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1.  Chromosome-level genome map provides insights into diverse defense mechanisms in the medicinal fungus Ganoderma sinense 
Scientific Reports  2015;5:11087.
Fungi have evolved powerful genomic and chemical defense systems to protect themselves against genetic destabilization and other organisms. However, the precise molecular basis involved in fungal defense remain largely unknown in Basidiomycetes. Here the complete genome sequence, as well as DNA methylation patterns and small RNA transcriptomes, was analyzed to provide a holistic overview of secondary metabolism and defense processes in the model medicinal fungus, Ganoderma sinense. We reported the 48.96 Mb genome sequence of G. sinense, consisting of 12 chromosomes and encoding 15,688 genes. More than thirty gene clusters involved in the biosynthesis of secondary metabolites, as well as a large array of genes responsible for their transport and regulation were highlighted. In addition, components of genome defense mechanisms, namely repeat-induced point mutation (RIP), DNA methylation and small RNA-mediated gene silencing, were revealed in G. sinense. Systematic bioinformatic investigation of the genome and methylome suggested that RIP and DNA methylation combinatorially maintain G. sinense genome stability by inactivating invasive genetic material and transposable elements. The elucidation of the G. sinense genome and epigenome provides an unparalleled opportunity to advance our understanding of secondary metabolism and fungal defense mechanisms.
doi:10.1038/srep11087
PMCID: PMC4457147  PMID: 26046933
2.  Vibration Training Triggers Brown Adipocyte Relative Protein Expression in Rat White Adipose Tissue 
BioMed Research International  2015;2015:919401.
Recently, vibration training is considered as a novel strategy of weight loss; however, its mechanisms are still unclear. In this study, normal or high-fat diet-induced rats were trained by whole body vibration for 8 weeks. We observed that the body weight and fat metabolism index, blood glucose, triglyceride, cholesterol, and free fatty acid in obesity rats decreased significantly compared with nonvibration group (n = 6). Although intrascapular BAT weight did not change significantly, vibration enhanced ATP reduction and increased protein level of the key molecule of brown adipose tissue (BAT), PGC-1α, and UCP1 in BAT. Interestingly, the adipocytes in retroperitoneal white adipose tissue (WAT) became smaller due to vibration exercise and had higher protein level of the key molecule of brown adipose tissue (BAT), PGC-1α, and UCP1 and inflammatory relative proteins, IL-6 and TNFα. Simultaneously, ATP content and PPARγ protein level in WAT became less in rats compared with nonvibration group. The results indicated that vibration training changed lipid metabolism in rats and promoted brown fat-like change in white adipose tissues through triggering BAT associated gene expression, inflammatory reflect, and reducing energy reserve.
doi:10.1155/2015/919401
PMCID: PMC4466483  PMID: 26125027
3.  Decreased expression of CHIP leads to increased angiogenesis via VEGF-VEGFR2 pathway and poor prognosis in human renal cell carcinoma 
Scientific Reports  2015;5:9774.
CHIP (c-terminal Hsp70-interacting protein) is an E3 ligase which may play different roles in different cancers. The elucidation of the VHL-HIF-1α(hypoxia inducible factor-1α)-VEGF (vascular endothelial growth factor) pathway has led to the development of targeted therapy in renal cell carcinoma (RCC). However, little is known about the role of CHIP and the relationship between CHIP and VEGF-VEGFR2 (VEGF receptor 2) pathway in RCC. In this study, we found that the expression of CHIP was downregulated and significantly correlated with pT status (P = 0.022) and TNM stage (P = 0.022) in 304 RCC and 35 normal renal tissues using tissue microarray. Moreover, low expression of CHIP is a strong and independent negative prognostic value for RCC. In vitro, CHIP negatively regulated RCC cell migration, invasion and angiogenesis. In addition, ELISA tests showed that restoration of CHIP inhibited, while knockdown promoted, the secreted level of VEGF. Furthermore, western blot indicated that the VEGFR2 protein level was reduced after CHIP overexpression. Our findings demonstrate for the first time that CHIP may be involved in RCC angiogenesis through regulating VEGF secretion and expression of VEGFR2. CHIP may serve as promising prognostic biomarker of angiogenesis and may constitute a potential therapeutic target in RCC.
doi:10.1038/srep09774
PMCID: PMC4448523  PMID: 26021863
4.  Longitudinal analysis of peripheral blood T cell receptor diversity in patients with systemic lupus erythematosus by next-generation sequencing 
Introduction
T cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Clonal expansion of T cells correlating with disease activity has been observed in peripheral blood (PB) of SLE subjects. Recently, next-generation sequencing (NGS) of the T cell receptor (TCR) β loci has emerged as a sensitive way to measure the T cell repertoire. In this study, we utilized NGS to assess whether changes in T cell repertoire diversity in PB of SLE patients correlate with or predict changes in disease activity.
Methods
Total RNA was isolated from the PB of 11 SLE patients. Each subject had three samples, collected at periods of clinical quiescence and at a flare. Twelve age-matched healthy controls (HC) were used for reference. NGS was used to profile the complementarity-determining region 3 (CDR3) of the rearranged TCR β loci.
