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1.  An ABA-mimicking ligand that reduces water loss and promotes drought resistance in plants 
Cell Research  2013;23(8):1043-1054.
Abscisic acid (ABA) is the most important hormone for plants to resist drought and other abiotic stresses. ABA binds directly to the PYR/PYL family of ABA receptors, resulting in inhibition of type 2C phosphatases (PP2C) and activation of downstream ABA signaling. It is envisioned that intervention of ABA signaling by small molecules could help plants to overcome abiotic stresses such as drought, cold and soil salinity. However, chemical instability and rapid catabolism by plant enzymes limit the practical application of ABA itself. Here we report the identification of a small molecule ABA mimic (AM1) that acts as a potent activator of multiple members of the family of ABA receptors. In Arabidopsis, AM1 activates a gene network that is highly similar to that induced by ABA. Treatments with AM1 inhibit seed germination, prevent leaf water loss, and promote drought resistance. We solved the crystal structure of AM1 in complex with the PYL2 ABA receptor and the HAB1 PP2C, which revealed that AM1 mediates a gate-latch-lock interacting network, a structural feature that is conserved in the ABA-bound receptor/PP2C complex. Together, these results demonstrate that a single small molecule ABA mimic can activate multiple ABA receptors and protect plants from water loss and drought stress. Moreover, the AM1 complex crystal structure provides a structural basis for designing the next generation of ABA-mimicking small molecules.
doi:10.1038/cr.2013.95
PMCID: PMC3731570  PMID: 23835477
abscisic acid; plant hormone; drought resistance; crystal structure; ABA-mimicking ligand
2.  3-Bromo-4-dibenzyl­amino-5-methoxy­furan-2(5H)-one 
In the the title compound, C19H18BrNO3, the furan­one ring is almost planar [maximum atomic deviation = 0.019 (3) Å] and is nearly perpendicular to the two phenyl rings, making dihedral angles of 88.96 (17) and 87.71 (17)°. Inter­molecular C—H⋯O hydrogen bonding is present in the crystal structure.
doi:10.1107/S1600536810008007
PMCID: PMC2983877  PMID: 21580613
3.  N-{4-Bromo-2-[(S)-menth­yloxy]-5-oxo-2,5-dihydro-3-fur­yl}-l-valine 
The title compound, C19H30BrNO5, was obtained via a tandem asymmetric Michael addition–elimination reaction of 3,4-dibromo-5-[(S)-l-menth­yloxy]furan-2(5H)-one and l-valine in the presence of potassium hydroxide. The mol­ecular structure contains an approximately planar (r.m.s. deviation = 0.0204 Å) five-membered furan­one ring and a six-membered menth­yloxy ring adopting a chair conformation. The crystal packing is stabilized by inter­molecular O—H⋯O and N—H⋯O hydrogen bonding.
doi:10.1107/S1600536809026129
PMCID: PMC2977280  PMID: 21583539
4.  N-[(2S)-4-Chloro-2-(l-menth­yloxy)-5-oxo-2,5-dihydro­furan-3-yl]-l-valine 
The title compound, C19H30ClNO5, was obtained by the tandem asymmetric Michael addition–elimination reaction of (5S)-3,4-dichloro-5-(l-menth­yloxy)furan-2(5H)-one and l-valine in the presence of potassium hydroxide. The furan­one unit is approximately planar (r.m.s. deviation = 0.0204 Å) and the six-membered cyclo­hexane ring adopts a chair conformation. The crystal structure is stabilized by a network of O—H⋯O and N—H⋯O hydrogen bonds.
doi:10.1107/S1600536809022120
PMCID: PMC2969247  PMID: 21582860
5.  N-[(2S)-4-Chloro-2-(l-menthyloxy)-5-oxo-2,5-dihydro-3-furyl]-l-alanine 
The title compound, C17H26ClNO5, was prepared via a tandem asymmetric Michael addition–elimination reaction of (5S)-3,4-dichloro-5-(l-menth­yloxy)furan-2(5H)-­one and l-alanine in the presence of potassium hydroxide. The five-membered furan­one ring is approximately planar while the six-membered menth­yloxy ring adopts a chair conformation. The crystal packing is stabilized by inter­molecular O—H⋯O and N—H⋯O hydrogen bonds.
doi:10.1107/S1600536809012720
PMCID: PMC2977713  PMID: 21583849
6.  Gene coexpression networks reveal key drivers of phenotypic divergence in porcine muscle 
BMC Genomics  2015;16(1):50.
