We report the draft genome sequence of the Rickettsia sp. strain MEAM1, which is a facultative symbiont from an invasive species of the whitefly Bemisia tabaci. The total length of the assembled genome is approximately 1.24 Mb, with 335 scaffolds and 1,247 coding sequences predicted within the genome.

AIM

Excessive dissolve of corneal tissue induced by MMPs which were activated by cytokins and chemokines will lead to corneal ulcer. The molecular mechanism of Lipoxin A4 (LXA4) on corneal collagen degradation in three dimensions was investigated.

METHODS

Rabbit corneal fibroblasts were harvested and suspended in serum-free MEM. Type I collagen, DMEM, collagen reconstitution buffer and corneal fibroblast suspension were mixed on ice. The resultant mixture solidified in an incubator, after which test reagents and plasminogen was overlaid and the cultures were returned to the incubator. The supernatants from collagen gel incubations were collected and the amount of hydroxyproline in the hydrolysate was measured. Immunoblot analysis of MMP-1, -3 and TMMP-1,-2 was performed. MMP-2,-9 was detected by the method of Gelatin zymography. Cytotoxicity assay was measured.

RESULTS

LXA4 inhibited corneal collagen degradation in a dose and time manner. LXA4 inhibited the IL-1β induced increases in the pro-MMP-1, -2, -3, -9 and active MMP-1, -2, -3, -9 in a concentration dependent manner. LXA4 could also inhibit the IL-1β induced increases in TIMP-1, -2.

CONCLUSION

As a potent anti-inflammation reagent, LXA4 can inhibit corneal collagen degradation induced by IL-1β in corneal fibroblasts thus inhibiting corneal dissolving pathology process.

“Candidatus Hamiltonella defensa” is a facultative endosymbiont of the whitefly Bemisia tabaci. Herein, we report the first draft genome sequence of “Candidatus Hamiltonella defensa” from the invasive Mediterranean cryptic species of the B. tabaci complex. The 1.84-Mbp genome sequence comprises 404 contigs and contains 1,806 predicted protein-coding genes.

The adoption of smart meters may bring new privacy concerns to the general public. Given the fact that metering data of individual homes/factories is accumulated every 15 minutes, it is possible to infer the pattern of electricity consumption of individual users. In order to protect the privacy of users in a completely de-centralized setting (i.e., individuals do not communicate with one another), we propose a novel protocol, which allows individual meters to report the true electricity consumption reading with a pre-determinted probability. Load serving entities (LSE) can reconstruct the total electricity consumption of a region or a district through inference algorithm, but their ability of identifying individual users’ energy consumption pattern is significantly reduced. Using simulated data, we verify the feasibility of the proposed method and demonstrate performance advantages over existing approaches.

Historically, probabilistic models for decision support have focused on discrimination, e.g., minimizing the ranking error of predicted outcomes. Unfortunately, these models ignore another important aspect, calibration, which indicates the magnitude of correctness of model predictions. Using discrimination and calibration simultaneously can be helpful for many clinical decisions. We investigated tradeoffs between these goals, and developed a unified maximum-margin method to handle them jointly. Our approach called, Doubly Optimized Calibrated Support Vector Machine (DOC-SVM), concurrently optimizes two loss functions: the ridge regression loss and the hinge loss. Experiments using three breast cancer gene-expression datasets (i.e., GSE2034, GSE2990, and Chanrion's datasets) showed that our model generated more calibrated outputs when compared to other state-of-the-art models like Support Vector Machine ( = 0.03,  = 0.13, and <0.001) and Logistic Regression ( = 0.006,  = 0.008, and <0.001). DOC-SVM also demonstrated better discrimination (i.e., higher AUCs) when compared to Support Vector Machine ( = 0.38,  = 0.29, and  = 0.047) and Logistic Regression ( = 0.38,  = 0.04, and <0.0001). DOC-SVM produced a model that was better calibrated without sacrificing discrimination, and hence may be helpful in clinical decision making.

