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1.  The Ubiquitin Ligase Stub1 Negatively Modulates Regulatory T cell Suppressive Activity by Promoting Degradation of the Transcription Factor Foxp3 
Immunity  2013;39(2):10.1016/j.immuni.2013.08.006.
Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharide lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo, and conferred a T helper 1 (Th1) cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection and cancer.
PMCID: PMC3817295  PMID: 23973223
2.  Illness and medical and other expenditures: observations from western and eastern China 
Illness and the medical expenditure that follows have a profound impact on the well-being of individuals and households. China is a huge country with significant regional differences. The goal of this study is to investigate the associations of illness and medical expenditure with other categories of household expenditures, with special attention paid to the differences in observations between the western and eastern regions.
A survey was conducted in six major cities in China, three in the east and three in the west, in 2011. Data on demographics, illness conditions, and medical and other expenditures were collected from 12,515 households.
In the analysis of the associations of illness conditions and medical expenditure with demographics, multiple significant associations were observed, and there are differences between the eastern and western regions. In univariate analyses, illness conditions and medical expenditure were found as having significant associations with other categories of expenditures. In multivariate analyses adjusting for household and household head characteristics, few associations were observed, and there exist differences between the regions.
This study has provided empirical evidence on the associations of illness/medical expenditure with demographics and with other categories of expenditures. Differences across regions were observed in multiple aspects. The reasons underlying such differences are worth investigating further.
PMCID: PMC4336723
Illness condition; Medical expenditure; Household expenditure; Cross-region difference; China
3.  Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development 
ACS Medicinal Chemistry Letters  2013;5(2):124-127.
The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.
PMCID: PMC4027646  PMID: 24900784
MDM2; p53; wild-type; small molecule; apoptosis; cancer
4.  Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing 
JAMA  2014;312(18):1870-1879.
Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.
To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.
Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient’s physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.
Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.
A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%–31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%–27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%–47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%–25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.
Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
PMCID: PMC4326249  PMID: 25326635
5.  Central obesity and nonalcoholic fatty liver disease risk after adjusting for body mass index 
AIM: To investigate whether central obesity is associated with nonalcoholic fatty liver disease (NAFLD) formation after adjusting for general obesity.
METHODS: The online databases PubMed, EMBASE, and ISI Web of Science were searched for studies estimating the influence of central obesity on NAFLD occurrence published through April 2014. Studies that did not adjust for body mass index (BMI) were excluded. In addition, the independent effect of BMI was also assessed with the included studies. The pooled effect sizes and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models based on the degree of heterogeneity. Furthermore, subgroup analyses, meta-regression, sensitivity analyses, and publication bias were performed.
RESULTS: Twenty eligible studies were identified. The summary odds ratio (OR) values per-unit increase in waist circumference (WC) and BMI for NAFLD formation were 1.07 (95%CI: 1.03-1.10, I2 = 73.9%, n = 11 studies) and 1.25 (95%CI: 1.13-1.38, I2 = 88.7%, n = 11 studies), respectively. When the indices were expressed as binary variables (with the non-obesity group as reference), the pooled OR in WC, waist-to-hip ratio, and BMI were 2.34 (95%CI: 1.83-3.00, I2 = 41.8%, n = 7 studies), 4.06 (95%CI: 1.53-10.79, I2 = 65.7%, n = 3 studies), and 2.85 (95%CI: 1.60-5.08, I2 = 57.8%, n = 5 studies), respectively. Using the same studies as the latter (n = 5), pooled OR in WC was 3.14 (95%CI: 2.07-4.77), which is greater than that in BMI.
CONCLUSION: Central obesity may pose a greater threat to national health than general obesity, although both are independently associated with increased risk of NAFLD.
