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1.  Genome-wide alteration of 5-hydroxymethylcytosine in a mouse model of fragile X-associated tremor/ataxia syndrome 
Human Molecular Genetics  2013;23(4):1095-1107.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder in which patients carry premutation alleles of 55–200 CGG repeats in the FMR1 gene. To date, whether alterations in epigenetic regulation modulate FXTAS has gone unexplored. 5-Hydroxymethylcytosine (5hmC) converted from 5-methylcytosine (5mC) by the ten-eleven translocation (TET) family of proteins has been found recently to play key roles in neuronal functions. Here, we undertook genome-wide profiling of cerebellar 5hmC in a FXTAS mouse model (rCGG mice) and found that rCGG mice at 16 weeks showed overall reduced 5hmC levels genome-wide compared with age-matched wild-type littermates. However, we also observed gain-of-5hmC regions in repetitive elements, as well as in cerebellum-specific enhancers, but not in general enhancers. Genomic annotation and motif prediction of wild-type- and rCGG-specific differential 5-hydroxymethylated regions (DhMRs) revealed their high correlation with genes and transcription factors that are important in neuronal developmental and functional pathways. DhMR-associated genes partially overlapped with genes that were differentially associated with ribosomes in CGG mice identified by bacTRAP ribosomal profiling. Taken together, our data strongly indicate a functional role for 5hmC-mediated epigenetic modulation in the etiology of FXTAS, possibly through the regulation of transcription.
doi:10.1093/hmg/ddt504
PMCID: PMC3900112  PMID: 24108107
2.  Is rs759853 polymorphism in promoter of aldose reductase gene a risk factor for diabetic nephropathy? A meta-analysis 
Background
So far, a number of case-control or cohort studies have been carried out to investigate the relationship between rs759853 polymorphism in the promoter of aldose reductase (AR) gene and the risk of diabetic nephropathy (DN). However, the results have generated considerable controversy. We performed this study to clarify the linkage between this gene mutation and the risk of DN.
Methods
A comprehensive literature search of electronic databases and a well-organized meta-analysis were conducted.
Results
Twelve comparisons and 4,735 individuals from nine published case-control or cohort studies were included finally. From none to large heterogeneity was observed, therefore, both fixed and random models were used. Significant differences were found between AR rs759853 polymorphism and susceptibility of DN from both type 1 and type 2 diabetes in all genetic models (allele contrast, OR = 1.37, CI (1.18, 1.59), P < 0.0001; additive model, OR = 1.78, CI (1.25, 2.53), P = 0.01; recessive model OR = 1.33 CI (1.08, 1.63), P = 0.008; dominant model, OR = 1.52, CI (1.26, 1.84), P < 0.0001; codominance model OR = 1.30 (1.15, 1.47), P < 0.0001). In stratified meta-analyses for type 2 diabetes by ethnicity, the significant relationship was found in allele contrast and dominant model in Caucasians, and in allele contrast and codominance model in Asians. However, data do not support the linkage between this gene mutation and the progression of DN. There was no significant publication bias.
Conclusions
The evidence currently available shows that the AR rs759853 polymorphism may correlate with the susceptibility of DN. However, data do not support the association between this DNA variation and the progression of DN.
doi:10.1186/s40001-015-0089-5
PMCID: PMC4335367
Aldose reductase; Diabetic nephropathy; Meta-analysis
3.  SynBioLGDB: a resource for experimentally validated logic gates in synthetic biology 
Scientific Reports  2015;5:8090.
Synthetic biologists have developed DNA/molecular modules that perform genetic logic operations in living cells to track key moments in a cell's life or change the fate of a cell. Increasing evidence has also revealed that diverse genetic logic gates capable of generating a Boolean function play critically important roles in synthetic biology. Basic genetic logic gates have been designed to combine biological science with digital logic. SynBioLGDB (http://bioinformatics.ac.cn/synbiolgdb/) aims to provide the synthetic biology community with a useful resource for efficient browsing and visualization of genetic logic gates. The current version of SynBioLGDB documents more than 189 genetic logic gates with experimental evidence involving 80 AND gates and 16 NOR gates, etc. in three species (Human, Escherichia coli and Bacillus clausii). SynBioLGDB provides a user-friendly interface through which conveniently to query and browse detailed information about these genetic logic gates. SynBioLGDB will enable more comprehensive understanding of the connection of genetic logic gates to execute complex cellular functions in living cells.
doi:10.1038/srep08090
PMCID: PMC4308699  PMID: 25627341
4.  Dosimetric comparison between jaw tracking and static jaw techniques in intensity-modulated radiotherapy 
Purpose
To compare the dosimetric differences between jaw tracking technique (JTT) and static jaw technique (SJT) in dynamic intensity-modulated radiotherapy (d-IMRT) and assess the potential advantages of jaw tracking technique.