Background
Domestication of the wild pig has led to obese and lean phenotype breeds, and evolutionary genome research has sought to identify the regulatory mechanisms underlying this phenotypic diversity. However, revealing the molecular mechanisms underlying muscle phenotype variation based on differentially expressed genes has proved to be difficult. To characterize the mechanisms regulating muscle phenotype variation under artificial selection, we aimed to provide an integrated view of genome organization by weighted gene coexpression network analysis.
Results
Our analysis was based on 20 publicly available next-generation sequencing datasets of lean and obese pig muscle generated from 10 developmental stages. The evolution of the constructed coexpression modules was examined using the genome resequencing data of 37 domestic pigs and 11 wild boars. Our results showed the regulation of muscle development might be more complex than had been previously acknowledged, and is regulated by the coordinated action of muscle, nerve and immunity related genes. Breed-specific modules that regulated muscle phenotype divergence were identified, and hundreds of hub genes with major roles in muscle development were determined to be responsible for key functional distinctions between breeds. Our evolutionary analysis showed that the role of changes in the coding sequence under positive selection in muscle phenotype divergence was minor.
Conclusions
Muscle phenotype divergence was found to be regulated by the divergence of coexpression network modules under artificial selection, and not by changes in the coding sequence of genes. Our results present multiple lines of evidence suggesting links between modules and muscle phenotypes, and provide insights into the molecular bases of genome organization in muscle development and phenotype variation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1238-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1238-5
PMCID: PMC4328970  PMID: 25651817
Muscle; Modules; Weighted gene coexpression network analysis; Phenotype variation; Artificial selection
7.  RhoC is a major target of microRNA-93-5P in epithelial ovarian carcinoma tumorigenesis and progression 
Molecular Cancer  2015;14(1):31.
Background
An increasing amount of evidence has revealed that microRNAs regulate various biological processes, including cell differentiation, cell proliferation, apoptosis, drug resistance, and fat metabolism. Studies have shown that miR-93’s targetome in cancer has not been fully defined. Moreover, the role of miR-93 in epithelial ovarian carcinoma (EOC) remains largely unknown.
Methods
MIR-93 mRNA expression in normal ovarian tissue, benign tumors, borderline tumors, primary ovarian carcinomas, and metastatic omentum was quantified. The ovarian carcinoma cell lines OVCAR3, SKOV3/DDP, and HO8910-PM were transfected with miR-93-5P, after which cell phenotype and expression of relevant molecules were assayed. Dual-luciferase reporter assay and a xenograft mouse model were used to examine miR-93 and its target gene RHOC (Ras homolog gene family member C).
Results
MIR-93 mRNA expression was significantly lower in ovarian carcinomas and borderline tumors than in normal ovarian tissues (p < 0.05), and was lower in metastatic omentum than in relative primary ovarian carcinomas (p < 0.05). MIR-93 mRNA expression was also negatively associated with differentiation (well vs. poor and moderate) and International Federation of Gynecology and Obstetrics staging (FIGO stage I/II vs. stage III/IV) in ovarian carcinoma (p < 0.05), besides, miR-93 was higher expressed in mucinous adenocarcinoma than the other types (p < 0.05). MiR-93-5P overexpression reduced proliferation (p < 0.05); promoted G1 or S arrest and apoptosis (p < 0.05); suppressed migration and invasion (p < 0.05); and reduced RhoC, P70S6 kinase, Bcl-xL, matrix metalloproteinase 9 (MMP9) mRNA or protein expression; conversely, it induced P53 and cleaved PARP expression (p < 0.05). Dual-luciferase reporter assay indicated that miR-93 directly targeted RhoC by binding its 3′ untranslated region. MiR-93-5P transfection also suppressed tumor development and RhoC expression (determined by immunohistochemistry) in vivo in the xenograft mouse model (p < 0.05).
Conclusions
This is the first demonstration that miR-93-5P may inhibit EOC tumorigenesis and progression by targeting RhoC. These findings indicate that miR-93-5P is a potential suppressor of ovarian cellular proliferation. The involvement of miR-93-5P–mediated RhoC downregulation in inhibiting EOC aggressiveness may provide extended insight into the molecular mechanisms underlying cancer aggressiveness.
doi:10.1186/s12943-015-0304-6
PMCID: PMC4328068  PMID: 25649143
MiR-93-5P; RhoC; Ovarian epithelial carcinoma; Tumorigenesis and progression
8.  Mitochondrial Variations in Non-Small Cell Lung Cancer (NSCLC) Survival 
Cancer Informatics  2015;14(Suppl 1):1-9.
