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1.  Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity 
Protein & Cell  2014;5(3):171-177.
Mammalian target of rapamycin (mTOR) plays essential roles in cell proliferation, survival and metabolism by forming at least two functional distinct multi-protein complexes, mTORC1 and mTORC2. External growth signals can be received and interpreted by mTORC2 and further transduced to mTORC1. On the other hand, mTORC1 can sense inner-cellular physiological cues such as amino acids and energy states and can indirectly suppress mTORC2 activity in part through phosphorylation of its upstream adaptors, IRS-1 or Grb10, under insulin or IGF-1 stimulation conditions. To date, upstream signaling pathways governing mTORC1 activation have been studied extensively, while the mechanisms modulating mTORC2 activity remain largely elusive. We recently reported that Sin1, an essential mTORC2 subunit, was phosphorylated by either Akt or S6K in a cellular context-dependent manner. More importantly, phosphorylation of Sin1 at T86 and T398 led to a dissociation of Sin1 from the functional mTORC2 holo-enzyme, resulting in reduced Akt activity and sensitizing cells to various apoptotic challenges. Notably, an ovarian cancer patient-derived Sin1-R81T mutation abolished Sin1-T86 phosphorylation by disrupting the canonical S6K-phoshorylation motif, thereby bypassing Sin1-phosphorylation-mediated suppression of mTORC2 and leading to sustained Akt signaling to promote tumorigenesis. Our work therefore provided physiological and pathological evidence to reveal the biological significance of Sin1 phosphorylation-mediated suppression of the mTOR/Akt oncogenic signaling, and further suggested that misregulation of this process might contribute to Akt hyper-activation that is frequently observed in human cancers.
doi:10.1007/s13238-014-0021-8
PMCID: PMC3967077  PMID: 24481632
2.  Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity 
Protein & Cell  2014;5(3):171-177.
Mammalian target of rapamycin (mTOR) plays essential roles in cell proliferation, survival and metabolism by forming at least two functional distinct multi-protein complexes, mTORC1 and mTORC2. External growth signals can be received and interpreted by mTORC2 and further transduced to mTORC1. On the other hand, mTORC1 can sense inner-cellular physiological cues such as amino acids and energy states and can indirectly suppress mTORC2 activity in part through phosphorylation of its upstream adaptors, IRS-1 or Grb10, under insulin or IGF-1 stimulation conditions. To date, upstream signaling pathways governing mTORC1 activation have been studied extensively, while the mechanisms modulating mTORC2 activity remain largely elusive. We recently reported that Sin1, an essential mTORC2 subunit, was phosphorylated by either Akt or S6K in a cellular context-dependent manner. More importantly, phosphorylation of Sin1 at T86 and T398 led to a dissociation of Sin1 from the functional mTORC2 holo-enzyme, resulting in reduced Akt activity and sensitizing cells to various apoptotic challenges. Notably, an ovarian cancer patient-derived Sin1-R81T mutation abolished Sin1-T86 phosphorylation by disrupting the canonical S6K-phoshorylation motif, thereby bypassing Sin1-phosphorylation-mediated suppression of mTORC2 and leading to sustained Akt signaling to promote tumorigenesis. Our work therefore provided physiological and pathological evidence to reveal the biological significance of Sin1 phosphorylation-mediated suppression of the mTOR/Akt oncogenic signaling, and further suggested that misregulation of this process might contribute to Akt hyper-activation that is frequently observed in human cancers.