Methods
Two techniques, jaw tracking and static jaw, were used respectively to develop the d-IMRT plans for 28 cancer patients with various lesion sites: head and neck, lungs, esophageal, abdominal, prostate, rectal and cervical. The dose volume histograms (DVH) and selected dosimetric indexes for the whole body and for organs at risk (OARs) were compared. A two dimensional ionization chamber Array Seven29 (PTW, Freiburg, Germany) and OCTAVIUS Octagonal phantom (PTW, Freiburg, Germany) were used to verify all the plans.
Results
For all patients, the treatment plans using both techniques met the clinical requirements. The V5, V10, V20, V30, V40 (volumes receiving 5, 10, 20, 30 and 40 Gy at least, respectively), mean dose (Dmean) for the whole body and V5, V10, V20, Dmean for lungs in the JTT d-IMRT plans were significantly less than the corresponding values of the SJT d-IMRT plans (p < 0.001). The JTT d-IMRT plans deposited lower maximum dose (Dmax) to the lens, eyes, brainstem, spinal cord, and right optic nerve, the doses reductions for these OARs ranged from 2.2% to 28.6%. The JTT d-IMRT plans deposited significantly lower Dmean to various OARs (all p values < 0.05), the mean doses reductions for these OARs ranged from 1.1% to 31.0%, and the value reductions depend on the volume and the location of the OARs. The γ evaluation method showed an excellent agreement between calculation and measurement for all techniques with criteria of 3%/3 mm.
Conclusions
Both jaw tracking and static jaw d-IMRT plans can achieve comparable target dose coverage. JTT displays superior OARs sparing than SJT plans. These results are of clinical importance, especially for the patients with large and complex targets but close to some highly radio-sensitive organs to spare, and for patients with local recurrent or secondary primary malignant lesion within a previously irradiated area.
doi:10.1186/s13014-015-0329-4
PMCID: PMC4326511  PMID: 25623899
Jaw tracking; IMRT; Dosimetry; OARs sparing
5.  Expression of EFR3A in the Mouse Cochlea during Degeneration of Spiral Ganglion following Hair Cell Loss 
PLoS ONE  2015;10(1):e0117345.
Retrograde degeneration of spiral ganglion cells in the cochlea following hair cell loss is similar to dying back in pathology. The EFR3A gene has recently been discovered to be involved in the pathogenesis of dying back. The relationship of EFR3A and spiral ganglion degeneration, however, was rarely investigated. In this study, we destroyed the hair cells of the mouse cochlea by co-administration of kanamycin and furosemide and then investigated the EFR3A expression during the induced spiral ganglion cell degeneration. Our results revealed that co-administration of kanamycin and furosemide quickly induced hair cell loss in the C57BL/6J mice and then resulted in progressive degeneration of the spiral ganglion beginning at day 5 following drug administration. The number of the spiral ganglion cells began to decrease at day 15. The expression of EFR3A increased remarkably in the spiral ganglion at day 5 and then decreased to near normal level within the next 10 days. Our study suggested that the change of EFR3A expression in the spiral ganglion was coincident with the time of the spiral ganglion degeneration, which implied that high expression of EFR3A may be important to prompt initiation of spiral ganglion degeneration following hair cell loss.
doi:10.1371/journal.pone.0117345
PMCID: PMC4306511  PMID: 25622037
6.  Isolated gastric recurrence from ovarian carcinoma: A case report 
Oncology Letters  2015;9(3):1173-1176.
Although ovarian metastasis secondary to gastric cancer (Krukenberg tumor) has been extensively described in the literature, gastric metastasis from ovarian carcinoma is rare. The present case report describes a patient with gastric metastasis from ovarian carcinoma. A 51-year-old female with previously treated ovarian carcinoma of stage III according to the International Federation of Gynecology and Obstetrics was admitted to the Department of Oncology, First Affiliated Hospital of Nanjing Medical University (Nanjing, China) with high serum carbohydrate antigen-125 levels. Endoscopic ultrasound and 18F-fluorodeoxyglucose positron emission tomography/computed tomography scanning revealed a lesion in the stomach with the typical appearance of a gastrointestinal stromal tumor. The histopathological examination revealed infiltration of the resected specimens by metastatic serous adenocarcinoma and a comparison with the previously resected ovarian specimen confirmed disease recurrence. Although isolated gastric recurrence from ovarian carcinoma is rare, when a patient has a history of ovarian carcinoma (particularly with a high CA-125 level) and when the imaging results show a mass in the stomach wall, metastasis from ovarian carcinoma should be considered.
doi:10.3892/ol.2015.2887
PMCID: PMC4315010  PMID: 25663876
gastric metastasis; ovarian carcinoma; International Federation of Gynecology and Obstetrics cancer staging; 18F-fluorodeoxyglucose positron emission tomography/computed tomography; recurrent disease; serum carbohydrate antigen-125
7.  Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions 
Cell  2014;156(0):45-68.