PMCID: PMC4316109  PMID: 25663786
Central obesity; General obesity; Nonalcoholic fatty liver disease; Body mass index; Waist circumference
6.  Belching, regurgitation, chest tightness and dyspnea: Not gastroesophageal reflux disease but asthma 
Belching is a common symptom of gastroesophageal reflux disease. If the symptoms are not relieved after anti-reflux treatment, another etiology should be considered. Here, we report a case of a 43-year-old man who presented with belching, regurgitation, chest tightness and dyspnea for 18 mo, which became gradually more severe. Gastroscopic examination suggested superficial gastritis. Twenty-four-hour esophageal pH monitoring showed that the Demeester score was 11.4, in the normal range. High-resolution manometry showed that integrated relaxation pressure and intrabolus pressure were higher than normal (20 mmHg and 22.4 mmHg, respectively), indicating gastroesophageal junction outflow tract obstruction. Pulmonary function test showed severe obstructive ventilation dysfunction [forced expiratory volume in 1 second (FEV1)/forced vital capacity 32%, FEV1 was 1.21 L, occupying 35% predicted value after salbuterol inhalation], and positive bronchial dilation test (∆FEV1 260 mL, ∆FEV1% 27%). Skin prick test showed Dermatophagoides farinae (++), house dust mite (++++), and shrimp protein (++). Fractional exhaled nitric oxide measurement was 76 ppb. All the symptoms were alleviated completely and pulmonary function increased after combination therapy with corticosteroids and long-acting β2-agonist. Bronchial asthma was eventually diagnosed by laboratory tests and the effect of anti-asthmatic treatment, therefore, physicians, especially the Gastrointestinal physicians, should pay attention to the belching symptoms of asthma.
PMCID: PMC4316114  PMID: 25663791
Asthma; Gastroesophageal reflux disease
7.  Long-Lasting Effects of Early-Life Antibiotic Treatment and Routine Animal Handling on Gut Microbiota Composition and Immune System in Pigs 
PLoS ONE  2015;10(2):e0116523.
In intensive pig husbandry systems, antibiotics are frequently administrated during early life stages to prevent respiratory and gastro-intestinal tract infections, often in combination with stressful handlings. The immediate effects of these treatments on microbial colonization and immune development have been described recently. Here we studied whether the early life administration of antibiotics has long-lasting effects on the pig’s intestinal microbial community and on gut functionality.
Methodology/Principal Findings
To investigate the long-lasting effect of early-life treatment, piglets were divided into three different groups receiving the following treatments: 1) no antibiotics and no stress, 2) antibiotics and no stress, and 3) antibiotics and stress. All treatments were applied at day four after birth. Sampling of jejunal content for community scale microbiota analysis, and jejunal and ileal tissue for genome-wide transcription profiling, was performed at day 55 (~8 weeks) and day 176 (~25 weeks) after birth. Antibiotic treatment in combination with or without exposure to stress was found to have long-lasting effects on host intestinal gene expression involved in a multitude of processes, including immune related processes.
The results obtained in this study indicate that early life (day 4 after birth) perturbations have long-lasting effects on the gut system, both in gene expression (day 55) as well as on microbiota composition (day 176). At day 55 high variance was observed in the microbiota data, but no significant differences between treatment groups, which is most probably due to the newly acquired microbiota during and right after weaning (day 28). Based on the observed difference in gene expression at day 55, it is hypothesized that due to the difference in immune programming during early life, the systems respond differently to the post-weaning newly acquired microbiota. As a consequence, the gut systems of the treatment groups develop into different homeostasis.
PMCID: PMC4319779  PMID: 25658611
8.  Identification of Synaptosomal Proteins Binding to Monomeric and Oligomeric α-Synuclein 
PLoS ONE  2015;10(2):e0116473.
Monomeric α-synuclein (αSN) species are abundant in nerve terminals where they are hypothesized to play a physiological role related to synaptic vesicle turn-over. In Parkinson’s disease (PD) and dementia with Lewy body (DLB), αSN accumulates as aggregated soluble oligomers in terminals, axons and the somatodendritic compartment and insoluble filaments in Lewy inclusions and Lewy neurites. The autosomal dominant heritability associated to mutations in the αSN gene suggest a gain of function associated to aggregated αSN. We have conducted a proteomic screen to identify the αSN interactome in brain synaptosomes. Porcine brain synaptosomes were fractionated, solubilized in non-denaturing detergent and subjected to co-immunoprecipitation using purified recombinant human αSN monomers or oligomers as bait. The isolated αSN binding proteins were identified with LC-LTQ-orbitrap tandem mass spectrometry and quantified by peak area using Windows client application, Skyline Targeted Proteomic Environment. Data are available via ProteomeXchange with identifier PXD001462. To quantify the preferential binding an average fold increase was calculated by comparing binding to monomer and oligomer. We identified 10 proteins preferentially binding monomer, and 76 binding preferentially to oligomer and a group of 92 proteins not displaying any preferred conformation of αSN. The proteomic data were validated by immunoprecipitation in both human and porcine brain extracts using antibodies against monomer αSN interactors: Abl interactor 1, and myelin proteolipid protein, and oligomer interactors: glutamate decarboxylase 2, synapsin 1, glial fibrillary acidic protein, and VAMP-2. We demonstrate the existence of αSN conformation selective ligands and present lists of proteins, whose identity and functions will be useful for modeling normal and pathological αSN dependent processes.
