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author:("Yang, buying")
1.  Efficacy and biological safety of lopinavir/ritonavir based anti-retroviral therapy in HIV-1-infected patients: a meta-analysis of randomized controlled trials 
Scientific Reports  2015;5:8528.
Lopinavir/ritonavir (LPV/r) is the first ritonavir-boosted protease-inhibitor used in second-line anti-retroviral treatment (ART) in resource-limited regions. To evaluate the efficacy and safety outcomes of LPV/r in treatment-naïve and -experienced HIV-infected adults and pregnant women, we performed a meta-analysis of randomized controlled trials. Ten cohorts from 8 articles involving 2,584 ART-naïve patients, 5 cohorts from 4 articles involving 1,124 ART-experienced patients, and 8 cohorts from 7 articles involving 2,191 pregnant women were selected for the meta-analyses. For ART-naïve patients, the virologic response rate (72.3%) of LPV/r combined with tenofovir (TDF) plus lamivudine/emtricitabine (3TC/FTC) arms was significantly greater than that of LPV/r plus non-TDF-FTC arms (65.5%, p = 0.047). For ART-experienced patients, the use of LPV/r revealed a 55.7% probability of virologic success. The incidence of abnormal total cholesterol (6.9%) for ART-experienced patients was significantly lower than that for ART-naïve patients (13.1%, p < 0.001). The use of LPV/r in pregnant women revealed a mother-to-child transmission (MTCT) rate of 1.1%, preterm birth rate of 13.2%, and low birth weight rate of 16.2%. Our meta-analysis indicated that LPV/r was an efficacious regimen for ART-naïve patients and was more tolerable for ART-experienced patients. LPV/r also displayed a significant effect in preventing MTCT.
PMCID: PMC4336931  PMID: 25704206
2.  The development and evaluation of a computerized diagnosis scheme for pneumoconiosis on digital chest radiographs 
To diagnose pneumoconiosis using a computer-aided diagnosis system based on digital chest radiographs.
Lung fields were first extracted by combining the traditional Otsu-threshold method with a morphological reconstruction on digital radiographs (DRs), and then subdivided into six non-overlapping regions (region (a-f)). Twenty-two wavelet-based energy texture features were calculated exclusively from each region and selected using a decision tree algorithm. A support vector machine (SVM) with a linear kernel was trained using samples with texture features to classify an individual region of a healthy subject or a pneumoconiosis patient. The final classification results were obtained by integrating these individual classifiers with the weighted voting method. All models were developed on a dataset of 85 healthy controls and 40 stage I or II pneumoconiosis patients and validated by using the bootstrap resampling with replacement method.
The areas under receiver operating characteristic curves (AUCs) of regions (c) and (f) were 0.688 and 0.563, which were worse than those of the other four regions. Region (c) and (f) were both excluded from the individual classifiers that were going to be assembled further. When built on the selected texture features, each individual SVM showed a higher diagnostic performance for the training set and the test set. The classification performance after an ensemble was 0.997 and 0.961 of the AUC value for the training and test sets, respectively. The final results were 0.974 ± 0.018 for AUC value and 0.929 ± 0.018 for accuracy.
The integrated SVM model built on the selected feature set showed the highest diagnostic performance among all individual SVM models. The model has good potential in diagnosing pneumoconiosis based on digital chest radiographs.
PMCID: PMC4271323  PMID: 25277489
Digital radiograph; Pneumoconiosis; Bootstrap resampling; Texture feature; Support vector machine
3.  Evaluating Total Lymphocyte Count as a Surrogate Marker for CD4 Cell Count in the Management of HIV-Infected Patients in Resource-Limited Settings: A Study from China 
PLoS ONE  2013;8(7):e69704.
To evaluate the correlation of total lymphocyte count (TLC) and CD4 cell count and the suitability of TLC as a surrogate marker for CD4 cell count of HIV-infected patients in China.
Usefulness of TLC as a surrogate marker for a CD4 cell count <350 cells/mm3 for HIV-positive patients in China was evaluated by 977 pairs of TLC and CD4 cell count from 977 outpatients. The result was then validated by a literature review which was conducted on 9 relevant articles. Further investigation using the 977 pairs of TLC and CD4 cell count data was done to determine a TLC threshold for predicting a CD4 cell count <500 cells/mm3. Correlation and receiver operating characteristic (ROC) analysis were performed for both CD4 cell counts, and the sensitivity and specificity were computed.