Results
Relative to the HC, SLE patients (at quiescence) demonstrated a 2.2-fold reduction in repertoire diversity in a given PB volume (P <0.0002), a more uneven distribution of the repertoire (Gini coefficient, HC vs SLE, P = 0.015), and a trend toward increased percentage of expanded clones in the repertoire (clone size >1.0 %, HC vs SLE, P = 0.078). No significant correlation between the overall repertoire diversity and clinical disease activity was observed for most SLE patients with only two of eleven SLE patients showing a decreasing trend in repertoire diversity approaching the flare time point. We did not observe any overlap of CDR3 amino acid sequences or a preferential Vβ or Jβ gene usage among the top 100 expanded clones from all SLE patients. In both HC and SLE, the majority of the expanded clones were remarkably stable over time (HC = 5.5 ±0.5 months, SLE = 7.2 ±2.4 months).
Conclusions
A significant decrease in T cell repertoire diversity was observed in PB of SLE patients compared to HC. However, in most SLE patients, repertoire diversity did not change significantly with increases in disease activity to a flare. Thus, without a priori knowledge of disease-specific clones, monitoring TCR repertoire in PB from SLE patients is not likely to be useful to predict changes in disease activity.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0655-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0655-9
PMCID: PMC4458014  PMID: 26001779
5.  A transgenic ginseng vaccine for bovine viral diarrhea 
Virology Journal  2015;12:73.
Background
Bovine viral diarrhea virus (BVDV) infections are endemic in cattle populations worldwide and cause major economic losses. Thus, an effective vaccine is needed against the transmission of BVDV. The glycoprotein Erns is one of the envelope proteins of this virus and shows BVDV-related immunogenicity. Here, we report the use of Panax ginseng as an alternative production platform for the expression of glycoprotein Erns via Agrobacterium-mediated transformation.
Result
Polymerase chain reaction (PCR) and reverse transcription (RT)-PCR analyses showed that pBI121-Erns was stably integrated into the chromosome of transformants. ELISA assay and Western blot analysis confirmed the antigenicity of plant-derived Erns glycoprotein. Immunogenicity was evaluated subcutaneously in deer using a soluble protein extract of dried transgenic ginseng hairy roots. Specific humoral and cell-mediated immune responses against BVDV were detected following immunization.
Conclusion
These results demonstrated that the Erns glycoprotein could be expressed in ginseng hairy roots and that plant-derived glycoprotein Erns retained its antigenicity and immunogenicity.
doi:10.1186/s12985-015-0301-9
PMCID: PMC4455706  PMID: 25948546
Bovine viral diarrhea virus; Transgenic ginseng vaccine; Erns
6.  FGF9 from cancer-associated fibroblasts is a possible mediator of invasion and anti-apoptosis of gastric cancer cells 
BMC Cancer  2015;15:333.
Background
Cancer-associated fibroblasts (CAFs), which reside around tumor cells, are suggested to play a pivotal role in tumor progression. Here we performed microarray analyses to compare gene expression profiles between CAFs and non-cancerous gastric fibroblasts (NGFs) from a patient with gastric cancer and found that fibroblast growth factor 9 (FGF9) was a novel growth factor overexpressed in CAFs. We then examined the biological effects of FGF9 during progression of gastric cancer.
Methods
Expression of FGF9 in CAFs and NGFs, and their secreted products, were examined by Western blotting. The effects of FGF9 on AGS and MKN28 gastric cancer cells in terms of proliferation, invasion and anti-apoptosis were assessed by WST-1 assay, invasion chamber assay and FACS, respectively. Furthermore, the intracellular signaling by which FGF9 exerts its biological roles was examined in vitro.
Results
FGF9 was strongly expressed in CAFs in comparison with NGFs, being compatible with microarray data indicating that FGF9 was a novel growth factor overexpressed in CAFs. Treatment with FGF9 promoted invasion and anti-apoptosis through activation of the ERK and Akt signaling pathways in AGS and MKN28 cells, whereas these effects were attenuated by treatment with anti-FGF9 neutralizing antibody. In addition, FGF9 treatment significantly enhanced the expression of matrix metalloproteinase 7 (MMP7) in both cell lines.
Conclusions
FGF9 is a possible mediator secreted by CAFs that promotes the anti-apoptosis and invasive capability of gastric cancer cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1353-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1353-3
PMCID: PMC4424580  PMID: 25925261
FGF; Cancer-associated fibroblast; Invasion; Anti-apoptosis; ERK; Akt; Gastric cancer
7.  Correlation between anatomical parameters of intertubercular sulcus and retroversion angle of humeral head 
Objective: To obtain anatomical data on intertubercular sulcus of humerus, evaluate the correlation between intertubercular sulcus and retroversion angle of humeral head, to guide the positioning of torsion angle of prosthesis during total shoulder arthroplasty and provide references for shoulder prosthesis design. Methods: Using a Siemens Ultrahigh speed 64- rows multi-slices spiral CT scanner and 20 dried adult humeral specimens (intact specimen, no fractures or pathological damage), of these, left lateral in 10 cases, right lateral in 10 cases, male or female all inclusive, specimens are all provided by Anatomy Department of Weifang Medical College, scan ranged from the highest point of humeral head to the distal ends of trochlea. And scanned data were subjected to statistical analysis. Results: There is a linear correlation between the distance from intertubercular sulcus to central axis line of humeral head, position angle of intertubercular sulcus and retroversion angle of humeral head at the beginning slice of intertubercular sulcus. There is a linear correlation between position angle of intertubercular sulcus and retroversion angle of humeral head at the slice of surgical neck. Conclusion: There is a linear correlation between position of intertubercular sulcus and retroversion angle of humeral head, in total shoulder arthroplasty, using intertubercular sulcus as anatomical landmark will help to accurately position torsion angle of individualized prosthesis. Position angle of intertubercular sulcus is an objective, flexible positioning indicator.