PMCID: PMC4319895  PMID: 25659148
9.  Ru(II)-Catalyzed Mild [3+2] Carbocyclization with Aromatic N-H Ketimines and Internal Alkynes Using N-Heterocyclic Carbene (NHC) Ligands 
A convenient and highly efficient synthesis of indenamines has been developed via ruthenium-catalyzed [3+2] carbocyclization under very mild conditions. A catalyst system of Ru(II) π-allyl precursor and N-heterocyclic carbene (NHC) ligand promotes facile coupling between aromatic N–H ketimines with internal alkynes at mild temperatures, without added oxidants or other metal salts, and in non-polar solvents. A proposed mechanism involves imine-directed activation of aromatic C–H bond, alkyne insertion, and carbocyclization by intramolecular imine insertion into Ru–alkenyl linkages.
PMCID: PMC4310470  PMID: 23696055
N-H ketimine; indenamine; C-H bond activation; ruthenium; N-heterocyclic carbene
10.  Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists 
A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists.
PMCID: PMC4027777  PMID: 24900774
RORγt; agonists; inverse agonists; Th17 cell differentiation; cocrystal structure; structure-based design
11.  Elafin is downregulated during breast and ovarian tumorigenesis but its residual expression predicts recurrence 
Breast Cancer Research : BCR  2014;16(6):3417.
Elafin is an endogenous serine protease inhibitor. The majority of breast cancer cell lines lack elafin expression compared to human mammary epithelial cells. In this study, we hypothesized that elafin is downregulated during breast and ovarian tumorigenesis.
We examined elafin expression by immunohistochemistry (IHC) in specimens of normal breast tissue (n = 24), ductal carcinoma in situ (DCIS) (n = 54), and invasive breast cancer (n = 793). IHC analysis of elafin expression was also performed in normal fallopian tube tissue (n = 20), ovarian cystadenomas (n = 9), borderline ovarian tumors (n = 21), and invasive ovarian carcinomas (n = 216). To understand the significance of elafin in luminal breast cancer cell lines, wild-type or M25G elafin (lacking the protease inhibitory function) were exogenously expressed in MCF-7 and T47D cells.
Elafin expression was downregulated in 24% of DCIS and 83% of invasive breast tumors when compared to elafin expression in the normal mammary epithelium. However, the presence of elafin-positive cells in invasive breast tumors, even at low frequency, correlated with poor recurrence-free survival (RFS), reduced overall survival (OS), and clinicopathological markers of aggressive tumor behavior. Elafin-positive cells were an especially strong and independent prognostic marker of reduced RFS in IHC-defined luminal A-like tumors. Elafin was also downregulated in 33% of ovarian cystadenomas, 43% of borderline ovarian tumors, and 86% of invasive ovarian carcinomas when compared to elafin expression in the normal fallopian tube. In ovarian tumors, elafin-positive cells were correlated with reduced RFS, OS and disease-specific survival (DSS) only in stage I/II patients and not in stage III/IV patients. Notably, exogenous expression of elafin or elafin M25G in the luminal breast cancer cell lines MCF-7 and T47D significantly decreased cell proliferation in a protease inhibitory domain-independent manner.
Elafin predicts poor outcome in breast and ovarian cancer patients and delineates a subset of endocrine receptor-positive breast cancer patients susceptible to recurrence who could benefit from more aggressive intervention. Our in vitro results suggest that elafin arrests luminal breast cancer cells, perhaps suggesting a role in tumor dormancy.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0497-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4326485  PMID: 25551582
12.  Horizontal and Vertical Cultural Differences in the Content of Advertising Appeals 
The distinction between vertical (emphasizing hierarchy) and horizontal (valuing equality) cultures yields novel predictions regarding the prevalence of advertising appeals. A content analysis of 1211 magazine advertisements in five countries (Denmark, Korea, Poland, Russia, U.S.) revealed differences in ad content that underscore the value of this distinction. Patterns in the degree to which ads emphasized status benefits and uniqueness benefits corresponded to the countries' vertical/horizontal cultural classification. These and other patterns of ad benefits are analyzed and the predictions afforded by the vertical/horizontal distinction versus the broader individualism-collectivism distinction are compared and tested.
