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1.  A New Chiral Pyrrolyl α-Nitronyl Nitroxide Radical Attenuates β-Amyloid Deposition and Rescues Memory Deficits in a Mouse Model of Alzheimer Disease 
Neurotherapeutics  2012;10(2):340-353.
The generation of reactive oxygen species causes cellular oxidative damage, and has been implicated in the etiology of Alzheimer’s disease (AD). L-NNNBP, a new chiral pyrrolyl α-nitronyl nitroxide radical synthesized in our department, shows potential antioxidant effects. The purpose of this study was to investigate the protective effects of L-NNNBP on β-amyloid (Aβ) deposition and memory deficits in an AD model of APP/PS1 mice. In cultured cortical neurons, L-NNNBP acted as an antioxidant by quenching reactive oxygen species, inhibiting lipid peroxidation, nitrosative stress, and stimulating cellular antioxidant defenses. L-NNNBP inhibited cell apoptosis induced by Aβ exposure. In vivo treatment with L-NNNBP for 1 month induced a marked decrease in brain Aβ deposition and tau phosphorylation in the blinded study on APP/PS1 transgenic mice (1 mM in drinking water, initiated when the mice were 6 months old). The L-NNNBP-treated APP/PS1 mice showed decreased astrocyte activation and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These actions were more potent compared with that of curcumin, a natural product, and TEMPO, a nitroxide radical, which are used as free radical scavengers in clinics. These results proved that the newly synthesized L-NNNBP was an effective therapeutic agent for the prevention and treatment of AD.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0168-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-012-0168-z
PMCID: PMC3625382  PMID: 23212232
Reactive oxygen species; Alzheimer disease; Nitroxide radical; L-NNNBP; β-amyloid
2.  MicroRNA319 Positively Regulates Cold Tolerance by Targeting OsPCF6 and OsTCP21 in Rice (Oryza sativa L.) 
PLoS ONE  2014;9(3):e91357.
The microRNA319 (miR319) family is conserved among diverse plant species. In rice (Oryza sativa L.), the miR319 gene family is comprised of two members, Osa-miR319a and Osa-miR319b. We found that overexpressing Osa-miR319b in rice resulted in wider leaf blades and delayed development. Here, we focused on the biological function and potential molecular mechanism of the Osa-miR319b gene in response to cold stress in rice. The expression of Osa-miR319b was down-regulated by cold stress, and the overexpression of Osa-miR319b led to an enhanced tolerance to cold stress, as evidenced by higher survival rates and proline content. Also, the expression of a handful of cold stress responsive genes, such as DREB1A/B/C, DREB2A, TPP1/2, was increased in Osa-miR319b transgenic lines. Furthermore, we demonstrated the nuclear localization of the transcription factors, OsPCF6 and OsTCP21, which may be Osa-miR319b-targeted genes. We also showed that OsPCF6 and OsTCP21 expression was largely induced by cold stress, and the degree of induction was obviously repressed in plants overexpressing Osa-miR319b. As expected, the down-regulation of OsPCF6 and OsTCP21 resulted in enhanced tolerance to cold stress, partially by modifying active oxygen scavenging. Taken together, our findings suggest that Osa-miR319b plays an important role in plant response to cold stress, maybe by targeting OsPCF6 and OsTCP21.
doi:10.1371/journal.pone.0091357
PMCID: PMC3965387  PMID: 24667308
3.  The sequence and de novo assembly of the giant panda genome 