PMCID: PMC4483891  PMID: 26131058
Intertubercular sulcus; position angle of intertubercular sulcus; retroversion angle of humeral head; measurement; correlation
8.  Epibatidine Blocks Eye-Specific Segregation in Ferret Dorsal Lateral Geniculate Nucleus during Stage III Retinal Waves 
PLoS ONE  2015;10(3):e0118783.
The segregation and maintenance of eye-specific inputs in the dorsal lateral geniculate nucleus (dLGN) during early postnatal development requires the patterned spontaneous activity of retinal waves. In contrast to the development of the mouse, ferret eye-specific segregation is not complete at the start of stage III glutamatergic retinal waves, and the remaining overlap is limited to the C/C1 lamina of the dLGN. To investigate the role of patterned spontaneous activity in this late segregation, we disrupted retinal waves pharmacologically for 5 day windows from postnatal day (P) 10 to P25. Multi-electrode array recordings of the retina in vitro reveal that the cholinergic agonist epibatidine disrupts correlated retinal activity during stage III waves. Epibatidine also prevents the segregation of eye-specific inputs in vivo during that period. Our results reveal a novel role for cholinergic influence on stage III retinal waves as an instructive signal for the continued segregation of eye-specific inputs in the ferret dLGN.
doi:10.1371/journal.pone.0118783
PMCID: PMC4368645  PMID: 25794280
9.  Disturbance of redox status enhances radiosensitivity of hepatocellular carcinoma 
American Journal of Cancer Research  2015;5(4):1368-1381.
Aims: High constitutive expression of Nrf2 has been found in many types of cancers, and this high level of Nrf2 also favors resistance to drugs and radiation. Here we investigate how isoliquiritigenin (ISL), a natural antioxidant, inhibits the Nrf2-dependent antioxidant pathway and enhances the radiosensitivity of HepG2 cells and HepG2 xenografts. Results: Treatment of HepG2 cells with ISL for 6 h selectively enhanced transcription and expression of Keap1. Keap1 effectively induced ubiquitination and degradation of Nrf2, and inhibited translocation of Nrf2 to the nucleus. Consequently, expression of Nrf2 downstream genes was reduced, and the Nrf2-dependent antioxidant system was suppressed. Endogenous ROS was higher than before ISL treatment, causing redox imbalance and oxidative stress in HepG2 cells. Moreover, pretreatment with ISL for 6 h followed by X-ray irradiation significantly increased γ-H2AX foci and cell apoptosis, and reduced clonogenic potential compared with cells irradiated with X-rays alone. In addition, HepG2 xenografts, ISL, and X-ray co-treatments induced greater apoptosis and tumor growth inhibition, when compared with X-ray treatments alone. Additionally, HepG2 xenografts, in which Nrf2 was expressed at very low levels due to ectopic expression of Keap1, showed that ISL-mediated radiosensitization was Keap1 dependent. Innovation and Conclusions: ISL inhibited the Nrf2-antioxidant pathway by increasing the levels of Keap1 and ultimately inducing oxidative stress via disturbance of the redox status. The antioxidant ISL possessed pro-oxidative properties, and enhanced the radiosensitivity of liver cancer cells, both in vivo and in vitro. Taken together, these results demonstrated the effectiveness of using ISL to decrease radioresistance, suggesting that ISL could be developed as an adjuvant radiosensitization drug. Disturbance of redox status could be a potential target for radiosensitization.
PMCID: PMC4473316  PMID: 26101703
Redox state; ROS; isoliquiritigenin; radiosensitization; Keap1/Nrf-2
10.  Potential Epigenetic Mechanism in Non-Alcoholic Fatty Liver Disease 
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver. It ranges from simple steatosis to its more aggressive form, non-alcoholic steatohepatitis (NASH), which may develop into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) if it persists for a long time. However, the exact pathogenesis of NAFLD and the related metabolic disorders remain unclear. Epigenetic changes are stable alterations that take place at the transcriptional level without altering the underlying DNA sequence. DNA methylation, histone modifications and microRNA are among the most common forms of epigenetic modification. Epigenetic alterations are involved in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines, all of which have been implicated in the development and progression of NAFLD. This review summarizes the current advances in the potential epigenetic mechanism of NAFLD. Elucidation of epigenetic factors may facilitate the identification of early diagnositic biomarkers and development of therapeutic strategies for NAFLD.
doi:10.3390/ijms16035161
PMCID: PMC4394469  PMID: 25751727
epigenetics; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); DNA methylation; histone modifications; microRNA
11.  Prediction of plant pre-microRNAs and their microRNAs in genome-scale sequences using structure-sequence features and support vector machine 
BMC Bioinformatics  2014;15(1):423.