Good correlation was noted between TLC and CD4 count (r = 0.60, 95% CI, 0.56–0.64). TLC obtained a relatively high diagnostic performance (area under ROC curve, 0.80) for predicting a CD4 cell count <350 cells/mm3, with a sensitivity of 0.65 (95% CI, 0.61–0.68) and a specificity of 0.80 (95% CI, 0.75–0.85) at the TLC threshold of 1570 cells/mm3. The literature review suggested that for a CD4 cell count <350 cells/mm3, the optimal TLC threshold was 1500 cells/mm3, which was similar to the figure presented in this observational study. As for predicting a CD4 cell count <500 cells/mm3, TLC obtained a high diagnostic performance (area under ROC curve, 0.82) as well with a sensitivity of 0.70 (95% CI, 0.67–0.73) and a specificity of 0.80 (95% CI, 0.73–0.87).
When considering the antiretroviral therapy for HIV-infected Chinese individuals, total lymphocyte count can be considered as an inexpensive and easily available surrogate marker for predicting two clinically important thresholds of CD4 count of 350 cells/mm3 and 500 cells/mm3.
PMCID: PMC3715444  PMID: 23874985
4.  Transcription of the Major Neurospora crassa microRNA–Like Small RNAs Relies on RNA Polymerase III 
PLoS Genetics  2013;9(1):e1003227.
Most plant and animal microRNAs (miRNAs) are transcribed by RNA polymerase II. We previously discovered miRNA–like small RNAs (milRNAs) in the filamentous fungus Neurospora crassa and uncovered at least four different pathways for milRNA production. To understand the evolutionary origin of milRNAs, we determined the roles of polymerases II and III (Pol II and Pol III) in milRNA transcription. Our results show that Pol III is responsible for the transcription of the major milRNAs produced in this organism. The inhibition of Pol III activity by an inhibitor or by gene silencing abolishes the production of most abundant milRNAs and pri–milRNAs. In addition, Pol III associates with these milRNA producing loci. Even though silencing of Pol II does not affect the synthesis of the most abundant milRNAs, Pol II or both Pol II and Pol III are associated with some milRNA–producing loci, suggesting a regulatory interaction between the two polymerases for some milRNA transcription. Furthermore, we show that one of the Pol III–transcribed milRNAs is derived from a tRNA precursor, and its biogenesis requires RNase Z, which cleaves the tRNA moiety to generate pre–milRNA. Our study identifies the transcriptional machinery responsible for the synthesis of fungal milRNAs and sheds light on the evolutionary origin of eukaryotic small RNAs.
Author Summary
microRNAs (miRNAs) are small RNAs that are used by many organisms to regulate a wide variety of molecular, developmental, and physiological activities. In higher eukaryotes, such as animals and plants, the majority of the independent transcribed miRNAs are produced by RNA polymerase II (Pol II), an enzyme that is also responsible for the production of most of the messenger RNAs. On the other hand, only a few tRNA–associated miRNAs are known to be produced by RNA polymerase III (Pol III), an enzyme that is responsible for the production of small sized RNAs such as tRNAs and 5s rRNA. We previously identified the first fungal miRNAs by identifying the small RNAs associated with an Argonaute protein in the filamentous fungus Neurospora crassa. In this study, we examined the role of Pol II and Pol III in the production of Neurospora miRNAs. We showed that, unlike in plants and animals, Pol III appears to be a major RNA polymerase responsible for miRNA production in this fungus. Our study identified the transcriptional machinery responsible for the synthesis of fungal miRNAs and shed light on the evolutionary origin of miRNAs.
PMCID: PMC3547838  PMID: 23349642
5.  RNA Interference in Fungi: Pathways, Functions, and Applications ▿ 
Eukaryotic Cell  2011;10(9):1148-1155.
Small RNA molecules of about 20 to 30 nucleotides function in gene regulation and genomic defense via conserved eukaryotic RNA interference (RNAi)-related pathways. The RNAi machinery consists of three core components: Dicer, Argonaute, and RNA-dependent RNA polymerase. In fungi, the RNAi-related pathways have three major functions: genomic defense, heterochromatin formation, and gene regulation. Studies of Schizosaccharomyces pombe and Neurospora, and other fungi have uncovered surprisingly diverse small RNA biogenesis pathways, suggesting that fungi utilize RNAi-related pathways in various cellular processes to adapt to different environmental conditions. These studies also provided important insights into how RNAi functions in eukaryotic systems in general. In this review, we will discuss our current understanding of the fungal RNAi-related pathways and their functions, with a focus on filamentous fungi. We will also discuss how RNAi can be used as a tool in fungal research.
PMCID: PMC3187057  PMID: 21724934
6.  The DNA/RNA-Dependent RNA Polymerase QDE-1 Generates Aberrant RNA and dsRNA for RNAi in a Process Requiring Replication Protein A and a DNA Helicase 
PLoS Biology  2010;8(10):e1000496.
The Neurospora RNA-dependent RNA polymerase QDE-1 is an RNA polymerase that can use both RNA and DNA as templates, suggesting a new mechanism for small RNA production.