Li, Ruiqiang | Fan, Wei | Tian, Geng | Zhu, Hongmei | He, Lin | Cai, Jing | Huang, Quanfei | Cai, Qingle | Li, Bo | Bai, Yinqi | Zhang, Zhihe | Zhang, Yaping | Wang, Wen | Li, Jun | Wei, Fuwen | Li, Heng | Jian, Min | Li, Jianwen | Zhang, Zhaolei | Nielsen, Rasmus | Li, Dawei | Gu, Wanjun | Yang, Zhentao | Xuan, Zhaoling | Ryder, Oliver A. | Leung, Frederick Chi-Ching | Zhou, Yan | Cao, Jianjun | Sun, Xiao | Fu, Yonggui | Fang, Xiaodong | Guo, Xiaosen | Wang, Bo | Hou, Rong | Shen, Fujun | Mu, Bo | Ni, Peixiang | Lin, Runmao | Qian, Wubin | Wang, Guodong | Yu, Chang | Nie, Wenhui | Wang, Jinhuan | Wu, Zhigang | Liang, Huiqing | Min, Jiumeng | Wu, Qi | Cheng, Shifeng | Ruan, Jue | Wang, Mingwei | Shi, Zhongbin | Wen, Ming | Liu, Binghang | Ren, Xiaoli | Zheng, Huisong | Dong, Dong | Cook, Kathleen | Shan, Gao | Zhang, Hao | Kosiol, Carolin | Xie, Xueying | Lu, Zuhong | Zheng, Hancheng | Li, Yingrui | Steiner, Cynthia C. | Lam, Tommy Tsan-Yuk | Lin, Siyuan | Zhang, Qinghui | Li, Guoqing | Tian, Jing | Gong, Timing | Liu, Hongde | Zhang, Dejin | Fang, Lin | Ye, Chen | Zhang, Juanbin | Hu, Wenbo | Xu, Anlong | Ren, Yuanyuan | Zhang, Guojie | Bruford, Michael W. | Li, Qibin | Ma, Lijia | Guo, Yiran | An, Na | Hu, Yujie | Zheng, Yang | Shi, Yongyong | Li, Zhiqiang | Liu, Qing | Chen, Yanling | Zhao, Jing | Qu, Ning | Zhao, Shancen | Tian, Feng | Wang, Xiaoling | Wang, Haiyin | Xu, Lizhi | Liu, Xiao | Vinar, Tomas | Wang, Yajun | Lam, Tak-Wah | Yiu, Siu-Ming | Liu, Shiping | Zhang, Hemin | Li, Desheng | Huang, Yan | Wang, Xia | Yang, Guohua | Jiang, Zhi | Wang, Junyi | Qin, Nan | Li, Li | Li, Jingxiang | Bolund, Lars | Kristiansen, Karsten | Wong, Gane Ka-Shu | Olson, Maynard | Zhang, Xiuqing | Li, Songgang | Yang, Huanming | Wang, Jian | Wang, Jun
Nature  2009;463(7279):311-317.
Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
doi:10.1038/nature08696
PMCID: PMC3951497  PMID: 20010809
5.  Impaired balance of T helper 17/T regulatory cells in carbon tetrachloride-induced liver fibrosis in mice 
AIM: To investigate the effect of T helper (Th) 17/T regulatory (Treg) cells on hepatic fibrosis in mice and its possible mechanism.
METHODS: Hepatic fibrosis was induced by intraperitoneal injection of carbon tetrachloride. Hepatic pathological changes were observed by hematoxylin and eosin staining; the protein levels of interleukin (IL)-6, transforming growth factor (TGF)-β and α-smooth muscle actin (SMA) in liver tissue were determined by Western blotting; and the frequency of Th17 and Treg cells in the liver was estimated by flow cytometry. In addition, hepatic stellate cells were isolated from healthy mouse liver and co-cultured with Th17 or Treg cells. Immunofluorescence staining and Western blotting were performed to determine the change in HSC activation.
RESULTS: In the model group, there were different degrees of fibroplasia, degeneration and necrosis. The protein levels of IL-6, TGF-β and α-SMA in liver tissue were significantly higher than those in the control group at 12 wk (P < 0.05). Compared with the control group, the frequency of Th17 cells in the model group was increased but the frequency of Treg cells decreased gradually. Furthermore, at 4, 8 and 12 wk, there were significant differences in the number of Th17 cells (0.52% ± 0.16%, 1.46% ± 0.24%, and 2.60% ± 0.41%, respectively, P < 0.05) and Treg cells (2.99% ± 0.40%, 2.16% ± 0.50%, and 1.49% ± 0.34%, respectively, P < 0.05). In vitro, Th17 cells promoted, whereas Treg cells inhibited the expression of α-SMA, both in a dose-dependent manner, compared with the control group.
CONCLUSION: Th17/Treg imbalance exists in mice with liver fibrosis, which potentially promotes liver fibrosis via HSC activation.
doi:10.3748/wjg.v20.i8.2062
PMCID: PMC3934476  PMID: 24616573
T helper 17 cell; Treg cell; Carbon tetrachloride; Hepatic fibrosis; Hepatic stellate cell
6.  Control of hematopoietic stem cell emergence by antagonistic functions of ribosomal protein paralogs 
Developmental cell  2013;24(4):411-425.