Methylation of cytosines in the mammalian genome represents a key epigenetic modification and is dynamically regulated during development. Compelling evidence now suggests that dynamic regulation of DNA methylation is mainly achieved through a cyclic enzymatic cascade comprised of cytosine methylation, iterative oxidation of methyl group by TET dioxygenases, and restoration of unmodified cytosines by either replication-dependent dilution or DNA glycosylase-initiated base excision repair. In this review, we discuss the mechanism and function of DNA demethylation in mammalian genomes, focusing particularly on how developmental modulation of the cytosine-modifying pathway is coupled to active reversal of DNA methylation in diverse biological processes.
doi:10.1016/j.cell.2013.12.019
PMCID: PMC3938284  PMID: 24439369
8.  Poor Sleep Quality of Third-Trimester Pregnancy is a Risk Factor for Postpartum Depression 
Background
The aim of this study was to investigate whether poor sleep quality of third-trimester pregnancy is a risk factor for postpartum depression.
Material/Methods
Third-trimester pregnant women (T0, n=293) were tested using the first socio-demographic, Pittsburgh Sleep Quality Index, and Edinburgh Postnatal Depression Scale assessments, and received a diagnosis of depression. Three months (T1, n=223) after delivery, scale filling was finished and the structured interview was performed again.
Results
We found that 73 persons (32.7%) were low income, 84 persons (37.7%) were middle-income, and 66 persons (29.6%) were higher income. The overall prevalence of postpartum depression was 9.4% (21 persons). After controlling for other factors, age, household income, marital satisfaction, and sleep quality were significantly related to postpartum depression, in which age and sleep quality scores (a higher score was associated with poorer sleep quality) were positively related to postpartum depression, and household income and marital satisfaction were negatively related to postpartum depression. Moreover, third-trimester sleep quality score was positively related to postpartum depressive symptoms.
Conclusions
Poor third-trimester subjective sleep quality is a risk factor for postpartum depression.
doi:10.12659/MSM.891222
PMCID: PMC4280053  PMID: 25526703
Depression, Postpartum; Pregnancy Trimester, Third; Risk Factors
9.  Synthesis and Characterization of an Antiapoptotic Immunosuppressive Compound for improving the Outcome of Islet Transplantation 
Bioconjugate chemistry  2013;24(12):2036-2044.
Mycophenolic acid (MPA) is a commonly used immunosuppressive drug for human islet transplantation. However, it is toxic to transplanted islets, causing primary nonfunction. We recently synthesized a quinic acid derivative, 1,3,4,5-tetrahydroxy-N-propylcyclohexanecarboxamide (KZ41), which hold anti-inflammatory and antiapoptotic effects. We hypothesized that the conjugate (E)-2,3,5-trihydroxy-5-(propylcarbamoyl) cyclohexyl 6-(4-ethoxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (JP-3-110), which is composed of KZ41 and MPA through esterification, can suppress the immune rejection while inducing less toxicity. Early characterization showed that the solubility of JP-3-110 was significantly higher than MPA though JP-3-110 was still poorly water soluble. The ester bond connecting KZ41 and MPA is stable for a limited duration (<4 weeks). Pharmacological studies demonstrated that JP-3-110 induced significantly less activated caspase 3 and apoptotic cell death of human islets than MPA, while maintaining equally potent immunosuppressive effect. Similar immunosuppressive effect of JP-3-110 and MPA in humanized NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NOD scid gamma, NSG) mice with adoptively transferred human immunity was observed. Taken together, our results demonstrated that JP-3-110 can be a safer immunosuppressive agent for human islet transplantation.
doi:10.1021/bc400369t
PMCID: PMC3919530  PMID: 24256337
Islet transplantation; immune rejection; primary nonfunction; mycophenolic acid
10.  Consistently High Unprotected Anal Intercourse (UAI) and factors correlated with UAI among men who have sex with men: implication of a serial cross-sectional study in Guangzhou, China 
BMC Infectious Diseases  2014;14(1):696.
Background
China experiencing an increasing HIV epidemic among men who have sex with men (MSM), and unprotected anal intercourse (UAI) has played a key role in this process. The aims of this study were to examine the trend of UAI and to explore the factors correlated with UAI among MSM in Guangzhou, China.
Methods
Data from 2008 to 2013 were retrieved from the annual serological and behavioral surveys system. We collected information on demographic, HIV related sexual behavior with men and women, access to HIV prevention services, and symptoms of sexually transmitted infections. Chi-square test was used to examine the similarity of the participants during the study period. Univariate and multivariate logistic regression were conducted to test the factors associated with UAI. Trend test was used to check the change of UAI in different characteristic stratums during the study period.