The production of aberrant RNA (aRNA) is the initial step in several RNAi pathways. How aRNA is produced and specifically recognized by RNA-dependent RNA polymerases (RdRPs) to generate double-stranded RNA (dsRNA) is not clear. We previously showed that in the filamentous fungus Neurospora, the RdRP QDE-1 is required for rDNA-specific aRNA production, suggesting that QDE-1 may be important in aRNA synthesis. Here we show that a recombinant QDE-1 is both an RdRP and a DNA-dependent RNA polymerase (DdRP). Its DdRP activity is much more robust than the RdRP activity and occurs on ssDNA but not dsDNA templates. We further show that Replication Protein A (RPA), a single-stranded DNA-binding complex that interacts with QDE-1, is essential for aRNA production and gene silencing. In vitro reconstitution assays demonstrate that QDE-1 can produce dsRNA from ssDNA, a process that is strongly promoted by RPA. Furthermore, the interaction between QDE-1 and RPA requires the RecQ DNA helicase QDE-3, a homolog of the human Werner/Bloom Syndrome proteins. Together, these results suggest a novel small RNA biogenesis pathway in Neurospora and a new mechanism for the production of aRNA and dsRNA in RNAi pathways.
Author Summary
Small RNA molecules (20–30 nucleotides) play important roles in many cellular processes in eukaryotic organisms by silencing gene expression. To generate the many forms of small RNAs, DNA is first transcribed to produce single-stranded RNA (ssRNA), which then is converted to double-stranded RNA (dsRNA) by an RNA-dependent RNA polymerase (RdRP). However, it is not clear how the ssRNA templates are synthesized from DNA and specifically recognized by RdRPs amidst a sea of single-stranded, cellular RNAs. We previously showed that in the filamentous fungus Neurospora the production of one type of small RNA called qiRNA, which is specifically induced after DNA damage, requires the RdRP QDE-1. Here, we investigated the precise contributions of QDE-1 to the synthesis of ssRNA and dsRNA. We show that QDE-1 is surprisingly promiscuous in its template choice in that it is able to synthesize RNA from both ssRNA and single-stranded DNA (ssDNA). These results suggest that QDE-1 first generates ssRNA from a DNA template and then converts the ssRNA into dsRNA; this combination of activities in one protein ensures the specific action by RdRP on aberrant RNA in lieu of other single-stranded cellular RNA. In addition, we identified Replication Protein A, a ssDNA-binding protein that interacts with QDE-1, as an essential factor for small RNA production. Furthermore, we were able to reconstitute synthesis of dsRNA from ssDNA in a test tube using purified QDE-1 and RPA proteins, demonstrating the ability of this relatively simple biosynthetic system to generate the nucleic acid trigger for gene regulation. Together, these results uncover the details of a new and important small RNA production mechanism in cells.
PMCID: PMC2950127  PMID: 20957187
7.  Maternal exposure to folic acid antagonists and placenta-mediated adverse pregnancy outcomes 
In previous studies, maternal exposure to folic acid antagonists was associated with increased risks of neural tube defects, cardiovascular defects, oral clefts and urinary tract defects. The objective of the current study was to assess the possible effects of using folic acid antagonists in pregnancy on placenta-mediated adverse outcomes of pregnancy.
We used data from an administrative database to retrospectively compare the occurrence of placenta-mediated adverse pregnancy outcomes between pregnant women exposed to folic acid antagonists and women without exposure to these agents.
We included in the analysis a total of 14 982 women who had been exposed to folic acid antagonists and 59 825 women who had not been exposed. Sulfamethoxazole–trimethoprim was the most frequently prescribed dihydrofolate reductase inhibitor (a total of 12 546 exposures during the preconception period and all 3 trimesters), and phenobarbital was the most frequently prescribed among the other folic acid antagonists (a total of 1565 exposures). The risks of preeclampsia (adjusted odds ratio [OR] 1.52, 95% confidence interval [CI] 1.39–1.66), severe preeclampsia (OR 1.77, 95% CI 1.38–2.28), placental abruption (OR 1.32, 95% CI 1.12–1.57), fetal growth restriction defined as less than the 10th percentile (OR 1.07, 95% CI 1.01–1.13), fetal growth restriction defined as less than the 3rd percentile (OR 1.22, 95% CI 1.11–1.34) and fetal death (OR 1.35, 95% CI 1.07–1.70) were greater among mothers with exposure to folic acid antagonists. In general, the risks associated with exposure to other folic acid antagonists were higher than those associated with exposure to dihydrofolate reductase inhibitors. Supplementary analyses involving tight matching with propensity score, restriction of the analysis to women with exposure during the first and second trimesters and restriction of the analysis to specific categories of folic acid antagonists yielded similar results.
Maternal exposure to folic acid antagonists appears to increase the risk of placenta-mediated adverse outcomes of pregnancy.
PMCID: PMC2585135  PMID: 19047607

Results 1-7 (7)