Prognostic models are increasingly being used in clinical practice. The benefit of adding variables (e.g., gene expression measurements) to an original set of variables (e.g., phenotypes) when building prognostic models is usually measured on a whole set of cases. In practice, however, including additional information only helps build better models for some subsets of cases. It is important to prioritize who should undergo further testing. We present a method that can help identify those patients might benefit from additional testing. Our experiments based on limited breast cancer data indicate that relatively old patients with large tumors and positive lymph nodes constitute a group for whom prognoses can be more accurate with the addition of gene expression measurements. The same is not true for some other groups.

It is now understood that virtually all human cancer types are the result of the accumulation of both genetic and epigenetic changes. DNA methylation is a molecular modification of DNA that is crucial for normal development. Genes that are rich in CpG dinucleotides are usually not methylated in normal tissues, but are frequently hypermethylated in cancer. With the advent of high-throughput platforms, large-scale structure of genomic methylation patterns is available through genome-wide scans and tremendous amount of DNA methylation data have been recently generated. However, sophisticated statistical methods to handle complex DNA methylation data are very limited. Here we developed a likelihood based Uniform-Normal-mixture model to select differentially methylated loci between case and control groups using Illumina arrays. The idea is to model the data as three types of methylation loci, one unmethylated, one completely methylated, and one partially methylated. A three-component mixture model with two Uniform distributions and one truncated normal distribution was used to model the three types. The mixture probabilities and the mean of the normal distribution were used to make inference about differentially methylated loci. Through extensive simulation studies, we demonstrated the feasibility and power of the proposed method. An application to a recently published study on ovarian cancer identified several methylation loci that are missed by the existing method.

The purpose of this paper is to study pharmacokinetics of cortisone (E) and its metabolite cortisol (F) in rats after administration of glycyrrhetinic acid (GA) and cortisone. Healthy male SD rats were randomized to be given 20 mg/kg E or E combined with 10 mg/kg GA. Blood samples were collected at 5, 10, 20, 40, 60, 90, 120, 150, 180, and 240 min after administration. The serum concentrations of E and F were determined by HLPC and pharmacokinetic parameters were calculated using DASver2.0 software. The parameters of AUC(0−t), AUC(0−∞), and Cmax for E in the group of E + GA were significantly higher than those in the group of E (P < 0.01); the half-time (t1/2β) was extended compared to E (P < 0.05) and CL/F was dropped obviously (P < 0.01). The rise in AUC(0−t), AUC(0−∞), and Cmax for cortisol in the group of E + GA was significantly compared to the group of E (P < 0.01). CL/F was lower than E (P < 0.01) and the half-time (t1/2β) was slightly extended. In this study, we find that GA restrains the metabolism of E and F and thus increases AUC, t1/2β, and Cmax of E and F, which may be related to its inhibition effect on 11β-hydroxysteroid dehydrogenase (11β-HSD).

Biomaterials are native or synthetic polymers that act as carriers for drug delivery or scaffolds for tissue regeneration. When implanted in vivo, biomaterials should be nontoxic and exert intended functions. For tooth regeneration, biomaterials have primarily served as a scaffold for (1) transplanted stem cells and/or (2) recruitment of endogenous stem cells. This article critically synthesizes our knowledge of biomaterial use in tooth regeneration, including the selection of native and/or synthetic polymers, three-dimensional scaffold fabrication, stem cell transplantation, and stem cell homing. A tooth is a complex biological organ. Tooth loss represents the most common organ failure. Tooth regeneration encompasses not only regrowth of an entire tooth as an organ, but also biological restoration of individual components of the tooth including enamel, dentin, cementum, or dental pulp. Regeneration of tooth root represents perhaps more near-term opportunities than the regeneration of the whole tooth. In the adult, a tooth owes its biological vitality, arguably more, to the root than the crown. Biomaterials are indispensible for the regeneration of tooth root, tooth crown, dental pulp, or an entire tooth.

AIM

To clarify the molecular mechanism of Celecoxib on corneal collagen degradation and corneal ulcer.