Results
In total, 58.4% (range from 54.5% to 62.0%) of the participants reported that they engaged in UAI in the past six months. Participants who aged less than 20 [Adjusted Odds Ratio (AOR): 2.22, 95% Confidential Interval (CI): 1.07-4.61], only attended elementary school (or less) (AOR: 1.41, 95% CI: 1.04-1.90), cohabiting with male partner (AOR: 2.15, 95% CI: 1.66-2.79), divorced or widowed (AOR: 2.80, 95% CI: 1.54-5.07), did not test for HIV in the past year (AOR: 1.36, 95% CI: 1.12-1.65), and had 10 or more partners in the past six months (AOR: 1.85, 95% CI: 1.18-2.91) had higher odds of UAI. However, the proportions of UAI were stable in different stratums during the study period.
Conclusions
The proportion of MSM engaged in UAI was consistently high during the study period. Effective intervention strategies, which include but not limit to risk reduction counseling and testing services, are urgently needed to bring down the risk behaviors of the MSM in Guangzhou, in order to control HIV/STIs epidemic in this specific population.
doi:10.1186/s12879-014-0696-8
PMCID: PMC4279965  PMID: 25519034
Unprotected anal intercourse (UAI); Men who have sex with men (MSM); Human immunodeficiency virus (HIV); Trend; Serial cross-sectional study; China
11.  A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination 
Cell reports  2014;7(5):1589-1600.
SUMMARY
Experience refines synaptic connectivity through neural activity-dependent regulation of transcription factors. Although activity-dependent regulation of transcription factors has been well described, it is unknown if synaptic activity and local, dendritic regulation of the induced transcripts are necessary for mammalian synaptic plasticity in response to transcription factor activation. Neuronal depolarization activates the Myocyte Enhancer Factor 2 (MEF2) family of transcription factors which suppresses excitatory synapse number. We report that activation of metabotropic glutamate receptor 5 (mGluR5) on the dendrites, but not cell soma, of hippocampal CA1 neurons is required for MEF2-induced functional and structural synapse elimination. We present evidence that mGluR5 is necessary for synapse elimination to stimulate dendritic translation of the MEF2-target gene Arc/Arg3.1. Arc is required for MEF2-induced synapse elimination, where it plays an acute, cell autonomous and postsynaptic role. This work reveals a role for dendritic activity in local translation of specific transcripts in synapse refinement.
doi:10.1016/j.celrep.2014.04.035
PMCID: PMC4057996  PMID: 24857654
12.  Totally laparoscopic gallbladder-preserving surgery: A minimally invasive and favorable approach for cholelithiasis 
The aim of the present study was to investigate the effectiveness of laparoscopic gallbladder-preserving surgery (L-GPS) for cholelithiasis and the feasibility and value of totally laparoscopic GPS (TL-GPS). A total of 517 patients underwent L-GPS, including 365 cases of laparoscopy-assisted GPS (LA-GPS), 143 cases of TL-GPS (preservation rate, 98.3%) and nine conversions to laparoscopic cholecystectomy. The surgeries were all performed by one medical team and the mean operating time was 72 min. All macroscopic calculi were removed through endoscopy. The number of calculi observed in the patients was between one and several dozen; diameters ranged between 0.1 and 2.5 cm. Only three cases of incisional infection were noted in the LA-GPS group and long-term follow-up showed a low recurrence rate of 1.2%. L-GPS is, therefore, an excellent approach to cure cholelithiasis and TL-GPS is a feasible and effective option that could avoid incisional complications.
doi:10.3892/etm.2014.2107
PMCID: PMC4280921  PMID: 25574204
gallbladder preservation; cholelithiasis; laparoscopic; cholecystoscope; choledochoscope
13.  Draft Genome Sequence of Bacillus subtilis GXA-28, a Thermophilic Strain with High Productivity of Poly-γ-Glutamic Acid 
Genome Announcements  2014;2(6):e01259-14.
Bacillus subtilis GXA-28 is a thermophilic strain that can produce high yield and high molecular weight of poly-γ-glutamic acid under high temperature. Here, we report the draft genome sequence of this strain, which may provide the genomic basis for the high productivity of poly-γ-glutamic acid.
doi:10.1128/genomeA.01259-14
PMCID: PMC4256194  PMID: 25477413
14.  Few-layer molybdenum disulfide transistors and circuits for high-speed flexible electronics 
Nature communications  2014;5:5143.
