cellular simplification is a process of Darwinian selection of those mutations with growth- or survival-advantages, from numerous ones that occur randomly and stochastically. Therefore, functional gain of growth- or survival-sustaining oncogenes and functional loss of differentiation-sustaining tumor suppressor genes, which are hallmarks of cancer cells and contribute to phenotypes of greater malignancy, are not drivers of carcinogenesis but are results from natural selection of advantageous mutations. Besides this mutation-load dependent survival mechanism that is evolutionarily low and of an asexual nature, cancer cells may also use cell fusion for survival, which is an evolutionarily-higher mechanism and is of a sexual nature. Assigning oncogenes or tumor suppressor genes or their mutants as drivers to induce cancer in animals may somewhat coerce them to create man-made oncogenic pathways that may not really be a course of sporadic cancer formations in the human.
PMCID: PMC4278337  PMID: 25594068
evolution; cancer; oncogenes; tumor suppressor genes; mutation
20.  Necrosis, and then stress induced necrosis-like cell death, but not apoptosis, should be the preferred cell death mode for chemotherapy: clearance of a few misconceptions 
Oncoscience  2014;1(6):407-422.
Cell death overarches carcinogenesis and is a center of cancer researches, especially therapy studies. There have been many nomenclatures on cell death, but only three cell death modes are genuine, i.e. apoptosis, necrosis and stress-induced cell death (SICD). Like apoptosis, SICD is programmed. Like necrosis, SICD is a pathological event and may trigger regeneration and scar formation. Therefore, SICD has subtypes of stress-induced apoptosis-like cell death (SIaLCD) and stress-induced necrosis-like cell death (SInLCD). Whereas apoptosis removes redundant but healthy cells, SICD removes useful but ill or damaged cells. Many studies on cell death involve cancer tissues that resemble parasites in the host patients, which is a complicated system as it involves immune clearance of the alien cancer cells by the host. Cancer resembles an evolutionarily lower-level organism having a weaker apoptosis potential and poorer DNA repair mechanisms. Hence, targeting apoptosis for cancer therapy, i.e. killing via SIaLCD, will be less efficacious and more toxic. On the other hand, necrosis of cancer cells releases cellular debris and components to stimulate immune function, thus counteracting therapy-caused immune suppression and making necrosis better than SIaLCD for chemo drug development.
PMCID: PMC4284620  PMID: 25594039
Apoptosis; Cancer therapy; Carcinogenesis; Evolution; Hyperthermia
21.  Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes 
Genome Biology  2014;15(2):R36.
Background
Although it has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified. Recent advances in high-throughput sequencing have made it feasible to analyze genome-wide patterns of genetic variation in human populations. Since traditionally such studies surveyed only a small fraction of the genome, interpretation of the results was limited.
Results
We report here the results of the first whole genome resequencing-based analysis identifying genes that likely modulate high altitude adaptation in native Ethiopians residing at 3,500 m above sea level on Bale Plateau or Chennek field in Ethiopia. Using cross-population tests of selection, we identify regions with a significant loss of diversity, indicative of a selective sweep. We focus on a 208 kbp gene-rich region on chromosome 19, which is significant in both of the Ethiopian subpopulations sampled. This region contains eight protein-coding genes and spans 135 SNPs. To elucidate its potential role in hypoxia tolerance, we experimentally tested whether individual genes from the region affect hypoxia tolerance in Drosophila. Three genes significantly impact survival rates in low oxygen: cic, an ortholog of human CIC, Hsl, an ortholog of human LIPE, and Paf-AHα, an ortholog of human PAFAH1B3.
Conclusions
Our study reveals evolutionarily conserved genes that modulate hypoxia tolerance. In addition, we show that many of our results would likely be unattainable using data from exome sequencing or microarray studies. This highlights the importance of whole genome sequencing for investigating adaptation by natural selection.
doi:10.1186/gb-2014-15-2-r36
PMCID: PMC4054780  PMID: 24555826
22.  NitroDIGE analysis reveals inhibition of protein S-nitrosylation by epigallocatechin gallates in lipopolysaccharide-stimulated microglial cells 
Background
Nitric oxide (NO) is a signaling molecule regulating numerous cellular functions in development and disease. In the brain, neuronal injury or neuroinflammation can lead to microglial activation, which induces NO production. NO can react with critical cysteine thiols of target proteins forming S-nitroso-proteins. This modification, known as S-nitrosylation, is an evolutionarily conserved redox-based post-translational modification (PTM) of specific proteins analogous to phosphorylation. In this study, we describe a protocol for analyzing S-nitrosylation of proteins using a gel-based proteomic approach and use it to investigate the modes of action of a botanical compound found in green tea, epigallocatechin-3-gallate (EGCG), on protein S-nitrosylation after microglial activation.
Methods/Results
To globally and quantitatively analyze NO-induced protein S-nitrosylation, the sensitive gel-based proteomic method, termed NitroDIGE, was developed by combining two-dimensional differential in-gel electrophoresis (2-D DIGE) with the modified biotin switch technique (BST) using fluorescence-tagged CyDye™ thiol reactive agents to label S-nitrosothiols. The NitroDIGE method showed high specificity and sensitivity in detecting S-nitrosylated proteins (SNO-proteins). Using this approach, we identified a subset of SNO-proteins ex vivo by exposing immortalized murine BV-2 microglial cells to a physiological NO donor, or in vivo by exposing BV-2 cells to endotoxin lipopolysaccharides (LPS) to induce a proinflammatory response. Moreover, EGCG was shown to attenuate S-nitrosylation of proteins after LPS-induced activation of microglial cells primarily by modulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress response.