Mutations in the mtDNA genome have long been suspected to play an important role in cancer. Although most cancer cells harbor mtDNA mutations, the question of whether such mutations are associated with clinical prognosis of lung cancer remains unclear. We resequenced the entire mitochondrial genomes of tumor tissue from a population of 250 Korean patients with non-small cell lung cancer (NSCLC). Our analysis revealed that the haplogroup (D/D4) was associated with worse overall survival (OS) of early-stage NSCLC [adjusted hazard ratio (AHR), 1.95; 95% CI, 1.14–3.33; Ptrend = 0.03]. By comparing the mtDNA variations between NSCLC tissues and matched blood samples, we found that haplogroups M/N and/or D/D4 were hotspots for somatic mutations, suggesting a more complicated mechanism of mtDNA somatic mutations other than the commonly accepted mechanism of sequential accumulation of mtDNA mutations.
doi:10.4137/CIN.S13976
PMCID: PMC4310616  PMID: 25657573
mitochondria genome; mitochondria mutations; lung cancer survival; haplogroup; mitochondrial genome resequencing
9.  The ABA Receptor PYL8 Promotes Lateral Root Growth by Enhancing MYB77-Dependent Transcription of Auxin-Responsive Genes 
Science signaling  2014;7(328):ra53.
The phytohormone abscisic acid (ABA) regulates plant growth, development, and abiotic stress responses. ABA signaling is mediated by a group of receptors known as the PYR1/PYL/RCAR family, which includes the pyrabactin resistance 1–like protein PYL8. Under stress conditions, ABA signaling activates SnRK2 protein kinases to inhibit lateral root growth after emergence from the primary root. However, even in the case of persistent stress, lateral root growth eventually recovers from inhibition. We showed that PYL8 is required for the recovery of lateral root growth, following inhibition by ABA. PYL8 directly interacted with the transcription factors MYB77, MYB44, and MYB73. The interaction of PYL8 and MYB77 increased the binding of MYB77 to its target MBSI motif in the promoters of multiple auxin-responsive genes. Compared to wild-type seedlings, the lateral root growth of pyl8 mutant seedlings and myb77 mutant seedlings was more sensitive to inhibition by ABA. The recovery of lateral root growth was delayed in pyl8 mutant seedlings in the presence of ABA, and the defect was rescued by exposing pyl8 mutant seedlings to the auxin IAA (3-indoleacetic acid). Thus, PYL8 promotes lateral root growth independently of the core ABA-SnRK2 signaling pathway by enhancing the activities of MYB77 and its paralogs, MYB44 and MYB73, to augment auxin signaling.
doi:10.1126/scisignal.2005051
PMCID: PMC4298826  PMID: 24894996
10.  Gut Microbiota of the Tick Vector Ixodes scapularis Modulate Colonization of the Lyme Disease Spirochete 
Cell host & microbe  2014;15(1):58-71.
SUMMARY
Arthopods, such as Ixodes ticks, serve as vectors for many human pathogens. The arthropod gut presents a pivotal microbial entry point and determines pathogen colonization and survival. We show that the gut microbiota of Ixodes scapularis, a major vector of the Lyme disease spirochete Borrelia burgdorferi, influence spirochete colonization of ticks. Perturbing the gut microbiota of larval ticks reduced Borrelia colonization, with dysbiosed larvae displaying decreased expression of the transcription factor STAT. Diminished STAT expression corresponded to lower expression of peritrophin, a key glycoprotein scaffold of the glycan-rich mucus-like peritrophic matrix (PM) that separates the gut lumen from the epithelium. The integrity of the I. scapularis PM was essential for B. burgdorferi to efficiently colonize the gut epithelium. These data elucidate a functional link between the gut microbiota, STAT-signaling, and pathogen colonization in the context of the gut epithelial barrier of an arthropod vector.
doi:10.1016/j.chom.2013.12.001
PMCID: PMC3905459  PMID: 24439898
Ixodes scapularis; gut microbiota; epithelial barrier; Borrelia burgdorferi
11.  Nickel-Catalyzed Regiodivergent Opening of Epoxides with Aryl Halides: Co-Catalysis Controls Regioselectivity 
Epoxides are versatile intermediates in organic synthesis, but have rarely been employed in cross-coupling reactions. We report that bipyridine-ligated nickel can mediate the addition of functionalized aryl halides, a vinyl halide, and a vinyl triflate to epoxides under reducing conditions. For terminal epoxides, the regioselectivity of the reaction depends upon the co-catalyst employed. Iodide co-catalysis results in opening at the less hindered position via an iodohydrin intermediate. Titanocene co-catalysis results in opening at the more hindered position, presumably via TiIII-mediated radical generation. 1,2-Disubstituted epoxides are opened under both conditions to form predominantly the trans product.