Background
MicroRNAs (miRNAs) are a family of non-coding RNAs approximately 21 nucleotides in length that play pivotal roles at the post-transcriptional level in animals, plants and viruses. These molecules silence their target genes by degrading transcription or suppressing translation. Studies have shown that miRNAs are involved in biological responses to a variety of biotic and abiotic stresses. Identification of these molecules and their targets can aid the understanding of regulatory processes. Recently, prediction methods based on machine learning have been widely used for miRNA prediction. However, most of these methods were designed for mammalian miRNA prediction, and few are available for predicting miRNAs in the pre-miRNAs of specific plant species. Although the complete Solanum lycopersicum genome has been published, only 77 Solanum lycopersicum miRNAs have been identified, far less than the estimated number. Therefore, it is essential to develop a prediction method based on machine learning to identify new plant miRNAs.
Results
A novel classification model based on a support vector machine (SVM) was trained to identify real and pseudo plant pre-miRNAs together with their miRNAs. An initial set of 152 novel features related to sequential structures was used to train the model. By applying feature selection, we obtained the best subset of 47 features for use with the Back Support Vector Machine-Recursive Feature Elimination (B-SVM-RFE) method for the classification of plant pre-miRNAs. Using this method, 63 features were obtained for plant miRNA classification. We then developed an integrated classification model, miPlantPreMat, which comprises MiPlantPre and MiPlantMat, to identify plant pre-miRNAs and their miRNAs. This model achieved approximately 90% accuracy using plant datasets from nine plant species, including Arabidopsis thaliana, Glycine max, Oryza sativa, Physcomitrella patens, Medicago truncatula, Sorghum bicolor, Arabidopsis lyrata, Zea mays and Solanum lycopersicum. Using miPlantPreMat, 522 Solanum lycopersicum miRNAs were identified in the Solanum lycopersicum genome sequence.
Conclusions
We developed an integrated classification model, miPlantPreMat, based on structure-sequence features and SVM. MiPlantPreMat was used to identify both plant pre-miRNAs and the corresponding mature miRNAs. An improved feature selection method was proposed, resulting in high classification accuracy, sensitivity and specificity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-014-0423-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-014-0423-x
PMCID: PMC4310204  PMID: 25547126
MiRNA; Pre-miRNA; Prediction; SVM; Feature selection
12.  Dacarbazine Combined Targeted Therapy versus Dacarbazine Alone in Patients with Malignant Melanoma: A Meta-Analysis 
PLoS ONE  2014;9(12):e111920.
Background
Malignant melanoma is the most aggressive and deadly form of skin cancer. Dacarbazine (DTIC) has been the approved first-line treatment for metastatic melanoma in routine clinical practice. However, response rates with single-agent DTIC are low. The objective of this study was to compare the efficacy and safety of DTIC with or without placebo and DTIC-based combination therapies in patients with advanced metastatic melanoma.
Methods
We searched from electronic databases such as The Cochrane Library, MEDLINE, EBSCO, EMBASE, Ovid, CNKI, and CBMDisc from 2003 to 2013. The primary outcome measures were overall response and 1-year survival, and the secondary outcome measurements were adverse events.
Results
Nine randomized controlled trials (RCTs) involving 2,481 patients were included in the meta-analysis. DTIC-based combination therapies was superior to DTIC alone in overall response (combined risk ratio [RR]  = 1.60, 95% confidence interval [CI]: 1.27–2.01) and 1-year survival (combined RR = 1.26, 95% CI: 1.14–1.39). Patients with DTIC-based combination therapies had higher incidence of adverse events including nausea (combined RR = 1.23, 95% CI: 1.10–1.36), vomiting (combined RR = 1.73, 95% CI: 1.41–2.12) and neutropenia (combined RR = 1.75, 95% CI: 1.42–2.16) compared to the group for DTIC alone.
Conclusion
These data suggested that DTIC-based combination therapies could moderately improve the overall response and the 1-year survival but increased the incidence of adverse events. Further large-scale, high-quality, placebo-controlled, double-blind trials are needed to confirm this conclusion.
doi:10.1371/journal.pone.0111920
PMCID: PMC4263472  PMID: 25502446
13.  Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress 
Antioxidants & Redox Signaling  2014;21(17):2271-2285.
Abstract
Aims: b-AP15 is a recently described inhibitor of the USP14/UCHL5 deubiquitinases (DUBs) of the 19S proteasome. Exposure to b-AP15 results in blocking of proteasome function and accumulation of polyubiquitinated protein substrates in cells. This novel mechanism of proteasome inhibition may potentially be exploited for cancer therapy, in particular for treatment of malignancies resistant to currently used proteasome inhibitors. The aim of the present study was to characterize the cellular response to b-AP15-mediated proteasome DUB inhibition. Results: We report that b-AP15 elicits a similar, but yet distinct, cellular response as the clinically used proteasome inhibitor bortezomib. b-AP15 induces a rapid apoptotic response, associated with enhanced induction of oxidative stress and rapid activation of Jun-N-terminal kinase 1/2 (JNK)/activating protein-1 signaling. Scavenging of reactive oxygen species and pharmacological inhibition of JNK reduced b-AP15-induced apoptosis. We further report that endoplasmic reticulum (ER) stress is induced by b-AP15 and is involved in apoptosis induction. In contrast to bortezomib, ER stress is associated with induction of α-subunit of eukaryotic initiation factor 2 phosphorylation. Innovation: The findings establish that different modes of proteasome inhibition result in distinct cellular responses, a finding of potential therapeutic importance. Conclusion: Our data show that enhanced oxidative stress and ER stress are major determinants of the strong apoptotic response elicited by the 19S DUB inhibitor b-AP15. Antioxid. Redox Signal. 21, 2271–2285.
