Many prediction tools for microRNA (miRNA) targets have been developed, but inconsistent predictions were observed across multiple algorithms, which can make further analysis difficult. Moreover, the ...nomenclature of human miRNAs changes rapidly. To address these issues, we developed a web-based system, miRSystem, for converting queried miRNAs to the latest annotation and predicting the function of miRNA by integrating miRNA target gene prediction and function/pathway analyses.
First, queried miRNA IDs were converted to the latest annotated version to prevent potential conflicts resulting from multiple aliases. Next, by combining seven algorithms and two validated databases, potential gene targets of miRNAs and their functions were predicted based on the consistency across independent algorithms and observed/expected ratios. Lastly, five pathway databases were included to characterize the enriched pathways of target genes through bootstrap approaches. Based on the enriched pathways of target genes, the functions of queried miRNAs could be predicted.
MiRSystem is a user-friendly tool for predicting the target genes and their associated pathways for many miRNAs simultaneously. The web server and the documentation are freely available at http://mirsystem.cgm.ntu.edu.tw/.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the past decades, efforts to eliminate lead from gasoline, paint and drinking water around the world have substantially reduced human blood lead levels. This study was therefore aimed at examining ...the global temporal trends in the blood lead levels of preschool children by the category of UN Human Development Index (HDI). In total, 103 blood lead records were retrieved from 51 articles searched from PubMed and Google Scholar, with study subjects aged up to 8years old. Collected preschool children blood lead levels were plotted chronologically by HDI category and their reciprocals were used in regression analysis against calendar year to establish their temporal transition trends in the past decades. Results show that the modes of blood lead level of the preschool children were reduced from 4–6μg/dL to 0.8–1.5μg/dL, from 6–15μg/dL to 3–6μg/dL and from 12–16 to 5–6μg/dL for the very high HDI countries, the high HDI countries and the medium/low HDI countries, respectively. The highest correlation coefficient, 0.849, between the reciprocal of blood lead level and the calendar year was found for the very high HDI countries. Based on the regression lines, the predicted preschool children mean blood lead levels in the year of 2030 are 0.74μg/dL, 2.21μg/dL and 2.86μg/dL, respectively, for the very high HDI countries, the high HDI countries and the medium/low HDI countries. Persistent differences in blood lead level prevailed among countries of different HDI category, suggesting the effects of disparities and inequalities, at the state level, on preschool children blood lead levels. Further action is warranted to reduce the already low environmental lead exposure to eliminate the developmental burden of lead on children through (1) identification of individual local factors for lead exposure and (2) averting health disparity and inequalities at the state level.
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•Preschool children blood lead levels continuously, but slowly, decrease globally.•Blood lead levels differed across countries of various UN Human Development Index.•It is ascribed to disparities and inequalities at the state level.•The findings help forming the next-stage strategy for environmental lead reduction.