METHODS

Rabbit corneal fibroblasts were harvested and suspended in serum-free MEM. Type I collagen, DMEM, collagen reconstitution buffer and corneal fibroblast suspension were mixed on ice. The resultant mixture solidify in an incubator, after which test reagents and plasminogen was overlaid and the cultures were returned to the incubator. The supernatants from collagen gel incubations were collected and the amount of hydroxyproline in the hydrolysate was measured. Immunoblot analysis of MMP1, 3 and TIMP1, 2 was performed. MMP2, 9 was detected by the method of Gelatin zymography. Cytotoxicity Assay was measured.

RESULTS

Celecoxib inhibited corneal collagen degradation in a dose and time manner; Celecoxib inhibited the IL-1ß induced increases in proMMP1, 2, 3, 9 and active MMP1, 2, 3, 9 in a concentration-depended manner. Celecoxib can also inhibit the IL-1ß induced increases in the TIMP1, 2.

CONCLUSION

Celecoxib can inhibit corneal collagen degradation induced by IL-1β, this effect is the consequence of the reduction of MMP1, 2, 3, 9 and TIMP1, 2. The results of the present study provide new insight into Celecoxib in corneal ulcer treatment.

In China, rubella vaccination was introduced into the national immunization program in 2008, and a rubella epidemic occurred in the same year. In order to know whether changes in the genotypic distribution of rubella viruses have occurred in the postvaccination era, we investigate in detail the epidemiological profile of rubella in China and estimate the evolutionary rate, molecular clock phylogeny, and demographic history of the predominant rubella virus genotypes circulating in China using Bayesian Markov chain Monte Carlo phylodynamic analyses. 1E was found to be the predominant rubella virus genotype since its initial isolation in China in 2001, and no genotypic shift has occurred since then. The results suggest that the global 1E genotype may have diverged in 1995 and that it has evolved at a mutation rate of 1.65 × 10−3 per site per year. The Chinese 1E rubella virus isolates were grouped into either cluster 1 or cluster 2, which likely originated in 1997 and 2006, respectively. Cluster 1 viruses were found in all provinces examined in this study and had a mutation rate of 1.90 × 10−3 per site per year. The effective number of infections remained constant until 2007, and along with the introduction of rubella vaccine into the national immunization program, although the circulation of cluster 1 viruses has not been interrupted, some viral lineages have disappeared, and the epidemic started a decline that led to a decrease in the effective population size. Cluster 2 viruses were found only in Hainan Province, likely because of importation.

Background: Experimental laboratory evidence suggests that bisphenol A (BPA), an endocrine disruptor, is a neurodevelopmental toxicant. However, there have been limited and inconclusive results with respect to sex-specific BPA effects on child behavior.

Objective: We examined the association between prenatal BPA exposure and child behavior, adjusting for postnatal BPA exposure and hypothesizing sex-specific effects.

Methods: We followed African-American and Dominican women and their children from pregnancy to child’s age 5 years, collecting spot urine samples from the mothers during pregnancy (34 weeks on average) and from children between 3 and 4 years of age to estimate BPA exposure. We assessed child behavior between 3 and 5 years of age using the Child Behavior Checklist (CBCL) and used generalized linear models to test the association between BPA exposure and child behavior, adjusting for potential confounders.

Results: The analysis was conducted on 198 children (87 boys and 111 girls). Among boys, high prenatal BPA exposure (highest quartile vs. the lowest three quartiles) was associated with significantly higher CBCL scores (more problems) on Emotionally Reactive [1.62 times greater; 95% confidence interval (CI): 1.13, 2.32] and Aggressive Behavior syndromes (1.29 times greater; 95% CI: 1.09, 1.53). Among girls, higher exposure was associated with lower scores on all syndromes, reaching statistical significance for Anxious/Depressed (0.75 times as high; 95% CI: 0.57, 0.99) and Aggressive Behavior (0.82 times as high; 95% CI: 0.70, 0.97).

Conclusion: These results suggest that prenatal exposure to BPA may affect child behavior, and differently among boys and girls.