doi:10.1007/s13238-014-0021-8
PMCID: PMC3967077  PMID: 24481632
3.  Increased IL-33 in Synovial Fluid and Paired Serum Is Associated with Disease Activity and Autoantibodies in Rheumatoid Arthritis 
Objectives. IL-33, a newly found cytokine which is involved in joint inflammation, could be blocked by a decoy receptor—sST2. The expression and correlation of IL-33 and sST2 in rheumatoid arthritis (RA) are of great interest. Methods. Synovial fluid (SF) was obtained from 120 RA and 30 osteoarthritis (OA) patients, and paired sera were collected from 54 of these RA patients. The levels of IL-33 and sST2 were measured by ELISA. Results. SF IL-33 was significantly higher in RA than in OA, which was correlated with disease activity score 28, erythrocyte sedimentation rate, rheumatoid factor (RF)-IgM, RF-IgG, glucose phosphate isomerase (GPI), and immunoglobulin. Serum IL-33 was correlated positively with SF IL-33 in RA. Furthermore, it was correlated with RF-IgM and GPI. sST2 was partly detectable in RA (13 out of 54, 24.1%), while not in OA. Serum sST2 in RA had no significant correlation with serum IL-33 or SF IL-33. However, SFs from both RA and OA patients did not express sST2. Conclusions. This study supported that IL-33 played an important role in the local pathogenesis of RA. Considering the tight correlation between IL-33 and clinical features, it may become a new target of local treatment.
doi:10.1155/2013/985301
PMCID: PMC3782822  PMID: 24106520
4.  HLA-DRB1 Shared Epitope-Dependent DR-DQ Haplotypes Are Associated with Both Anti-CCP–Positive and –Negative Rheumatoid Arthritis in Chinese Han 
PLoS ONE  2013;8(8):e71373.
The association between Human Leukocyte Antigen (HLA) class II and rheumatoid arthritis (RA) has been extensively studied, but few reported DR-DQ haplotype. Here we investigated the association of HLA-DRB1, DQA1, DQB1, and DR-DQ haplotypes with RA susceptibility and with anti-CCP antibodies in 281 RA patients and 297 control in Han population. High-resolution genotyping were performed. The HLA-DRB1 shared epitope (SE)-encoding allele *0405 displayed the most significant RA association (P = 1.35×10−6). The grouped DRB1 SE alleles showed great association with RA (P = 3.88×10−13). The DRB1 DRRAA alleles displayed significant protective effects (P = 0.021). The SE-dependent DR-DQ haplotype SE-DQ3/4/5 remained strong association with both anti-CCP -positive (P = 3.71×10−13) and -negative RA (P = 3.89×10−5). Our study revealed that SE alleles and its haplotypes SE-DQ3/4/5 were highly associated with RA susceptibility in Han population. The SE-DQ3/4/5 haplotypes were associated with both anti-CCP positive RA and -negative RA.
doi:10.1371/journal.pone.0071373
PMCID: PMC3741114  PMID: 23951149
5.  Follow-up study of abnormal biological indicators and gene expression in the peripheral blood of three accidentally exposed persons 
Journal of Radiation Research  2013;54(5):840-851.
In order to identify biomarkers for early diagnosis and/or for therapeutic targets in the delayed health effects of ionizing radiation, we analyzed the subgroups of lymphocytes, serum protein levels and gene expression profiles in the peripheral blood of three 60Co γ-ray accidentally exposed persons during the three years after irradiation. Flow cytometry analyses and agarose gel electrophoresis were applied to investigate the subgroups of lymphocytes and the composition of serum proteins, respectively. Gene expression profiling was obtained using a whole genome gene expression chip assay. Both the percentage of CD4+ T lymphocytes and the ratio of Th to Ts were reduced compared with the normal control values. The percentage of albumin decreased whereas beta globulin increased. There were 285 up-regulated and 446 down-regulated genes in irradiated samples relative to the control samples. The expression of KDR, CEACAM8 and OSM was validated by RT-PCR. The majority of the differentially expressed genes encode proteins associated with the immune response, inflammation, oncogenesis, cell structure, oxidative stress, neuro-hormone regulation, reproduction, susceptibility to psychiatric disorders, or transcriptional regulation. We have identified a number of promising novel candidates that have potential for serving as biomarkers for delayed damage. Furthermore, the changes in the immunological indicator CD4+ T cells, and the ratio of CD4+ T to CD8+ T cells may be biomarkers for the prediction of delayed damage by ionizing radiation. The findings of our study are useful for forming a comprehensive understanding of the mechanisms underlying the delayed effects of ionizing radiation.
doi:10.1093/jrr/rrt022
PMCID: PMC3766294  PMID: 23559597
accidental exposure; gene expression profile; ratio of Th to Ts; radiation biomarkers
6.  Evaluating Spatial-Temporal Dynamics of Net Primary Productivity of Different Forest Types in Northeastern China Based on Improved FORCCHN 
PLoS ONE  2012;7(11):e48131.