Two-dimensional layered materials, such as molybdenum disulfide, are emerging as an exciting material system for future electronics due to their unique electronic properties and atomically thin geometry. Here we report a systematic investigation of MoS2 transistors with optimized contact and device geometry, to achieve self-aligned devices with performance including an intrinsic gain over 30, an intrinsic cut-off frequency fT up to 42 GHz and a maximum oscillation frequency fMAX up to 50 GHz, exceeding the reported values for MoS2 transistors to date (fT ~ 0.9 GHz, fMAX ~ 1 GHz). Our results show that logic inverters or radio frequency amplifiers can be formed by integrating multiple MoS2 transistors on quartz or flexible substrates with voltage gain in the gigahertz regime. This study demonstrates the potential of two-dimensional layered semiconductors for high-speed flexible electronics.
doi:10.1038/ncomms6143
PMCID: PMC4249646  PMID: 25295573
15.  N-cadherin prevents the premature differentiation of anterior heart field progenitors in the pharyngeal mesodermal microenvironment 
Cell Research  2014;24(12):1420-1432.
The cardiac progenitor cells (CPCs) in the anterior heart field (AHF) are located in the pharyngeal mesoderm (PM), where they expand, migrate and eventually differentiate into major cell types found in the heart, including cardiomyocytes. The mechanisms by which these progenitors are able to expand within the PM microenvironment without premature differentiation remain largely unknown. Through in silico data mining, genetic loss-of-function studies, and in vivo genetic rescue studies, we identified N-cadherin and interaction with canonical Wnt signals as a critical component of the microenvironment that facilitates the expansion of AHF-CPCs in the PM. CPCs in N-cadherin mutant embryos were observed to be less proliferative and undergo premature differentiation in the PM. Notably, the phenotype of N-cadherin deficiency could be partially rescued by activating Wnt signaling, suggesting a delicate functional interaction between the adhesion role of N-cadherin and Wnt signaling in the early PM microenvironment. This study suggests a new mechanism for the early renewal of AHF progenitors where N-cadherin provides additional adhesion for progenitor cells in the PM, thereby allowing Wnt paracrine signals to expand the cells without premature differentiation.
doi:10.1038/cr.2014.142
PMCID: PMC4260345  PMID: 25367124
N-cadherin; anterior heart field; cardiac progenitor cells; premature differentiation; Wnt signaling; microenvironment
16.  Transportation of Berberine into HepG2, HeLa and SY5Y Cells: A Correlation to Its Anti-Cancer Effect 
PLoS ONE  2014;9(11):e112937.
The anti-cancer activities of berberine (BBR) have been reported extensively in various cancer cell lines. However, the minimal inhibitory concentrations of BBR varied greatly among different cell lines and very few studies have been devoted to elucidate this aspect. In this study, we employed three cancer cell lines, HepG2, HeLa and SY5Y, to compare the transportation and distribution of BBR. HPLC results demonstrated that BBR was capable of penetrating all the cell lines whereas the cumulative concentrations were significantly different. HepG2 cells accumulated higher level of BBR for longer duration than the other two cell lines. Molecular docking studies revealed the BBR binding site on P-glycoprotein 1 (P-gp). In addition, we elucidated that BBR regulated P-gp at both mRNA and protein levels. BBR induced the transcription and translation of P-gp in HeLa and SY5Y cells, whereas BBR inhibited P-gp expression in HepG2 cells. Further study showed that BBR regulates P-gp expression depending on different mechanisms (or affected by different factors) in different cell lines. To summarize, our study has revealed several mechanistic aspects of BBR regulation on P-gp in different cancer cell lines and might shed some useful insights into the use of BBR in the anti-cancer drug development.
doi:10.1371/journal.pone.0112937
PMCID: PMC4234535  PMID: 25402492
17.  Intestinal ischemia-reperfusion of macaques triggers a strong innate immune response 
World Journal of Gastroenterology : WJG  2014;20(41):15327-15334.
AIM: To investigate inflammatory injury in the intestinal mucosa after intestinal ischemia-reperfusion (IIR) with Toll-like receptor (TLR)-mediated innate immunity.
METHODS: Ten macaques were randomized into control and IIR groups. The distribution and expression level of TLR2, TLR4, MD2, nuclear factor (NF)-κB p65 and interferon (IFN)-γ were measured by immunohistochemical stain and western blotting. The mRNA expression of TLR4, TLR2, MD2, interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured by reverse transcriptase-polymerase chain reaction. The cytokine levels in blood and intestinal tissues were measured by ELISA.