Amylosucrase (AS) is a kind of glucosyltransferases (E.C. 2.4.1.4) belonging to the Glycoside Hydrolase (GH) Family 13. In the presence of an activator polymer, in vitro, AS is able to catalyze the synthesis of an amylose-like polysaccharide composed of only α-1,4-linkages using sucrose as the only energy source. Unlike AS, other enzymes responsible for the synthesis of such amylose-like polymers require the addition of expensive nucleotide-activated sugars. These properties make AS an interesting enzyme for industrial applications. In this work, the structures and topology of the two AS were thoroughly investigated for the sake of explaining the reason why Deinococcus geothermalis amylosucrase (DgAS) is more stable than Neisseria polysaccharea amylosucrase (NpAS). Based on our results, there are two main factors that contribute to the superior thermostability of DgAS. On the one hand, DgAS holds some good structural features that may make positive contributions to the thermostability. On the other hand, the contacts among residues of DgAS are thought to be topologically more compact than those of NpAS. Furthermore, the dynamics and unfolding properties of the two AS were also explored by the gauss network model (GNM) and the anisotropic network model (ANM). According to the results of GNM and ANM, we have found that the two AS could exhibit a shear-like motion, which is probably associated with their functions. What is more, with the discovery of the unfolding pathway of the two AS, we can focus on the weak regions, and hence designing more appropriate mutations for the sake of thermostability engineering. Taking the results on structure, dynamics and unfolding properties of the two AS into consideration, we have predicted some novel mutants whose thermostability is possibly elevated, and hopefully these discoveries can be used as guides for our future work on rational design.

Genomic imprinting is a form of epigenetic regulation in mammals in which the same allele of a gene is expressed differently depending on the parental origin of the allele. Traditionally, the detection of imprinted genes that affect complex diseases has been focused on linkage designs with pedigrees or case-parent designs with case-parent trios. In the past two decades, the birth cohort design with mother-offspring pairs has been applied to understand better the effect of environmental influences during pregnancy and beginning of life on the growth and development of children. No work has been done on the detection of imprinted genes using birth cohort designs. Moreover, although the importance of imprinting has been well recognized, no study has looked at how environmental exposures modify the effects of imprinted genes. In this study, we show that the proposed imprinting test using the birth cohort design with mother-offspring pairs is an efficient test for testing the interactions between imprinted genes and environmental exposures. Through extensive simulation studies and a real data application, the proposed imprinting test has demonstrated much improved power in detecting gene-environment in teractions than that of a test assuming the Mendelian dominant model when the true underlying genetic model is imprinting.

It has been suggested that children with larger brains tend to perform better on IQ tests or cognitive function tests. Prenatal head growth and head growth in infancy are two crucial periods for subsequent intelligence. Studies have shown that environmental exposure to air pollutants during pregnancy is associated with fetal growth reduction, developmental delay, and reduced IQ. Meanwhile, genetic polymorphisms may modify the effect of environment on head growth. However, studies on gene–environment or gene–gene interactions on growth trajectories have been quite limited partly due to the difficulty to quantitatively measure interactions on growth trajectories. Moreover, it is known that assessing the significance of gene–environment or gene–gene interactions on cross-sectional outcomes empirically using the permutation procedures may bring substantial errors in the tests. We proposed a score that quantitatively measures interactions on growth trajectories and developed an algorithm with a parametric bootstrap procedure to empirically assess the significance of the interactions on growth trajectories under the likelihood framework. We also derived a Wald statistic to test for interactions on growth trajectories and compared it to the proposed parametric bootstrap procedure. Through extensive simulation studies, we demonstrated the feasibility and power of the proposed testing procedures. We applied our method to a real dataset with head circumference measures from birth to age 7 on a cohort currently being conducted by the Columbia Center for Children's Environmental Health (CCCEH) in Krakow, Poland, and identified several significant gene–environment interactions on head circumference growth trajectories.

The draft genome sequence (4,398,155 bp, with 65.35% G+C content) of Halobiforma lacisalsi AJ5, an extremely halophilic archaeon isolated from a salt lake, is reported here. This is the first genome report for a species of the Halobiforma genus.