An improved individual-based forest ecosystem carbon budget model for China (FORCCHN) was applied to investigate the spatial-temporal dynamics of net primary productivity of different forest types in northeastern China. In this study, the forests of northeastern China were categorized into four ecological types according to their habitats and generic characteristics (evergreen broadleaf forest, deciduous broadleaf forest, evergreen needleleaf forest and deciduous needleleaf forest). The results showed that distribution and change of forest NPP in northeastern China were related to the different forest types. From 1981 to 2002, among the forest types in northeastern China, per unit area NPP and total NPP of deciduous broadleaf forest were the highest, with the values of 729.4 gC/(m2•yr) and 106.0 TgC/yr, respectively, followed by mixed broadleaf- needleleaf forest, deciduous needleleaf forest and evergreen needleleaf forest. From 1981 to 2002, per unit area NPP and total NPP of different forest types in northeastern China exhibited significant trends of interannual increase, and rapid increase was found between the 1980s and 1990s. The contribution of the different forest type’s NPP to total NPP in northeastern China was clearly different. The greatest was deciduous broadleaf forest, followed by mixed broadleaf- needleleaf forest and deciduous needleleaf forest. The smallest was evergreen needleleaf forest. Spatial difference in NPP between different forest types was remarkable. High NPP values of deciduous needleleaf forest, mixed broadleaf- needleleaf forest and deciduous broadleaf forest were found in the Daxing’anling region, the southeastern of Xiaoxing’anling and Jilin province, and the Changbai Mountain, respectively. However, no regional differences were found for evergreen needleleaf NPP. This study provided not only an estimation NPP of different forest types in northeastern China but also a useful methodology for estimating forest carbon storage at regional and global levels.
doi:10.1371/journal.pone.0048131
PMCID: PMC3492339  PMID: 23144853
7.  A Replication Study Confirms the Association of Dendritic Cell Immunoreceptor (DCIR) Polymorphisms with ACPA - Negative RA in a Large Asian Cohort 
PLoS ONE  2012;7(7):e41228.
Objectives
Dendritic cell immunoreceptor (DCIR) has been implicated in development of autoimmune disorders in rodent and DCIR polymorphisms were associated with anti-citrullinated proteins antibodies (ACPA)-negative rheumatoid arthritis (RA) in Swedish Caucasians. This study was undertaken to further investigate whether DCIR polymorphisms are also risk factors for the development of RA in four Asian populations originated from China and Malaysia.
Methods
We genotyped two DCIR SNPs rs2377422 and rs10840759 in Han Chinese population (1,193 cases, 1,278 controls), to assess their association with RA. Subsequently, rs2377422 was further genotyped in three independent cohorts of Malaysian-Chinese subjects (MY_Chinese, 254 cases, 206 controls), Malay subjects (MY_ Malay, 515 cases, 986 controls), and Malaysian-Indian subjects (MY_Indian, 378 cases, 285 controls), to seek confirmation of association in various ethnic groups. Meta-analysis was preformed to evaluate the contribution of rs2377422 polymorphisms to the development of ACPA-negative RA in distinct ethnic groups. Finally, we carried out association analysis of rs2377422 polymorphisms with DCIR mRNA expression levels.