RESULTS: Obvious hemorrhage and erosion of mucosae were seen in the IIR group. Expression of TLR2, TLR4, MD2, NF-κB p65 and IFN-γ was significantly higher in the IIR group than in the control group (0.13 ± 0.04, 0.22 ± 0.04, 0.16 ± 0.06, 0.65 ± 0.12, 0.38 ± 0.10 vs 0.07 ± 0.04, 0.08 ± 0.03, 0.04 ± 0.02, 0.19 ± 0.06, 0.14 ± 0.05, P < 0.05). In addition, the expression of TLR2, TLR4, MD2, IL-1β and TNF-α mRNA in the IIR group were significantly higher than those of control group(1.52 ± 0.15, 1.39 ± 0.06, 1.94 ± 0.12, 1.48 ± 0.15, 0.66 ± 0.08 vs 0.31 ± 0.05, 0.5 ± 0.04, 0.77 ± 0.05, 0.35 ± 0.08, 0.18 ± 0.04, P < 0.05). Furthermore, IL-1β, IL-6 and TNF-α levels in the macaques ileum and plasma were significantly higher than in the control group (plasma: 86.3 ± 15.2, 1129 ± 248.3, 77.8 ± 16.2 vs 29.5 ± 7.3, 19.8 ± 8.2, 5.6 ± 1.7; ileum: 273.4. ± 44.7, 1636 ± 168.0, 205.5 ± 30.7 vs 76.8 ± 20.5, 663.4 ± 186.9, 49.0 ± 9.4; P < 0.05).
CONCLUSION: After IIR, general inflammatory injury in the intestinal mucosa is correlated with a strong innate immune response, mediated by activation of the TLR-NF-κB-cytokine pathway.
doi:10.3748/wjg.v20.i41.15327
PMCID: PMC4223266  PMID: 25386081
Intestine ischemia reperfusion; Toll-like receptors; Nuclear factor-κB; Cytokine; Macaques
18.  A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis 
Nature neuroscience  2005;8(5):616-625.
During development of the CNS, neurons and glia are generated in a sequential manner. The mechanism underlying the later onset of gliogenesis is poorly understood, although the cytokine-induced Jak-STAT pathway has been postulated to regulate astrogliogenesis. Here, we report that the overall activity of Jak-STAT signaling is dynamically regulated in mouse cortical germinal zone during development. As such, activated STAT1/3 and STAT-mediated transcription are negligible at early, neurogenic stages, when neurogenic factors are highly expressed. At later, gliogenic periods, decreased expression of neurogenic factors causes robust elevation of STAT activity. Our data demonstrate a positive autoregulatory loop whereby STAT1/3 directly induces the expression of various components of the Jak-STAT pathway to strengthen STAT signaling and trigger astrogliogenesis. Forced activation of Jak-STAT signaling leads to precocious astrogliogenesis, and inhibition of this pathway blocks astrocyte differentiation. These observations suggest that autoregulation of the Jak-STAT pathway controls the onset of astrogliogenesis.
doi:10.1038/nn1440
PMCID: PMC4222251  PMID: 15852015
19.  Asymmetric Localization of CK2α During Xenopus Oogenesis 
The establishment of the dorso-ventral axis is a fundamental process that occurs after fertilization. Dorsal axis specification in frogs starts immediately after fertilization, and depends upon activation of Wnt/β-catenin signaling. The protein kinase CK2α can modulate Wnt/β-catenin signaling and is necessary for dorsal axis specification in Xenopus laevis. Our previous experiments show that CK2α transcripts and protein are animally localized in embryos, overlapping the region where Wnt/β-catenin signaling is activated. Here we determined whether the animal localization of CK2α in the embryo is preceded by its localization in the oocyte. We found that CK2α transcripts were detected from stage I, their levels increased during oogenesis, and were animally localized as early as stage III. CK2α transcripts were translated during oogenesis and CK2α protein was localized to the animal hemisphere of stage VI oocytes. We cloned the CK2α 3’UTR and showed that the 2.8 kb CK2α transcript containing the 3’UTR was enriched during oogenesis. By injecting ectopic mRNAs, we demonstrated that both the coding and 3’UTR regions were necessary for proper CK2α transcript localization. This is the first report showing the involvement of coding and 3’UTR regions in animal transcript localization. Our findings demonstrate the pre-localization of CK2α transcript and thus, CK2α protein, in the oocyte. This may help restrict CK2α expression in preparation for dorsal axis specification.
doi:10.4172/2161-0436.S4-001
PMCID: PMC4207361  PMID: 25346867
CK2α; Animal; Xenopus oocyte; RNA localization; Protein localization; 3’UTR; Coding; Asymmetry
20.  The Eag Domain Regulates the Voltage-Dependent Inactivation of Rat Eag1 K+ Channels 
PLoS ONE  2014;9(10):e110423.