doi:10.1021/ja410704d
PMCID: PMC3916904  PMID: 24341892
12.  Quality Assessment of Compounded 17-hydroxyprogesterone Caproate 
Objective
To evaluate the quality of compounded 17-hydroxyprogesterone caproate (17-OHPC)
Study Design
Compounded 17-OHPC was obtained from 15 compounding pharmacies throughout the U.S. and analyzed for potency, impurities, sterility, and pyrogen status.
Results
Eighteen samples were supplied by 15 compounding pharmacies. The concentration of 17-OHPC in all samples was within the specification limits and all tested samples passed sterility and pyrogen testing. Only 1 of 18 samples was out of specification limits for impurities.
Conclusion
Compounded 17-OHPC obtained from 15 pharmacies throughout the U.S. did not raise safety concerns when assessed for potency, sterility, pyrogen status or impurities.
doi:10.1016/j.ajog.2013.09.039
PMCID: PMC3939712  PMID: 24200163
compounded 17-OHPC; impurity analysis; potency; sterility and pyrogen status
13.  Tentative identification, quantitation, and principal component analysis of green pu-erh, green, and white teas using UPLC/DAD/MS 
Food chemistry  2011;126(3):1269-1277.
Tea (Camellia sinensis L.), an important drink and a natural medicine for thousands of years, contains many health beneficial compounds. Growing season, geographical region, and fermentation methods create many variations in tea compositions, which contribute to each tea's uniqueness. In this study, a simple, rapid, and efficient ultra-performance liquid chromatography (UPLC) method combined with diode array detector (DAD) and mass spectroscopic (MS) detection and chemometrics analysis was used to analyse three different types of teas (green pu-erh, green tea, white tea). Using the developed method, 68 compounds were identified and 54 were quantified based on retention times, UV spectra, and MS spectra by referencing to available standards and data in the literatures. The results showed the chemical differences between the tested teas. Principal component analysis (PCA) was applied to classify and distinguish between tea samples.
doi:10.1016/j.foodchem.2010.11.055
PMCID: PMC4276396  PMID: 25544798
Camellia sinensis; Tentative identification; Quantification; UPLC/DAD/MS; PCA
14.  Current evidence on the relationship between rs1256049 polymorphism in estrogen receptor-β gene and cancer risk 
Previous studies have suggested that estrogen receptor-β (ESR2) rs1256049 polymorphism is associated with the susceptibility of cancer. However, the results are inconsistent. We performed a meta-analysis to evaluate the association between the rs1256049 polymorphism and cancer risk. PubMed, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure (CNKI), were searched for eligible studies. The odds ratios (ORs) with 95% confidence interval (CI) were used to assess the strength of association. 22 studies including 22,994 cases and 30,514 controls were identified. There was no significant association between rs1256049 and cancer risk in the overall population. Stratified analysis by ethnicity revealed that the rs1256049 polymorphism was associated with cancer risk in Caucasians (A vs. G: OR = 1.09, 95% CI = 1.01-1.16; GA vs. GG: OR = 1.10, 95% CI = 1.02-1.18; AA+GA vs. GG: OR = 1.09, 95% CI = 1.02-1.17), but not in Asians. Further subgroup analysis by cancer type indicated that the rs1256049 polymorphism may contribute to prostate cancer risk (AA vs. GG: OR = 1.41, 95% CI = 1.02-1.96; AA vs. GG+GA: OR = 1.52, 95% CI = 1.10-2.10), whereas negative results were obtained for breast cancer in any genetic model. This meta-analysis suggested that the ESR2 rs1256049 polymorphism is a candidate gene polymorphism for cancer susceptibility in Caucasians, especially in prostate cancer.
PMCID: PMC4307449  PMID: 25664002
ESR2; cancer risk; polymorphism; meta-analysis
15.  An Updated Meta-Analysis of Randomized Controlled Trials Assessing the Effect of Sorafenib in Advanced Hepatocellular Carcinoma 
PLoS ONE  2014;9(12):e112530.
Background
The efficacy of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of sorafenib for treating patients with advanced HCC.