Results
DCIR rs2377422 was found to be significantly associated with ACPA -negative RA in Han Chinese (OR 1.92, 95% CI 1.27–2.90, P = 0.0020). Meta-analysis confirms DCIR rs2377422 as a risk factor for ACPA-negative RA across distinct ethnic groups (ORoverall = 1.17, 95% CI 1.06–1.30, P = 0.003). The SNP rs2377422 polymorphism showed significant association with DCIR mRNA expression level, i.e. RA-risk CC genotype exhibit a significant increase in the expression of DCIR (P = 0.0023, Kruskal–Wallis).
Conclusions
Our data provide evidence for association between DCIR rs2377422 and RA in non-Caucasian populations and confirm the influence of DCIR polymorphisms on RA susceptibility, especially on ACPA-negative RA.
doi:10.1371/journal.pone.0041228
PMCID: PMC3400585  PMID: 22829930
8.  Correction: Rhodacyanine Derivative Selectively Targets Cancer Cells and Overcomes Tamoxifen Resistance 
PLoS ONE  2012;7(7):10.1371/annotation/7493e5d2-4c1a-43eb-a83f-16814861ff13.
doi:10.1371/annotation/7493e5d2-4c1a-43eb-a83f-16814861ff13
PMCID: PMC3398052
9.  Rhodacyanine Derivative Selectively Targets Cancer Cells and Overcomes Tamoxifen Resistance 
PLoS ONE  2012;7(4):e35566.
MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB). Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.
doi:10.1371/journal.pone.0035566
PMCID: PMC3338522  PMID: 22563386
11.  Association of TTR polymorphisms with hippocampal atrophy in Alzheimer disease families 
Neurobiology of aging  2009;32(2):249-256.
In vitro and animal model studies suggest that transthyretin (TTR) inhibits the production of the amyloid β protein, a major contributor to Alzheimer disease (AD) pathogenesis. We evaluated the association of 16 TTR single nucleotide polymorphisms (SNPs) with AD risk in 158 African American and 469 Caucasian discordant sibships from the MIRAGE Study. There was no evidence for association of TTR with AD in either population sample. To examine the possibility that TTR SNPs affect specific components of the AD process, we tested association of these SNPs with four measures of neurodegeneration and cerebrovascular disease defined by magnetic resonance imaging (MRI) in a subset of 48 African American and 265 Caucasian sibships. Five of seven common SNPs and several haplotypes were significantly associated with hippocampal atrophy in the Caucasian sample. Two of these SNPs also showed marginal evidence for association in the African American sample. Results for the other MRI traits were unremarkable. This study highlights the potential value of neuroimaging endophenotypes as a tool for finding genes influencing AD pathogenesis.
doi:10.1016/j.neurobiolaging.2009.02.014
PMCID: PMC2930090  PMID: 19328595
12.  Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis 
Arthritis Research & Therapy  2010;12(6):R210.
Introduction
Rheumatoid arthritis (RA) is a T-cell-mediated systemic autoimmune disease, characterized by synovium inflammation and articular destruction. Bone marrow mesenchymal stem cells (MSCs) could be effective in the treatment of several autoimmune diseases. However, there has been thus far no report on umbilical cord (UC)-MSCs in the treatment of RA. Here, potential immunosuppressive effects of human UC-MSCs in RA were evaluated.
Methods
The effects of UC-MSCs on the responses of fibroblast-like synoviocytes (FLSs) and T cells in RA patients were explored. The possible molecular mechanism mediating this immunosuppressive effect of UC-MSCs was explored by addition of inhibitors to indoleamine 2,3-dioxygenase (IDO), Nitric oxide (NO), prostaglandin E2 (PGE2), transforming growth factor β1 (TGF-β1) and interleukin 10 (IL-10). The therapeutic effects of systemic infusion of human UC-MSCs on collagen-induced arthritis (CIA) in a mouse model were explored.