doi:10.1089/ars.2013.5322
PMCID: PMC4241954  PMID: 24011031
14.  Arthroscopy-assisted reconstruction of coracoclavicular ligament by Endobutton fixation for treatment of acromioclavicular joint dislocation 
Objective
The aim of this study was to evaluate the clinical outcomes of arthroscopy-assisted reconstruction of the coracoclavicular (CC) ligament using Endobutton for treating acromioclavicular (AC) joint dislocation.
Methods
From March 2012 to May 2013, a total of 22 patients with fresh AC joint dislocation (Rockwood type III and type V) were treated with arthroscopy-assisted Endobutton reconstruction of the CC ligament. The regular post-operation follow-up was performed. Shoulder joint function was assessed with Constant–Murley scores. Postoperative efficacy of the surgery was evaluated using the Karlsson criterion.
Results
The 22 patients were followed postoperatively for an average of 24 months (16–31 months). Among them, 20 patients achieved good functional recovery with no pain. Two patients had slight pain in the acromion during shoulder joint motion with limited abduction at 3 months, both of whom had recovered at 6 months. Radiography confirmed anatomical reduction of the AC joint in all patients. At 1 year, the Constant–Murley scores were 93.1 ± 2.4 points on the injured side versus 94.2 ± 2.7 points on the uninjured side. The difference did not reach statistical significance (P > 0.05). Postoperative Karlsson evaluation ranked 20 patients (90.9 %) as grade A and 2 as grade B (9.1 %) at the 3-month follow-up. All patients had become grade A at 6 months. None of the patients had brachial plexus or peripheral vascular injuries.
Conclusion
Arthroscopy-assisted reconstruction of the coracoclavicular ligament by Endobutton fixation is a safe, easy method for treating AC joint dislocation. It provides reliable fixation, causes little trauma, and has a fast recovery.
doi:10.1007/s00402-014-2117-2
PMCID: PMC4281352  PMID: 25421528
Arthroscopy; Endobutton; Coracoclavicular ligament; Acromioclavicular dislocation; Ligament repair
15.  Diagnosis of 65 cases of ampullary renal pelvis after postnatal follow-up of 1,167 newborn infants with prenatally suspected hydronephrosis 
The aim of the present study was to assess the morbidity of ampullary renal pelvis (ARP) and document its natural history in post-natal life. A total of 1,167 newborn infants with prenatally suspected hydronephrosis were retrospectively analyzed. Of these, 65 patients were diagnosed with ARP by computed tomography urography (CTU) and/or magnetic resonance urography (MRU). All cases were followed up with ultrasonogrophy at 1, 3, 6 and 12 months after birth, and one case was followed up for 5 years. Changes in the separation of the renal pelvis collection system were recorded. Children with ARP accounted for 5.57% of the total cases (65/1,167) followed-up. No lack of connection between the renal calyces and the renal pelvis was detected. The long-term follow-up revealed that the separation of the renal pelvis collection system did not tend to increase over time. In addition to imaging examinations, long-term follow-up observation is recommended for the accurate diagnosis of pediatric ARP, particularly for differentiation from hydronephrosis.
doi:10.3892/etm.2014.2076
PMCID: PMC4247286  PMID: 25452792
hydronephrosis; ampullary renal pelvis; follow-up studies
16.  Whole Genome Sequencing Reveals a Chromosome 9p Deletion Causing DOCK8 Deficiency in an Adult Diagnosed with Hyper IgE Syndrome Who Developed Progressive Multifocal Leukoencephalopathy 
Purpose
A 30 year-old man with a history of recurrent skin infections as well as elevated serum IgE and eosinophils developed neurological symptoms and had T2-hyperintense lesions observed in cerebral MRI. The immune symptoms were attributed to Hyper IgE syndrome (HIES) and the neurological symptoms with presence of JC virus in cerebrospinal fluid were diagnosed as Progressive Multifocal Leukoencephalopathy (PML). The patient was negative for STAT3 mutations. To determine if other mutations explain HIES and/or PML in this subject, his DNA was analyzed by whole genome sequencing.
Methods
Whole genome sequencing was completed to 30X coverage, and whole genome SNP typing was used to complement these data. The methods revealed single nucleotide variants, structural variants, and copy number variants across the genome. Genome-wide data were analyzed for homozygous or compound heterozygous null mutations for all protein coding genes. Mutations were confirmed by PCR and/or Sanger sequencing.
Results
Whole genome analysis revealed deletions near the telomere of both copies of chromosome 9p. Several genes, including DOCK8, were impacted by the deletions but it was unclear whether each chromosome had identical or distinct deletions. PCR across the impacted region combined with Sanger sequencing of selected fragments confirmed a homozygous deletion from position 10,211 to 586,751.
Conclusion
While several genes are impacted by the deletion, DOCK8 deficiency is the most probable cause of HIES in this patient. DOCK8 deficiency may have also predisposed the patient to develop PML.