PMCID: PMC4279851  PMID: 25554720
13.  Evaluation and Comparison of GLM- and CVA-based fMRI Processing Pipelines with Java-based fMRI Processing Pipeline Evaluation System 
NeuroImage  2008;41(4):1242-1252.
Activation patterns identified by fMRI processing pipelines or fMRI software packages are usually determined by the preprocessing options, parameters, and statistical models used. Previous studies that evaluated options of GLM (General Linear Model)-based fMRI processing pipelines are mainly based on simulated data with receiver operating characteristics (ROC) analysis, but evaluation of such fMRI processing pipelines on real fMRI data is rare. To understand the effect of processing options on performance of GLM-based fMRI processing pipelines with real fMRI data, we investigated the impact of commonly-used fMRI preprocessing steps; optimized the associated GLM-based single-subject processing pipelines; and quantitatively compared univariate GLM (in FSL.FEAT and NPAIRS.GLM) and multivariate CVA (Canonical Variates Analysis) (in NPAIRS.CVA)-based analytic models in single-subject analysis with a recently developed fMRI processing pipeline evaluation system based on prediction accuracy (classification accuracy) and reproducibility performance metrics. For block-design data, we found that with GLM analysis (1) slice timing correction and global intensity normalization have little consistent impact on fMRI processing pipelines, spatial smoothing and high-pass filtering or temporal detrending significantly increases pipeline performance and thus are essential for robust fMRI statistical analysis; (2) combined optimization of spatial smoothing and temporal detrending improves pipeline performance; and (3) in general, the prediction performance of multivariate CVA is higher than that of the univariate GLM, while univariate GLM is more reproducible than multivariate CVA. Because of the different bias-variance trade-offs of univariate and multivariate models, it may be necessary to consider a consensus approach to obtain more accurate activation patterns in fMRI data.
PMCID: PMC4277234  PMID: 18482849
fMRI; GLM; CVA; Prediction accuracy; Classification accuracy; Reproducibility
14.  Electrical Stimulation over Bilateral Occipito-Temporal Regions Reduces N170 in the Right Hemisphere and the Composite Face Effect 
PLoS ONE  2014;9(12):e115772.
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that can modulate cortical excitability. Although the clinical value of tDCS has been advocated, the potential of tDCS in cognitive rehabilitation of face processing deficits is less understood. Face processing has been associated with the occipito-temporal cortex (OT). The present study investigated whether face processing in healthy adults can be modulated by applying tDCS over the OT. Experiment 1 investigated whether tDCS can affect N170, a face-sensitive ERP component, with a face orientation judgment task. The N170 in the right hemisphere was reduced in active stimulation conditions compared with the sham stimulation condition for both upright faces and inverted faces. Experiment 2 further demonstrated that tDCS can modulate the composite face effect, a type of holistic processing that reflects the obligatory attention to all parts of a face. The composite face effect was reduced in active stimulation conditions compared with the sham stimulation condition. Additionally, the current polarity did not modulate the effect of tDCS in the two experiments. The present study demonstrates that N170 can be causally manipulated by stimulating the OT with weak currents. Furthermore, our study provides evidence that obligatory attention to all parts of a face can be affected by the commonly used tDCS parameter setting.
PMCID: PMC4274090  PMID: 25531112
15.  Transcriptome analysis of carbohydrate metabolism during bulblet formation and development in Lilium davidii var. unicolor 
BMC Plant Biology  2014;14(1):358.
The formation and development of bulblets are crucial to the Lilium genus since these processes are closely related to carbohydrate metabolism, especially to starch and sucrose metabolism. However, little is known about the transcriptional regulation of both processes. To gain insight into carbohydrate-related genes involved in bulblet formation and development, we conducted comparative transcriptome profiling of Lilium davidii var. unicolor bulblets at 0 d, 15 d (bulblets emerged) and 35 d (bulblets formed a basic shape with three or four scales) after scale propagation.