Since brain tissue is not readily accessible, a new focus in search of biomarkers for schizophrenia is blood-based expression profiling of non-protein coding genes such as microRNAs (miRNAs), which ...regulate gene expression by inhibiting the translation of messenger RNAs. This study aimed to identify potential miRNA signature for schizophrenia by comparing genome-wide miRNA expression profiles in patients with schizophrenia vs. healthy controls. A genome-wide miRNA expression profiling was performed using a Taqman array of 365 human miRNAs in the mononuclear leukocytes of a learning set of 30 cases and 30 controls. The discriminating performance of potential biomarkers was validated in an independent testing set of 60 cases and 30 controls. The expression levels of the miRNA signature were then evaluated for their correlation with the patients' clinical symptoms, neurocognitive performances, and neurophysiological functions. A seven-miRNA signature (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) was derived from a supervised classification with internal cross-validation, with an area under the curve (AUC) of receiver operating characteristics of 93%. The putative signature was then validated in the testing set, with an AUC of 85%. Among these miRNAs, miR-34a was differentially expressed between cases and controls in both the learning (P = 0.005) and the testing set (P = 0.002). These miRNAs were differentially correlated with patients' negative symptoms, neurocognitive performance scores, and event-related potentials. The results indicated that the mononuclear leukocyte-based miRNA profiling is a feasible way to identify biomarkers for schizophrenia, and the seven-miRNA signature warrants further investigation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The availability of high-throughput genomic data has led to several challenges in recent genetic association studies, including the large number of genetic variants that must be considered and the ...computational complexity in statistical analyses. Tackling these problems with a marker-set study such as SNP-set analysis can be an efficient solution. To construct SNP-sets, we first propose a clustering algorithm, which employs Hamming distance to measure the similarity between strings of SNP genotypes and evaluates whether the given SNPs or SNP-sets should be clustered. A dendrogram can then be constructed based on such distance measure, and the number of clusters can be determined. With the resulting SNP-sets, we next develop an association test HDAT to examine susceptibility to the disease of interest. This proposed test assesses, based on Hamming distance, whether the similarity between a diseased and a normal individual differs from the similarity between two individuals of the same disease status. In our proposed methodology, only genotype information is needed. No inference of haplotypes is required, and SNPs under consideration do not need to locate in nearby regions. The proposed clustering algorithm and association test are illustrated with applications and simulation studies. As compared with other existing methods, the clustering algorithm is faster and better at identifying sets containing SNPs exerting a similar effect. In addition, the simulation studies demonstrated that the proposed test works well for SNP-sets containing a large proportion of neutral SNPs. Furthermore, employing the clustering algorithm before testing a large set of data improves the knowledge in confining the genetic regions for susceptible genetic markers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Current algorithms for gene regulatory network construction based on Gaussian graphical models focuses on the deterministic decision of whether an edge exists. Both the probabilistic inference of ...edge existence and the relative strength of edges are often overlooked, either because the computational algorithms cannot account for this uncertainty or because it is not straightforward in implementation. In this study, we combine the Bayesian Markov random field and the conditional autoregressive (CAR) model to tackle simultaneously these two tasks. The uncertainty of edge existence and the relative strength of edges can be measured and quantified based on a Bayesian model such as the CAR model and the spike-and-slab lasso prior. In addition, the strength of the edges can be utilized to prioritize the importance of the edges in a network graph. Simulations and a glioblastoma cancer study were carried out to assess the proposed model’s performance and to compare it with existing methods when a binary decision is of interest. The proposed approach shows stable performance and may provide novel structures with biological insights.
Although cigarette smoking is the major risk factor for lung cancer, only 7% of female lung cancer patients in Taiwan have a history of smoking. The genetic mechanisms of carcinogenesis in nonsmokers ...are unclear, but semaphorins have been suggested to play a role as lung tumor suppressors. This report is a comprehensive analysis of the molecular signature of nonsmoking female lung cancer patients in Taiwan, with a particular focus on the semaphorin gene family.
Sixty pairs of tumor and adjacent normal lung tissue specimens were analyzed by using Affymetrix U133plus2.0 expression arrays. Differentially expressed genes in tumor tissues were identified by a paired t test and validated by reverse transcriptase-PCR and immunohistochemistry. Functional analysis was conducted by using Ingenuity Pathway Analysis as well as gene set enrichment analysis and sigPathway algorithms. Kaplan-Meier survival analyses were used to evaluate the association of SEMA5A expression and clinical outcome.
We identified 687 differentially expressed genes in non-small cell lung carcinoma (NSCLC). Many of these genes, most notably the semaphorin family, were participants in the axon guidance signaling pathway. The downregulation of SEMA5A in tumor tissue, both at the transcriptional and translational levels, was associated with poor survival among nonsmoking women with NSCLC.
In summary, several semaphorin gene family members were identified as potential therapeutic targets, and SEMA5A may be useful as a prognostic biomarker for NSCLC, which may also be gender specific in Taiwanese patients.
A novel biomarker for NSCLC is identified.