Electronic supplementary material
The online version of this article (doi:10.1007/s10875-014-0114-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s10875-014-0114-4
PMCID: PMC4306731  PMID: 25388448
Hyper IgE Syndrome; DOCK8 deficiency; primary immune deficiency; Progressive Multifocal Leukoencephalopathy (PML); JC virus
17.  Eye-specific retinogeniculate segregation proceeds normally following disruption of patterned spontaneous retinal activity 
Neural Development  2014;9:25.
Background
Spontaneous retinal activity (SRA) is important during eye-specific segregation within the dorsal lateral geniculate nucleus (dLGN), but the feature(s) of activity critical for retinogeniculate refinement are controversial. Pharmacologically or genetically manipulating cholinergic signaling during SRA perturbs correlated retinal ganglion cell (RGC) spiking and disrupts eye-specific retinofugal refinement in vivo, consistent with an instructive role for SRA during visual system development. Paradoxically, ablating the starburst amacrine cells (SACs) that generate cholinergic spontaneous activity disrupts correlated RGC firing without impacting retinal activity levels or eye-specific segregation in the dLGN. Such experiments suggest that patterned SRA during retinal waves is not critical for eye-specific refinement and instead, normal activity levels are permissive for retinogeniculate development. Here we revisit the effects of ablating the cholinergic network during eye-specific segregation and show that SAC ablation disrupts, but does not eliminate, retinal waves with no concomitant impact on normal eye-specific segregation in the dLGN.
Results
We induced SAC ablation in postnatal ferret pups beginning at birth by intraocular injection of a novel immunotoxin selective for the ferret vesicular acetylcholine transporter (Ferret VAChT-Sap). Through dual-patch whole-cell and multi-electrode array recording we found that SAC ablation altered SRA patterns and led to significantly smaller retinal waves compared with controls. Despite these defects, eye-specific segregation was normal. Further, interocular competition for target territory in the dLGN proceeded in cases where SAC ablation was asymmetric in the two eyes.
Conclusions
Our data demonstrate normal eye-specific retinogeniculate development despite significant abnormalities in patterned SRA. Comparing our current results with earlier studies suggests that defects in retinal wave size, absolute levels of SRA, correlations between RGC pairs, RGC burst frequency, high frequency RGC firing during bursts, and the number of spikes per RGC burst are each uncorrelated with abnormalities in eye-specific segregation in the dLGN. An increase in the fraction of asynchronous spikes occurring outside of bursts and waves correlates with eye-specific segregation defects in studies reported to date. These findings highlight the relative importance of different features of SRA while providing additional constraints for computational models of Hebbian plasticity mechanisms in the developing visual system.
Electronic supplementary material
The online version of this article (doi:10.1186/1749-8104-9-25) contains supplementary material, which is available to authorized users.
doi:10.1186/1749-8104-9-25
PMCID: PMC4289266  PMID: 25377639
Retinogeniculate; Eye-specific segregation; Retinal wave; Spontaneous activity; Retinal ganglion cell; Dorsal lateral geniculate nucleus
18.  Cone beam computed tomographic analyses of alveolar bone anatomy at the maxillary anterior region in Chinese adults 
Journal of Biomedical Research  2013;28(6):498-505.
To provide an anatomical basis for clinical implant esthetics, we evaluated the morphology of the nasopalatine canal (NPC) and analyzed labial and interproximal bone anatomy at the maxillary anterior region. We sought to investigate the effect of maxillary protrusion and tooth labiolingual inclination on labial bone anatomy in Chinese adults. Three dimensional (3D) images were reconstructed using cone-beam computed tomography (CBCT) images from 80 Chinese subjects and by SimPlant 11.04. The dimensions of the NPC, the thickness and profile of the labial bone, the width and height of the interproximal bone, angle sella-nasion-subspinale (SNA) and angle upper central incisor-nasion,subspinale (U1-NA) were measured. The incisive foramen of the NPC was markedly wider than its nasal foramen. The dimension of its labial bone wall demonstrated an increasing width from the crestal to apical measurements. The labial bone at the maxillary anterior region was rather thin, especially at 3 mm below the cemento-enamel junction (CEJ) and the mid-root level; the profile of the labial bone was more curved at the central incisor, and the interproximal bone became wider and shorter posteriorly. There were significant relationships between maxillary protrusion and labial bone profile, tooth labiolingual inclination and labial bone thickness (P < 0.02). To achieve optimal esthetic outcome of implant, bone augmentation is necessary at the maxillary anterior region. For immediate or early placement at the maxillary anterior region, the implant should be located palatally to reduce labial bone resorption and marginal recession; its apex should be angulated palatally to avoid labial perforation at the apical region. To protect the NPC, implants at the central incisor region should be placed away from NPC.
doi:10.7555/JBR.27.20130002
PMCID: PMC4250963  PMID: 25469120
cone beam computed tomography (CBCT); nasopalatine canal (NPC); alveolar bone; maxillary anterior region; implant esthetics
19.  The beneficial fungus Piriformospora indica protects Arabidopsis from Verticillium dahliae infection by downregulation plant defense responses 
BMC Plant Biology  2014;14:268.
Background
Verticillium dahliae (Vd) is a soil-borne vascular pathogen which causes severe wilt symptoms in a wide range of plants. The microsclerotia produced by the pathogen survive in soil for more than 15 years.