Background: Airborne polycyclic aromatic hydrocarbons (PAH) are widespread urban air pollutants from fossil fuel burning and other combustion sources. We previously reported that a broad spectrum of combustion-related DNA adducts in cord blood was associated with attention problems at 6–7 years of age in the Columbia Center for Children’s Environmental Health (CCCEH) longitudinal cohort study.

Objectives: We evaluated the relationship between behavioral problems and two different measures of prenatal exposure—both specific to PAH—in the same cohort.

Methods: Children of nonsmoking African-American and Dominican women in New York City (NYC) were followed from in utero to 6–7 years. Prenatal PAH exposure was estimated by personal air monitoring of the mothers during pregnancy as well as by the measurement of DNA adducts specific to benzo[a]pyrene (BaP), a representative PAH, in maternal and cord blood. At 6–7 years of age, child behavior was assessed using the Child Behavior Checklist (CBCL) (n = 253). Generalized linear models were used to test the association between prenatal PAH exposure and behavioral outcomes.

Results: In multivariate analyses, high prenatal PAH exposure, whether characterized by personal air monitoring (greater than the median of 2.27 ng/m3) or maternal and cord adducts (detectable or higher), was positively associated with symptoms of Anxious/Depressed and Attention Problems (p ≤ 0.05).

Conclusion: These results provide additional evidence that environmental levels of PAH encountered in NYC air can adversely affect child behavior.

Background

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown antitumor activity in various cancer cells. Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is regarded as a promising anticancer agent, but chemoresistance affects its efficacy as a treatment strategy. Apoptosis induced by the combination of DHA and Apo2L/TRAIL has not been well documented, and the mechanisms involved remain unclear.

Methodology/Principal Findings

Here, we report that DHA enhances the efficacy of Apo2L/TRAIL for the treatment of pancreatic cancer. We found that combined therapy using DHA and Apo2L/TRAIL significantly enhanced apoptosis in BxPC-3 and PANC-1 cells compared with single-agent treatment in vitro. The effect of DHA was mediated through the generation of reactive oxygen species, the induction of death receptor 5 (DR5) and the modulation of apoptosis-related proteins. However, N-acetyl cysteine significantly reduced the enhanced apoptosis observed with the combination of DHA and Apo2L/TRAIL. In addition, knockdown of DR5 by small interfering RNA also significantly reduced the amount of apoptosis induced by DHA and Apo2L/TRAIL.

Conclusions/Significance

These results suggest that DHA enhances Apo2L/TRAIL-mediated apoptosis in human pancreatic cancer cells through reactive oxygen species-mediated up-regulation of DR5.

The incidence of measles in China from 1991 to 2008 was reviewed, and the nucleotide sequences from 1507 measles viruses (MeV) isolated during 1993 to 2008 were phylogenetically analyzed. The results showed that measles epidemics peaked approximately every 3 to 5 years with the range of measles cases detected between 56,850 and 140,048 per year. The Chinese MeV strains represented three genotypes; 1501 H1, 1 H2 and 5 A. Genotype H1 was the predominant genotype throughout China continuously circulating for at least 16 years. Genotype H1 sequences could be divided into two distinct clusters, H1a and H1b. A 4.2% average nucleotide divergence was found between the H1a and H1b clusters, and the nucleotide sequence and predicted amino acid homologies of H1a viruses were 92.3%–100% and 84.7%–100%, H1b were 97.1%–100% and 95.3%–100%, respectively. Viruses from both clusters were distributed throughout China with no apparent geographic restriction and multiple co-circulating lineages were present in many provinces. Cluster H1a and H1b viruses were co-circulating during 1993 to 2005, while no H1b viruses were detected after 2005 and the transmission of that cluster has presumably been interrupted. Analysis of the nucleotide and predicted amino acid changes in the N proteins of H1a and H1b viruses showed no evidence of selective pressure. This study investigated the genotype and cluster distribution of MeV in China over a 16-year period to establish a genetic baseline before MeV elimination in Western Pacific Region (WPR). Continuous and extensive MeV surveillance and the ability to quickly identify imported cases of measles will become more critical as measles elimination goals are achieved in China in the near future. This is the first report that a single endemic genotype of measles virus has been found to be continuously circulating in one country for at least 16 years.