Summary
It remains controversial whether the highly-homologous ribosomal protein (RP) paralogs found in lower eukaryotes have distinct functions and this has not been explored in vertebrates. Here we demonstrate that despite ubiquitous expression, the RP paralogs, Rpl22 and Rpl22-like1 (Rpl22l1) play essential, distinct, and antagonistic roles in hematopoietic development. Knockdown of rpl22 in zebrafish embryos selectively blocks the development of T lineage progenitors after they have seeded the thymus. In contrast, knockdown of the rpl22 paralog, rpl22l1, impairs the emergence of hematopoietic stem cells (HSC) in the aorta-gonad-mesonephros by abrogating Smad1 expression and the consequent induction of essential transcriptional regulator, Runx1. Indeed, despite the ability of both paralogs to bind Smad1 RNA, Rpl22 and Rpl22l1 have opposing effects on Smad1 expression. Accordingly, circumstances that tip the balance of these paralogs in favor of Rpl22 (e.g., Rpl22l1 knockdown or Rpl22 overexpression) result in repression of Smad1 and blockade of HSC emergence.
doi:10.1016/j.devcel.2013.01.018
PMCID: PMC3586312  PMID: 23449473
ribosomal protein; paralog; T cell development; hematopoietic stem cell; Rpl22; Rpl22l1
7.  All Solution-processed Stable White Quantum Dot Light-emitting Diodes with Hybrid ZnO@TiO2 as Blue Emitters 
Scientific Reports  2014;4:4085.
White quantum dot light-emitting diodes (QD-LEDs) have been a promising candidate for high-efficiency and color-saturated displays. However, it is challenging to integrate various QD emitters into one device and also to obtain efficient blue QDs. Here, we report a simply solution-processed white QD-LED using a hybrid ZnO@TiO2 as electron injection layer and ZnCdSeS QD emitters. The white emission is obtained by integrating the yellow emission from QD emitters and the blue emission generated from hybrid ZnO@TiO2 layer. We show that the performance of white QD-LEDs can be adjusted by controlling the driving force for hole transport and electroluminescence recombination region via varying the thickness of hole transport layer. The device is demonstrated with a maximum luminance of 730 cd/m2 and power efficiency of 1.7 lm/W, exhibiting the Commission Internationale de l'Enclairage (CIE) coordinates of (0.33, 0.33). The unencapsulated white QD-LED has a long lifetime of 96 h at its initial luminance of 730 cd/m2, primarily due to the fact that the device with hybrid ZnO@TiO2 has low leakage current and is insensitive to the oxygen and the moisture. These results indicate that hybrid ZnO@TiO2 provides an alternate and effective approach to achieve high-performance white QD-LEDs and also other optoelectronic devices.
doi:10.1038/srep04085
PMCID: PMC3923213  PMID: 24522341
8.  Low-dose capecitabine (Xeloda) for treatment for gastrointestinal cancer 
The prodrug capecitabine (Xeloda) has been an important drug for treatment for gastrointestinal cancer (GI-cancer). This study explores the efficacy of continuous metronomic Xeloda, as well as tolerability and best response during treatment. Patients (n = 35) with stage IV GI-cancer were included in the study and were divided into two groups; upper (n = 13) and lower (n = 22) GI-cancer. All patients were given continuous metronomic Xeloda (500 mg × 2). Best response was measured by radiological and clinical examination including laboratory results. Standard RECIST criteria were used. Median age was 66 (range 29–86). Those patients who received first and second line had the longest duration of treatment. For patients with metastatic gastrointestinal cancer, metronomic capecitabine (Xeloda) may be beneficial both as far as tumor control and quality of life is concerned. In this pilot study, palliation for more than 2 years is observed for 6 of the 35 patients.
doi:10.1007/s12032-014-0870-2
PMCID: PMC3933740  PMID: 24510794
Capecitabine; Gastrointestinal cancer; Metronomic treatment; Response; QoL
9.  Xiaocheng Gu (1930-2012) 
Cell Research  2013;23(2):167.
doi:10.1038/cr.2013.18
PMCID: PMC3567824
10.  A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis 
Nature  2013;500(7460):93-97.
Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression1. AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia (AML), is a transcription factor implicated in both gene repression and activation2. AML1-ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis3–6, making it important to identify coregulatory factors that “read” the NHR2 oligomerization and contribute to leukaemogenesis4. We now show that, in leukaemic cells, AML1-ETO resides in and functions through a stable protein complex (AETFC) that contains several haematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, colocalize genome-wide, cooperatively regulate gene expression, and contribute to leukaemogenesis. Within the AETFC complex, AML1-ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis of the NHR2-N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1-ETO–induced haematopoietic stem/progenitor cell self-renewal and leukaemogenesis. These results reveal new mechanisms of action of AML1-ETO and a potential therapeutic target in t(8;21)+ AML.