Results
Here we demonstrate that an exudate preparation induces cytoplasmic calcium elevation in Arabidopsis roots, and the disease development requires the ethylene-activated transcription factor EIN3. Furthermore, the beneficial endophytic fungus Piriformospora indica (Pi) significantly reduced Vd-mediated disease development in Arabidopsis. Pi inhibited the growth of Vd in a dual culture on PDA agar plates and pretreatment of Arabidopsis roots with Pi protected plants from Vd infection. The Pi-pretreated plants grew better after Vd infection and the production of Vd microsclerotia was dramatically reduced, all without activating stress hormones and defense genes in the host.
Conclusions
We conclude that Pi is an efficient biocontrol agent that protects Arabidopsis from Vd infection. Our data demonstrate that Vd growth is restricted in the presence of Pi and the additional signals from Pi must participate in the regulation of the immune response against Vd.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0268-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-014-0268-5
PMCID: PMC4198706  PMID: 25297988
Calcium; Defense; Ethylene; Jasmonic acid; Piriformospora indica; Salicylic acid; Verticillium dahliae
20.  Elevation of Proteasomal Substrate Levels Sensitizes Cells to Apoptosis Induced by Inhibition of Proteasomal Deubiquitinases 
PLoS ONE  2014;9(10):e108839.
Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. The mechanisms underlying the therapeutic efficacy of these drugs and their selective toxicity towards cancer cells are not known. Here, we show that increasing the cellular levels of proteasome substrates using an inhibitor of Sec61-mediated protein translocation significantly increases the extent of apoptosis that is induced by inhibition of proteasomal deubiquitinase activity in both cancer derived and non-transformed cell lines. Our results suggest that increased generation of misfolded proteasome substrates may contribute to the mechanism(s) underlying the increased sensitivity of tumor cells to inhibitors of the ubiquitin-proteasome system.
doi:10.1371/journal.pone.0108839
PMCID: PMC4186810  PMID: 25286379
21.  Clinical presentations of gastric small gastrointestinal stromal tumors mimics functional dyspepsia symptoms 
World Journal of Gastroenterology : WJG  2014;20(33):11800-11807.
AIM: To explore whether clinical presentations of gastric small gastrointestinal tumors (GISTs) mimics gastrointestinal dyspepsia symptoms.
METHODS: The endosonographic data of 167 patients who underwent endoscopic submucosal dissection at the Tianjin Medical University General Hospital, China between 2009 and 2011 were analyzed. GISTs and leiomyomas had a similar intragastric distribution and similar locations within the gastric wall. Therefore, patients with GISTs were chosen as the study group and those with leiomyomas were chosen as the control group. Dyspepsia symptom questionnaires were used to investigate and compare the gastrointestinal symptoms of patients with GISTs and those with gastric leiomyomas before and after endoscopic submucosal dissection (ESD). The questionnaires evaluated symptoms such as epigastric pain, heartburn, regurgitation, epigastric discomfort, nausea and vomiting, abdominal bloating, and eructation. Symptoms were assessed using a four-point scoring scale.
RESULTS: GISTs were the most common gastric submucosal lesion (67 cases, 40.12%), followed by leiomyomas (38 cases, 22.75%). Both groups were similar in terms of gender distribution (P = 0.49), intragastric location (P = 0.525), and originating layer within the gastric wall (P = 0.449), but leiomyomas were more commonly found in the proximal fundus (P < 0.05). Overall, 94.2% of the patients with small GISTs and 93.5% of those with gastric leiomyomas experienced some dyspepsia; however, total symptom scores were significantly lower in the GIST group than in the leiomyoma group (1.34 ± 1.27 vs 2.20 ± 1.70, P < 0.05). Each component of the symptom score demonstrated a statistically significant improvement in the GIST patients after ESD (P < 0.05), including epigastric pain (0.80 ± 0.90 vs 0.13 ± 0.46), heartburn (0.63 ± 1.08 vs 0.13 ± 0.41), regurgitation (0.55 ± 0.87 vs 0.22 ± 0.57), epigastric discomfort (0.70 ± 0.98 vs 0.32 ± 0.47), nausea and vomiting (0.27 ± 0.62 vs 0.05 ± 0.21), abdominal bloating (0.70 ± 0.90 vs 0.27 ± 0.49), and eructation (0.36 ± 0.61 vs 0.21 ± 0.46). For leiomyoma patients, symptoms such as heartburn, nausea, vomiting, and eructation improved after treatment; however, these improvements were not statistically significant (P > 0.05). Thus, the pathophysiology of dyspepsia symptoms may be different between the two groups.
CONCLUSION: Symptoms of gastric small GISTs may mimic those of functional dyspepsia. An alternative diagnosis should be considered in patients with functional dyspepsia and treatment failure.
doi:10.3748/wjg.v20.i33.11800
PMCID: PMC4155371  PMID: 25206285
Gastric small gastrointestinal stromal tumor; Gastric leiomyoma; Clinical presentation; Endoscopic ultrasonography
22.  Dynamic behaviors of approximately ellipsoidal microbubbles photothermally generated by a graphene oxide-microheater 
Scientific Reports  2014;4:6086.