Eag (Kv10) and Erg (Kv11) belong to two distinct subfamilies of the ether-à-go-go K+ channel family (KCNH). While Erg channels are characterized by an inward-rectifying current-voltage relationship that results from a C-type inactivation, mammalian Eag channels display little or no voltage-dependent inactivation. Although the amino (N)-terminal region such as the eag domain is not required for the C-type inactivation of Erg channels, an N-terminal deletion in mouse Eag1 has been shown to produce a voltage-dependent inactivation. To further discern the role of the eag domain in the inactivation of Eag1 channels, we generated N-terminal chimeras between rat Eag (rEag1) and human Erg (hERG1) channels that involved swapping the eag domain alone or the complete cytoplasmic N-terminal region. Functional analyses indicated that introduction of the homologous hERG1 eag domain led to both a fast phase and a slow phase of channel inactivation in the rEag1 chimeras. By contrast, the inactivation features were retained in the reverse hERG1 chimeras. Furthermore, an eag domain-lacking rEag1 deletion mutant also showed the fast phase of inactivation that was notably attenuated upon co-expression with the rEag1 eag domain fragment, but not with the hERG1 eag domain fragment. Additionally, we have identified a point mutation in the S4–S5 linker region of rEag1 that resulted in a similar inactivation phenotype. Biophysical analyses of these mutant constructs suggested that the inactivation gating of rEag1 was distinctly different from that of hERG1. Overall, our findings are consistent with the notion that the eag domain plays a critical role in regulating the inactivation gating of rEag1. We propose that the eag domain may destabilize or mask an inherent voltage-dependent inactivation of rEag1 K+ channels.
doi:10.1371/journal.pone.0110423
PMCID: PMC4204861  PMID: 25333352
21.  Long-term survival after enucleation of a giant esophageal gastrointestinal stromal tumor 
World Journal of Gastroenterology : WJG  2014;20(37):13632-13636.
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms of the gastrointestinal tract. Less than 1% occurs in the esophagus. Surgery is the primary treatment for patients with GISTs. We report a 29-year-old male was admitted after the detection of a posterior mediastinal mass during work-up with routine examination. He did not have any disease-related symptoms. The physical examination was unremarkable. Chest computed tomographic scan, the barium esophagogram and endoscopic esophageal ultrasound showed benign neoplasm. The patient was performed an enucleation surgery through the right posterolateral thoracotomy. The pathology revealed a 13.0 cm × 12.0 cm × 5.0 cm mass. The tumor was CD117 (C-kit), PDGFRA and DOG1 positive. These findings were consistent with a GIST of the esophagus. So the diagnosis of GIST of esophagus was confirmed. The pathological diagnosis of low grade of GIST of esophagus was confirmed. The patient has no evidence of recurrence and is in good clinical conditions up-to date, five years after surgery.
doi:10.3748/wjg.v20.i37.13632
PMCID: PMC4188917  PMID: 25309096
Esophageal gastrointestinal stromal tumor; Long-term survival; Enucleation; Surgery; Follow-up
22.  Insights into the Role of Bcl6 in Follicular Helper T Cells Using a New Conditional Mutant Mouse Model 
The transcriptional repressor Bcl6 controls development of the follicular helper T cell (TFH) lineage, however the precise mechanisms by which Bcl6 regulates this process are unclear. A model has been proposed whereby Bcl6 represses the differentiation of T cells into alternative effector lineages, thus favoring TFH differentiation. Analysis of T cell differentiation using Bcl6-deficient mice has been complicated by the strong pro-inflammatory phenotype of Bcl6-deficient myeloid cells. Here, we report data from a novel mouse model where Bcl6 is conditionally deleted in T cells (Bcl6fl/flCreCD4 mice). After immunization, PD-1high TFH cells in Bcl6fl/flCreCD4 mice are decreased over 90% compared to control mice, and antigen-specific IgG is sharply reduced. Residual PD-1high CXCR5+ TFH cells in Bcl6fl/flCreCD4 mice show a significantly higher rate of apoptosis than PD-1high CXCR5+ TFH cells in control mice. Immunization of Bcl6fl/flCreCD4 mice did not reveal enhanced differentiation into TH1, TH2 or TH17 lineages, although IL-10 expression by CD4 T cells was markedly elevated. Thus, T cell extrinsic factors appear to promote the increased TH1, TH2 and TH17 responses in germ-line Bcl6-deficient mice. Furthermore, IL-10 may be a key target gene for Bcl6 in CD4 T cells, which enables Bcl6 to promote the TFH cell phenotype. Finally, our data reveal a novel mechanism for the role of Bcl6 in promoting TFH cell survival.
doi:10.4049/jimmunol.1300378
PMCID: PMC3783642  PMID: 23980208
23.  MiR-136 modulates glioma cell sensitivity to temozolomide by targeting astrocyte elevated gene-1 
Diagnostic Pathology  2014;9(1):173.