Analysis of the transcriptome revealed that a total of 52,901 unigenes with an average sequence size of 630 bp were generated. Based on Clusters of Orthologous Groups (COG) analysis, 8% of the sequences were attributed to carbohydrate transport and metabolism. The results of KEGG pathway enrichment analysis showed that starch and sucrose metabolism constituted the predominant pathway among the three library pairs. The starch content in mother scales and bulblets decreased and increased, respectively, with almost the same trend as sucrose content. Gene expression analysis of the key enzymes in starch and sucrose metabolism suggested that sucrose synthase (SuSy) and invertase (INV), mainly hydrolyzing sucrose, presented higher gene expression in mother scales and bulblets at stages of bulblet appearance and enlargement, while sucrose phosphate synthase (SPS) showed higher expression in bulblets at morphogenesis. The enzymes involved in the starch synthetic direction such as ADPG pyrophosphorylase (AGPase), soluble starch synthase (SSS), starch branching enzyme (SBE) and granule-bound starch synthase (GBSS) showed a decreasing trend in mother scales and higher gene expression in bulblets at bulblet appearance and enlargement stages while the enzyme in the cleavage direction, starch de-branching enzyme (SDBE), showed higher gene expression in mother scales than in bulblets.
An extensive transcriptome analysis of three bulblet development stages contributes considerable novel information to our understanding of carbohydrate metabolism-related genes in Lilium at the transcriptional level, and demonstrates the fundamentality of carbohydrate metabolism in bulblet emergence and development at the molecular level. This could facilitate further investigation into the molecular mechanisms underlying these processes in lily and other related species.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0358-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4302423  PMID: 25524032
Lilium; Bulblet formation and development; Transcriptome; Starch and sucrose metabolism; Gene expression file
16.  ABA-Mediated ROS in Mitochondria Regulate Root Meristem Activity by Controlling PLETHORA Expression in Arabidopsis 
PLoS Genetics  2014;10(12):e1004791.
Although research has determined that reactive oxygen species (ROS) function as signaling molecules in plant development, the molecular mechanism by which ROS regulate plant growth is not well known. An aba overly sensitive mutant, abo8-1, which is defective in a pentatricopeptide repeat (PPR) protein responsible for the splicing of NAD4 intron 3 in mitochondrial complex I, accumulates more ROS in root tips than the wild type, and the ROS accumulation is further enhanced by ABA treatment. The ABO8 mutation reduces root meristem activity, which can be enhanced by ABA treatment and reversibly recovered by addition of certain concentrations of the reducing agent GSH. As indicated by low ProDR5:GUS expression, auxin accumulation/signaling was reduced in abo8-1. We also found that ABA inhibits the expression of PLETHORA1 (PLT1) and PLT2, and that root growth is more sensitive to ABA in the plt1 and plt2 mutants than in the wild type. The expression of PLT1 and PLT2 is significantly reduced in the abo8-1 mutant. Overexpression of PLT2 in an inducible system can largely rescue root apical meristem (RAM)-defective phenotype of abo8-1 with and without ABA treatment. These results suggest that ABA-promoted ROS in the mitochondria of root tips are important retrograde signals that regulate root meristem activity by controlling auxin accumulation/signaling and PLT expression in Arabidopsis.
Author summary
Abscisic acid (ABA) plays crucial roles in plant growth and development, and also in plant responses to abiotic and biotic stresses. ABA can stimulate the production of reactive oxygen species (ROS) that act as signals in low concentrations, but as cell-damaging agents in high concentrations. A mutation in ABO8, encoding a pentatricopeptide repeat (PPR) protein responsible for the splicing of NAD4 intron 3, leads to hypersensitivity to ABA in root growth, and root tips of the abo8-1 mutants accumulate more ROS than those of the wild type; this accumulation of ROS in abo8-1 root tips is enhanced by ABA treatment. We also found that auxin signaling and/or accumulation is greatly reduced in root tips of the abo8-1 mutants. Addition of the reducing agent GSH to the growth medium partially recovers the root hypersensitivity to ABA, and also the ABA-inhibited expression of PLT1/2 in abo8-1. Furthermore, the inducible expression of PLT2 largely rescues the root growth defect of abo8-1 with and without ABA treatment. Our results reveal the important roles of ROS in regulating root meristem activity in the ABA signaling pathway.
PMCID: PMC4270459  PMID: 25522358
17.  Recombinant Treponema pallidum Protein Tp0965 Activates Endothelial Cells and Increases the Permeability of Endothelial Cell Monolayer 
PLoS ONE  2014;9(12):e115134.
The recombinant Treponema pallidum protein Tp0965 (rTp0965), one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs) with rTp0965 resulted in increased levels of ICAM-1, E-selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells) to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis.