Thermal microbubbles generally grow directly from the heater and are spherical to minimize surface tension. We demonstrate a novel type of microbubble indirectly generated from a graphene oxide-microheater. Graphene oxide's photothermal properties allowed for efficient generation of a thermal gradient field on the microscale. A series of approximately ellipsoidal microbubbles were generated on the smooth microwire based on heterogeneous nucleation. Other dynamic behaviors induced by the microheater such as constant growth, directional transport and coalescence were also investigated experimentally and theoretically. The results are not only helpful for understanding the bubble dynamics but also useful for developing novel photothermal bubble-based devices.
doi:10.1038/srep06086
PMCID: PMC4133711  PMID: 25124694
23.  Clinical features and outcome of acute hepatitis B in pregnancy 
BMC Infectious Diseases  2014;14:368.
Background
The impact of pregnancy on the clinical course of acute hepatitis B (AHB) is still largely unclear, mainly because most studies have not included matched controls. This study was conducted to investigate the clinical features and outcome of AHB in pregnancy using matched controls.
Methods
Consecutive AHB inpatients who were admitted to Jinan Infectious Disease Hospital, Jinan, between January 2006 and December 2010 were evaluated and followed. Demographic data, clinical manifestations, and results of laboratory tests were compared between pregnant patients and age and sex matched non-pregnant patients at admission, discharge, and final follow-up.
Results
A total of 618 AHB inpatients were identified during the study period. 22 pregnant patients and 87 age and sex matched non-pregnant patients were enrolled in this study. Prodromal fever was less common (0% vs. 20.7%, P = 0.02), serum alanine aminotransferase levels were significantly lower, and HBsAg > 250 IU/mL rate and serum bilirubin levels were significantly higher in pregnant patients than in non-pregnant patients. After a mean (range) of 7(5.2-8.3) months follow-up, 18.2% pregnant patients and 4.6% non-pregnant patients were still HBsAg positive (P = 0.03). For pregnant patients, the relative risk (95% confidence interval) of HBsAg positive at the end of follow-up was 4.6 (1.1-20.2). The median (95% confidence interval) days of HBsAg seroclearance form disease onset in pregnant and non-pregnant patients were 145.0 (110.5-179.5) and 80.0 (62.6-97.4), respectively.
Conclusions
The HBsAg loss and seroconversion were delayed and lower in pregnant patients. Pregnancy might be a possible risk of chronicity following acute HBV infection.
doi:10.1186/1471-2334-14-368
PMCID: PMC4096733  PMID: 24993389
Acute hepatitis B; Pregnancy; Clinical features; Outcome; Hepatitis B surface antigen; Chronicity
24.  Mechanisms, function and clinical applications of DNp73 
Cell Cycle  2013;12(12):1861-1867.
p73, has two distinct promoters, which allow the formation of two protein isoforms: full-length transactivating (TA) p73 and an N-terminally truncated p73 species (referred to as DNp73) that lacks the N-terminal transactivating domain. Although the exact cellular function of DNp73 is unclear, the high expression levels of the genes have been observed in a variety of human cancers and cancer cell lines and have been connected to pro-tumor activities. Hence the aim of this review is to summarize DNp73 expression status in cancer in the current literature. Furthermore, we also focused on recent findings of DNp73 related to the biological functions from apoptosis, chemosensitivity, radiosensitibity, differentiation, development, etc. Thus this review highlights the significance of DNp73 as a marker for disease severity in patients and as target for cancer therapy.
doi:10.4161/cc.24967
PMCID: PMC3735700  PMID: 23708520
DNp73; alternative splicing; apoptosis; cancer; chemosensitivity; radiotherapy; tumorigenesis
25.  Transcriptome profiling and comparative analysis of Panax ginseng adventitious roots 
Journal of Ginseng Research  2014;38(4):278-288.
Background
Panax ginseng Meyer is a traditional medicinal plant famous for its strong therapeutic effects and serves as an important herbal medicine. To understand and manipulate genes involved in secondary metabolic pathways including ginsenosides, transcriptome profiling of P. ginseng is essential.
Methods
RNA-seq analysis of adventitious roots of two P. ginseng cultivars, Chunpoong (CP) and Cheongsun (CS), was performed using the Illumina HiSeq platform. After transcripts were assembled, expression profiling was performed.
Results
Assemblies were generated from ∼85 million and ∼77 million high-quality reads from CP and CS cultivars, respectively. A total of 35,527 and 27,716 transcripts were obtained from the CP and CS assemblies, respectively. Annotation of the transcriptomes showed that approximately 90% of the transcripts had significant matches in public databases. We identified several candidate genes involved in ginsenoside biosynthesis. In addition, a large number of transcripts (17%) with different gene ontology designations were uniquely detected in adventitious roots compared to normal ginseng roots.
Conclusion
This study will provide a comprehensive insight into the transcriptome of ginseng adventitious roots, and a way for successful transcriptome analysis and profiling of resource plants with less genomic information. The transcriptome profiling data generated in this study are available in our newly created adventitious root transcriptome database (http://im-crop.snu.ac.kr/transdb/index.php) for public use.
doi:10.1016/j.jgr.2014.05.008
PMCID: PMC4213845  PMID: 25379008
adventitious root; de novo assembly; next-generation sequencing; Panax ginseng; transcriptome

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