To determine associations between dyslipidemia and ocular diseases, the population-based Beijing Eye Study 2006 examined 3251 subjects (age≥45 years) who underwent a detailed ophthalmic examination and biochemical blood analysis. Dyslipidemia was defined as any of the following: hypercholesterolemia (total cholesterol concentration≥5.72 mmol/L (220 mg/dL)) or hypertriglyceridemia (triglyceride concentration≥1.70 mmol/L (150 mg/dL)) or low high-density lipoprotein-cholesterol (HDL-C concentration≤0.91 mmol/L (35 mg/dL)). Biochemical blood examinations were available for 2945 (90.6%) subjects. After adjustment for age, gender, habitation region, body mass index, self reported income, blood glucose concentration, diastolic blood pressure and smoking, dyslipidemia was significantly associated with higher intraocular pressure (P<0.001) and beta zone of parapapillary atrophy (P = 0.03). Dyslipidemia was not significantly associated with the prevalence of glaucoma (P = 0.99), retinal vein occlusions (P = 0.92), diabetic retinopathy (P = 0.49), presence of retinal vascular abnormalities such as focal or general arteriolar narrowing, age-related macular degeneration (P = 0.27), nuclear cataract (P = 0.14), cortical cataract (P = 0.93), and subcapsular cataract (P = 0.67). The results make one conclude that, controlled for systemic and socioeconomic parameters, dyslipidemia was not associated with common ophthalmic disorders including glaucoma and age-related macular degeneration.

The induction of relatively weak immunity by DNA vaccines in humans can be largely attributed to the low efficiency of transduction of somatic cells. Although formulation with liposomes has been shown to enhance DNA transduction of cultured cells, little, if any, effect is observed on the transduction of somatic tissues and cells. To improve the rate of transduction, DNA vaccine delivery by gene gun and the recently developed electroporation techniques have been employed. We report here that to circumvent requirement for such equipment, amiloride, a drug that is prescribed for hypertension treatment, can accelerate plasmid entry into antigen presenting cells (APCs) both in vitro and in vivo. The combination induced APCs more dramatically in both maturation and cytokine secretion. Amiloride enhanced development of full CD8 cytolytic function including induction of high levels of antigen specific CTL and expression of IFN-γ+perforin+granzymeB+ in CD8+ T cells. Thus, amiloride is a facilitator for DNA transduction into host cells which in turn enhances the efficiency of the immune responses.

Purpose

To examine associations between neuroretinal rim area, pressure related factors and anthropometric parameters in a population-based setting.

Methods

The population-based cross-sectional Beijing Eye Study 2006 included 3251 subjects with an age of 45+ years. The participants underwent a detailed ophthalmic examination. Exclusion criteria for our study were high myopia of more than -8 diopters and angle-closure glaucoma.

Results

The study included 2917 subjects with a mean age of 59.8±9.8 years (range: 45–89 years). Mean neuroretinal rim area was 1.97±0.38 mm2, mean intraocular pressure 15.6±3.0 mmHg, mean diastolic blood pressure 79.0±5.9 mm Hg, mean systolic blood pressure 133.5±11.1 mmHg, and mean body mass index was 25.5±3.7. In univariate analysis, neuroretinal rim area was significantly associated with optic disc size, open-angle glaucoma, refractive error, age and gender. After adjustment for these parameters in a multivariate analysis, a larger neuroretinal rim area was significantly correlated with a higher body mass index (P<0.001), in addition to be associated with a lower intraocular pressure (P = 0.004), lower mean blood pressure (P = 0.02), and higher ocular perfusion pressure.

Conclusions

In a general population, neuroretinal rim as equivalent of the optic nerve fibers is related to a higher body mass index, after adjustment for disc area, refractive error, age, gender, open-angle glaucoma, intraocular pressure, blood pressure and ocular perfusion pressure. Since body mass index is associated with cerebrospinal fluid pressure, the latter may be associated with neuroretinal rim area. It may serve as an indirect hint for an association between cerebrospinal fluid pressure and glaucoma.