PMCID: PMC4267829  PMID: 25514584
18.  Screening and bioinformatic analysis of microRNA-associated immune clearance in patients with chronic hepatitis B 
Objective: This study aimed to perform screening and bioinformatic analysis of microRNA (miRNA) molecules associated with immune clearance in chronic hepatitis B (CHB) patients. Methods: Peripheral blood mononuclear cells (PBMCs) of CHB patients and healthy individuals were collected and detected by microarray. The target genes of differentially expressed miRNA molecules were predicted using three databases. Their molecular pathways and functions were analyzed by bioinformatics methods. Results: Compared with healthy individuals, 52 differentially expressed miRNA molecules were found in PBMCs of CHB patients, of which 33 were up-regulated and 19 were down-regulated. A total of 354 target genes were predicted in up-regulated miRNA molecules, and 1935 target genes were predicted in down-regulated miRNA molecules. MiRNA-mRNA network analysis showed that some target genes might be regulated, and constituted complex molecular networks with hsa-miR-520d-5p, hsa-miR-106a-5p, hsa-miR-30a-5p, and hsa-miR-29b-3p. Gene ontology and pathway analyses showed that several molecular pathways might be affected by up- or down-regulated miRNA molecules. Conclusion: Abnormal expression of multiple miRNA molecules in PBMCs of CHB patients might be involved in immune clearance pathogenesis through the regulation of multiple molecular pathways and target genes.
PMCID: PMC4307436  PMID: 25663989
Chronic hepatitis B; microRNA; immune clearance
19.  Genome-wide mapping of DNA methylation in the human malaria parasite Plasmodium falciparum 
Cell host & microbe  2013;14(6):696-706.
Cytosine DNA methylation is an epigenetic mark in most eukaryotic cells that regulates numerous processes, including gene expression and stress responses. We performed a genome-wide analysis of DNA methylation in the human malaria parasite Plasmodium falciparum. We mapped the positions of methylated cytosines and identified a single functional DNA methyltransferase, PfDNMT, that may mediate these genomic modifications. These analyses revealed that the malaria genome is asymmetrically methylated, in which only one DNA strand is methylated, and shares common features with undifferentiated plant and mammalian cells. Notably, core promoters are hypomethylated and transcript levels correlate with intra-exonic methylation. Additionally, there are sharp methylation transitions at nucleosome and exon-intron boundaries. These data suggest that DNA methylation could regulate virulence gene expression and transcription elongation. Furthermore, the broad range of action of DNA methylation and uniqueness of PfDNMT suggest that the methylation pathway is a potential target for anti-malarial strategies.
PMCID: PMC3931529  PMID: 24331467
20.  Mini Profile of Potential Anticancer Properties of Propofol 
PLoS ONE  2014;9(12):e114440.
Propofol (2, 6-diisopropylphenol) is an intravenous sedative-hypnotic agent administered to induce and maintain anesthesia. It has been recently revealed that propofol has anticancer properties including direct and indirect suppression of the viability and proliferation of cancer cells by promoting apoptosis in some cancer cell lines.
Methodology/Principal Findings
This study aimed to establish a profile to quantitatively and functionally evaluate the anticancer properties of propofol in three cancer cell lines: non-small cell lung carcinoma cell line A549, human colon carcinoma cell line LoVo, and human breast cancer cell line SK-BR-3. We demonstrated that the expression level of caspase-3, an apoptosis biomarker, significantly increased in a dose-dependent manner after 24-h stimulation with 100 µM propofol in A549 cells, and slightly increased in LoVo cells. However, there was no change in caspase-3 expression in SK-BR-3 cells. High caspase-3 expression in A549 cells may be modulated by the ERK1/2 pathway because phosphorylated ERK1/2 dramatically reduced after propofol treatment. BAX, a major protein that promotes apoptosis in the regulation phase, was highly expressed in A549 cells after treatment with 25 µM propofol. Apoptosis induced by propofol may be associated with cancer cells carrying Kras mutations.
Our results suggest that the anti-cancer effects of propofol, which are consistent with those of previous studies, are likely associated with the Kras mutation status. Only Kras mutation in Codon 12 instead of other Kras status has been demonstrated to play an important role in sensitizing the propofol-induced apoptosis in cancer cell lines from our study. These findings may enable us a detailed investigation of propofol/Kras-mediated cancer cell apoptosis in the future.