To identify and prioritize the influential hub genes in a gene-set or biological pathway, most analyses rely on calculation of marginal effects or tests of statistical significance. These procedures ...may be inappropriate since hub nodes are common connection points and therefore may interact with other nodes more often than non-hub nodes do. Such dependence among gene nodes can be conjectured based on the topology of the pathway network or the correlation between them.
Here we develop a pathway activity score incorporating the marginal (local) effects of gene nodes as well as intra-network affinity measures. This score summarizes the expression levels in a gene-set/pathway for each sample, with weights on local and network information, respectively. The score is next used to examine the impact of each node through a leave-one-out evaluation. To illustrate the procedure, two cancer studies, one involving RNA-Seq from breast cancer patients with high-grade ductal carcinoma in situ and one microarray expression data from ovarian cancer patients, are used to assess the performance of the procedure, and to compare with existing methods, both ones that do and do not take into consideration correlation and network information. The hub nodes identified by the proposed procedure in the two cancer studies are known influential genes; some have been included in standard treatments and some are currently considered in clinical trials for target therapy. The results from simulation studies show that when marginal effects are mild or weak, the proposed procedure can still identify causal nodes, whereas methods relying only on marginal effect size cannot.
The NetworkHub procedure proposed in this research can effectively utilize the network information in combination with local effects derived from marker values, and provide a useful and complementary list of recommendations for prioritizing causal hubs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Preventive parental behavior may play an important role in the outcomes of children’s myopia. We investigated associations between parental behavior and children’s myopia status ...and daily activities using data from the most recent myopia survey in Taiwan.
Methods
In total, 3845 children aged 3 to 18 years who completely responded to the questionnaire were included (total score ranging from 0 to 75). A score of ≥ 50 was considered to indicate beneficial parental behavior. Time allocation data for near-work activities, using electronic devices, and outdoor activities were collected using a separate self-reported questionnaire. Associations between beneficial parental behavior and children’s myopia status and activity patterns were analyzed and stratified by school level.
Results
Beneficial parental behavior was positively associated with children’s myopia in the overall samples adj. odds ratio (OR): 1.31, 95% confidence interval (CI): 1.08–1.59,
p
= 0.006) and at the elementary school level (adj. OR: 1.43, 95% CI: 1.11–1.83,
p
= 0.005). However, a negative association with high myopia was observed in the overall samples (adj. OR: 0.71, 95% CI: 0.50–0.99,
p
= 0.049) and high school level (adj. OR: 0.62, 95% CI: 0.41–0.92,
p
= 0.02). Beneficial parental behavior was associated with less time spent on near work (≥ 180 min/day) and electronic device use (≥ 60 min/day), but not with outdoor activities.
Conclusion
In Taiwan, children’s myopia is associated with higher rate of parents’ beneficial behaviors, which suggests that regular vision surveillance is necessary to promote better parental behavior toward children’s eye care. Certain parental practices may influence children’s behavior pattern and reduce the risk of children’s high myopia development in the long run.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Triple-negative breast cancer is a subtype of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for ...triple-negative breast cancer are few and recurrence rates are high. Although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis is not yet possible.
Clinicopathological information and microarray data from 157 invasive breast carcinomas were collected at National Taiwan University Hospital from 1995 to 2008. Gene expression data of 51 triple-negative and 106 luminal breast cancers were generated by oligonucleotide microarrays. Hierarchical clustering analysis revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A 45-gene prognostic signature giving 98% predictive accuracy in distant recurrence of our triple-negative patients was determined using the receiver operating characteristic analysis and leave-one-out cross validation. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% confidence interval (CI) 1.04-5.06, Cox P=0.04), outperforming five other published breast cancer prognostic signatures. The 45-gene signature identified in this study revealed that TGF-β signaling of immune/inflammatory regulation may play an important role in distant metastatic invasion of triple-negative breast cancer.
Gene expression data and recurrence information of triple-negative breast cancer were collected and analyzed in this study. A novel set of 45-gene signature was found to be statistically predictive in disease recurrence of triple-negative breast cancer. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of distant recurrence for early-stage triple-negative patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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