Methods
The PubMed, Embase, and Web of Science databases were searched. Eligible studies were randomized controlled trials (RCTs) that assessed sorafenib therapy in patients with advanced HCC. The outcomes included overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicities. Hazard ratio (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals (CIs).
Results
Seven RCTs, with a total of 3807 patients, were included in this meta-analysis. All patients received sorafenib alone, or with other chemotherapeutic regimens. Pooled estimates showed that sorafenib improved the OS (HR = 0.74, 95% CI: 0.61, 0.90; P = 0.002), or TTP outcomes (HR = 0.69, 95% CI: 0.55, 0.86; P = 0.001). Subgroup analysis revealed that sorafenib was more effective in the patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1–2 (HR = 0.77, 95% CI: 0.60, 1.0; P = 0.05), or macroscopic vascular invasion (MVI), and/or extrahepatic spread (EHS) (HR = 0.65, 95% CI: 0.46, 0.93; P = 0.02), in terms of OS. Patients who received sorafenib did not have a higher ORR (RR = 0.85, 95% CI: 0.65, 1.11; P = 0.10). In addition, there was a slight increase in toxicity in the sorafenib group.
Conclusion
Treatment with sorafenib significantly improved OS and TTP in patients with advanced HCC. Additional large-scale, well-designed RCTs are needed to evaluate the efficacy of sorafenib-based therapy in the treatment of advanced HCC.
doi:10.1371/journal.pone.0112530
PMCID: PMC4251972  PMID: 25460347
16.  H2O2 Inhibits ABA-Signaling Protein Phosphatase HAB1 
PLoS ONE  2014;9(12):e113643.
Due to its ability to be rapidly generated and propagated over long distances, H2O2 is an important second messenger for biotic and abiotic stress signaling in plants. In response to low water potential and high salt concentrations sensed in the roots of plants, the stress hormone abscisic acid (ABA) activates NADPH oxidase to generate H2O2, which is propagated in guard cells in leaves to induce stomatal closure and prevent water loss from transpiration. Using a reconstituted system, we demonstrate that H2O2 reversibly prevents the protein phosphatase HAB1, a key component of the core ABA-signaling pathway, from inhibiting its main target in guard cells, SnRK2.6/OST1 kinase. We have identified HAB1 C186 and C274 as H2O2-sensitive thiols and demonstrate that their oxidation inhibits both HAB1 catalytic activity and its ability to physically associate with SnRK2.6 by formation of intermolecular dimers.
doi:10.1371/journal.pone.0113643
PMCID: PMC4252038  PMID: 25460914
17.  Interactions between soybean ABA receptors and type 2C protein phosphatases 
Plant molecular biology  2013;83(6):10.1007/s11103-013-0114-4.
The plant hormone abscisic acid (ABA) plays important roles in regulating plant growth, development, and responses to environmental stresses. Proteins in the PYR/PYL/RCAR family (hereafter referred to as PYLs) are known as ABA receptors. Since most studies thus far have focused on Arabidopsis PYLs, little is known about PYL homologs in crop plants. We report here the characterization of 21 PYL homologs (GmPYLs) in soybean. Twenty three putative GmPYLs can be found from soybean genome sequence and categorized into three subgroups. GmPYLs interact with AtABI1 and two GmPP2Cs in diverse manners. A lot of the subgroup I GmPYLs interact with PP2Cs in an ABA-dependent manner, whereas most of the subgroup II and III GmPYLs bind to PP2Cs in an ABA-independent manner. The subgroup III GmPYL23, which cannot interact with any of the tested PP2Cs, differs from other GmPYLs. The CL2/gate domain is crucial for GmPYLs-PP2Cs interaction, and a mutation in the conserved proline (P109S) abolishes the interaction between GmPYL1 and AtABI1. Furthermore, the ABA dependence of GmPYLs-PP2Cs interactions are partially correlated with two amino acid residues preceding the CL2/gate domain of GmPYLs. We also show that GmPYL1 interacts with AtABI1 in an ABA-dependent manner in plant cells. Three GmPYLs differentially inhibit AtABI1 and GmPP2C1 in an ABA-dependent or -enhanced manner in vitro. In addition, ectopically expressing GmPYL1 partially restores ABA sensitivity of the Arabidopsis triple mutant pyr1/pyl1/pyl4. Taken together, our results suggest that soybean GmPYLs are ABA receptors that function by interacting and inhibiting PP2Cs.
doi:10.1007/s11103-013-0114-4
PMCID: PMC3834219  PMID: 23934343
PYL; GmPYL; ABI1; PP2C; GmPP2C; abiotic stress
18.  The unique mode of action of a divergent member of the ABA-receptor protein family in ABA and stress signaling 
Cell Research  2013;23(12):1380-1395.
