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1.  ER stress–mediated autophagy promotes Myc-dependent transformation and tumor growth 
The Journal of Clinical Investigation  2012;122(12):4621-4634.
The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc–induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/–) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc–induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.
PMCID: PMC3533536  PMID: 23143306
2.  Brain cell apoptosis and enhancement of nervous excitability in pregnant rats with high plasma levels of homocysteine☆ 
Neural Regeneration Research  2012;7(28):2199-2205.
Hyperhomocysteinemia is an important risk factor for preeclampsia-eclampsia. This study established a pregnant rat model of hyperhomocysteinemia, in which blood plasma homocysteine concentrations were twice or three times greater than that of normal pregnant rats. TUNEL revealed an increase in the number of apoptotic cells in the frontal cortex of pregnant rats with hyperhomocysteinemia. In addition, immunohistochemical staining detected activated nuclear factor-κB-positve cells in the frontal cortex. Reverse transcription-PCR detected that mRNA expression of the anti-apoptotic gene bcl-2 diminished in the frontal cortex. In situ hybridization and western blotting revealed that N-methyl-D-aspartate receptor 1 mRNA and protein expression was upregulated in the frontal cortex and hippocampus. These results indicate that hyperhomocysteinemia can induce brain cell apoptosis, increase nerve excitability, and promote the occurrence of preeclampsia in pregnant rats.
PMCID: PMC4268719  PMID: 25538740
hyperhomocysteinemia; homocysteine; preeclampsia; frontal cortex; N-methyl-D-aspartate receptor; nerve excitability; cell apoptosis; pregnancy; brain; neural regeneration
3.  Inhibition of Glycogen Synthase Kinase 3β Ameliorates D-GalN/LPS-Induced Liver Injury by Reducing Endoplasmic Reticulum Stress-Triggered Apoptosis 
PLoS ONE  2012;7(9):e45202.
Glycogen synthase kinase 3β(GSK3β) is a ubiquitous serine-threonine protein kinase that participates in numerous cellular processes and disease pathophysiology. We aimed to determine therapeutic potential of GSK3β inhibition and its mechanism in a well-characterized model of lipopolysaccharide (LPS)-induced model of acute liver failure (ALF).
In a murine ALF model induced by D-GalN(700 mg/kg)/LPS(10 µg/kg), we analyzed GSK3β mechanisms using a specific chemical inhibitor, SB216763, and detected the role of endoplasmic reticulum stress (ERS). Mice were administered SB216763 at 2 h before or after D-GalN/LPS injection, respectively, and then sacrificed 6 h after D-GalN/LPS treatment to evaluate its prophylactic and therapeutic function. The lethality rate, liver damage, ERS, cytokine expression, MAP kinase, hepatocyte apoptosis and expression of TLR 4 were evaluated, respectively. Whether the inhibition of GSK3β activation protected hepatocyte from ERS-induced apoptosis was investigated in vitro.
Principal Findings
GSK3β became quickly activated (dephosphorylated) upon D-GalN/LPS exposure. Administration of SB216763 not only ameliorated liver injury, as evidenced by reduced transaminase levels, and well-preserved liver architecture, but also decreased lethality. Moreover, GSK3β inhibition resulted in down-regulation of pro-apoptotic proteins C/EBP–homologous protein(CHOP) and caspase-12, which are related to ERS. To further demonstrate the role of ERS, we found that GSK3β inhibition protected hepatocyte from ERS-induced cell death. GSK3β inhibition down-regulated the MAPK pathways, reduced expression of inflammatory cytokines and decreased expression of TLR4.
Our findings demonstrate the key function of GSK3β signaling in the pathophysiology of ALF, especially in regulating the ERS, and provide a rationale for targeting GSK3β as a potential therapeutic strategy to ameliorate ALF.
PMCID: PMC3461002  PMID: 23028846
4.  A cohort study evaluating paraaortic lymphadenectomy in endometrial cancer 
Oncology Letters  2012;4(6):1361-1365.