Background
Recent studies have linked chemotherapy resistance to the altered expression of microRNAs (miRNAs). Thus, miRNA-based approaches to modulating sensitivity to temozolomide (TMZ) may overcome chemoresistance. The aim of the present study was to investigate whether miR-136 could modulates glioma cell sensitivity to TMZ.
Methods
The proliferation of glioma U251 cell line was evaluated by MTT assay. The expression of astrocyte elevated gene-1 (AEG-1)was detected by real‑time polymerase chain reaction (RT-PCR)and Western blot. The luciferase reporter gene was used to test whether AEG-1 was the target of the miR-136.
Results
The MTT assay showed that U251 cells with miR-136 overexpression were significantly more sensitive to the therapy of TMZ than control cells. Luciferase assays revealed that miR-136 directly targeted the 3’UTR of AEG-1. qRT–PCR and western blotting analysis found that AEG-1 expression at the mRNA and protein levels decreased in the miR-136 mimic-treatment group relative to control group. Downregulation of AEG-1 expression by siRNAs, U251 cells became more sensitive to the therapy of TMZ. In addition, the enhanced growth-inhibitory effect by the miR-136 mimics transfection was enhanced after the addition of AEG-1 siRNA.
Conclusions
The present study provides the first evidence that miR-136 plays a key role in TMZ resistance by targeting the AEG-1 protein in glioma cell line, suggesting that miR-136 can be used to predict a patient’s response to TMZ therapy as well as serve as a novel potential maker for glioma therapy.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_173
doi:10.1186/s13000-014-0173-0
PMCID: PMC4195982  PMID: 25266957
Glioma, miR-136; Sensitivity; Temozolomide; AEG-1
24.  Expression and prognostic value of MAGE-A9 in laryngeal squamous cell carcinoma 
Background: Melanoma-associated antigen (MAGE) family genes are reported to play important roles in the development of human cancers. However, the relationship between the expression of MAGE-A9 and clinicopathological characteristics in human laryngeal carcinoma remains unclear. This study aimed to examine the expression of MAGE-A9, and to evaluate the clinical significance of its expression in human laryngeal squamous cell carcinoma (LSCC). Methods: Quantitative real-time reverse transcription-PCR (qPCR) and immunohistochemistry (IHC) were performed to characterize the expression of MAGE-A9 in LSCC tissues and tumor-adjacent normal tissues. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of patients with LSCC. Results: The expression of MAGE-A9 was significantly higher in LSCC than in tumor-adjacent normal tissues. Cytoplasmic expression of MAGE-A9 was detected in 70 of 123 (56.9%) LSCC specimens. Levels of MAGE-A9 in LSCC were related to histopathological grade (P = 0.024). Kaplan-Meier survival and Cox regression analysis revealed that MAGE-A9 expression level and lymph node metastasis were independent prognostic factors of LSCC (P = 0.005; P = 0.001, respectively). Conclusions: Our study suggests that MAGE-A9 expression is a prognostic biomarker for LSCC patients. High expression of MAGE-A9 indicates unfavorable survival outcome in LSCC patients.
PMCID: PMC4230163  PMID: 25400753
Laryngeal squamous cell carcinoma; MAGE-A9; prognosis
25.  γδ T Cells Are Involved in Acute HIV Infection and Associated with AIDS Progression 
PLoS ONE  2014;9(9):e106064.
Background
Early diagnosis is vital to HIV control. γδ T cells play critical roles in viral infections, but their activation in acute HIV infected patients and follow up to 18 months has not been described.
Methods
Changes in γδ T cells, including subsets, function and activation, in treated and untreated acutely HIV-infected patients (n = 79) were compared by cytotoxicity assay and flow cytometry with healthy controls (n = 21) at month 0, 6, 12 and 18.
Results
In acutely HIV-infected patients, Vδ1 cell proportion was elevated (P = 0.027) with Vδ2 population reduced (P = 0.002). Effector and central memory γδ T cell factions were decreased (P = 0.006 and P = 0.001, respectively), while proportion of terminal γδ T cells increased (P = 0.002). γδ T cell cytotoxicity was compromised over time. Fraction of IL-17-producing cells increased (P = 0.008), and IFN-γ-producing cells were unaffected (P = 0.115). Elevation of a microbial translocation marker, sCD14, was associated with γδ T cell activation (P = 0.001), which increased in a time-dependent manner, correlating with CD4/CD8 T cell activation set-points and CD4 counts. Antiretroviral therapy did not affect these changes.
Conclusions
γδ T cell subpopulation and functions change significantly in acute HIV infection and over time. Early γδ T cell activation was associated with CD4/CD8 T cell activation set-points, which predict AIDS progression. Therefore, γδ T cell activation represents a potential surrogate marker of AIDS progression.
doi:10.1371/journal.pone.0106064
PMCID: PMC4154895  PMID: 25188438

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