doi:10.1038/nature12287
PMCID: PMC3732535  PMID: 23812588
11.  A clinical study of metastasized rectal cancer treatment: assessing a multimodal approach 
Metastasized rectal cancer has long been considered incurable. During recent years, the treatment of rectal cancer patients has been improved, and nowadays, a subgroup of patients might even be cured. The aim of this study was to investigate the optimal timing of treatment in a multimodal therapy schedule in order to see whether the addition of bevacizumab (Avastin) to conventional chemotherapy was effective. The study included 39 patients with metastatic rectal cancer between 2009 and 2011, and three were excluded due to the lack of metastases or lack of follow-up information. The remaining 36 patients were divided into groups by treatment intention. The group with curative intention received mainly oxaliplatin (Eloxatin) in combination with capecitabine (Xeloda) with or without bevacizumab (Avastin) for 2 months followed by preoperative radiotherapy (RT) and surgery. Palliative patients had very different treatments depending on their needs of palliation. The median survival time for patients with curative intention was 31 months and for the palliative patients 12 months. Four of the patients (11 %) with curative intention were considered cured at the end of follow-up. The response to chemotherapy after 2-month treatment is a good prognostic sign for which patients can be cured. Long-lasting palliation can be obtained with this treatment schedule. The main side effects were gastrointestinal events, including bowel perforation, neuropathy, thrombo-embolic disease and reduced general condition. All side effects are known, and the treatment is considered tolerable. We conclude that a good treatment schedule would be oxaliplatin (Eloxatin) in combination with capecitabine (Xeloda) with or without bevacizumab (Avastin) for 2 months, followed by preoperative RT and surgery.
doi:10.1007/s12032-014-0839-1
PMCID: PMC3933738  PMID: 24477647
Rectal cancer; Metastasis; Bevacizumab; Chemotherapy
12.  Mysterious abrupt carbon-14 increase in coral contributed by a comet 
Scientific Reports  2014;4:3728.
A large and sudden increase in radiocarbon (14C) around AD 773 are documented in coral skeletons from the South China Sea. The 14C increased by ~ 15‰ during winter, and remain elevated for more than 4 months, then increased and dropped down within two months, forming a spike of 45‰ high in late spring, followed by two smaller spikes. The 14C anomalies coincide with an historic comet collision with the Earth's atmosphere on 17 January AD 773. Comas are known to have percent-levels of nitrogen by weight, and are exposed to cosmic radiation in space. Hence they may be expected to contain highly elevated 14C/12C ratios, as compared to the Earth's atmosphere. The significant input of 14C by comets may have contributed to the fluctuation of 14C in the atmosphere throughout the Earth's history, which should be considered carefully to better constrain the cosmic ray fluctuation.
doi:10.1038/srep03728
PMCID: PMC3893640  PMID: 24430984
13.  Variants of the PPARD Gene and Their Clinicopathological Significance in Colorectal Cancer 
PLoS ONE  2013;8(12):e83952.
Background
Peroxisome proliferator-activated receptor delta (PPARD) is nuclear hormone receptor involved in colorectal cancer (CRC) differentiation and progression. The purpose of this study was to determine prevalence and spectrum of variants in the PPARD gene in CRC, and their contribution to clinicopathological endpoints.
Methods and Findings
Direct sequencing of the PPARD gene was performed in 303 primary tumors, in blood samples from 50 patients with ≥3 affected first-degree relatives, 50 patients with 2 affected first-degree relatives, 50 sporadic patients, 360 healthy controls, and in 6 colon cancer cell lines. Mutation analysis revealed 22 different transversions, 7 of them were novel. Three of all variants were somatic (c.548A>G, p.Y183C, c.425-9C>T, and c.628-16G>A). Two missense mutations (p.Y183C and p.R258Q) were pathogenic using in silico predictive program. Five recurrent variants were detected in/adjacent to the exons 4 (c.1-87T>C, c.1-67G>A, c.130+3G>A, and c.1-101-8C>T) and exon 7 (c.489T>C). Variant c.489C/C detected in tumors was correlated to worse differentiation (P = 0.0397).
Conclusions
We found 7 novel variants among 22 inherited or acquired PPARD variants. Somatic and/or missense variants detected in CRC patients are rare but indicate the clinical importance of the PPARD gene.
doi:10.1371/journal.pone.0083952
PMCID: PMC3877104  PMID: 24391853
14.  The nucleosome regulates the usage of polyadenylation sites in the human genome 
BMC Genomics  2013;14:912.
Background
It has been reported that 3' end processing is coupled to transcription and nucleosome depletion near the polyadenylation sites in many species. However, the association between nucleosome occupancy and polyadenylation site usage is still unclear.