Proteins in the PYR/PYL/RCAR family (PYLs) are known as receptors for the phytohormone ABA. Upon ABA binding, PYL adopts a conformation that allows it to interact with and inhibit clade A protein phosphatase 2Cs (PP2Cs), which are known as the co-receptors for ABA. Inhibition of the PP2Cs then leads to the activation of the SnRK2 family protein kinases that phosphorylate and activate downstream effectors in ABA response pathways. The PYL family has 14 members in Arabidopsis, 13 of which have been demonstrated to function as ABA receptors. The function of PYL13, a divergent member of the family, has been enigmatic. We report here that PYL13 differs from the other PYLs in three key residues that affect ABA perception, and mutations in these three residues can convert PYL13 into a partially functional ABA receptor. Transgenic plants overexpressing PYL13 show increased ABA sensitivity in seed germination and postgermination seedling establishment as well as decreased stomatal conductance, increased water-use efficiency, accelerated stress-responsive gene expression, and enhanced drought resistance. pyl13 mutant plants are less sensitive to ABA inhibition of postgermination seedling establishment. PYL13 interacts with and inhibits some members of clade A PP2Cs (PP2CA in particular) in an ABA-independent manner. PYL13 also interacts with the other PYLs and antagonizes their function as ABA receptors. Our results show that PYL13 is not an ABA receptor but can modulate the ABA pathway by interacting with and inhibiting both the PYL receptors and the PP2C co-receptors.
doi:10.1038/cr.2013.149
PMCID: PMC3847577  PMID: 24189045
abiotic stress; drought; stress resistance; PYL; PP2C; SnRK2
19.  Kaposi's Sarcoma-Associated Herpesvirus ORF45 Mediates Transcriptional Activation of the HIV-1 Long Terminal Repeat via RSK2 
Journal of Virology  2014;88(12):7024-7035.
ABSTRACT
Robust activation of human immunodeficiency virus type 1 (HIV-1) gene expression occurs upon superinfection with Kaposi's sarcoma-associated herpesvirus (KSHV), a common AIDS-associated pathogen. Though the mechanisms underlying this phenotype remain unknown, several KSHV-encoded factors have been reported to stimulate HIV-1 long terminal repeat (LTR) activity. Here, we systematically evaluated the ability of KSHV tegument proteins to modulate the activation of an integrated HIV-1 LTR and revealed that the most potent individual activator is ORF45. ORF45 directs an increase in RNA polymerase II recruitment to the HIV-1 LTR, leading to enhanced transcriptional output. ORF45 is a robust activator of the p90 ribosomal S6 kinases (RSK), and we found that this activity is necessary but not sufficient to increase transcription from the LTR. Of the three widely expressed RSK isoforms, RSK2 appears to be selectively involved in LTR stimulation by both KSHV ORF45 and HIV-1 Tat. However, constitutively active RSK2 is unable to stimulate the LTR, suggesting that ORF45 may preferentially direct this kinase to a specific set of targets. Collectively, our findings reveal a novel transcriptional activation function for KSHV ORF45 and highlight the importance of RSK2 in shaping the transcriptional environment during infection.
IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is a prominent AIDS-associated pathogen. Previous studies have shown that infection of cells containing human immunodeficiency virus type 1 (HIV-1) with KSHV leads to potent stimulation of HIV-1 gene expression by activating the HIV-1 promoter, termed the long terminal repeat (LTR). Here, we compared the abilities of various KSHV proteins to activate gene expression from the HIV-1 LTR and found that KSHV ORF45 is the most potent activator. ORF45 is known to induce cell signaling through ribosomal S6 kinase (RSK) and enhance protein translation. However, we revealed that the activation of a specific isoform of RSK by ORF45 also leads to increased mRNA synthesis from the LTR by the host RNA polymerase. Collectively, our findings provide new insight into the interviral interactions between KSHV and HIV that may ultimately impact disease.
doi:10.1128/JVI.00931-14
PMCID: PMC4054375  PMID: 24719417
20.  Two-Wave Nanotherapy to Target the Stroma and Optimize Gemcitabine Delivery to a Human Pancreatic Cancer Model in Mice 
ACS nano  2013;7(11):10.1021/nn404083m.
Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access, because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance in addition to causing other problems. In order to improve the delivery of gemcitabine, a first line chemotherapeutic agent, a PEGylated drug-carrying liposome was developed, using a transmembrane ammonium sulfate gradient to encapsulate the protonated drug up to 20% w/w. However, because the liposome was precluded from entering the xenograft site due to the stromal interference, we developed a first wave nanocarrier that decreases pericyte coverage of the vasculature through interference in the pericyte recruiting TGF-β signaling pathway. This was accomplished using a polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecular complexation to a small molecule TGF-β inhibitor, LY364947. LY364947 contains a nitrogen atom that attaches, through H-bonding, to PEI amines with a high rate of efficiency. The co-polymer coating also facilitates systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH dependent LY364947 release from the MSNPs, we achieved rapid entry of IV injected liposomes and MSNPs at the PDAC tumor site. This two-wave approach provided effective shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with free drug or gemcitabine-loaded liposomes only. Not only does this approach overcome stromal resistance to drug delivery in PDAC, but also introduces the concept of using a step-wise engineered approach to address a range of biological impediments that interfere in nanocancer therapy in a spectrum of cancers.
doi:10.1021/nn404083m
PMCID: PMC3878438  PMID: 24143858
Nano engineered approach; two-wave; pancreatic cancer; pericyte and stroma; TGF-β; gemcitabine; mesoporous silica nanoparticles; and liposome
21.  A New 3-Dimensional Dynamic Quantitative Analysis System of Facial Motion: An Establishment and Reliability Test 
PLoS ONE  2014;9(11):e113115.
This study aimed to establish a 3-dimensional dynamic quantitative facial motion analysis system, and then determine its accuracy and test-retest reliability. The system could automatically reconstruct the motion of the observational points. Standardized T-shaped rod and L-shaped rods were used to evaluate the static and dynamic accuracy of the system. Nineteen healthy volunteers were recruited to test the reliability of the system. The average static distance error measurement was 0.19 mm, and the average angular error was 0.29°. The measuring results decreased with the increase of distance between the cameras and objects, 80 cm of which was considered to be optimal. It took only 58 seconds to perform the full facial measurement process. The average intra-class correlation coefficient for distance measurement and angular measurement was 0.973 and 0.794 respectively. The results demonstrated that we successfully established a practical 3-dimensional dynamic quantitative analysis system that is accurate and reliable enough to meet both clinical and research needs.
doi:10.1371/journal.pone.0113115
PMCID: PMC4229263  PMID: 25390881
22.  Sperm motility inversely correlates with seminal leptin levels in idiopathic asthenozoospermia 
Background: Asthenozoospermia is one kind cause of male infertility. Nevertheless, no specific etiology can be identified by routine tests in some cases. Recently, it has been shown that leptin plays a critical role in male fertility. However, the link between leptin and sperm motility is yet to be determined. The aim of this study was to explore association between seminal and serum leptin levels and sperm motility in idiopathic asthenozoospermia. Methods: Our study included 79 asthenozoospermic men and 77 normozoospermic men. Semen was assessed by volume, sperm concentration, motility and morphology. Serum gonadotropic and sex hormones were determined by a chemiluminescent assay. The leptin levels in serum and seminal plasma were detected with ELISA. Results: The mean seminal leptin level in asthenozoospermic group was significantly higher than that in control group, but there was no significant difference in the serum leptin levels between these two groups. The serum leptin had no significant correlation with sperm motility. The seminal leptin had significantly negative correlation with sperm progressive motility and serum total testosterone. Conclusions: The findings indicate a pathophysiological relevance of seminal leptin in sperm motility.
PMCID: PMC4238556  PMID: 25419396
Idiopathic asthenozoospermia; seminal leptin; serum leptin; sperm motility
23.  Characterization of PHB1 and Its Role in Mitochondrial Maturation and Yolk Platelet Degradation during Development of Artemia Embryos 
PLoS ONE  2014;9(10):e109152.
Background
To cope with harsh environments, crustaceans such as Artemia produce diapause gastrula embryos (cysts) with suppressed metabolism. Metabolism and development resume during post-diapause development, but the mechanism behind these cellular events remains largely unknown.
Principal Finding
Our study investigated the role of prohibitin 1 (PHB1) in metabolic reinitiation during post-diapause development. We found that PHB1 was developmentally regulated via changes in phosphorylation status and localization. Results from RNA interference experiments demonstrated PHB1 to be critical for mitochondrial maturation and yolk degradation during development. In addition, PHB1 was present in yolk platelets, and it underwent ubiquitin-mediated degradation during the proteolysis of yolk protein.