The current study sought to assess the role of paraaortic lymphadenectomy (LNE) in females with endometrial cancer. A retrospective analysis of patients diagnosed with endometrial cancer of stage IA to II preoperatively, between 2009 and 2011 was conducted. Patients were included who had suffered from endometrial cancer without preoperative adjuvant therapy and who underwent hysterectomy plus systematic pelvic LNE and paraaortic LNE by laparoscopy or laparotomy. A total of 54 patients who underwent surgery for preoperative endometrial cancer were selected. All patients underwent LNE. The incidences of pelvic and paraaortic lymph node metastases were 11.1% (6/54) and 7.4% (4/54), with a total positive lymph node rate of 14.8% (8/54). In addition, among the 8 positive cases, 5 patients underwent laparotomy and 3 underwent laparoscopy; 3 cases were classified as stage I and 5 as stage II preoperatively. Of these, 7 patients were identified with pathology-related risk factors, including low differentiation or clear cell adenocarcinoma postoperatively. Discordance of pathological differentiation between the pre- and postoperative stages reached 57.1% (4/7). The results revealed the high occurrence of positive lymph nodes in endometrial cancer which demonstrate the importance of systematic LNE. Additonally, no severe complications were caused by LNE besides lymph cysts. In summary, it is neccesary to perform LNE, particularly the removal of the paraaortic lymph node, in patients with endometrial cancers in order to improve postoperative therapy. Laparoscopy has similar surgical effects as laparotomy, but has a number of advantages.
PMCID: PMC3506758  PMID: 23205136
lymphadenectomy; endometrial cancer; paraaortic
5.  Cadmium toxicity 
Plant Signaling & Behavior  2012;7(3):345-348.
Cadmium is a well-known environmental pollutant with distinctly toxic effects on plants. It can displace certain essential metals from a wealth of metalloproteins, and thus disturb many normal physiological processes and cause severe developmental aberrant. The harmful effects of cadmium stress include, but are not limited to: reactive oxygen species overproduction, higher lipid hydroperoxide contents, and chloroplast structure change, which may lead to cell death. Plants have developed diverse mechanisms to alleviate environmental cadmium stress, e.g., cadmium pump and transporting cadmium into the leaf vacuoles. This mini-review focuses on the current research into understanding the cellular mechanisms of cadmium toxicity on cytoskeleton, vesicular trafficking and cell wall formation in plants.
PMCID: PMC3443916  PMID: 22499203
actin cytoskeleton; cadmium; cell wall construction; vesicular trafficking
6.  Identification and characterization of small non-coding RNAs from Chinese fir by high throughput sequencing 
BMC Plant Biology  2012;12:146.
Small non-coding RNAs (sRNAs) play key roles in plant development, growth and responses to biotic and abiotic stresses. At least four classes of sRNAs have been well characterized in plants, including repeat-associated siRNAs (rasiRNAs), microRNAs (miRNAs), trans-acting siRNAs (tasiRNAs) and natural antisense transcript-derived siRNAs. Chinese fir (Cunninghamia lanceolata) is one of the most important coniferous evergreen tree species in China. No sRNA from Chinese fir has been described to date.
To obtain sRNAs in Chinese fir, we sequenced a sRNA library generated from seeds, seedlings, leaves, stems and calli, using Illumina high throughput sequencing technology. A comprehensive set of sRNAs were acquired, including conserved and novel miRNAs, rasiRNAs and tasiRNAs. With BLASTN and MIREAP we identified a total of 115 conserved miRNAs comprising 40 miRNA families and one novel miRNA with precursor sequence. The expressions of 16 conserved and one novel miRNAs and one tasiRNA were detected by RT-PCR. Utilizing real time RT-PCR, we revealed that four conserved and one novel miRNAs displayed developmental stage-specific expression patterns in Chinese fir. In addition, 209 unigenes were predicted to be targets of 30 Chinese fir miRNA families, of which five target genes were experimentally verified by 5' RACE, including a squamosa promoter-binding protein gene, a pentatricopeptide (PPR) repeat-containing protein gene, a BolA-like family protein gene, AGO1 and a gene of unknown function. We also demonstrated that the DCL3-dependent rasiRNA biogenesis pathway, which had been considered absent in conifers, existed in Chinese fir. Furthermore, the miR390-TAS3-ARF regulatory pathway was elucidated.
We unveiled a complex population of sRNAs in Chinese fir through high throughput sequencing. This provides an insight into the composition and function of sRNAs in Chinese fir and sheds new light on land plant sRNA evolution.
PMCID: PMC3462689  PMID: 22894611
Chinese fir; miRNA; rasiRNA; tasiRNA; Cunninghamia lanceolata
7.  Grey and white matter abnormalities in chronic obstructive pulmonary disease: a case–control study 
BMJ Open  2012;2(2):e000844.
The irreversible airflow limitation characterised by chronic obstructive pulmonary disease (COPD) causes a decrease in the oxygen supply to the brain. The aim of the present study was to investigate brain structural damage in COPD.
Retrospective case–control study. Patients with COPD and healthy volunteers were recruited. The two groups were matched in age, gender and educational background.
A hospital and a number of communities: they are all located in southern Fujian province, China.