Results
By systematic analysis of high-throughput sequencing datasets from the human genome, we found that nucleosome occupancy patterns are different around the polyadenylation sites, and that the patterns associate with both transcription termination and recognition of polyadenylation sites. Upstream of proximal polyadenylation sites, RNA polymerase II accumulated and nucleosomes were better positioned compared with downstream of the sites. Highly used proximal polyadenylation sites had higher upstream nucleosome levels and RNA polymerase II accumulation than lowly used sites. This suggests that nucleosomes positioned upstream of proximal sites function in the recognition of proximal polyadenylation sites and in the preparation for 3' end processing by slowing down transcription speed. Both conserved distal polyadenylation sites and constitutive sites showed stronger nucleosome depletion near polyadenylation sites and had intrinsically better positioned downstream nucleosomes. Finally, there was a higher accumulation of RNA polymerase II downstream of the polyadenylation sites, to guarantee gene transcription termination and recognition of the last polyadenylation sites, if previous sites were missed.
Conclusions
Our study indicates that nucleosome arrays play different roles in the regulation of the usage of polyadenylation sites and transcription termination of protein-coding genes, and form a dual pausing model of RNA polymerase II in the alternative polyadenylation sites’ region, to ensure effective 3' end processing.
doi:10.1186/1471-2164-14-912
PMCID: PMC3879661  PMID: 24365105
15.  Quantitative T2 mapping to characterize the process of intervertebral disc degeneration in a rabbit model 
Background
To investigate the potential of T2 mapping for characterizing the process of intervertebral disc degeneration (IDD) in a rabbit model.
Methods
Thirty-five rabbits underwent an annular stab to the L4/5 discs (L5/6 discs served as internal normal controls). Degenerative changes were graded according to the modified Thompson classification and quantified in T2 respectively at pre-operation, 1, 3, 6, 12 and 24 weeks postoperatively. After MRI analysis, expression analysis of aggrecan and type II collagen gene in nucleus pulposus (NP) was performed using real time polymerase chain reaction (real-time PCR). The longitudinal changes in NP T2 and gene expressions were studied by repeated measures and ANOVA, linear regression was performed for their correlations through the process of IDD. The reliability analysis of method of measurement of NP T2 was also performed.
Results
There was a strong inverse correlation between NP T2 and Thompson grades (r = -0.85). The decline of L4/5 NP T2 through 24 weeks was nonlinear, the most significant decrease was observed in 3 weeks postoperatively (P<0.05). The tendency was confirmed at gene expression levels. NP T2 correlated strongly with aggrecan (R2 = 0.85, P<0.01) and type II collagen (R2 = 0.78, P<0.01) gene expressions. The intraclass correlation coefficients for interobserver and intraobserver reliability were 0.963 and 0.977 respectively.
Conclusions
NP T2 correlates well with aggrecan and type II collagen gene expressions. T2 mapping could act as a sensitive, noninvasive tool for quantitatively characterizing the process of IDD in longitudinal study, help better understanding of the pathophysiology of IDD, assist us to detect the degenerative cascade, and develop a T2-based quantification scale for evaluation of IDD and efficacy of therapeutic interventions.
doi:10.1186/1471-2474-14-357
PMCID: PMC3878325  PMID: 24344686
Intervertebral disc; Degeneration; Animal model; MRI; T2 mapping
16.  Livin expression is an independent factor in rectal cancer patients with or without preoperative radiotherapy 
Background
This study was aimed to investigate the expression significance of Livin in relation to radiotherapy (RT), clinicopathological and biological factors of rectal cancer patients.
Methods
This study included 144 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative radiotherapy. Tissue microarray samples from the excised primary rectal cancers, normal mucosa and lymph node metastases were immunostained with Livin antibody. The proliferation of colon cancer cell lines SW620 and RKO was assayed after Livin knock-down.
Results
The expression of Livin was significantly increased from adjacent (P = 0.051) or distant (P = 0.028) normal mucosa to primary tumors. 15.4% (2/13) and 39.7% (52/131) patients with Livin-negative and positive tumors died at 180 months after surgery, and the difference tended to be statistically significant (P = 0.091). In multivariate analyses, the difference achieved statistical significance, independent of TNM stage, local and distant recurrence, grade of differentiation, gender, and age (odds ratio = 5.09, 95% CI: 1.01-25.64, P = 0.048). The in vitro study indicated colon cancer cells with Livin knock-down exhibited decreased proliferation compared with controls after RT.