Results
In vitro, UC-MSCs were capable of inhibiting proliferation of FLSs from RA patients, via IL-10, IDO and TGF-β1. Furthermore, the invasive behavior and IL-6 secretion of FLSs were also significantly suppressed. On the other hand, UC-MSCs induced hyporesponsiveness of T cells mediated by PGE2, TGF-β1 and NO and UC-MSCs could promote the expansion of CD4+ Foxp3+ regulatory T cells from RA patients. More importantly, systemic infusion of human UC-MSCs reduced the severity of CIA in a mouse model. Consistently, there were reduced levels of proinflammatory cytokines and chemokines (TNF-α, IL-6 and monocyte chemoattractant protein-1) and increased levels of the anti-inflammatory/regulatory cytokine (IL-10) in sera of UC-MSCs treated mice. Moreover, such treatment shifted Th1/Th2 type responses and induced Tregs in CIA.
Conclusions
In conclusion, human UC-MSCs suppressed the various inflammatory effects of FLSs and T cells of RA in vitro, and attenuated the development of CIA in vivo, strongly suggesting that UC-MSCs might be a therapeutic strategy in RA. In addition, the immunosuppressive activitiy of UC-MSCs could be prolonged by the participation of Tregs.
doi:10.1186/ar3187
PMCID: PMC3046518  PMID: 21080925
13.  Association of Distinct Variants in SORL1 With Cerebrovascular and Neurodegenerative Changes Related to Alzheimer Disease 
Archives of neurology  2008;65(12):1640-1648.
Background
Single-nucleotide polymorphisms (SNPs) in 2 distinct regions of the gene for the sortilin-related receptor (SORL1) (bounded by consecutively numbered SNPs 8−10 and 22−25) were shown to be associated with Alzheimer disease (AD) in multiple ethnically diverse samples.
Objective
To test the hypothesis that SORL1 is associated with brain magnetic resonance imaging (MRI) measurements of atrophy and/or vascular disease.
Design, Setting, and Patients
We evaluated the association of 30 SNPs spanning SORL1 with MRI measures of general cerebral atrophy, hippocampal atrophy, white matter hyperintensities, and overall cerebrovascular disease in 44 African American and 182 white sibships from the MIRAGE Study. We performed single-and 3-SNP haplotype association analyses using family-based tests. Haplotypes found to be significantly associated with at least 1 MRI trait were tested for association with 6 pathological traits in a separate sample of 69 white patients with autopsy-confirmed AD.
Results
In white patients, white matter hyperintensities were associated with multiple markers in the region encompassing SNPs 6 to 10, whereas cerebral and hippocampal atrophy were associated with markers from the region including SNPs 21 to 26. Examination of specific 3-SNP haplotypes from these 2 regions in the autopsy-confirmed cases of AD revealed association of white matter disease with SNPs 8 to 10 and association of hippocampal atrophy with SNPs 22 to 26. The haplotype CGC at SNPs 8 to 10 was associated with fewer white matter changes in the clinical (P<.001) and autopsy (P=.02) samples.
Conclusions
Variants of SORL1 previously associated with AD are also associated with MRI and neuropathological measures of neurodegenerative and cerebrovascular disease. These findings not only support the hypothesis that multiple areas in SORL1 are of functional importance but also raise the possibility that multiple SORL1 variants influence amyloid precursor protein or endothelial lipoprotein processing or both in different regions of the brain.
doi:10.1001/archneur.65.12.1640
PMCID: PMC2719762  PMID: 19064752
14.  Ammonium diphenyl­phosphinate monohydrate 
In the title salt, NH4 +·C12H10O2P−·H2O, the ion pair and water mol­ecule inter­act through hydrogen bonds to form a layer structure.
doi:10.1107/S1600536808012907
PMCID: PMC2961549  PMID: 21202543
15.  Bis[1,3-bis­(diphenyl­phosphinoylimino)isoindolinato-κ3 O,N,O′]calcium(II) 
In the title compound, [Ca(C32H24N3O2P2)2], the 1,3-bis­(diphenyl­phosphinoylimino)isoindoline ligand adopts a tridentate coordination mode. The compound exhibits a distorted octa­hedral geometry. The Ca atom lies on a twofold rotation axis.
doi:10.1107/S1600536807065440
PMCID: PMC2915098  PMID: 21200510

Results 1-15 (15)