25 stable patients and 25 controls were enrolled from December 2009 to May 2011.
Using voxel-based morphometry and tract-based spatial statistics based on MRI to analyse grey matter (GM) density and white matter fractional anisotropy (FA), respectively, and a battery of neuropsychological tests were performed.
Patients with COPD (vs controls) showed decreased GM density in the limbic and paralimbic structures, including right gyrus rectus, left precentral gyrus, bilateral anterior and middle cingulate gyri, bilateral superior temporal gyri, bilateral anterior insula extending to Rolandic operculum, bilateral thalamus/pulvinars and left caudate nucleus. Patients with COPD (vs controls) had decreased FA values in the bilateral superior corona radiata, bilateral superior and inferior longitudinal fasciculus, bilateral optic radiation, bilateral lingual gyri, left parahippocampal gyrus and fornix. Lower FA values in these regions were associated with increased radial diffusivity and no changes of longitudinal diffusivity. Patients with COPD had poor performances in the Mini-Mental State Examination, figure memory and visual reproduction. GM density in some decreased regions in COPD had positive correlations with arterial blood Po2, negative correlations with disease duration and also positive correlations with visual tasks.
The authors demonstrated that COPD exhibited loss of regional GM accompanied by impairment of white matter microstructural integrity, which was associated with disease severity and may underlie the pathophysiological and psychological changes of COPD.
Article summary
Article focus
Decreased oxygen supply to brain may cause neuronal damage in COPD. However, the damage remains largely uninvestigated.
Key messages
We found that COPD extends to the brain, with the loss of regional cortical grey matter accompanied by impairment in the white matter microstructural integrity.
Our findings would be help for clinical therapy of COPD.
Strengths and limitations of this study
Multiple analyses were used based on MR images. The statistic power for FA analysis was weak.
PMCID: PMC3341600  PMID: 22535793
8.  Transcriptome-wide identification and characterization of miRNAs from Pinus densata 
BMC Genomics  2012;13:132.
MicroRNAs (miRNAs) play key roles in diverse developmental processes, nutrient homeostasis and responses to biotic and abiotic stresses. The biogenesis and regulatory functions of miRNAs have been intensively studied in model angiosperms, such as Arabidopsis thaliana, Oryza sativa and Populus trichocarpa. However, global identification of Pinus densata miRNAs has not been reported in previous research.
Here, we report the identification of 34 conserved miRNAs belonging to 25 miRNA families from a P. densata mRNA transcriptome database using local BLAST and MIREAP programs. The primary and/or precursor sequences of 29 miRNAs were further confirmed by RT-PCR amplification and subsequent sequencing. The average value of the minimal folding free energy indexes of the 34 miRNA precursors was 0.92. Nineteen (58%) mature miRNAs began with a 5' terminal uridine residue. Analysis of miRNA precursors showed that 19 mature miRNAs were novel members of 14 conserved miRNA families, of which 17 miRNAs were further validated by subcloning and sequencing. Using real-time quantitative RT-PCR, we found that the expression levels of 7 miRNAs were more than 2-fold higher in needles than in stems. In addition, 72 P. densata mRNAs were predicted to be targets of 25 miRNA families. Four target genes, including a nodal modulator 1-like protein gene, two GRAS family transcription factor protein genes and one histone deacetylase gene, were experimentally verified to be the targets of 3 P. densata miRNAs, pde-miR162a, pde-miR171a and pde-miR482a, respectively.
This study led to the discovery of 34 conserved miRNAs comprising 25 miRNA families from Pinus densata. These results lay a solid foundation for further studying the regulative roles of miRNAs in the development, growth and responses to environmental stresses in P. densata.
PMCID: PMC3347991  PMID: 22480283
Pinus densata; miRNA; Transcriptome
9.  Co-Inoculation with Rhizobia and AMF Inhibited Soybean Red Crown Rot: From Field Study to Plant Defense-Related Gene Expression Analysis 
PLoS ONE  2012;7(3):e33977.
Soybean red crown rot is a major soil-borne disease all over the world, which severely affects soybean production. Efficient and sustainable methods are strongly desired to control the soil-borne diseases.