Conclusions
The expression of Livin was was independently related to survival in rectal cancer patients, suggesting Livin as a useful prognostic factor for rectal cancer patients.
doi:10.1186/1748-717X-8-281
PMCID: PMC3904757  PMID: 24295240
Rectal cancer; Livin; Radiotherapy
17.  E Proteins regulate osteoclast maturation and survival 
Osteoclasts are bone specific polykarons derived from myeloid precursors under the stimulation of MCSF and RANKL. E proteins are basic helix-loop-helix (bHLH) transcription factors that modulate lymphoid versus myeloid cell fate decisions. To study the role of E proteins in osteoclasts, myeloid specific E protein gain-of-function transgenic mice were generated. These mice have high bone mass due to decreased osteoclast numbers and increased osteoclast apoptosis leading to overall reductions in resorptive capacity. The molecular mechanism of decreased osteoclast numbers and resorption is due, in part, to elevated expression of CD38, a regulator of intracellular calcium pools with known anti-osteoclastogenic properties, which increases sensitivity to apoptosis. In vivo, exogenous RANKL stimulation can overcome this inhibition to drive osteoclastogenesis and bone loss. In vitro derived ET2 osteoclasts are more spread and more numerous with increases in RANK, TREM2, and NFATc1 compared to wild type. However, their resorptive capacity does not increase accordingly. Thus, E proteins participate in osteoclast maturation and survival in homeostatic bone remodeling.
doi:10.1002/jbmr.1707
PMCID: PMC3495082  PMID: 22807064
Osteoclast; E proteins; CD38; transcription factor
18.  Safety of in vitro amplified HLA-haploidentical donor immune cell infusions for childhood malignancies 
Chinese Journal of Cancer  2013;32(12):661-666.
In vitro amplified human leukocyte antigen (HLA)-haploidentical donor immune cell infusion (HDICI) is not commonly used in children. Therefore, our study sought to evaluate its safety for treating childhood malignancies. Between September 2011 and September 2012, 12 patients with childhood malignancies underwent HDICI in Sun Yat-sen University Cancer Center. The median patient age was 5.1 years (range, 1.7-8.4 years). Of the 12 patients, 9 had high-risk neuroblastoma (NB) [7 showed complete response (CR), 1 showed partial response (PR), and 1 had progressive disease (PD) after multi-modal therapies], and 3 had Epstein-Barr virus (EBV)-positive lymphoproliferative disease (EBV-LPD). The 12 patients underwent a total of 92 HDICIs at a mean dose of 1.6×108 immune cells/kg body weight: 71 infusions with natural killer (NK) cells, 8 with cytokine-induced killer (CIK) cells, and 13 with cascade primed immune cells (CAPRIs); 83 infusions with immune cells from the mothers, whereas 9 with cells from the fathers. Twenty cases (21.7%) of fever, including 6 cases (6.5%) accompanied with chills and 1 (1.1%) with febrile convulsion, occurred during infusions and were alleviated after symptomatic treatments. Five cases (5.4%) of mild emotion changes were reported. No other adverse events occurred during and after the completion of HDIDIs. Neither acute nor chronic graft versus host disease (GVHD) was observed following HDICIs. After a median of 5.0 months (range, 1.0-11.5 months) of follow-up, the 2 NB patients with PR and PD developed PD during HDICIs. Of the other 7 NB patients in CR, 2 relapsed in the sixth month of HDICIs, and 5 maintained CR with disease-free survival (DFS) ranging from 4.5 to 11.5 months (median, 7.2 months). One EBV-LPD patient achieved PR, whereas 2 had stable disease (SD). Our results show that HDICI is a safe immunotherapy for childhood malignancies, thus warranting further studies.
doi:10.5732/cjc.012.10298
PMCID: PMC3870850  PMID: 23706769
Childhood malignancies; HLA-haploidentical donor cells; immunotherapy; safety
19.  Lymphoma and cerebral vasculitis in association with X-linked lymphoproliferative disease 
Chinese Journal of Cancer  2013;32(12):673-677.
Lymphoma is seen in up to 30% of patients with X-linked lymphoproliferative disease (XLP), but cerebral vasculitis related with XLP after cure of Burkitt lymphoma is rarely reported. We describe a case of a 5-year-old boy with XLP who developed cerebral vasculitis two years after cure of Burkitt lymphoma. He had Burkitt lymphoma at the age of 3 years and received chemotherapy (non-Hodgkin's lymphoma-Berlin-Frankfurt-Milan-90 protocol plus rituximab), which induced complete remission over the following two years. At the age of 5 years, the patient first developed headache, vomiting, and then intellectual and motorial retrogression. His condition was not improved after anti-infection, dehydration, or dexamethasone therapy. No tumor cells were found in his cerebrospinal fluid. Magnetic resonance imaging showed multiple non-homogeneous, hypodense masses along the bilateral cortex. Pathology after biopsy revealed hyperplasia of neurogliocytes and vessels, accompanied by lymphocyte infiltration but no tumor cell infiltration. Despite aggressive treatment, his cognition and motor functions deteriorated in response to progressive cerebral changes. The patient is presently in a vegetative state. We present this case to inform clinicians of association between lymphoma and immunodeficiency and explore an optimal treatment for lymphoma patients with compromised immune system.