Conclusions
These results demonstrate that NitroDIGE is an effective proteomic strategy for “top-down” quantitative analysis of protein S-nitrosylation in multi-group samples in response to nitrosative stress due to excessive generation of NO in cells. Using this approach, we have revealed the ability of EGCG to down-regulate protein S-nitrosylation in LPS-stimulated BV-2 microglial cells, consistent with its known antioxidant effects.
doi:10.1186/1742-2094-11-17
PMCID: PMC3922161  PMID: 24472655
Epigallocatechin-3-gallate; Lipopolysaccharides; Microglia; Neuroinflammation; Nitric oxide; S-Nitrosylation
23.  RiceWiki: a wiki-based database for community curation of rice genes 
Nucleic Acids Research  2013;42(Database issue):D1222-D1228.
Rice is the most important staple food for a large part of the world’s human population and also a key model organism for biological studies of crops as well as other related plants. Here we present RiceWiki (http://ricewiki.big.ac.cn), a wiki-based, publicly editable and open-content platform for community curation of rice genes. Most existing related biological databases are based on expert curation; with the exponentially exploding volume of rice knowledge and other relevant data, however, expert curation becomes increasingly laborious and time-consuming to keep knowledge up-to-date, accurate and comprehensive, struggling with the flood of data and requiring a large number of people getting involved in rice knowledge curation. Unlike extant relevant databases, RiceWiki features harnessing collective intelligence in community curation of rice genes, quantifying users' contributions in each curated gene and providing explicit authorship for each contributor in any given gene, with the aim to exploit the full potential of the scientific community for rice knowledge curation. Based on community curation, RiceWiki bears the potential to make it possible to build a rice encyclopedia by and for the scientific community that harnesses community intelligence for collaborative knowledge curation, covers all aspects of biological knowledge and keeps evolving with novel knowledge.
doi:10.1093/nar/gkt926
PMCID: PMC3964990  PMID: 24136999
24.  Stress Responsive Proteins Are Actively Regulated during Rice (Oryza sativa) Embryogenesis as Indicated by Quantitative Proteomics Analysis 
PLoS ONE  2013;8(9):e74229.
Embryogenesis is the initial step in a plant’s life, and the molecular changes that occur during embryonic development are largely unknown. To explore the relevant molecular events, we used the isobaric tags for relative and absolute quantification (iTRAQ) coupled with the shotgun proteomics technique (iTRAQ/Shotgun) to study the proteomic changes of rice embryos during embryogenesis. For the first time, a total of 2 165 unique proteins were identified in rice embryos, and the abundances of 867 proteins were actively changed based on the statistical evaluation of the quantitative MS/MS signals. The quantitative data were then confirmed using multiple reactions monitoring (MRM) and were also supported by our previous study based on two-dimensional gel electrophoresis (2 DE). Using the proteome at 6 days after pollination (DAP) as a reference, cluster analysis of these differential proteins throughout rice embryogenesis revealed that 25% were up-regulated and 75% were down-regulated. Gene Ontology (GO) analysis implicated that most of the up-regulated proteins were functionally categorized as stress responsive, mainly including heat shock-, lipid transfer-, and reactive oxygen species-related proteins. The stress-responsive proteins were thus postulated to play an important role during seed maturation.
doi:10.1371/journal.pone.0074229
PMCID: PMC3776822  PMID: 24058531
25.  Quantitative Evaluation of the Mitochondrial Proteomes of Drosophila melanogaster Adapted to Extreme Oxygen Conditions 
PLoS ONE  2013;8(9):e74011.
Mitochondria are the primary organelles that consume oxygen and provide energy for cellular activities. To investigate the mitochondrial mechanisms underlying adaptation to extreme oxygen conditions, we generated Drosophila strains that could survive in low- or high-oxygen environments (LOF or HOF, respectively), examined their mitochondria at the ultrastructural level via transmission electron microscopy, studied the activity of their respiratory chain complexes, and quantitatively analyzed the protein abundance responses of the mitochondrial proteomes using Isobaric tag for relative and absolute quantitation (iTRAQ). A total of 718 proteins were identified with high confidence, and 55 and 75 mitochondrial proteins displayed significant differences in abundance in LOF and HOF, respectively, compared with the control flies. Importantly, these differentially expressed mitochondrial proteins are primarily involved in respiration, calcium regulation, the oxidative response, and mitochondrial protein translation. A correlation analysis of the changes in the levels of the mRNAs corresponding to differentially regulated mitochondrial proteins revealed two sets of proteins with different modes of regulation (transcriptional vs. post-transcriptional) in both LOF and HOF. We believe that these findings will not only enhance our understanding of the mechanisms underlying adaptation to extreme oxygen conditions in Drosophila but also provide a clue in studying human disease induced by altered oxygen tension in tissues and cells.
doi:10.1371/journal.pone.0074011
PMCID: PMC3771901  PMID: 24069262

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