Principal Findings
We firstly investigated the disease incidence and index of soybean red crown rot under different phosphorus (P) additions in field and found that the natural inoculation of rhizobia and arbuscular mycorrhizal fungi (AMF) could affect soybean red crown rot, particularly without P addition. Further studies in sand culture experiments showed that inoculation with rhizobia or AMF significantly decreased severity and incidence of soybean red crown rot, especially for co-inoculation with rhizobia and AMF at low P. The root colony forming unit (CFU) decreased over 50% when inoculated by rhizobia and/or AMF at low P. However, P addition only enhanced CFU when inoculated with AMF. Furthermore, root exudates of soybean inoculated with rhizobia and/or AMF significantly inhibited pathogen growth and reproduction. Quantitative RT-PCR results indicated that the transcripts of the most tested pathogen defense-related (PR) genes in roots were significantly increased by rhizobium and/or AMF inoculation. Among them, PR2, PR3, PR4 and PR10 reached the highest level with co-inoculation of rhizobium and AMF.
Our results indicated that inoculation with rhizobia and AMF could directly inhibit pathogen growth and reproduction, and activate the plant overall defense system through increasing PR gene expressions. Combined with optimal P fertilization, inoculation with rhizobia and AMF could be considered as an efficient method to control soybean red crown rot in acid soils.
PMCID: PMC3307780  PMID: 22442737
10.  Transcriptional Profiling of ESTs from the Biocontrol Fungus Chaetomium cupreum 
The Scientific World Journal  2012;2012:340565.
Comparative analysis was applied to two cDNA/ESTs libraries (C1 and C2) from Chaetomium cupreum. A total of 5538 ESTs were sequenced and assembled into 2162 unigenes including 585 contigs and 1577 singletons. BlastX analysis enabled the identification of 1211 unigenes with similarities to sequences in the public databases. MFS monosaccharide transporter was found as the gene expressed at the highest level in library C2, but no expression in C1. The majority of unigenes were library specific. Comparative analysis of the ESTs further revealed the difference of C. cupreum in gene expression and metabolic pathways between libraries. Two different sequences similar to the 48-KDa endochitinase and 46-KDa endochitinase were identified in libraries C1 and C2, respectively.
PMCID: PMC3289965  PMID: 22448129
11.  Automatic categorization of diverse experimental information in the bioscience literature 
BMC Bioinformatics  2012;13:16.
Curation of information from bioscience literature into biological knowledge databases is a crucial way of capturing experimental information in a computable form. During the biocuration process, a critical first step is to identify from all published literature the papers that contain results for a specific data type the curator is interested in annotating. This step normally requires curators to manually examine many papers to ascertain which few contain information of interest and thus, is usually time consuming. We developed an automatic method for identifying papers containing these curation data types among a large pool of published scientific papers based on the machine learning method Support Vector Machine (SVM). This classification system is completely automatic and can be readily applied to diverse experimental data types. It has been in use in production for automatic categorization of 10 different experimental datatypes in the biocuration process at WormBase for the past two years and it is in the process of being adopted in the biocuration process at FlyBase and the Saccharomyces Genome Database (SGD). We anticipate that this method can be readily adopted by various databases in the biocuration community and thereby greatly reducing time spent on an otherwise laborious and demanding task. We also developed a simple, readily automated procedure to utilize training papers of similar data types from different bodies of literature such as C. elegans and D. melanogaster to identify papers with any of these data types for a single database. This approach has great significance because for some data types, especially those of low occurrence, a single corpus often does not have enough training papers to achieve satisfactory performance.
We successfully tested the method on ten data types from WormBase, fifteen data types from FlyBase and three data types from Mouse Genomics Informatics (MGI). It is being used in the curation work flow at WormBase for automatic association of newly published papers with ten data types including RNAi, antibody, phenotype, gene regulation, mutant allele sequence, gene expression, gene product interaction, overexpression phenotype, gene interaction, and gene structure correction.
Our methods are applicable to a variety of data types with training set containing several hundreds to a few thousand documents. It is completely automatic and, thus can be readily incorporated to different workflow at different literature-based databases. We believe that the work presented here can contribute greatly to the tremendous task of automating the important yet labor-intensive biocuration effort.
PMCID: PMC3305665  PMID: 22280404
12.  Humidity-Induced Charge Leakage and Field Attenuation in Electric Field Microsensors 
Sensors (Basel, Switzerland)  2012;12(4):5105-5115.
The steady-state zero output of static electric field measuring systems often fluctuates, which is caused mainly by the finite leakage resistance of the water film on the surface of the electric field microsensor package. The water adsorption has been calculated using the Boltzmann distribution equation at various relative humidities for borosilicate glass and polytetrafluoroethylene surfaces. At various humidities, water film thickness has been calculated, and the induced charge leakage and field attenuation have been theoretically investigated. Experiments have been performed with microsensors to verify the theoretical predictions and the results are in good agreement.
PMCID: PMC3355460  PMID: 22666077
electric field sensor; charge leakage; electric field attenuation; water film thickness; MEMS

Results 1-12 (12)