doi:10.5732/cjc.012.10238
PMCID: PMC3870852  PMID: 23816555
Burkitt lymphoma; cerebral vasculitis; X-linked lymphoproliferative disease; Epstein-Barr virus
20.  Evaluation of Anxiolytic-Like Effect of Aqueous Extract of Asparagus Stem in Mice 
There are few studies on the neuropharmacological properties of asparagus, which was applied in Chinese traditional medicine as a tonic and heat-clearing agent. The present study was designed to investigate the anxiolytic-like activity of the aqueous extract of asparagus stem (AEAS) using elevated plus maze (EPM) and Vogel conflict tests (VCT) in mice. AEAS significantly increased the percentage of time spent in open arms in EPM, when compared with control group. In the Vogel conflict drinking test, the numbers of punished licks increased to 177% and 174% by the treatment of AEAS at the doses of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight), compared with control group. The serum cortisol level decreased significantly, at the same time. In conclusion, these findings indicated that the aqueous extract of asparagus stem exhibited a strong anxiolytic-like effect at dose of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight) in experimental models of anxiety and may be considered an alternative approach for the management of anxiety disorder.
doi:10.1155/2013/587260
PMCID: PMC3853311  PMID: 24348707
21.  Exercise Promotes Axon Regeneration of Newborn Striatonigral and Corticonigral Projection Neurons in Rats after Ischemic Stroke 
PLoS ONE  2013;8(11):e80139.
Newborn striatal neurons induced by middle cerebral artery occlusion (MCAO) can form functional projections targeting into the substantia nigra, which should be very important for the recovery of motor function. Exercise training post-stroke improves motor recovery in clinic patients and increases striatal neurogenesis in experimental animals. This study aimed to investigate the effects of exercise on axon regeneration of newborn projection neurons in adult rat brains following ischemic stroke. Rats were subjected to a transient MCAO to induce focal cerebral ischemic injury, followed by 30 minutes of exercise training daily from 5 to 28 days after MCAO. Motor function was tested using the rotarod test. We used fluorogold (FG) nigral injection to trace striatonigral and corticonigral projection neurons, and green fluorescent protein (GFP)-targeting retroviral vectors combined with FG double labeling (GFP+ -FG+) to detect newborn projection neurons. The results showed that exercise improved the recovery of motor function of rats after MCAO. Meanwhile, exercise also increased the levels of BDNF and VEGF, and reduced Nogo-A in ischemic brain. On this condition, we further found that exercise significantly increased the number of GFP+ -FG+ neurons in the striatum and frontal and parietal cortex ipsilateral to MCAO, suggesting an increase of newborn striatonigral and corticonigral projection neurons by exercise post-stroke. In addition, we found that exercise also increased NeuN+ and FG+ cells in the striatum and frontal and parietal cortex, the ischemic territory, and tyrosine hydroxylase (TH) immunopositive staining cells in the substantia nigra, a region remote from the ischemic territory. Our results provide the first evidence that exercise can effectively enhance the capacity for regeneration of newborn projection neurons in ischemic injured mammalian brains while improving motor function. Our results provide a very important cellular mechanism to illustrate the effectiveness of rehabilitative treatment post-stroke in the clinic.
doi:10.1371/journal.pone.0080139
PMCID: PMC3833893  PMID: 24260348
22.  Transgenic Bt Rice Does Not Challenge Host Preference of the Target Pest of Rice Leaffolder, Cnaphalocrocis medinalis (Lepidoptera: Pyralidae) 
PLoS ONE  2013;8(11):e79032.
Background
Transgenic Bt rice line T2A-1 expresses a synthesized cry2A gene that shows high resistance to Lepidoptera pests, including Cnaphalocrocis medinalis (Guenée) (Lepidoptera: Pyralidae). Plant volatile orientation cues and the physical characteristics of the leaf surface play key roles in host location or host-plant acceptance of phytophagous insects. These volatile compounds and physical traits may become altered in Bt rice and it is not known whether this influences the behavior of C. medinalis when searching for oviposition sites.
Results
The results of electronic nose analysis showed that the Radar map of Bt rice cultivars was analogous to the non- Bt rice cultivars at each growing stage. PCA analysis was able to partly discriminate between some of the Bt vs. non-Bt rice sensors, but could not to separate Bt cultivars from non-Bt cultivars. The total ion chromatogram between Bt and non-Bt rice cultivars at the seedling, booting and tillering stages were similar and 25 main compounds were identified by GC-MS. For most compounds, there was no significant difference in compound quantities between Bt and non-Bt rice cultivars at equivalent growth stages. The densities of the tubercle papicles and the trichomes on the upper and lower surfaces were statistically equal in Bt and non-Bt rice. The target pest, C. medinalis, was attracted to host rice plants, but it could not distinguish between the transgenic and the isogenic rice lines.