PMCID: PMC4263663  PMID: 25502773
21.  Re-emergent Human Adenovirus Genome Type 7d Caused an Acute Respiratory Disease Outbreak in Southern China After a Twenty-one Year Absence 
Scientific Reports  2014;4:7365.
Human adenoviruses (HAdVs) are highly contagious pathogens causing acute respiratory disease (ARD), among other illnesses. Of the ARD genotypes, HAdV-7 presents with more severe morbidity and higher mortality than the others. We report the isolation and identification of a genome type HAdV-7d (DG01_2011) from a recent outbreak in Southern China. Genome sequencing, phylogenetic analysis, and restriction endonuclease analysis (REA) comparisons with past pathogens indicate HAdV-7d has re-emerged in Southern China after an absence of twenty-one years. Recombination analysis reveals this genome differs from the 1950s-era prototype and vaccine strains by a lateral gene transfer, substituting the coding region for the L1 52/55 kDa DNA packaging protein from HAdV-16. DG01_2011 descends from both a strain circulating in Southwestern China (2010) and a strain from Shaanxi causing a fatality and outbreak (Northwestern China; 2009). Due to the higher morbidity and mortality rates associated with HAdV-7, the surveillance, identification, and characterization of these strains in population-dense China by REA and/or whole genome sequencing are strongly indicated. With these accurate identifications of specific HAdV types and an epidemiological database of regional HAdV pathogens, along with the HAdV genome stability noted across time and space, the development, availability, and deployment of appropriate vaccines are needed.
PMCID: PMC4258649  PMID: 25482188
22.  Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial–mesenchymal transition 
BMC Genomics  2014;15(1):1079.
DNA methylation is associated with aberrant gene expression in cancer, and has been shown to correlate with therapeutic response and disease prognosis in some types of cancer. We sought to investigate the biological significance of DNA methylation in lung cancer.
We integrated the gene expression profiles and data of gene promoter methylation for a large panel of non-small cell lung cancer cell lines, and identified 578 candidate genes with expression levels that were inversely correlated to the degree of DNA methylation. We found these candidate genes to be differentially methylated in normal lung tissue versus non-small cell lung cancer tumors, and segregated by histologic and tumor subtypes. We used gene set enrichment analysis of the genes ranked by the degree of correlation between gene expression and DNA methylation to identify gene sets involved in cellular migration and metastasis. Our unsupervised hierarchical clustering of the candidate genes segregated cell lines according to the epithelial-to-mesenchymal transition phenotype. Genes related to the epithelial-to-mesenchymal transition, such as AXL, ESRP1, HoxB4, and SPINT1/2, were among the nearly 20% of the candidate genes that were differentially methylated between epithelial and mesenchymal cells. Greater numbers of genes were methylated in the mesenchymal cells and their expressions were upregulated by 5-azacytidine treatment. Methylation of the candidate genes was associated with erlotinib resistance in wild-type EGFR cell lines. The expression profiles of the candidate genes were associated with 8-week disease control in patients with wild-type EGFR who had unresectable non-small cell lung cancer treated with erlotinib, but not in patients treated with sorafenib.
Our results demonstrate that the underlying biology of genes regulated by DNA methylation may have predictive value in lung cancer that can be exploited therapeutically.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1079) contains supplementary material, which is available to authorized users.
PMCID: PMC4298954  PMID: 25486910
DNA methylation; Epithelial-mesenchymal transition; Erlotinib; Lung cancer
23.  Sevoflurane Postconditioning Protects Rat Hearts against Ischemia-Reperfusion Injury via the Activation of PI3K/AKT/mTOR Signaling 
Scientific Reports  2014;4:7317.
Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway plays a key role in myocardial ischemia-reperfusion (I/R) injury. Mammalian target of rapamycin (mTOR), a downstream target of PI3K/AKT signaling, is necessary and sufficient to protect the heart from I/R injury. Inhaled anesthetic sevoflurane is widely used in cardiac surgeries because its induction and recovery are faster and smoother than other inhaled anesthetics. Sevoflurane proved capable of inducing postconditioning effects in the myocardium. However, the underlying molecular mechanisms for sevoflurane-induced postconditioning (SPC) were largely unclear. In the present study, we demonstrated that SPC protects myocardium from I/R injury with narrowed cardiac infarct focus, increased ATP content, and decreased cardiomyocyte apoptosis, which are mainly due to the activation of PI3K/AKT/mTOR signaling and the protection of mitochondrial energy metabolism. Application of dactolisib (BEZ235), a PI3K/mTOR dual inhibitor, abolishes the up-regulation of pho-AKT, pho-GSK, pho-mTOR, and pho-p70s6k induced by SPC, hence abrogating the anti-apoptotic effect of sevoflurane and reducing SPC-mediated protection of heart from I/R injury. As such, this study proved that PI3K/AKT/mTOR pathway plays an important role in SPC induced cardiac protection against I/R injury.