Conclusions/Significance
PHB1 has an indispensable role in coordinating mitochondrial maturation and yolk platelet degradation during development in Artemia. This novel function of PHB1 provides new clues to comprehend the roles of PHB1 in metabolism and development.
doi:10.1371/journal.pone.0109152
PMCID: PMC4195616  PMID: 25310573
24.  Combined Effects of Admission Serum Creatinine Concentration with Age and Gender on the Prognostic Significance of Subjects with Acute ST-Elevation Myocardial Infarction in China 
PLoS ONE  2014;9(10):e108986.
Objective
to explore the impact of admission serum creatinine concentration on the in-hospital mortality and its interaction with age and gender in patients with acute ST-segment elevation myocardial infarction (STEMI) in China.
Methods
1424 acute STEMI patients were enrolled in the study. Anthropometric and laboratory measurements were collected from every patient. A Cox proportional hazards regression model was used to determine the relationships between the admission serum creatinine level (Cr level), age, sex and the in-hospital mortality. A crossover analysis and a stratified analysis were used to determine the combined impact of Cr levels with age and gender.
Results
Female (HR 1.687, 95%CI 1.051∼2.708), elevated Cr level (HR 5.922, 95%CI 3.780∼9,279) and old age (1.692, 95%CI 1.402∼2.403) were associated with a high risk of death respectively. After adjusting for other confounders, the renal dysfunction was still independently associated with a higher risk of death (HR 2.48, 95% CI 1.32∼4.63), while female gender (HR 1.19, 95%CI 0.62∼2.29) and old age (HR 1.77, 95%CI 0.92∼3.37) was not. In addition, crossover analysis revealed synergistic effects between elevated Cr level and female gender (SI = 3.01, SIM = 2.10, AP = 0.55). Stratified analysis showed that the impact of renal dysfunction on in-hospital mortality was more pronounced in patients <60 years old (odds ratios 11.10, 95% CI 3.72 to 33.14) compared with patients 60 to 74 years old (odds ratios 5.18, 95% CI 2.48∼10.83) and patients ≥75years old (odds ratios 3.99, 95% CI 1.89 to 8.42).
Conclusion
Serum Cr concentration on admission was a strong predictor for in-hospital mortality among Chinese acute STEMI patients especially in the young and the female.
doi:10.1371/journal.pone.0108986
PMCID: PMC4193830  PMID: 25303229
25.  RASSF1A Promoter Hypermethylation Is a Strong Biomarker of Poor Survival in Patients with Salivary Adenoid Cystic Carcinoma in a Chinese Population 
PLoS ONE  2014;9(10):e110159.
In addition to the clinicopathological parameters, molecular biomarkers are becoming increasingly important in the prognostic evaluation of cancer patients. This study aimed to determine the molecular alterations in the RAS association domain family protein1A gene (RASSF1A) in salivary adenoid cystic carcinoma (ACC) and to evaluate the potential of such alterations as prognostic markers. One hundred and sixty-seven ACC tumor tissues and 50 samples of matched normal salivary gland tissues from the same patients were analyzed for RASSF1A promoter methylation status by bisulfite sequencing PCR (BSP) and/or methylation-specific PCR (MSP). Fifty ACC tumor tissues and matched normal salivary gland tissues were analyzed for loss of heterozygosity (LOH) by examining two microsatellite markers (D3S1478, D3S1621) at 3p21. RASSF1A gene mutations were detected by direct sequencing of all six exons in 50 tumor and normal tissue specimens. Over-all, RASSF1A promoter hypermethylation was detected in 35.3% (59/167) of ACC tissues and was associated with histologically solid tumor pattern (P = 0.002) and advanced TNM stage (P = 0.014). RASSF1A LOH was observed in 18.0% (9/50) of cases, and no somatic mutation of RASSF1A was detected in any cases. RASSF1A promoter methylation was associated with the poor over-all survival (Log-rank test, P <0.001) and disease-free survival (Log-rank test, P <0.001) and identified as an independent predicator of over-all patient survival (P = 0.009) and disease-free survival (P <0.001). It was concluded that RASSF1A methylation is involved in the development, differentiation and progression of ACC and is a strong independent biomarker of poor survival in ACC patients in a Chinese population.
doi:10.1371/journal.pone.0110159
PMCID: PMC4193867  PMID: 25302792

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