Conclusions
There were no significant differences between the Bt rice line, T2A-1 and the non-Bt rice for volatiles produced or in its physical characteristics and there were no negative impacts on C. medinalis oviposition behavior. These results add to the mounting evidence that Bt rice has no negative impact on the target insect oviposition behavior.
doi:10.1371/journal.pone.0079032
PMCID: PMC3823965  PMID: 24244410
23.  Correlated Biogeographic Variation of Magnesium across Trophic Levels in a Terrestrial Food Chain 
PLoS ONE  2013;8(11):e78444.
Using samples from eastern China (c. 25 – 41° N and 99 – 123° E) and from a common garden experiment, we investigate how Mg concentration varies with climate across multiple trophic levels. In soils, plant tissue (Oriental oak leaves and acorns), and a specialist acorn predator (the weevil Curculio davidi), Mg concentration increased significantly with different slopes from south to north, and generally decreased with both mean annual temperature (MAT) and precipitation (MAP). In addition, soil, leaf, acorn and weevil Mg showed different strengths of association and sensitivity with climatic factors, suggesting that distinct mechanisms may drive patterns of Mg variation at different trophic levels. Our findings provide a first step toward determining whether anticipated changes in temperature and precipitation due to climate change will have important consequences for the bioavailability and distribution of Mg in food chain.
doi:10.1371/journal.pone.0078444
PMCID: PMC3817214  PMID: 24223807
24.  Comparison of Endoscopic Ultrasonography and Multislice Spiral Computed Tomography for the Preoperative Staging of Gastric Cancer - Results of a Single Institution Study of 610 Chinese Patients 
PLoS ONE  2013;8(11):e78846.
Background
This study compared the performance of endoscopic ultrasonography (EUS) and multislice spiral computed tomography (MSCT) in the preoperative staging of gastric cancer.
Methodology/Principal Findings
A total of 610 patients participated in this study, all of whom had undergone surgical resection, had confirmed gastric cancer and were evaluated with EUS and MSCT. Tumor staging was evaluated using the Tumor-Node-Metastasis (TNM) staging and Japanese classification. The results from the imaging modalities were compared with the postoperative histopathological outcomes. The overall accuracies of EUS and MSCT for the T staging category were 76.7% and 78.2% (P=0.537), respectively. Stratified analysis revealed that the accuracy of EUS for T1 and T2 staging was significantly higher than that of MSCT (P<0.001 for both) and that the accuracy of MSCT in T3 and T4 staging was significantly higher than that of EUS (P<0.001 and 0.037, respectively). The overall accuracy of MSCT was 67.2% when using the 13th edition Japanese classification, and this percentage was significantly higher than the accuracy of EUS (49.3%) and MSCT (44.6%) when using the 6th edition UICC classification (P<0.001 for both values).
Conclusions/Significance
Our results demonstrated that the overall accuracies of EUS and MSCT for preoperative staging were not significantly different. We suggest that a combination of EUS and MSCT is required for preoperative evaluation of TNM staging.
doi:10.1371/journal.pone.0078846
PMCID: PMC3815220  PMID: 24223855
25.  Identification of Novel MicroRNAs in Primates by Using the Synteny Information and Small RNA Deep Sequencing Data 
Current technologies that are used for genome-wide microRNA (miRNA) prediction are mainly based on BLAST tool. They often produce a large number of false positives. Here, we describe an effective approach for identifying orthologous pre-miRNAs in several primates based on syntenic information. Some of them have been validated by small RNA high throughput sequencing data. This approach uses the synteny information and experimentally validated miRNAs of human, and incorporates currently available algorithms and tools to identify the pre-miRNAs in five other primates. First, we identified 929 potential pre-miRNAs in the marmoset in which miRNAs have not yet been reported. Then, we predicted the miRNAs in other primates, and we successfully re-identified most of the published miRNAs and found 721, 979, 650 and 639 new potential pre-miRNAs in chimpanzee, gorilla, orangutan and rhesus macaque, respectively. Furthermore, the miRNA transcriptome in the four primates have been re-analyzed and some novel predicted miRNAs have been supported by the small RNA sequencing data. Finally, we analyzed the potential functions of those validated miRNAs and explored the regulatory elements and transcription factors of some validated miRNA genes of interest. The results show that our approach can effectively identify novel miRNAs and some miRNAs that supported by small RNA sequencing data maybe play roles in the nervous system.
doi:10.3390/ijms141020820
PMCID: PMC3821645  PMID: 24135875
genome-wide; miRNA; mammalian genome; synteny; deep sequencing

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