PMCID: PMC4255182  PMID: 25471136
24.  Risk factors associated with prevalent and incident syphilis among an HIV-infected cohort in Northeast China 
BMC Infectious Diseases  2014;14(1):658.
Sexually transmitted infections (STIs) increase HIV infectivity through local inflammatory processes. Prevalent and incident STIs among people who live with HIV/AIDS (PLWHA) are indicators of high-risk sexual behaviors and imply potential spread of HIV. Little is known about the prevalence and incidence of concurrent syphilis and associated risk behaviors among PLWHA in China.
A retrospective cohort study was conducted among PLWHA who attended the outpatient clinic of a designated AIDS treatment hospital in Shenyang, China, between March 2009 and May 2013. Physical examinations and syphilis serology were conducted at each visit. A questionnaire on demographic characteristics was also collected.
A total of 1010 PLWHA were enrolled, of whom 77.0% were men who have sex with men (MSM). The baseline syphilis prevalence among PLWHA was 19.8% (95% confidence interval [CI]:17.3–22.3%). During follow-up, 78.3% retained in the cohort, and contributed a median follow-up of 9.4 months (interquartile range: 5.9-18.7 months). Syphilis incidence among PLWHA was 18.7 (95% CI: 15.5–21.8) per 100 person years. Mulitvariate logistic analysis showed that receiving antiretroviral therapy (ART) (adjusted OR [aOR] = 0.48), older age (≥40 years vs. ≤24 years, aOR = 2.43), being MSM (aOR = 2.30) and having higher baseline HIV viral load (>100000 copies/mL vs. ≤100000 copies/mL, aOR = 1.56) were independent predictors for syphilis infection among PLWHA at enrollment (p < 0.05 for all). Mulivariate Cox regression found that receiving ART (adjusted hazard ratio [aHR] = 1.81), older age (≥40 years vs. ≤24 years, aHR: 5.17) and MSM status (aHR = 2.68) were independent risk factors for syphilis seroconversion (each p < 0.05).
Syphilis prevalence and incidence were high among PLWHA in Shenyang. A campaign focusing on detection and treatment of syphilis among PLWHA is urgently needed, especially one with a focus on MSM who are at a higher risk for syphilis.
PMCID: PMC4265485  PMID: 25471736
Retrospective cohort study; Syphilis; Prevalence; Incidence; Antiretroviral therapy (ART)
25.  Renal Water Molecular Diffusion Characteristics in Healthy Native Kidneys: Assessment with Diffusion Tensor MR Imaging 
PLoS ONE  2014;9(12):e113469.
To explore the characteristics of diffusion tensor imaging (DTI) and magnetic resonance (MR) imaging in healthy native kidneys.
Seventy-three patients without chronic kidney disease underwent DTI-MRI with spin echo-echo planar (SE-EPI) sequences accompanied by an array spatial sensitivity encoding technique (ASSET). Cortical and medullary mean, axial and radial diffusivity (MD, AD and RD), fractional anisotropy (FA) and primary, secondary and tertiary eigenvalues (λ1, λ2, λ3) were analysed in both kidneys and in different genders.
Cortical MD, λ2, λ3, and RD values were higher than corresponding medullary values. The cortical FA value was lower than the medullary FA value. Medullary λ1 and RD values in the left kidney were lower than in the right kidney. Medullary λ2, and λ3 values in women were higher than those in men. Medullary FA values in women were lower than those in men. Medullary FA (r = 0.351, P = 0.002) and λ1 (r = 0.277, P = 0.018) positively correlated with eGFR. Medullary FA (r = −0.25, P = 0.033) negatively correlated with age.
Renal water molecular diffusion differences exist in human kidneys and genders. Age and eGFR correlate with medullary FA and primary eigenvalue.
PMCID: PMC4254455  PMID: 25470776

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