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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.
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.
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.
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.
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.
PMCID: PMC2977713  PMID: 21583849
6.  Chemoprevention of Head and Neck Cancer with Celecoxib and Erlotinib: Results of a Phase Ib and Pharmacokinetic Study 
Epidermal growth factor receptor (EGFR) and cyclooxygenase 2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions.
Patients and Methods
36 subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100mg orally daily and celecoxib was fixed at 400mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6 and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects.
The maximum tolerated dose of erlotinib with celecoxib 400mg BID was 50mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response 43%, partial response 14%, stable disease 29%, disease progression 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (∼308L) and CL/F (8.3L/hr) compared to previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6hr.
Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.
PMCID: PMC4351876  PMID: 24085777
7.  A genome-wide gene–gene interaction analysis identifies an epistatic gene pair for lung cancer susceptibility in Han Chinese 
Carcinogenesis  2013;35(3):572-577.
Lung cancer is the leading cause of cancer-related deaths worldwide. By now, genome-wide association studies (GWAS) have identified numerous loci associated with the risk of developing lung cancer. However, these loci account for only a small fraction of the familial lung cancer risk. We hypothesized that epistasis may contribute to the missing heritability. To test this hypothesis, we systematically evaluated the association of epistasis of genetic variants with risk of lung cancer in Han Chinese cohorts. We conducted a pairwise genetic interaction analysis of 591370 variants, using BOolean Operation-based Screening and Testing (BOOST), in an ongoing GWAS of lung cancer that includes 2331 cases and 3077 controls. Pairs of epistatic loci with P BOOST ≤ 1.00×10−6 were further evaluated by a logistic regression model (LRM) with covariate adjustment. Four promising epistatic pairs identified at the screening stage (P LRM ≤ 2.86×10− 13) were validated in two replication cohorts: the first from Beijing (1534 cases and 1489 controls) and the second from Shenyang and Guangzhou (2512 cases and 2449 controls). Using this combined analysis, we identified an interaction between rs2562796 and rs16832404 at 2p32.2 that was significantly associated with the risk of developing lung cancer (P LRM = 1.03×10−13 in total 13 392 subjects). This study is the first investigation of epistasis for lung cancer on a genome-wide scale in Han Chinese. It addresses part of the missing heritability in lung cancer risk and provides novel insight into the multifactorial etiology of lung cancer.
PMCID: PMC3941747  PMID: 24325914
8.  Gene coexpression networks reveal key drivers of phenotypic divergence in porcine muscle 
BMC Genomics  2015;16(1):50.
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.
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.
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.
PMCID: PMC4328970  PMID: 25651817
Muscle; Modules; Weighted gene coexpression network analysis; Phenotype variation; Artificial selection
9.  RhoC is a major target of microRNA-93-5P in epithelial ovarian carcinoma tumorigenesis and progression 
Molecular Cancer  2015;14(1):31.
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.
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).
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).
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.
PMCID: PMC4328068  PMID: 25649143
MiR-93-5P; RhoC; Ovarian epithelial carcinoma; Tumorigenesis and progression
10.  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.
PMCID: PMC4310616  PMID: 25657573
mitochondria genome; mitochondria mutations; lung cancer survival; haplogroup; mitochondrial genome resequencing
11.  Diagnosis and treatment of penile verrucous carcinoma 
Oncology Letters  2015;9(4):1687-1690.
Penile verrucous carcinoma is an extremely rare disease that, at present, has not been well characterized. The etiology, diagnosis and treatment of this carcinoma remain poorly understood, particularly in the Chinese population. The aim of the present study was to discuss the methods of diagnosis and treatment of penile verrucous carcinoma in the Chinese population. The clinical and pathological data of 10 patients with penile verrucous carcinoma were analyzed alongside a literature review. All the tumors were exophytic papillary lesions, ranging between 0.4 and 4 cm in diameter and all 10 patients underwent partial penectomy with tumor-negative surgical margins. None of the 10 patients underwent ilioinguinal lymphadenectomy. All patients were regularly followed up for 0.7–9 years, which revealed that no patients developed recurrence, and only one case resulted in mortality due to unassociated causes. It was found that penile verrucous carcinoma is a well-differentiated disease with low malignant potential and locally aggressive features, which seldom metastasizes to regional lymph nodes or distant regions. However, misdiagnosis may occur due to an incorrect biopsy. Favorable outcomes can be achieved by surgery, even without any adjuvant therapy, but patients should be carefully followed up.
PMCID: PMC4356329  PMID: 25789024
penile verrucous carcinoma; condyloma acuminatum; surgical treatment; diagnosis
12.  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.
PMCID: PMC4298826  PMID: 24894996
13.  Gut Microbiota of the Tick Vector Ixodes scapularis Modulate Colonization of the Lyme Disease Spirochete 
Cell host & microbe  2014;15(1):58-71.
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.
PMCID: PMC3905459  PMID: 24439898
Ixodes scapularis; gut microbiota; epithelial barrier; Borrelia burgdorferi
14.  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.
PMCID: PMC3916904  PMID: 24341892
15.  Quality Assessment of Compounded 17-hydroxyprogesterone Caproate 
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.
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.
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.
PMCID: PMC3939712  PMID: 24200163
compounded 17-OHPC; impurity analysis; potency; sterility and pyrogen status
16.  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.
PMCID: PMC4276396  PMID: 25544798
Camellia sinensis; Tentative identification; Quantification; UPLC/DAD/MS; PCA
17.  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
18.  An Updated Meta-Analysis of Randomized Controlled Trials Assessing the Effect of Sorafenib in Advanced Hepatocellular Carcinoma 
PLoS ONE  2014;9(12):e112530.
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.
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).
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.
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.
PMCID: PMC4251972  PMID: 25460347
19.  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.
PMCID: PMC4252038  PMID: 25460914
20.  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.
PMCID: PMC3834219  PMID: 23934343
PYL; GmPYL; ABI1; PP2C; GmPP2C; abiotic stress
21.  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.
PMCID: PMC3847577  PMID: 24189045
abiotic stress; drought; stress resistance; PYL; PP2C; SnRK2
22.  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.
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.
PMCID: PMC4054375  PMID: 24719417
23.  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.
PMCID: PMC3878438  PMID: 24143858
Nano engineered approach; two-wave; pancreatic cancer; pericyte and stroma; TGF-β; gemcitabine; mesoporous silica nanoparticles; and liposome
24.  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.
PMCID: PMC4229263  PMID: 25390881
25.  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

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